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1. Business
Overview
We
are a clinical stage biotechnology company developing cellular therapies for specific aging-related and life-threatening conditions.
Our lead investigational product is the LOMECEL-B™ cell-based therapy product (“Lomecel-B”), which is derived from
culture-expanded medicinal signaling cells (MSCs) that are sourced from bone marrow of young healthy adult donors. We believe that by
using the same cells that promote tissue repair, organ maintenance, and immune system function, we can develop safe and effective therapies
for some of the most difficult disorders associated with the aging process and other conditions.
We
are currently sponsoring or have sponsored Phase 1 and 2 clinical trials in the following indications: Aging Frailty, Alzheimer’s
disease (AD), the Metabolic Syndrome, Acute Respiratory Distress Syndrome (ARDS), and hypoplastic left heart syndrome (HLHS). Our mission
is to advance Lomecel-B and other cell-based product candidates into pivotal Phase 3 trials, with the goal of achieving regulatory approvals,
subsequent commercialization and broad use by the healthcare community.
Our
philosophy is that healthy aging can be improved through regenerative medicine approaches. Life expectancy has substantially increased
over the past century as a result of medical and public health advancements. However, this increase in longevity has not been paralleled
by the number of years a person is expected to live in relatively good health, with limited chronic disease and disabilities of aging
– a period known as healthspan. As we age, we experience: a decline in our own stem cells; a decrease in immune system function,
known as immunosenescence; diminished blood vessel functioning; chronic inflammation, known as “inflammaging”; and other
aging-related declines. Our preliminary clinical data suggest that Lomecel-B can potentially address these problems through multiple
mechanisms of action, or MOAs, that simultaneously target key aging-related processes.
Improving
healthspan is an imperative for governmental health agencies. The National Institute on Aging (NIA), an institute of the National Institutes
of Health (NIH), has promoted the concept of geroscience – the idea that aging itself is the biggest risk factor for aging-related
human diseases and that aging can be approached as a treatable disease to improve healthspan. The geroscience hypothesis provides a strong
rationale for the approach of treating underlying biological processes contributing to aging as a way to reduce disease burden and advance
global human health. Our investments into developing and testing product candidates are aimed at reducing aging-related disease burden
and improving healthspan.
Our
Strategy
Our
core business strategy is to become a world leading regenerative medicine company through the development and commercialization of novel
cell therapy products for unmet medical needs, with emphasis on aging-related indications. Key elements of our business strategy are
as follows.
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Advance
Lomecel-B and other regenerative medicine products to market. We are advancing Lomecel-B into later stage clinical trials for
the purpose of achieving commercialization in one or more indications. Our studies throughout the clinical development process are
intended to generate safety and efficacy data needed to advance these programs, and establish foundations for subsequent development
and expansion into new areas. We will continue to leverage our technical and clinical expertise, and relationships with clinical
investigators, treatment centers, and other key stakeholders, to explore new opportunities. |
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Expand
our manufacturing capabilities to commercial-scale production. We operate a good manufacturing practice (GMP) – compliant
manufacturing facility and produce our own product candidates for testing. We continue to improve and expand our capabilities with
the goal of achieving cost-effective large-scale manufacturing to meet future commercial demand. |
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Non-dilutive
funding. Our clinical programs have received over $16.0 million in competitive extramural grant awards ($11.9 million which has
been directly awarded to us and which are recognized as revenue when the performance obligations are met) from the NIH, Alzheimer’s
Association, and Maryland Stem Cell Research Fund (MSCRF). These prestigious funding awards are non-dilutive and allow us to collaborate
with state and federal partners in pursuing safe and effective therapeutics for disorders that have few, if any, available approved
treatments. |
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Continue
to develop our existing international programs. We have selected Japan as our first non-U.S. territory for a randomized,
double-blinded, placebo-controlled clinical trial to evaluate Lomecel-B for Aging Frailty. We intend to explore other indications
and other international locations for further development and commercialization. |
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Collaboration
arrangements and out-licensing opportunities. We will be opportunistic and consider entering into co-development, out-licensing,
commercialization or other collaboration agreements for the purpose of commercializing Lomecel-B and other products domestically
and internationally. |
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Product
candidate development pipeline through internal research and development, and in-licensing. Through our research and development
program, and through strategic in-licensing agreements, or other business development arrangements, we continue to actively explore
promising potential additions to our pipeline of product candidates. |
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Continue
to expand our intellectual property portfolio. Our intellectual property is vitally important to our business strategy, and we
take significant steps to develop this property and protect its value. Results from our ongoing research and development efforts
are intended to add to our existing intellectual property portfolio. |
Clinical
Development Pipeline
Since
our founding in 2014, we have initiated six clinical studies under five U.S. Food and Drug Administration (FDA) Investigational New Drug
applications (INDs) for the purpose of evaluating the safety and efficacy of Lomecel-B (See Figure 1).
![](https://content.edgar-online.com/edgar_conv_img/2022/03/11/0001213900-22-011894_img_001.jpg)
Figure
1: Lomecel-B clinical development pipeline
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Aging
Frailty. Aging Frailty is a life-threatening geriatric condition that disproportionately increases a patient’s risk for
poor clinical outcomes due to disease and injury. It is believed by geriatricians to be treatable, although no approved pharmaceutical
or biologic treatments currently exist for the condition. The definition of Aging Frailty lacks consensus, and would be a new indication
from a regulatory standpoint. As such, any approval of Lomecel-B for gaining Frailty indication will therefore require additional
clinical data and continued discussion with the U.S. FDA and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). |
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We
have completed two U.S. clinical trials under FDA investigational new drug application (IND) 016644: (1) a multicenter, randomized,
placebo-controlled Phase 2b trial (“Phase 2b Trial”) evaluating whether Lomecel-B can improve physical function, reduce
inflammation, and improve quality of life, among other endpoints, in Aging Frailty subjects; and (2) a multicenter, randomized, placebo-controlled
Phase 1/2 trial (“HERA Trial”) to evaluate safety, and to explore the effect Lomecel-B may have on biomarkers of immune
system function in Aging Frailty subjects receiving the influenza vaccine. Older individuals are often more vulnerable to infection
and may be inadequately protected from infection following vaccination due to an aging-related degeneration of the immune system.
Data from the Phase 2b Trial was announced in August of 2021 and data from the HERA trial are pending. |
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Japan
Clinical Trial: The Japanese PMDA has approved a Clinical Trial Notification (CTN), which is equivalent to a U.S. IND, allowing
an Investigator-sponsored Phase 2 clinical study for Aging Frailty patients in Japan. Based on feedback from Japan’s National
Center for Geriatrics and Gerontology (NCGG), we anticipate that this trial will open for enrollment in the first half of 2022. |
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The
Bahamas Registry Trial: We sponsor and operate a Registry Trial in Nassau, The Bahamas, where participants may receive Lomecel-B
for Aging Frailty and other indications, at the participant’s own expense. Lomecel-B is designated as an investigational product
in The Bahamas. |
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Alzheimer’s
Disease (AD). We have completed a double-blinded, randomized, placebo-controlled Phase 1 clinical trial under FDA IND 016524
to evaluate the safety and tolerability of Lomecel-B in individuals with mild AD. The ongoing subsequent Phase 2a study is a 48-patient,
randomized, double-blind and controlled clinical trial designed to evaluate single and multiple infusions of Lomecel-B in subjects
with mild AD. |
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The
Metabolic Syndrome1. The Metabolic Syndrome is an insidious condition which, over the course of years to decades,
leads to cardiovascular disease (CVD) and type II diabetes mellitus (T2MD). There are no approved therapies for the Metabolic Syndrome,
aside from symptomatic treatments. Under FDA IND 016644, we are conducted a sub-study to evaluate whether Lomecel-B may improve the
symptoms of the Metabolic Syndrome in Aging Frailty patients, and evaluate the effects of this comorbidity on responses of Aging
Frailty subjects to Lomecel-B. Results from this substudy are expected in first half of 2022. The Metabolic Syndrome presently does
not have an accepted consensus definition as an indication for regulatory purposes, and will therefore require additional clinical
data and discussion with FDA before additional trials. |
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Acute
Respiratory Distress Syndrome (ARDS) due to Viral Infection. ARDS can result in both short-term severe consequences (e.g., prolonged
and expensive hospitalization, and death), and long-term debilitating consequences (e.g., severe lung scarring and lung dysfunction).
Older persons, those with Aging Frailty, and those with the Metabolic Syndrome are at increased risk for developing ARDS due to viral
infection, as the COVID-19 pandemic has demonstrated, in which nearly 75% of deaths in the U.S. have occurred in individuals 65 years
of age and older. We are conducting a multicenter, randomized, placebo-controlled Phase 1 trial under FDA IND 019668 to evaluate
the safety and to explore the potential efficacy of Lomecel-B for treating ARDS due to influenza or SARS-CoV-2 virus infection. The
trial is expected to continue enrollment in 2022. As of February 2022, 6 patients have been enrolled in our COVID-19-ARDS trial,
and 4 additional patients were treated as part of our COVID-19-ARDS Expanded Access program. |
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Hypoplastic
Left Heart Syndrome (HLHS). Lomecel-B is being investigated in an ongoing Phase 2 clinical trial (ELPIS II) clinical trial
under FDA IND 017677. ELPIS II is a 38-subject, randomized, double-blind, controlled clinical trial designed to evaluate safety
and efficacy of Lomecel-B in conjunction with reconstructive surgery compared to surgery alone. The trial is funded in part by
the National Heart, Lung, and Blood Institute (NHLBI, part of the NIH).
Previously,
we completed a Phase 1 study under FDA IND 017677 to evaluate the safety, tolerability and provisional efficacy of Lomecel-B
as a combinatorial therapy to surgery for this ultra-rare congenital heart defect. Babies born with this condition have an underdeveloped
left ventricle, and undergo a series of three surgeries to prevent certain death. Despite these life-saving surgeries, HLHS patients
still have a high early mortality rate. We are investigating whether Lomecel-B, directly injected into the heart during the second
stage HLHS open-heart surgery, is safe and can improve short- and long-term outcomes in these vulnerable patients. These outcomes
include heart function, and heart-transplant-free survival. The Phase 1 study met the primary safety endpoint: no major adverse
cardiac events (MACE), nor any treatment-related infections during the first month post-treatment FDA granted our MSCs both Rare
Pediatric Disease (RPD) Designation and Orphan Drug Designation (ODD) by the FDA in the third quarter of 2021 for the treatment
of HLHS. |
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Metabolic Syndrome study was conducted as a sub-study of patients enrolled in our two US Aging Frailty clinical trials. |
Lomecel-B
for Aging-Related Indications: a Geroscience Approach
While
the exact mechanisms of action of Lomecel-B, and MSCs in general, are still active areas of research, based on current evidence, we believe
Lomecel-B may treat multiple facets of aging-related disorders simultaneously through multiple mechanisms of actions that may include
the following.
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Improve
vascular function. Lomecel-B has the potential to improve overall functioning of the blood vessels (called the vasculature).
The potential broad impact is to improve blood supply to the muscles, bones, and organs, including the brain (the neurovasculature),
and thereby improve nutrient supply and waste removal. |
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Reduce
inflammation. A pro-inflammatory state is a common attribute among many aging-related disorders. Lomecel-B has the potential
to reduce inflammation without leading to toxic immunosuppression, as well as the potential to promote activation of anti-inflammatory
biochemical pathways. Broadly speaking, this includes reducing harmful pro-inflammatory proteins that negatively affect muscles,
bones, and joints, as well as the brain (inflammation in the brain is called neuroinflammation).
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Improve
immune function. Lomecel-B has the potential to improve immune system function, such as the ability to make antibodies. |
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Activate
intrinsic repair and regenerative mechanisms. Intrinsic ability to regenerate and repair tissue declines with aging. Lomecel-B
has the potential to stimulate these regenerative and repair pathways to promote recovery from damage and a more healthful state. |
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Home
to sites of inflammation and damage. A well-known property of MSCs is that they are attracted to sites of inflammation and damage
within the body. This property may be advantageous for treating aging-related diseases where the damage can be diffuse. Therefore,
by delivering Lomecel-B into the blood via intravenous infusion, it may more readily be able to flow to these diffuse sites. |
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Compensate
for aging-related loss of MSCs. Lomecel-B may compensate for diminished MSC activity and numbers in the recipient, which are
dramatically reduced as a function of aging. |
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Biochemical
Properties of Lomecel-B
The
proposed mechanisms of action of Lomecel-B derive from intrinsic cellular features (See Figure 2). The cells in Lomecel-B cells
secrete numerous proteins that include cytokines and growth factors, which are believed to be responsible for decreasing inflammation
and promoting repair.
The
cells in Lomecel-B also secretes exosomes, which are biochemically active membrane spheres (called vesicles) that carry cargo composed
of proteins, ribonucleic acid (RNA), and other molecules. These secreted products can potentially have beneficial effects on numerous
targets, even over large distances, in treated subjects. Using exosomes as a therapeutic is an emerging therapeutic approach that we
are pursuing through our research and development.
Lomecel-B
cells can also potentially regulate endogenous cells through actions that include direct cell-cell interactions that can allow for exchange
of RNAs, proteins, and other cellular content between the cells through linkages called connexin-mediated gap-junctions. MSCs can also
form tunneling nanotubes (TNTs) that allow for exchange of larger cytoplasmic content, including mitochondria (the energy-generating
portions of cells). Such exchanges have been documented to occur between MSCs and neuronal stem cells, cardiomyocytes, corneal epithelial
cells, lung epithelial cells, retinal ganglion cells, renal epithelial cells, and macrophages.
In
the context of treating aging-related disorders, such exchange of mitochondria, proteins, RNA, and other cargo from Lomecel-B sourced
from young donors may suggest cellular regenerative mechanisms for older cells of the recipient which have depleted of mitochondria,
have reduced metabolic functioning, etc. In fact, mitochondria released from damaged cells appears to be a signal to induce regenerative
mechanisms in MSCs, which can promote a desired shift in energy metabolism in the recipient cells.
![](https://content.edgar-online.com/edgar_conv_img/2022/03/11/0001213900-22-011894_img_002.jpg)
Figure
2. Potential mechanisms of action of Lomecel-B. (1) Lomecel-B cells release growth factors and other proteins, such as anti-inflammatory
cytokines. These have the potential to reduce inflammation, and stimulate nearby stem cells and other cells (called paracrine activity)
to promote regenerative and repair responses. There is also potential for these factors to be released into the blood and work at a distance,
called endocrine activity. (2) Lomecel-B cells also have the potential to engage in direct cell-cell interactions to induce positive
pathways in contacted cells. (3) Lomecel-B cells release exosomes, which have cargo consisting of RNA, proteins, and other molecules
that can be taken up by other cells to provide beneficial effects. (4) Lomecel-B cells also have the potential to form nanotube bridges
or TNTs, which can allow the exchange of mitochondria and other cellular contents between cells.
Our
Aging Frailty Research Program
Aging
Frailty is a clinically-defined and extreme form of unsuccessful aging. It is readily recognized by the hallmark signs of weakness, slowness,
fatigue, unintentional weight loss, and low activity. Those with Aging Frailty are disproportionately compromised in their ability to
cope with every day and acute stressors, are at increased vulnerability to disease and injury, have lowered tolerance to medications,
and are at risk for poor outcomes, including disability and death. Even normally “minor” insults (e.g., minor infection)
can have significant consequences, and lead to a spiral of decline to debility in these patients.
The
necessity for identifying patients with Aging Frailty is well-acknowledged in the geriatric community, and the treatment of Aging Frailty
and promotion of healthful aging are recognized priorities of the National Academy of Medicine and NIA/NIH. Despite the pressing need
for interventions, there are no FDA-approved therapies that can slow down, reverse, or prevent Aging Frailty.
Biological
Underpinnings of Aging Frailty
Aging
Frailty is a multifaceted biologically-driven process that is distinct from normal aging. While all of the biological mechanisms underlying
frailty are still being elucidated, it is thought to involve a low-level chronic pro-inflammatory state referred to as inflammaging.
This loss of control over inflammation can be attributed to an imbalance between levels of inflammatory promoters and anti-inflammatory
mediators, as well as diminished capacity to restore equilibrium once an inflammatory stimulus has subsided. The ultimate result is measurable
elevated serum levels of pro-inflammatory signaling molecules, such as tumor necrosis factor-α (TNF-α), and diminished levels
of anti-inflammatory mediators, such as interleukin-10 (IL-10).
Inflammation
can contribute to the physical decline in Aging Frailty through multiple mechanisms, including detrimental effects on muscles, bone tissue,
the immune system, cardiovascular function, and cognition. In muscle cells, pro-inflammatory mediators such as TNF-α stimulate
catabolic biochemical pathways that break down muscle tissue, which can explain the clinically observed atrophy, decreased strength and
endurance, and increased exhaustion seen in Aging Frailty. Inflammation can also severely diminish immune system function, and accelerate
the aging-related decline in the immune system, known as immunosenescence. This ultimately leads to an immune system that is hyporesponsive,
making these patients highly vulnerable to disease and cancer.
Aging
Frailty (and aging in general) is also characterized by reductions in the number and function of circulating MSCs. Therefore, treatments
that can positively affect and/or replenish these endogenous stem cell functions could be of therapeutic value for Aging Frailty.
The
culmination of these organ system declines can explain the common clinical manifestations of Aging Frailty, such as sarcopenia and cachexia,
and forms the basis for the resulting heightened vulnerability to injury, disease, adverse health outcomes, and mortality.
Lomecel-B
for the Potential Treatment of Aging Frailty
We
are evaluating Lomecel-B as a therapy for Aging Frailty because the potential mechanisms of action may suitably address many of the features
and underpinnings of this condition. Lomecel-B has the potential to reduce inflammation associated with Aging Frailty, and to promote
an anti-inflammatory state by releasing anti-inflammatory molecules, which can promote physiological restoration to a more normal state.
We believe current clinical data suggests Lomecel-B may be able to improve aspects of physical functioning, specifically exercise tolerance
and endurance in mobility-impaired older, frail individuals. Furthermore, we believe our current clinical and biomarker data suggest
that Lomecel-B may improve functioning of the vasculature, which in itself may result in certain systemic benefits to patients.
Market
Potential
U.S.
leading geriatricians and epidemiologists from Johns Hopkins University estimate approximately 15% of community-dwelling individuals
65 years and older in the U.S. have Aging Frailty, per the Cardiovascular Health Study (CHS) frailty phenotype definition. Another 45%
are considered at risk for becoming frail, or “pre-frail”. These equate to 8.1 million and 24.3 million people, respectively.
By 2035, the number of individuals with Aging Frailty is projected to reach over 11.4 million. Those with Aging Frailty are disproportionately
high consumers of healthcare resources whose cost of care may have significant economic consequences. Developing effective interventions
to prevent or reverse frailty is a priority for many countries with single-payor healthcare systems.
Japan
is considered to be a “super-aged” society, with approximately 28% of the population aged 65 or older in 2021, representing
some 35.9 million individuals. The pooled prevalence of frailty amongst this demographic per CHS frailty phenotype or modified version
definition, is estimated to be 7.4%.
For
the US and Japanese markets, and any other territory, the market size ultimately will be dependent on many factors, but the precise definition
used to define the condition/patient population for regulatory approval purposes in the U.S. and in Japan will likely result in a refined
market size that may be a subset of the frail population.
Aging
Frailty Clinical Trials and Regulatory Trial in the Bahamas
We
have completed two multicenter trials in the U.S. for Aging Frailty, and have received Japanese PMDA approval to conduct a Phase 2 Aging
Frailty clinical trial in Japan which is expected to initiate in the first half of 2022. We have government approval to administer Lomecel-B
for Aging Frailty participants in a Registry Trial that is actively enrolling in The Bahamas.
U.S.
Phase 2b Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial
The
Phase 2b Trial is our most advanced clinical trial in our Aging Frailty program (ClinicalTrials.gov #NCT03169231). The trial design was
guided by input from FDA’s Center for Biologics Evaluation and Research (CBER), and Longeveron’s scientific and clinical
advisors. Longeveron designated this as a “Phase 2b” trial because its objectives included a preliminary assessment of Lomecel-B
effectiveness for an Aging Frailty indication. Longeveron did not conduct a “Phase 2a” trial.
The
specific objectives of this trial were to evaluate the effectiveness of Lomecel-B in multiple domain measures of Aging Frailty: physical
functioning biomarkers; patient-reported outcomes (PROs); quality-of-life measures (QOLs); frailty status; and clinical outcomes and
other endpoints applicable to Aging Frailty. In addition, this trial assessed a dose-range of Lomecel-B to further our understanding
of evidence of a dose-response relationship that could support the product’s pharmacological bioactivity. The target population
was comprised of: individuals aged 70–85 years who were considered mild to moderately frail per the CSHA Clinical Frailty Scale
(CFS), could walk between 200 and 400 meters at baseline; and had systemic inflammation evidenced by elevated tumor necrosis factor-α
(TNF-α).
The
primary efficacy endpoint in this clinical trial was the change from baseline in the six-minute walk test (6MWT) at six months for investigational
treatment compared to placebo treatment. The primary endpoint included a primary analysis (comparing mean change from baseline for investigational
arms compared to placebo arm), and a secondary analysis (evaluating whether a dose-response relationship exists). The 6MWT is a functional
assessment that engages several organ systems, including the cardiopulmonary, musculoskeletal, and neurologic systems, is a reliable
indicator of frailty status, and may correlate with an individual’s ability to perform basic activities of daily living (ADLs).
This validated and easily-administered test measures how many meters a person can walk in six minutes, and is a general evaluation of
mobility and exercise tolerance or endurance. We intend to evaluate the full spectrum of results from both US Aging Frailty trials, and
depending on the data and input from our advisors, we may choose to engage FDA to discuss whether a regulatory pathway to pivotal clinical
trial(s) can be identified. These discussions would need to include evaluation of an acceptable and appropriate primary efficacy endpoint(s),
in an approvable indication with a mutually agreeably-defined patient population.
Phase
2b Aging Frailty Trial Results
One
hundred and forty-eight (148) subjects were randomized and received a single peripheral intravenous infusion of Lomecel-B (25 million
cells, 50 million cells, 100 million cells or 200 million cells), or placebo, followed by a 52-week observation period to evaluate safety
and efficacy. The Phase 2b trial was conducted at eight hospitals and clinics, primarily in South Florida, including the Miami Veterans
Administration (VA) Healthcare System, and was funded by a Small Business Innovation Research (SBIR) grant from the NIH’s NIA.
The trial was completed in the first quarter of 2021 and the topline results were announced on August 13, 2021.
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Primary
analysis of the primary efficacy endpoint: Despite showing a statistically significant increase in 6MWT for the highest 3 dose
levels of Lomecel-B compared to baseline at Month 6 post-treatment (25 million=7.8 meters, p=0.5040; 50 million=35.8 meters, p=0.0053;
100 million=24.9 meters p=0.0443; 200 million=49.3 meters, p=0.0065; placebo=8.0 meters, p=0.5371), the change in the Lomecel-B groups
were not statistically significantly different from the change in placebo group at Month 6 post-treatment, which was the primary
efficacy endpoint. However, statistically significant differences from placebo were observed 90 days later at Month 9 post-treatment,
which was a pre-specified exploratory endpoint (25 million Δ=27.5, p=0.1530; 50 million Δ=49.2, p=0.0122; 100 million
Δ=31.0, p=0.1071; 200 million Δ=63.4, p=0.0077). When pooling all Lomecel-B-treated subjects together, the mean change
from baseline compared to placebo at Day 270 was statistically significant (all Lomecel-B Δ=42.8, p=0.0079). |
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Secondary
analysis of the primary efficacy endpoint: The secondary analysis was to determine whether a dose-response relationship exists
between Lomecel-B and post-treatment changes in 6MWT distance. The results showed a statistically significant dose-response curve
at Month 6. Among the various dose-response curves evaluated (Emax, Linear, Exponential, Quadratic, and Sigmoid Emax),
all had p-values of less than 0.05, with the Sigmoid Emax model having the most significant dose-response relationship
(p=0.0170). |
The
study’s key secondary endpoints were 6 month change in the patient reported outcome questionnaire PROMIS—Physical Function—Short
Form 20a (SF-20a) total score and 6 month change in serum levels of TNF-α, a pro-inflammatory cytokine. Lomecel-B cohorts did not
show a statistically significant difference compared to the placebo cohort in the SF-20a score or the TNF-α results. The remainder
of the efficacy endpoints, which included assessments of physical function, sexual function, fear and risk of falling, depression, cognition,
frailty status, pulmonary function, and clinical outcomes, were considered exploratory and Lomecel-B-treated groups did not show statistically
significant differences versus placebo at most of the time points.
We
are continuing to further evaluate the clinical and biomarker data, and perform subgroup analysis, in conjunction with working with our
Frailty Steering Committee and other advisors to determine next steps in the clinical development plan for this indication.
U.S.
Phase 1/2 HERA Trial: Lomecel-B as a Potential Vaccine Adjuvant
The
aging-related diminution of the immune system (immunosenescence) makes Aging Frailty patients vulnerable to infection and disease. Immunosenescence
is the basis for a generally muted response to any type of immune challenge in these patients, including disproportionately low response
to vaccines, such as the influenza vaccine.
Many
efforts are made to try to boost vaccine effectiveness by manipulation of the vaccines themselves, such as increasing vaccine dosage
in the case of the High-Dose Flu Vaccine given to older recipients. However, this approach often falls short of providing the sought-after
immune protection because of the patients’ diminished intrinsic ability to mount an effective immune response and furthermore,
may be associated with increased incidence of adverse events. To date, there are no approved therapeutics shown to improve the intrinsic
competence of the immune system (immunocompetence).
In
this clinical program, Lomecel-B is being explored as a candidate for improving immunocompetence in older frail individuals receiving
influenza vaccine. The HERA Trial was designed to evaluate safety, to explore whether Lomecel-B infusion may have a positive effect on
the aging immune system in response to influenza vaccine, and to evaluate Lomecel-B’s possible effects on Aging Frailty status
and endpoints (ClinicalTrials.gov #NCT02982915).
Trial
Status. The trial is complete and data from the randomized, placebo-controlled phase is pending. The Phase 1 component of the trial
was a 22-patient multicenter, open-label, randomized trial. Phase 2 was a multicenter, randomized, double-blinded, placebo-controlled
trial. The Phase 2 portion of the trial had a target enrollment of up to 60 subjects, and enrolled a total of 39 subjects before it was
closed for enrollment at the conclusion of the 2020 flu season at the onset of the COVID-19 pandemic in the U.S. Clinical data from the
randomized, placebo-controlled Phase 2 trial is pending.
Aging
Frailty Phase 1 Results
HERA
Immune-Response Data. Phase 1 of the HERA Trial was an open-label study conducted during the 2017 – 2018 flu season. The primary
goal was to evaluate the safety of Lomecel-B as a vaccine adjuvant, and evaluate how a short (1 week) or longer (4 week) interval between
Lomecel-B infusion and vaccination might impacted the immune response to the vaccine. Subjects enrolled had mild to moderate Aging Frailty
per the CSHA CFS, and received the Fluzone High-Dose Vaccine (Sanofi Pasteur Inc.).
Interim
results from the Phase 1 portion of the trial showed that both groups (1 week and 4 week interval between infusion and vaccination) showed
statistically significant positive antibody responses as determined by the blood levels of IgM and IgG antibodies raised against influenza
A and B strains. IgM antibodies appear early in a normal immune response, and are normally followed by IgG antibodies which appear later.
Antibody levels ≥ 1.1 index value (IV) indicate positive antibody response. Average IgM levels prior to receiving vaccine were <
1.1 IV at the Infusion Visit and Vaccination Visit, where blood samples were taken prior to Lomecel-B administration and vaccination,
respectively. Post-vaccination, these increased to > 1.1 IV, with every subject showing an increase from baseline for all four antibodies
(IgG and IgM for influenza A and B viruses). These increases did not significantly differ between the two study arms (1-week and 4-week
interval between Lomecel-B infusion and vaccination).
We
also examined potential to neutralize the specific influenza virus strains that the vaccine was directed against (Michigan, Hong Kong,
and Brisbane viruses). This used a test called the hemagglutinin inhibition (HAI) assay. Overall, the 1-week interval group showed significantly
higher HAI results (meaning better performance) compared to the 4-week interval group. Based on these preliminary findings, we elected
to use a 1-week interval between infusion with Lomecel-B and vaccination in Phase 2 of HERA.
We
view these results as encouraging, in light of the reported suboptimal efficacy of the 2017 – 2018 Fluzone High-Dose Vaccine.
The Centers for Disease Control & Prevention (CDC) found an overall adjusted vaccine effectiveness (VE) of just 18% against
flu-associated medically-attended acute respiratory illness in those ≥ 65 years of age (CI = -25–47%). At the
approximate mid-point of Phase 2 of the HERA Trial, we performed a planned interim analysis in order to re-assess study powering. We
evaluated the 6MWT and other physical function measures of Aging Frailty as part of this analysis.
The
HERA Phase 2 interim analysis showed that the 6MWT increased in the Lomecel-B arm by 45.20 ± 81.03 meters (n=14) at six
months post-administration, versus a decrease of 21.40 ± 81.87 meters (n=15) in the placebo arm (mean ± standard
deviation; six-month difference from placebo: 66.60 meters. 95%CI: -4.70 – 137.89. p = 0.0656). A similar trend was seen
in the open-label HERA Phase 1 (59.59 ± 140.57 meters. 95%CI: -12.68 – 131.86. n=19. p=0.0996). We performed
an analysis using the pooled data from patients in the Phase 1 arm combined with those from the Phase 2 interim analysis Lomecel-B arms.
At six months post-infusion, there was a statistically significant improvement in the combined Phase 1 & 2 Lomecel-B arms from Baseline
relative to placebo (six-month difference from placebo: 75.65 meters. 95%CI: 0.71 – 150.60. p=0.0480). By 12 months post-infusion,
the improvements had waned in the Lomecel-B groups (Phase 1, Phase 2 interim analysis, and combined), and were no longer significantly
different from placebo (12-month difference from placebo: 35.31 meters. 95%CI: -16.99 – 87.61. p=0.1796).
Japanese
Phase 2 Aging Frailty Trial
The
PMDA has approved an investigator-initiated CTN application for a multicenter Phase 2 clinical study of Lomecel-B infusion in older Japanese
subjects with mild to moderate Aging Frailty. The trial is similar in design to our U.S. Phase 2b Trial, and is expected to initiate
in first half of 2022. The CTN applicant is the NCGG, and we are engaged in trial planning with the NCGG and Juntendo University Hospital,
as the other clinical trial site.
Under
the 2014 law passed by the Japanese government, two new Acts were added that regulate regenerative medicine development and offer two
pathways to market for regenerative medicine product candidates: The Act on the Safety of Regenerative Medicine (ASRM) and the Pharmaceutical
and Medical Devices Act (PMD Act). A summary of the primary differences and benefits of the two Acts is described in “Japanese
Laws and Regulations” within the Business section of this report.
The
Bahamas Registry Trial
In
2017, we were granted approval by the Bahamian government to sponsor a Registry Trial in Nassau, The Bahamas. Eligible subjects with
Aging Frailty who meet Registry eligibility requirements may receive Lomecel-B at their own expense at one of two medical centers with
which we are partnered. The medical providers are responsible for the administration of Lomecel-B to these individuals as well as their
care and Registry Trial-specific follow-up. The program is regulated by the Stem Cell Research and Therapy Act of 2013, and the Stem
Cell Research and Therapy Regulations passed in 2014. Under the terms of the approval, participants in the Registry pay a fee directly
to us, and we in turn pay a fee to the medical providers who administer Lomecel-B to the participant. Data collected from the Registry
Trial contribute to our overall understanding of the safety profile of Lomecel-B, and for gathering real-world evidence on possible efficacy.
Lomecel-B is not licensed for commercial sale in the Bahamas and is considered an investigational therapeutic.
In
2019, we received approval to expand the Registry for the following indications: mild cognitive impairment; AD and related dementias;
frailty due to reasons other than aging, including overuse and injury; and osteoarthritis. The Registry Trial has specified baseline
assessments and a prescribed follow up schedule over a 12-month post-administration time period. Participants are expected to follow
up with their local physician at the specified time points so that we may collect safety data and gain additional efficacy information,
specifically with respect to physical function, the individual’s global impressions of change, biomarkers, and other indication-specific
measures.
Participation
in the Registry Trial has been adversely impacted by the COVID-19 pandemic due to travel restrictions. Starting on July 22, 2020, the
Bahamian government halted travel from the U.S. into The Bahamas, which resulted in the temporary cessation of participation in The Bahamas
Registry Trial. While this travel restriction has now been lifted, participation in the Bahamas Registry Trial remains lower than anticipated,
due in part to pandemic-related effects on international travel.
Lomecel-B
for Alzheimer’s Disease
AD
is the leading form of dementia. This disease affects millions of Americans, leads to early mortality, and creates a tremendous burden
on families and society that costs the U.S. hundreds of billions of dollars annually in direct costs and lost productivity.
Patients
afflicted with AD have characteristic brain changes that include abnormal protein deposits in the brain, called β-amyloid deposits.
Another feature that occurs within the neurons themselves is called neurofibrillary tangles, which interferes with the structure and
function of the neurons, and leads to neuron death. Inflammation in the brain – a process called neuroinflammation – is also
a key feature of AD. This pro-inflammatory state appears essential for the clinical manifestation of dementia resulting from AD. In addition,
the functioning of the blood vessels in the brain are often compromised in AD, the consequences of which include impaired exchange across
the barrier between the blood and the brain, called the blood-brain barrier (BBB). Ultimately, these pathological processes lead to the
structural changes in the brain and resulting dementia.
We
are testing Lomecel-B as a potential treatment for AD based on the hypothesis that its multiple MOAs can simultaneously address multiple
features of AD. Preclinical studies show that MSCs can potentially reduce AD-associated brain inflammation, improve the function of blood
vessels in the brain, and reduce brain damage due to AD progression, and promote regenerative responses. We have completed a multicenter,
randomized, double-blinded, placebo-controlled Phase 1 safety study of subjects with mild AD. The trial met its primary safety endpoint,
and also provided preliminary evidence suggestive of efficacy. Based on the results, we are preparing a larger Phase 2 study. If successful
in clinical studies and approved by FDA, we hope that Lomecel-B may prove to be a disease-modifying therapy for AD.
Prevalence
of AD and Market Potential
The
Alzheimer’s Association estimates that 6.2 million Americans have AD, and as many as 12.7 million Americans will be afflicted by
2050 barring significant medical breakthroughs. An estimated 35.6 million people are affected with AD worldwide, and that number is expected
to quadruple by 2050. Among individuals age 85 and older, over a third have AD. AD is currently the sixth leading cause of death in the
U.S., taking more lives annually than breast cancer and prostate cancer combined, underscoring the critical importance for developing
a therapeutic intervention that can delay or reverse the progression of the disease. Arguably, AD represents the only leading cause of
death that cannot be prevented, cured, or slowed using existing approved therapies with the possible exception of Aduhelm in certain
patients. This disease has a tremendous impact on the quality of lives of the patients and their caregivers, costing American society
an estimated $355 billion for health-care, long-term care, and hospice services in 2021, and over $256.7 billion in unpaid dementia caregiving
(usually borne by family members) based on 2020 estimates.
Analysts
have suggested that any disease-modifying AD drug that makes it all the way to market could rapidly achieve over $10 billion in sales.
Without a major market competitor, analysts have predicted that that figure could balloon to over $20 billion by 2030.
Phase
1 Alzheimer’s Disease Clinical Trial
We
have conducted a double-blind, randomized, placebo-controlled Phase 1 trial to evaluate the safety and explore whether there was any
preliminary evidence of efficacy of Lomecel-B in subjects with mild AD (ClinicalTrials.gov #NCT02600130). Each subject received a single
infusion of low-dose of Lomecel-B (20 million cells), high-dose of Lomecel-B (100 million cells), or placebo. The observation period
was 12 months post-infusion. Our results support the safety and tolerability of using Lomecel-B in individuals with AD, in which the
primary safety endpoint was met, and no product-associated SAEs were observed.
Results
from the AD Phase 1 Trial
While
this Phase 1 study was powered for safety as the primary endpoint, it was also designed to evaluate the potential effects of Lomecel-B
in multiple efficacy domains that include cognition, ADLs, QOL, and biomarkers.
The
Mini Mental State Exam (MMSE) is a validated and commonly used assessment of cognitive function. A decreased score on the MMSE indicates
worsening, and a 6-month change of ~1.4 points has been calculated to be a minimally clinically important difference (MCID). Statistically
significant differences on the MMSE were found between the low-dose Lomecel-B and placebo groups. The placebo group showed a fairly steady
decline on the MMSE over the course of a year (p < 0.05 at Weeks 13, 39, and 52 post-treatment versus baseline). However, the
low-dose Lomecel-B group showed no significant change from baseline until Week 52 (1 year) post-infusion. At Week 39, average MMSE scores
were 19.78 ± 3.347 in low-dose Lomecel-B arm (Δ from baseline= -1.22 ± 2.728, n = 11) versus 15.43 ± 4.117
in the placebo group (Δ from baseline= -5.09 ± 3.854, n = 7). The difference in change from baseline between the low-dose
Lomecel-B arm and placebo was 3.87 points (p = 0.0236; 95%CI: 0.59 – 7.14 points). The high-dose Lomecel-B arm showed no
significant changes from baseline or versus placebo. Other cognitive assessments (such as the “Alzheimer’s Disease Assessment
Scale – Cognitive”) showed no significant differences between the Lomecel-B and placebo groups.
Phase
2a Alzheimer’s Disease Trial
In
the last quarter of 2021, we initiated this 48-patient, Phase 2a, randomized, placebo-controlled multicenter study enrolling mild to
moderate AD patients. The study is currently actively screening patients for enrollment. This study is designed to measure brain changes
using MRI, and include detailed biomarker assessments of the inflammatory and vascular systems thought to contribute to the worsening
of AD, in addition to cognitive function, ADLs, safety, and other endpoints.
Lomecel-B
for the Metabolic Syndrome
We
conducted a clinical sub-study to our Aging Frailty studies to explore whether Lomecel-B may improve the Metabolic Syndrome, and if the
Metabolic Syndrome presents confounding issues for this treatment approach in Aging Frailty patients. This sub-study primarily focuses
upon blood-based biomarker changes, and non-invasive evaluation of vascular (blood vessel) functioning.
For
the purpose of analysis, we are evaluating the Metabolic Syndrome in subjects enrolled in our Phase 2b Trial and HERA Aging Frailty trials,
and dividing them into two groups: those with and without the Metabolic Syndrome. We will look at the effect of Lomecel-B relative to
placebo on the two groups with respect to effect changes relevant to the Metabolic Syndrome. Approximately 40% of Aging Frailty patients
have been reported to have the Metabolic Syndrome, which we have empirically confirmed from our Phase 2b Trial and HERA clinical trial,
in which we have identified approximately 45% and 33% of enrolled subjects, respectively, who meet the criteria for the Metabolic Syndrome.
The Metabolic Syndrome is also becoming a well-recognized contributor to AD and related dementias.
The
Metabolic Syndrome is a clinically-defined condition (ICD-10: code 277.7) that increases the chances of developing CVD and T2DM. It is
also known as X syndrome, insulin resistance syndrome, cardiometabolic syndrome, and Reaven’s syndrome. The Metabolic Syndrome
lacks consensus definition regarding the specific variables amongst clinicians and researchers. The Metabolic Syndrome is defined as
a cluster of risk factors for which at least three of the following five criteria must be met.
|
● |
Elevated
serum triglycerides. |
|
|
|
|
● |
Reduced
high-density lipoprotein (good cholesterol). |
|
|
|
|
● |
Elevated
blood pressure. |
|
|
|
|
● |
Elevated
fasting glucose. |
|
|
|
|
● |
Increased
waist circumference (central or apple-shaped obesity). |
The
Metabolic Syndrome is associated with vascular dysfunction and damage, and a proinflammatory state marked by elevated serum levels
of C-reactive protein (CRP), interleukin-6 (IL-6), and D-dimer. Obesity also directly contributes to this proinflammatory state and
the Metabolic Syndrome. Compared to unaffected individuals, patients with the Metabolic Syndrome are twice as likely to
develop CVD in 5 – 10 years, five-times as likely for developing T2DM, over twice as likely to have a stroke, over three-times
as likely to have a heart attack, and have double the risk of dying from such events. The incidence of the Metabolic Syndrome has
reached epidemic proportions and continues to increase, as the overall prevalence in the U.S. is approximately 35% of the total
population, or over 80 million individuals.
Lomecel-B
may be a potential candidate for the Metabolic Syndrome through multiple potential MOAs that include the potential to reduce associated
inflammation and improve vascular function. Preclinical studies support the clinical benefits of allogeneic MSC therapy for treating
the Metabolic Syndrome, which resulted in improvements in vascular function, atherosclerosis, and glucose homeostasis.
Lomecel-B
for Acute Respiratory Distress Syndrome (ARDS)
We
are conducting a multicenter, double-blinded, randomized, placebo-controlled trial for ARDS due to COVID-19 or influenza virus
infection. ARDS can be rapidly induced by a variety of insults, such as coronavirus and influenza virus infection.
Approximately 200,000 people suffer from ARDS in the U.S. annually, with a mortality rate of about 40%. These numbers may increase
as a result of COVID-19, which could become a seasonal epidemic. Older persons, those with Aging Frailty, and those with the
Metabolic Syndrome, are at significantly increased risk for severely poor outcomes from ARDS due to viral infection, including
prolonged hospitalization and death.
Viral
infection leading to ARDS can result in severe inflammation called a “cytokine storm”, most pronounced by severely elevated
serum levels of CRP and IL-6. This in turn leads to disruption of the lung cell layers (the endothelial and epithelial barriers), and
consequently, to severe inhibition of pulmonary exchange. ARDS can result in long-term adverse effects on patients, such as lung scarring
(fibrosis). As now widely appreciated due to COVID-19, there is a dearth of treatment options available for ARDS, and first-line defense
measures often have sub-optimal palliative effects.
Lomecel-B
has the potential to be a treatment for ARDS due to the previously described MOAs. These include the potential to treat the cytokine
storm induced in ARDS without leading to toxic immunosuppression, reduce fibrotic damage, promote reparative mechanisms, and improve
immune functioning.
Status
of Clinical Trial. This trial is currently enrolling and we expect enrollment to continue through 2022.
Grant
Funding Award. This study is being supported in part by a grant award from the MSCRF, part of Maryland TEDCO.
Emergency
Use Expanded Access. In addition to our clinical trial, four patients with ARDS have been treated with Lomecel-B under FDA emergency-use
expanded-access through individual physician-filed applications.
Lomecel-B
for Hypoplastic Left Heart Syndrome (HLHS)
We
are testing Lomecel-B as a potential combinatorial therapy candidate to surgical intervention for HLHS. The scientific goal underlying
this study builds on surgical advances of the past thirty years, and is intended to address remaining obstacles to improving long-term
cardiac function in HLHS patients.
HLHS
is a severe congenital birth defect in which the left ventricle of the heart is either severely underdeveloped or missing. As a consequence,
babies born with this condition have severely diminished systemic blood flow, which previously led to a 100% mortality rate shortly after
birth. Babies born with HLHS now undergo a complex three stage heart reconstruction over the course of years, in which the single remaining
right ventricle is used to support systemic circulation (the right ventricle is normally used for lung circulation, which is a much lower
load). While these children can now live into adulthood, early mortality is still extremely high in this population due to right ventricle
failure, which is not meant for the increased load demanded for systemic circulation. Furthermore, HLHS patients after undergoing heart
reconstructive surgery are often not ideal candidates for a heart transplant. As such, there is an important unmet medical need to improve
right ventricular function in these patients to improve both short-term and long-term outcomes.
We
believe that Lomecel-B has potential as a combinatorial therapy with HLHS surgery to improve both short- and long-term clinical outcomes.
We are evaluating whether a direct injection in the heart can improve right ventricle function by promoting regenerative and repair responses.
In animal studies, this combinatorial approach resulted in a 10 – 15% improvement in right ventricle function.
Prevalence of HLHS. HLHS is a rare indication,
occurring at approximately 2 – 3 cases per 10,000 live births, or roughly 1,000 children annually in the U.S. FDA has granted both
RPD Designation and ODD for the treatment of HLHS.
Results
from Phase 1 HLHS Clinical Trial
We
have completed a multicenter, open-label, uncontrolled Phase 1 clinical trial in HLHS (ELPIS I, NCT02587572). This study was designed
to assess safety of intramyocardial injection of Lomecel-B administered to 10 infants with HLHS during Stage 2 bidirectional cavopulmonary
anastomosis (BDCPA, or “Glenn procedure”) surgeries. Children with HLHS undergoing Stage 2 surgery (Glenn procedure) were
treated via intramyocardial (direct heart) injection of Lomecel-B. This study met the primary safety endpoint: no major adverse cardiac
events (MACE), nor any treatment-related infections during the first month post-treatment.
Phase
2 Hypoplastic Left Heart Syndrome Clinical Trial
A
randomized, double-blind and controlled Phase 2 clinical trial designed to evaluate the efficacy of Lomecel-B in conjunction with reconstructive
surgery compared to surgery alone, is currently actively enrolling (ELPIS II, NCT04925024). With a target enrollment of 38 infants, we
expect ELPIS II to enroll in approximately 7 children’s hospitals in major metropolitan centers located throughout the U.S.
Phase
2 supported by Grant Funding Award. A grant from the NIH’s NHLBI (Grant number 1UG3HL148318), was awarded to the Principal
Investigator. We are a subawardee and provide clinical trial material (Lomecel-B) and other support. We may provide additional financial
and organizational support for this trial in the future.
Expanded
Access. In addition to the clinical trial, one HLHS baby has received Lomecel-B under FDA expanded access, or “compassionate
use” approval through an individual physician request.
Other
Investigational Products in Development
We
have conducted preclinical research and development work for additional cellular therapy product candidates, including exosomes and CD271+
cells. While similar to Lomecel-B, CD271+ cells may have characteristics that could lead to a next generation product and may have additional
uses. We conduct research and development for other cellular-based experimental products called exosomes, which are small membrane-bound
products secreted by cells, including MSCs, which contain bioactive cargo.
Manufacturing
The
manufacture and delivery of cell therapy products to patients involves complex, integrated processes. Commercial success in this area
requires manufacturing processes that are reliable, scalable, and economical. We currently operate a manufacturing facility in Miami,
FL, which supplies Lomecel-B for our clinical trials and also serves as our corporate headquarters. We have and will continue to devote
significant resources to optimization of process development and manufacturing to reduce per-unit manufacturing costs and to enable quick
scale-up of production upon approval of any of our candidates in a particular country. We also intend to expand the manufacturing capacities
in the U.S. and potentially Japan or other regions in Asia.
We also intend to expand
the manufacturing capacities in the U.S. and potentially Japan or other regions in Asia for commercialization at both a regional and
global scale upon regulatory approvals.
Our
GMP facility went online in early 2017, and consists of 4,150 ft2 (385.5 m2) with approximately 3,000 ft2
(279 m2) of GMP space comprised of ISO 7 cleanrooms, and ISO 8 ancillary areas and 1,150 ft2 (107 m2)
of warehouse, research and development and Quality Control space. The GMP cleanrooms are used exclusively for the manufacture of human
cellular therapy products for use in clinical trials. The facility is in compliance with FDA regulations in 21 CFR Parts 210 and 211.
Our
lead product, Lomecel-B, consists of human allogeneic bone-marrow derived MSCs as the active ingredient. These cells undergo culture-expansion
using proprietary processes, and are then formulated, packaged and stored frozen (cryopreserved) until shortly before use. Fresh
bone marrow is procured from established, licensed U.S.-based third-party tissue suppliers, which harvest the tissue from young, healthy
consenting donors. Lomecel-B is produced using processes that FDA has reviewed and authorized as part of our INDs. We currently have
bone marrow supply contracts in place with two suppliers: the Oklahoma Blood Institute and Vista Health Research. These suppliers provide
adequate bone marrow for our current and anticipated needs; however, if one or both suppliers were to no longer provide bone marrow,
alternate suppliers would be needed or our ability to produce Lomecel-B in the future could be impacted.
Technology
Capabilities
From
the commencement of operations in 2014, we recognized the potential for a cellular therapy product to be a novel therapeutic candidate
in our chosen indications. We have assembled a team of experts and proprietary technologies that we believe enables us to take a systematic
approach to rapidly develop improved cell therapies. We believe having established manufacturing capabilities and operations within the
U.S. early in the development of our product candidates is a competitive advantage. Over time, we expect to expand regional manufacturing
capacity and potentially add external supply nodes to meet projected product requirements for commercialization. We believe that anticipated
future clinical and commercial demand for Lomecel-B and new pipeline programs can be met, as our process has been designed to meet these
demands as milestones are achieved. We believe our scalable robust manufacturing process, along with our proprietary technologies and
our industry experienced team, would be challenging and costly for potential competitors to replicate.
Contract
Development and Manufacturing Services
We
produce all of our product candidates in the ISO 7 cleanrooms of our GMP facility to satisfy our ongoing clinical studies, and The Bahamas
Registry Trial. As a revenue-generating opportunity, occasionally we utilize excess capacity, when available, to provide contract manufacturing
and development services to third parties; however, our business development activity is limited in this area.
Commercialization
We
currently have no established sales, marketing or product distribution infrastructure. In order to commercialize any of our product
candidates if approved for commercial sale, we will need a sales and marketing organization with technical expertise and supporting
distribution capabilities or collaborate with third parties that have sales and marketing experience. As we move our product
candidates through development toward regulatory approval, we will evaluate several options for each product candidate’s
commercialization strategy. These options include further building an internal sales force, entering into a joint marketing
collaboration with another pharmaceutical or biotechnology company, or out-licensing any future approved product to another
pharmaceutical or biotechnology company.
Competition
The
field of regenerative medicine, which includes gene therapies, cell therapies (such as Lomecel-B), and tissue-engineered products, is
broadly defined as “products intended to repair, replace or regenerate organs, tissues, cells, genes, and metabolic processes in
the body,” per the Alliance for Regenerative Medicine (ARM), an international advocacy organization. Regenerative medicine companies
number over 1,000 worldwide as of the first half of 2021.
In
some of our indications, we face competition from both cellular therapy companies, and pharmaceutical/biotechnology companies. The following
table is a general, non-comprehensive list of cellular therapy companies that we believe could be considered our primary competition
on the basis that these companies are developers of living cell-based therapies, albeit for different indications in most cases.
Name |
|
Corporate
Headquarters |
|
Clinical
stage pipeline indication(s) |
Athersys,
Inc. |
|
U.S. |
|
Ischemic
stroke; ARDS; GvHD; Acute Myocardial Infarction |
BioCardia,
Inc. |
|
U.S. |
|
Heart
failure; Acute myocardial infarction |
BrainStorm
Cell Therapeutics |
|
U.S. |
|
ALS;
MS |
Caladrius
Biosciences |
|
U.S. |
|
CLI;
refractory disabling angina; CMD |
Corestem |
|
South
Korea |
|
ALS
(Commercial in South Korea); Lupus |
Cynata
Therapeutics |
|
Australia |
|
GvHD |
Healios
K.K. |
|
Japan |
|
Ischemic
stroke; ARDS |
Medipost |
|
South
Korea |
|
Osteoarthritis
(commercial); BPD; AD |
Mesoblast
Ltd. |
|
Australia |
|
Heart
failure, low back pain, GvHD; ARDS; Crohn’s Disease |
Pluristem
Therapeutics, Inc. |
|
Israel |
|
CLI;
ARDS; ARS; GvHD |
ReNeuron |
|
U.K. |
|
Ischemic
stroke; Retinitis pigmentosa |
SanBio
Co., Ltd. |
|
Japan |
|
Ischemic
stroke; Traumatic brain injury |
Stemedica
Cell Technologies |
|
U.S. |
|
Ischemic
stroke; heart failure; AD |
ARDS
= Acute Respiratory Distress Syndrome; GvHD = Graft versus host disease; ALS = Amyotrophic lateral sclerosis; MS = Multiple sclerosis;
BPD = Bronchopulmonary dysplasia; CLI = Critical limb ischemia; CMD = coronary microvascular disease; ARS = Acute radiation syndrome.
Biology
of Aging Research Companies
To
our knowledge, there are no other companies currently conducting clinical trials for Aging Frailty using a regenerative medicine
approach. However, this is likely to change as the emphasis on developing an effective treatment grows. Per clincialtrials.gov, as
of March 1, 2022, there are a few groups testing different types of stem cells for frailty:
|
● |
The
Foundation for Orthopedics and Regenerative Medicine, Antigua and Barbuda are recruiting subjects to evaluate the safety of cultured
allogeneic adult umbilical cord derived mesenchymal stem cell intravenous infusion for aging frailty; |
|
● |
Shanghai
East Hospital in Shanghai, China is recruiting subjects for a multicenter, randomized, double-blind, placebo-controlled Phase 2 clinical
study of umbilical cord MSC infusion for Aging Frailty; and |
|
● |
Vinmec
Research Institute of Stem Cell and Gene Technology is planning to initiate a trial to investigate the safety and potential therapeutic
efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with standard frailty treatment in
Vietnam. |
The
University of Texas Health Science Center in San Antonio is collaborating with the NIH to conduct a randomized, placebo-controlled Phase
2 clinical trial of metformin, the Type-2 diabetes medication, for the prevention of frailty in subjects aged 65 to 95. Other academic
groups or hospitals have or are testing hormonal treatments such as ghrelin or testosterone to prevent or treat frailty. The vast majority
of interventional trials typically involve lifestyle intervention, specifically evaluating diet, dietary supplements, or exercise modifications,
or a combination thereof. A number of companies are researching different approaches and therapeutics in the broad “anti-aging”
category, developing therapies that may extend “healthspan” by slowing or reversing diseases associated with aging, or the
aging process itself.
|
● |
Calico
Life Sciences, LLC: This Google-backed company is researching compounds that are intended to treat aging-related diseases
and conditions; however, its first clinical study involves patients with advanced solid tumor cancers. |
|
|
|
|
● |
Unity
Biotechnology: Unity’s focus is to “extend human health span, the period in one’s life unburdened by the
disease of aging.” UBX is targeting senescence (the process whereby cells cease to divide, and linger in the body releasing
harmful proteins) and is in the category called “senolytic medicines”. |
|
|
|
|
● |
AgeX
Therapeutics: AgeX is a pre-clinical stage company testing telomerase-expressing Pluripotent Stem Cells (PSCs) in an attempt
to reverse cell aging, and extend human health and life spans. |
Competition
in Alzheimer’s Disease
There
are several companies currently testing cellular therapy in neurologic and cognitive disorders. However, in the U.S., we believe we are
the furthest advanced in the clinical development of a regenerative medicine approach to treating AD. The following companies have publicly
indicated that they are conducting, or intend to conduct, cell therapy clinical trials in AD.
|
● |
Brainstorm
Cell Therapeutics: In 2020, Brainstorm Cell Therapeutics, a U.S. company, announced its intention to initiate a multinational
Phase 2 trial to test its autologous MSC neurotrophic factor investigational product in AD. |
|
|
|
|
● |
Medipost
Co. Ltd.: Medipost, a South Korean company, has reported that it has completed a Phase 2a study in AD using its umbilical
cord-derived allogeneic MSCs. |
|
|
|
|
● |
CHABiotech
Ltd.: This South Korea-based company is conducting a Phase 1/2 trial of enhanced placenta-derived stem cells in AD, according
to its website. |
There
are many other pharmaceutical and biotechnology companies that are conducting clinical trials of various therapeutics for the treatment
of AD. According to the Alzheimer’s Association, in 2021 there were 121 unique therapies registered on ClinicalTrials.gov. Some
of the more established and well-known companies in this group include Biogen, Novartis, Eisai, and Eli Lilly.
Competition
in HLHS
Currently
there are no FDA-approved treatments for HLHS. In addition to our HLHS clinical program, Boston Children’s Hospital is sponsoring
a study of allogeneic mesenchymal precursor cells (rexlemestrocel-L) in HLHS with cells provided by Mesoblast Ltd. According to clinicaltrials.gov,
ReGen Theranostics is sponsoring an active trial of intramyocardial injection of autologous umbilical cord blood derived mononuclear cells during
surgical repair of HLHS.
Competition
in ARDS
Currently
there are no FDA-approved treatments for ARDS. The COVID-19 pandemic has resulted in a spike in research on the potential for allogeneic
MSCs to treat acute lung injury resulting from infection with the SARS-CoV-2 virus. Several cellular therapy companies had ongoing ARDS
programs prior to the pandemic, and several other companies, including us, initiated clinical studies during the pandemic.
|
● |
Athersys:
Athersys is a U.S.-based cell therapy company developing an allogeneic bone-marrow derived stem cell product. Athersys is
currently conducting a Phase 2/3 trial in ARDS, and has received both Regenerative Medicine Advanced Therapy (RMAT) and Fast Track
Designations from the FDA. Athersys had previously conducted Phase 1/2 trials in ARDS prior to the COVID-19 pandemic. |
|
● |
Mesoblast:
Mesoblast, an Australia-based company, is conducting a multi-country Phase 2/3 clinical study for ARDS related to COVID-19
using its allogeneic bone-marrow MSC product remestemcel-L. |
|
|
|
|
● |
Pluristem:
Israeli company Pluristem has initiated Phase 2 trials in the U.S. and Germany for testing its placenta-tissue stem cell
product. |
Intellectual
Property
We
seek to protect our proprietary technology, inventions, and improvements that are commercially important to the development of our business
by seeking, maintaining, and defending patent rights, whether developed internally, acquired from third parties, or licensed from third
parties. We also intend to seek and rely on any statutory or regulatory protections, including FDA’s expedited review program,
data exclusivity, market exclusivity and patent term extensions where available.
We
have a combination of Company-owned and in-licensed patents and patent applications related to cell-based therapy and its various uses.
This portfolio includes patent applications directed to use of allogeneic MSCs to (a) increase humoral immunity; (b) treat sexual dysfunction;
and (c) act as adjuvants for vaccines. We also have in-licensed a patent family directed to methods of use of CD271+ MSC precursor cells.
Our patent applications contain claims that, if allowed, specifically protect the use of our product in individuals with Aging Frailty,
immunosenescence, and other age-related diseases. We also rely on trade secrets that may be important to the development of our business.
Trade secrets are difficult to protect and enforce and therefore provide us with only limited protection.
We
expect to file additional patent applications in support of current and new product candidates, as well as for process and manufacturing-related
improvements or inventions, should these arise. These expected additional patent applications may be related to existing patent applications
or may create new patent families. Our commercial success will depend in part on obtaining and maintaining patent protection and trade
secret protection for our current and future product candidates and the methods used to develop, manufacture, administer, and use them.
Our commercial success will also depend on successfully defending our patents against third-party challenges and operating without infringing
on the proprietary rights of others. We are aware of several U.S. patents held by third parties covering potentially similar or related
products, and their manufacture and use. Generally, conducting clinical trials and other acts relating to FDA approval are not considered
acts of infringement in the U.S. If and when Lomecel-B MSCs are approved by the FDA, third parties may seek to enforce their patents
by filing a patent infringement lawsuit against us. Our ability to deter and, if necessary, to stop third parties from making, using,
selling, offering to sell or importing our products or products that are similar to our products depends on the extent to which we have
rights under valid and enforceable patents or trade secrets that cover these activities. We can neither be sure that patents will be
granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future,
nor can we be sure that any patents that may be granted to us in the future will be commercially useful in protecting our product candidates,
discovery programs and processes. Unpublished third-party patent applications may exist that would have an effect on our freedom to operate.
For this and more comprehensive risks related to our intellectual property, please see “Risk Factors—Risks Related to
Intellectual Property.”
The
term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most jurisdictions
where we file, including the U.S., the patent term is 20 years from the earliest date of filing a non-provisional patent application.
In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays
by the U.S. Patent and Trademark Office (USPTO), in examining and granting a patent. Patent term in the U.S. may be shortened if a patent
is subject to a terminal disclaimer over another patent. Delays on the part of a patentee may decrease patent term adjustment.
In
the U.S., the term of a patent that covers an FDA-approved “active ingredient” or methods of its use may also be eligible
for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review
process. The Drug Price Competition and Patent Term Restoration Act of 1984, the Hatch-Waxman Amendments, or the Biologics Price Competition
and Innovation Act of 2009 permit a patent term extension of up to five years beyond the expiration of the statutory term of a patent,
including any patent term adjustment to which the patent is entitled. The length of the patent term extension is related to the length
of time the active ingredient or method is under regulatory review. Patent term extension cannot extend the remaining term of a patent
beyond a total of 14 years from the date of product approval, only one patent applicable to an approved drug may be extended and only
those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. Similar provisions
are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug. In the future, if
and when our products receive FDA approval, we expect to apply for patent term extensions on patents covering those products. We plan
to seek patent term extensions for any issued patents we may obtain in any jurisdiction where such patent term extensions are available.
We are not assured that the applicable authorities, including the FDA in the U.S., will agree with our assessment of whether such extensions
should be granted, and if granted, the length of those extensions. For more information regarding the risks related to our intellectual
property, see “Risk Factors—Risks Related to Intellectual Property.”
We
may file patent applications directly with the USPTO as provisional applications. We may file U.S. non-provisional applications, direct
foreign applications under the Paris Convention and the Agreement on Trade Related Aspects of Intellectual Property Rights, and Patent
Cooperation Treaty, or PCT, applications. Those applications may claim the benefit of the priority date of one or more earlier filed
provisional applications, when applicable. The PCT system allows a single application to be filed within 12 months of the original priority
date of the patent application, and to designate all of the PCT member states in which national or regional patent applications can later
be pursued based on the PCT application.
For
all patent applications, we determine claim strategy on a case-by-case basis. Advice of counsel and our business model and needs are
considered. We seek to file patents containing claims for protection of all useful applications of our proprietary technologies and any
products, as well as all new applications and/or uses we discover for existing technologies and products, assuming these are strategically
valuable. We routinely reassess the number and type of patent applications, as well as the pending and issued patent claims to pursue
maximum coverage and value for our processes and compositions. Further, we may modify claims during patent prosecution to meet our intellectual
property and business needs.
We
recognize that the ability to obtain patent protection and the degree of such protection depends on a number of factors. These include
the volume and scope of the prior art, the novelty, non-obviousness, and utility of the invention, and the ability to satisfy the written
description and enablement requirements of the patent laws. In addition, the coverage claimed in a patent application can be significantly
narrowed before the patent is issued, and its scope can be reinterpreted or further altered even after patent issuance. Consequently,
we may not obtain or maintain adequate patent protection for any of our future product candidates or for our technology platform. We
cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether
the claims of any issued patents will provide sufficient protection from copying by competitors. Any patents that we hold may be challenged,
circumvented, or invalidated by third parties. We cannot predict whether, in certain jurisdictions, a third-party will use a method confidentially
that we later independently discover and patent, which may result in a limited grant to the third party of the ability to continue to
practice that method despite our patent.
In
addition to patent protection, we rely on trademark registration, trade secrets, know how, other proprietary information and continuing
technological innovation to develop and maintain our competitive position. We seek to protect and maintain the confidentiality of proprietary
information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
Although we take steps to protect our proprietary information and trade secrets, including through contracts with our employees and consultants,
third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our
trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets indefinitely.
We
require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality
agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all confidential information
concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship
with us is to be kept confidential and not disclosed to third parties except under specific circumstances. Our agreements with employees
also provide that all inventions conceived by the employee in the course of employment with us or from the employee’s use of our
confidential information are our exclusive property. However, such confidentiality agreements and invention assignment agreements can
be breached, and we may not have adequate remedies for any such breach. In addition, our trade secrets may otherwise become known or
be independently discovered by competitors. To the extent that our consultants, contractors or collaborators use intellectual property
owned by others in their work for us, disputes may arise as to the rights in related or resulting trade secrets, know-how and inventions.
For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Intellectual
Property.”
The
patent positions of biotechnology companies like ours are generally uncertain and involve complex legal, scientific and factual questions.
Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. Third-party patents could
require us to alter our development or commercial strategies or our products or processes, to obtain licenses or to cease certain activities.
Our breach of any license agreements or our failure to obtain a license to proprietary rights required to develop or commercialize our
future products may have a material adverse impact on us. If third parties prepare and file patent applications in the U.S. that also
claim technology to which we have rights, we may have to participate in interference or derivation proceedings in the USPTO to determine
priority of invention. If third parties file requests for inter partes review of our patents, then we may have to defend those
patents in the USPTO. For more information, see “Risk Factors—Risks Related to Intellectual Property.”
When
available to expand market exclusivity, our strategy is to obtain, or license additional intellectual property related to current or
contemplated development platforms, core elements of technology and/or clinical candidates.
Company-Owned
Intellectual Property
Mesenchymal
Stem Cells as Vaccine Adjuvants and Methods for Using the Same. The claims within this patent application family are currently directed
to methods of enhancing the immune response to vaccination, which is one of the research objectives of our Phase 1/2 HERA Trial. This
research is relevant to Aging Frailty subjects, who are particularly vulnerable to the effects of viral contagion, such as influenza
or COVID-19, and who may be lacking in immunoprotection. Certain claims address the ability to enhance a subject’s immune response
to a vaccine through the administration of a therapeutically effective amount of allogeneic mesenchymal stem cells in a subject that
exhibits “Inflammaging.” In this family we own one pending U.S. patent application, 9 patent applications outside of the
U.S. (in nine jurisdictions), and two patent registrations in South Africa. All of the patent applications are national or regional phase
applications based on a PCT application filed in February 2017 and claiming priority to a U.S. provisional application filed in February
2016. National or regional phase applications were filed in the U.S., Australia, Canada, the European Patent Organization, Hong Kong,
Israel, Japan, South Korea, New Zealand, Singapore, and South Africa. If issued and assuming all maintenance and annuity fees are paid,
patents arising from these applications are projected to expire in 2037.
Methods
of Using Human Mesenchymal Stem Cells to Effect Cellular and Humoral Immunity. Certain claims in this family of patent applications
relate to the ability for mesenchymal stem cell therapy to improve the immune system function in patients with chronic systemic inflammation,
a hallmark of frailty. It is believed that raising or lowering specific biomarkers after therapeutic intervention by a minimum amount
may provide broad protection from an intellectual property standpoint and reflects clinical goals of treatment and treatment response.
In
this family we own one pending U.S. patent application, 12 patent applications outside of the U.S. (in 12 jurisdictions), and a patent
registration in South Africa. With two exceptions (The Bahamas and Taiwan), all of the applications are national or regional phase applications
based on a PCT application filed in November 2017 and claiming priority to a U.S. provisional application filed in November 2016. The
applications in The Bahamas and Taiwan claim priority to that same provisional application but were not filed using the PCT. In addition
to the applications in Taiwan and The Bahamas, PCT national or regional phase applications were filed in the U.S., Australia, Canada,
China, the European Patent Organization, Israel, Japan, South Korea, New Zealand, Singapore, South Africa, and Hong Kong. If issued and
assuming all maintenance and annuity fees are paid, patents arising from these applications are projected to expire in 2037.
Treatment
of Sexual Dysfunction and Improvement in Sexual Quality of Life. This application family is directed towards increasing libido
and improving sexual function and satisfaction in a female patient through the use of allogeneic or autologous MSC therapy, whether derived
from bone marrow, adipose tissue or induced pluripotent stem cells (iPSCs). In this family we own one pending U.S. patent application,
12 patent applications outside of the U.S. (in 12 jurisdictions), and a patent registration in South Africa. With two exceptions (The
Bahamas and Taiwan), all of the applications are national or regional phase applications based on a PCT application filed in June 15,
2018 and claiming priority to a U.S. provisional application filed in June 2017. The applications in The Bahamas and Taiwan claim priority
to that same provisional application but were not filed using the PCT. In addition to the applications in Taiwan and The Bahamas, PCT
national or regional phase applications were filed in Australia, Canada, China, the European Patent Organization, Hong Kong, Israel,
Japan, South Korea, New Zealand, Singapore, South Africa, and the U.S. If issued and assuming all maintenance and annuity fees are paid,
patents arising from these applications are projected to expire in June 2038.
Potency
Assay. We own one PCT patent application relating to examination of protein production by human mesenchymal stem cells in response
to stimuli. That application was filed in April 2021 and claims priority to a U.S. provisional application filed in April 2020. National
phase applications, if any, are not required to be filed until October 2022 at the earliest.
Treatment
of Alzheimer’s Disease with Allogeneic Mesenchymal Stem Cells. We own one PCT patent application related to treatment of AD
with allogeneic mesenchymal stem cells. That application was filed in September 2021 and claims priority to three separate U.S. provisional
applications, the earliest of which was filed in September 2020. National phase applications, if any, are not required to be filed until
March 2023 at the earliest.
Use
of Mesenchymal Stem Cells in Treatment of Juvenile Hypoplastic Left Heart Syndrome. We own one U.S. provisional patent application
related to treatment of hypoplastic left heart syndrome with allogeneic mesenchymal stem cells. That application was filed in July 2021.
Related applications, if any, are not required to be filed until July 2022.
Administration
of Mesenchymal Stem Cells for Aging Frailty. We own one U.S. provisional patent application related to administration of mesenchymal
stem cells for aging frailty. That application was filed in September 2021. Related applications, if any, are not required to be filed
until September 2022.
License
Agreements and Strategic Collaborations
The
University of Miami (UM)
On
November 20, 2014, we entered into an Exclusive License Agreement with UM (the “UM License”) for the use of certain Aging
Frailty-related MSC technology rights developed by our Chief Science Officer at UM. The UM License is a worldwide, exclusive license,
with right to sublicense, with respect to any and all know-how specifically related to the development of the culture-expanded MSCs for
aging-related frailty used at the Interdisciplinary Stem Cell Institute of UM (“IMSCs”), all SOPs used to create the IMSCs,
and all data supporting isolation, culture, expansion, processing, cryopreservation and management of the IMSCs. We are required to pay
UM (i) a license issue fee of $5,000, (ii) a running royalty in an amount equal to three percent of annual net sales on products or services
developed from the technology, which amounts are payable on a country-by-country basis beginning on the date of first commercial sale
and ending on the expiration or termination of the UM License Agreement, and which may be reduced to the extent we are required to pay
royalties to a third party for the same product or process, (iii) escalating annual cash payments on the anniversary date of the agreement
of ten, fifteen, twenty-five, forty and fifty thousand dollars, which amounts may be offset by other consideration paid. UM also received
a one percent (1%) equity grant, which is subject to certain anti-dilution provisions.
The
agreement extends for up to 20 years from the last date a product or process is commercialized from the technology. This agreement was
amended on December 11, 2017. The 2017 amendment modified the dates of the milestone completions under the original UM License.
To date, the Company has made payments totaling $140,000 to UM, and as of December 31, 2021, we had accrued $50,000 in milestone fees
payable to UM and $100,000 for patent related reimbursements based on the estimated progress to date.
The
agreement was further amended on March 3, 2021 to increase the license fee due to UM. The Company agreed to pay UM an additional fee
of $100,000, to defray patent costs, with $70,000 due within thirty (30) days of the effective date of the amendment, and the remainder
to be paid in equal installments of $7,500 on the 2nd, 3rd, and 5th year anniversaries of the effective
date. The Company also agreed to issue an additional 110,387 unregistered shares of Class A Common Stock shares to UM. The Company and
UM agreed to the following modification of the milestone payments: (a) No payment will be due upon the completion of Phase 2 clinical
trials for the product; (b) a one-time payment of $500,000, payable within six months of the completion of the first Phase 3 clinical
trial of the products (based upon the final data unblinding); (c) a one-time payment of $500,000 payable within six months of the receipt
by the Company of approval for the first new drug application (“NDA”), biologics application (“BLA”), or other
marketing or licensing application for the product; and (d) a one-time payment of $500,000 payable within six months of the first sale
following product approval. “Approval” refers to Product approval, licensure, or other marketing authorization by the U.S.
Food and Drug Administration, or any successor agency. The amendment also provided for the Company’s license of additional technology,
to the extent not previously included in the UM License, and granted the Company an exclusive option to obtain an exclusive license for
(a) the HLHS IND with ckit+ cells; and (b) UMP-438 titled “Method of Determining Responsiveness to Cell Therapy in Dilated Cardiomyopathy.”
We
have the right to terminate the UM License upon 60 days’ prior written notice, and either party has the right to terminate upon
a breach of the UM License.
JMH
MD Holdings
On
December 22, 2016, we entered into a worldwide exclusive license agreement with JMH MD Holdings (“JMHMD”), an affiliate of
our Chief Science Officer, for the use of CD271+ technology, a subpopulation of bone marrow-derived MSCs. We are required to pay JMHMD
a running royalty in an amount equal to one percent of the annual net sales of the licensed product(s) used, leased, or sold by or for
us by any sub-licensees, which amounts are payable on a country-by-country basis beginning on the date of first commercial sale and ending
on the latter of expiration of the last to expire patent rights in such country or ten years from the first commercial sale in such country
(provided that if all claims within the patent rights have expired or been finally deemed invalid then the royalty will be reduced by
50%), and which may also be reduced to the extent we are required to pay royalties to a third party for the same product or process.
We are also required to pay an initial fee and, by the first day of each anniversary of the Agreement, starting with the second anniversary,
a minimum royalty of ten thousand dollars. JMHMD also received an equity grant equal to one-half of one percent of the then outstanding
units of the Company on a fully-diluted basis. If we sublicense the technology, we are also required to pay an amount equal to 10% of
the net sales of the sub-licensees.
Under
the agreement, the Company is required to use commercially reasonable efforts to achieve the following milestones: (i) submit an
investigational new drug application to FDA (or international equivalent) within one year of effective date of agreement, (ii)
initiate a clinical trial utilizing bone marrow derived CD271+ Precursor Cells within three years of the effective date; provided,
that any of the milestones may be extended for up to six months for a total of three times by notice and payment of a five thousand
dollar extension fee. Failure to achieve these milestones within five years of the effective date triggers a right of termination by
JMHMD. Otherwise, the agreement is to remain in effect until either the date all issued patents and filed patent applications have
expired or been abandoned, or 20 years after the date of FDA approval of the last commercialized product or process arising from the
patent rights whichever comes later. Further, each party has the right to terminate upon sixty days’ prior written notice, or
in the event of breach. If the Company sublicenses the technology, it is also required to pay an amount equal to 10% of the net
sales of the sub-licensees. In addition, on December 23, 2016, as required by the license agreement the Company paid an initial fee
of $250,000 to JMHMD, and issued to it 10,000 Series C Units, valued at $250,000. The $500,000 of value provided to JMHMD for
the license agreement, along with professional fees of approximately $27,000, were recorded as an intangible asset that is amortized
over the life of the license agreement which was defined as 20 years. The Company to date has not incurred any royalty or sublicense
related expense, but has paid $45,000 in license fees($10,000 per year for 2021, 2020 and 2019) and for a $15,000 extension fee. In
addition, the Company paid legal fees of approximately, $25,000 for each of the years ended December 31, 2021 and 2020,
in connection with the patent prosecution, issuance, and maintenance fees related to CD271+ technology.
In-licensed
Patents and Applications
Bone
Marrow Derived CD271+ Precursor Cells for Cardiac Repair. We have in-licensed the exclusive right to use CD271+ MSC precursors from
bone marrow to treat certain aging-related conditions and diseases, such as frailty, Metabolic Syndrome, loss of muscle due to aging
or frailty and neurocognitive disorders. That patent has issued in Australia, China, Israel, Japan, South Korea, Mexico, New Zealand,
Germany, Spain, France, the United Kingdom, Italy, Sweden, and Singapore. The patent application remains pending in U.S. (where there
are two pending utility applications), Canada, and Brazil. The Canadian and Brazilian applications have both been allowed. One of the
U.S. applications is currently under appeal with the USPTO. While method of use claims may relate to the use of CD271+ cells for cardiac
repair, our license terms exclude our use of CD271+ cells for preventing and treating cardiovascular diseases or disorders, including
congenital cardiovascular defects. Assuming that all maintenance and annuity fees are paid, patents in this family are expected to expire
in August 2031.
Trademarks
We
have registered trademarks or applied for registered trademarks for “Longeveron” in the following jurisdictions. We have
begun to phase out the registrations and applications for “LMSC” in favor of registrations for “LOMECEL-B”. In
some jurisdictions multiple registrations and/or applications exist so that multiple goods and/or services may be listed:
Territory |
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“LOMECEL-B” |
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“Longeveron” |
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“LMSC” |
The
Bahamas |
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Registered |
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Closed |
Brazil |
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Registered |
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Canada |
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Registered |
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China |
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Registered |
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Registered |
European
Union |
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Registered |
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Hong
Kong |
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Registered |
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India |
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Registered |
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Japan |
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Registered |
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Registered |
South
Korea |
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Registered |
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Morocco |
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Registered |
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Registered |
Panama |
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Registered |
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Switzerland |
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Registered |
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Taiwan |
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Registered |
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U.S. |
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Allowed |
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Allowed |
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Pending |
Vietnam |
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Registered |
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Government
Regulation and Biologic Drug Approval
Government
authorities in the U.S., at the federal, state and local level, and other countries extensively regulate, among other things, the research,
development, testing, manufacture, quality control, approval, labeling, packaging, storage, recordkeeping, promotion, advertising, distribution,
marketing and export and import of products such as those we are developing. We believe that the FDA will regulate Lomecel-B as a biologic
drug (i.e., a biologic) through the biologics license application (BLA) process under the jurisdiction of the Center for Biologics Evaluation
and Research (CBER). We will work with FDA to confirm that a BLA is the most appropriate pathway and that CBER will be the FDA center
responsible for review and licensure (i.e., approval). However, FDA may disagree with us, in which case we will follow FDA’s recommendation.
For future product candidates we will also confirm the appropriate approval pathway (i.e., BLA or new drug application (NDA)) and the
appropriate FDA center with regulatory oversight (i.e., CBER or the Center for Drug Evaluation and Research (CDER)).
U.S.
Biologic Drug Development Process
In
the U.S., biologic drugs—or simply “biologics”—are regulated under two statutes: The Public Health Service Act
(PHS Act) and the federal Food, Drug, and Cosmetic Act (FFDCA) and their implementing regulations. However, approval of only one application—typically
either a BLA or an NDA—is required prior to marketing. Numerous FDA “Guidance Documents” and other materials address
specific aspects of development for specific types of product candidates (e.g., cells, tissues, gene therapies, or vaccines). The process
of obtaining approval and complying with applicable statutes and regulations requires substantial time and financial resources. Failure
to comply with the applicable U.S. requirements before, during, or after approval may subject an applicant to administrative or judicial
sanctions. These sanctions could include the FDA’s refusal to approve pending applications, withdrawal of an approval, imposition
of a clinical hold on ongoing clinical trials, issuance of warning or untitled letters, product recalls, product seizures, total or partial
suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or
criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.
The
process required by the FDA before a biologic may be marketed in the U.S. generally involves the following steps:
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completion
of preclinical laboratory tests, animal studies and formulation studies in accordance applicable regulations; |
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submission
to of an IND, which must become effective before human clinical trials may begin; |
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approval
by an independent IRB at each clinical site (or by one “commercial IRB”) before each trial may be initiated; |
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performance
of adequate and well-controlled human clinical trials in accordance with current good clinical practice (cGCP) requirements to establish
the safety, purity, and potency (i.e., efficacy) of the proposed biologic for its intended use; |
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submission
of a BLA after completion of all clinical trials; |
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satisfactory
outcome of an FDA advisory committee review, if applicable; |
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satisfactory
completion of an FDA inspection of clinical investigation sites and the manufacturing facility or facilities at which the biologic
is produced; and |
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FDA
review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S. |
The
specific preclinical studies and clinical testing that is required for a BLA varies widely depending upon the specific type of product
candidate under development. Prior to beginning a human clinical trial with either a biologic or drug product candidate in the U.S.,
we must submit an IND that must become effective. The focus of an IND is the general investigational plan and protocol for the proposed
clinical study. The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology,
and pharmacodynamic characteristics of the product; chemistry, manufacturing, and controls (CMC) information; and any available human
data or literature to support the use of the investigational product. The IND automatically becomes effective 30 days after receipt by
the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial. In such
a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before
the clinical hold is lifted and the clinical trial can begin. Submission of an IND therefore may or may not result in FDA authorization
to begin a clinical trial.
Clinical
trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in
accordance with GCPs, including that all research subjects provide their informed consent to participate. Clinical trials are conducted
under protocols detailing, among other things, the study objectives, safety monitoring, and effectiveness criteria. A separate submission
to the existing IND must be made for each successive clinical trial conducted during product development. Other submissions to an IND
include protocol amendments, information amendments, IND safety reports and annual reports. Furthermore, an independent IRB for each
clinical trial site (or a single “commercial IRB” must review and approve the protocol and informed consent form before the
clinical trial may begin. The IRB also monitors the clinical trial until completed.
Regulatory
authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects
are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some clinical trials also
include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data monitoring committee
(DMC). A DMC authorizes whether or not a study may move forward at designated check points based on access to certain data from the trial.
The DMC may halt the clinical trial based on an unacceptable safety risk or on other grounds, such as a failure to demonstrate efficacy.
Related reporting requirements for the sponsor, clinical investigator, and/or IRB also include IND safety reports and updating clinical
trial results in public registries (e.g., ClinicalTrials.gov).
Human
clinical trials are typically conducted in three sequential phases that may overlap or be combined:
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Phase
1: The product candidate is initially introduced into healthy human subjects to test the safety, dosage tolerance, absorption, metabolism,
distribution, excretion, side effects, and, if possible, early evidence of effectiveness. In the case of some products for severe
or life-threatening diseases when the product may be too inherently toxic to ethically administer it to healthy volunteers, Phase
1 studies may instead be conducted in individuals who have the targeted disease or condition instead of healthy subjects. |
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Phase
2: The product candidate is administered to a limited population of individuals who have the specified disease or condition to evaluate
safety, preliminary efficacy, optimal dosages and dosing schedule, possible adverse side effects and safety risks. Multiple Phase
2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 (i.e., pivotal) clinical
trials. |
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Phase
3: Phase 3 clinical trials are generally the largest studies conducted at multiple clinical trial sites. The product candidate is
administered to an expanded population that has the specified disease or condition to further evaluate dosage, provide statistically
significant evidence of clinical efficacy and gain additional safety data. These clinical trials are intended to establish the overall
risk/benefit ratio of the investigational product and to provide an adequate basis for product approval. |
Concurrent
with clinical trials, sponsors usually complete additional animal studies, develop information about the chemical and physical characteristics
of the biologic and finalize a process for manufacturing the product in commercial quantities in accordance with GMP requirements. The
manufacturing process must consistently produce quality batches of the product candidate. Furthermore, the manufacturer must develop
methods for testing the identity, strength, quality and purity of the final biologic. In addition, the sponsor must develop and test
appropriate packaging, and conduct stability studies to demonstrate that it does not undergo unacceptable deterioration over its shelf
life.
During
the development of a new biologic, sponsors are given opportunities to meet with the FDA. These meetings typically occur prior to submission
of an IND (i.e., pre-IND meeting), at the end of Phase 2 (i.e., EOP2 meeting), and before a BLA is submitted (i.e., pre-BLA meeting).
Meetings at other times may be requested. These meetings provide an opportunity for the sponsor to share information about the data gathered
to date, for the FDA to provide advice, and for the sponsor and the FDA to reach agreement on the next phase of development. Sponsors
typically use EOP2 meetings to discuss Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe
will support approval of the new biologic.
U.S.
Review and Approval Process for Biologic Drugs
Assuming
successful completion of all required testing, the sponsor submits a BLA containing the results of product development, preclinical and
other non-clinical studies and clinical trials, descriptions of the manufacturing process, analytical testing, proposed labeling and
other relevant information. The submission of a BLA is subject to the payment of a substantial application fee under the Prescription
Drug User Fee Amendments (PDUFA). PDUFA fees apply to both drugs and biologics. Sponsors may seek a waiver of these fees in certain limited
circumstances, including a waiver of the application fee for the first BLA or NDA submitted by a small business. Product candidates with
an orphan drug designation (ODD) are not subject to the BLA application fee unless the product application also includes a non-orphan
indication.
The
FDA reviews a BLA to determine, among other things, whether a biologic is safe, pure, and potent (i.e., effective) for its intended use
and whether its manufacturing is GMP-compliant to assure the product’s identity, strength, quality and purity. Under PDUFA, the
FDA has a goal date of ten months from the date of “filing” to review and act on the submission. However, the time between
submission and filing can add an additional two months as FDA conducts a preliminary review to ensure that the BLA is sufficiently complete
to permit substantive review. Formal FDA review of the BLA does not begin until FDA has accepted it for filing. The FDA may refer an
application in some cases to an advisory committee for its independent review. An advisory committee is a panel of independent experts,
including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation to FDA as to whether the application
should be approved and under what conditions. The FDA is not bound by advisory committee recommendations, but it considers them carefully
when making decisions.
Before
approving a BLA, the FDA will typically inspect the locations where the product is manufactured. The FDA will not approve an application
unless it determines that the manufacturing processes and facilities are in compliance with GMPs, and are adequate to assure consistent
production of the product within required specifications. An important part of a BLA is a lot release protocol that the sponsor will
use to test each lot of product made after BLA approval, as well as the FDA’s own test plan that will be used for confirmatory
testing of each post-approval product lot that is made before it is released to the public. If the FDA determines that the data and information
in the application, are not acceptable, then the FDA will outline the deficiencies and often will request additional testing or information.
Notwithstanding the submission of any requested additional information, the FDA may decide that the application does not satisfy the
regulatory criteria for approval.
After
the FDA evaluates a BLA, it will either issue an approval letter or a Complete Response Letter (CRL). The approval letter authorizes
commercial marketing of the biologic with approved prescribing information for specific approved indications. On the other hand, a CRL
indicates that the review cycle of the application is complete but the BLA cannot be approved in its present form. A CRL usually describes
the specific deficiencies and the actions the sponsor must take to correct those deficiencies. A sponsor that receives a CRL must resubmit
the BLA after addressing the deficiencies, withdraw the application, or request a hearing. Even if such additional data and information
are submitted, the FDA may decide the resubmitted BLA still does not satisfy the approval criteria.
Following
marketing approval, a sponsor may need to fulfill certain post-marketing requirements (PMRs) or post-marketing commitments (PMCs). These
may include Phase 4 studies that used to gain additional experience from the treatment of patients for the intended therapeutic indication.
The trials may be agreed upon prior to approval, or the FDA may require them if new safety issues emerge. A deferred pediatric study,
if required (and not waived) under the Pediatric Research Equity Act (PREA), may also be conducted post-approval if the product includes
a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.
BLA
approval may also include a risk evaluation and mitigation strategy (REMS) that requires sponsor post-marketing regulatory efforts. A
REMS is a safety strategy to manage a known or potential serious risk associated with a drug or biologic and to enable patients to have
continued access to such medicines by managing their safe use. A REMS may include medication guides, physician communication plans, or
elements to assure safe use (ETASU) such as restricted distribution methods, patient registries, and other risk minimization tools.
FDA
may withdraw the product approval if the sponsor does not comply with PMRs, PMCs, a REMS program, or other post-marketing requirements.
The FDA may also request that a product be recalled for an identified safety issue. Finally, new legislative or regulatory requirements
may be enacted or established, or FDA policies may change, all of which could impact the timeline for development programs and regulatory
approval.
FDA
Expedited Review Programs for Serious Conditions
Under
various statutory and regulatory authorities, the FDA has authority to review and approve certain products on an expedited basis if they
are intended to treat a serious condition and meet other requirements. These expedited programs are discussed below.
RMAT
Designation. In 2017, the FDA established the regenerative medicine advanced therapy (RMAT) designation as part of its implementation
of the 21st Century Cures Act. Regenerative medicine therapies to treat, modify, reverse, or cure serious conditions and that meet the
appropriate criteria may be eligible for RMAT designation as well as FDA’s other expedited programs (i.e., fast track, breakthrough
therapy, or priority review designations or accelerated approval). Regenerative medicine therapies receiving RMAT designation must meet
the same standards for approval as any other biological product, including demonstrating the product’s safety and effectiveness.
As described in Section 3033 of the 21st Century Cures Act, an investigational product is eligible for RMAT designation if:
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It
is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue
product, or any combination product using such therapies or products (except for those regulated solely under Section 361 of the
PHS Act and 21 C.F.R. Part 1271); |
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It
is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and |
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Preliminary
clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition. |
A
request for an RMAT designation can be included in a new IND, or submitted as an amendment to an existing IND. As with other expedited
programs, the FDA can withdraw an RMAT designation that has been granted if the designation criteria are no longer met. Benefits of the
designation include, among others, early FDA interactions, and the RMAT designation does not require evidence to indicate that the drug
may offer a substantial improvement over available therapies.
Fast-Track
Designation. The fast-track designation is intended to expedite or facilitate the process for reviewing new drug and biologic drug products
that meet certain criteria. Specifically, products are eligible for this designation if they are intended to treat a serious or life-threatening
disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. FDA may review sections
of the marketing applications on a rolling basis before the complete application is submitted if the sponsor provides a schedule for
the submission of the application sections, the FDA agrees to accept sections of the application and determines that the schedule is
acceptable, and the sponsor pays any required user fees upon submission of the first section.
Priority
Review Designation. A product is eligible for priority review designation if it has the potential to provide a safe and effective therapy
where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis or prevention of a disease
compared to marketed products. The FDA will attempt to direct additional resources to the evaluation of an application for a priority
review-designated product in an effort to facilitate the review. The FDA endeavors to review applications with priority review designations
within six months of the filing date as compared to the standard ten months for review.
Breakthrough
Therapy Designation. A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy” if the product
is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and
preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more
clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes
all of the features of a fast-track designation, as well as more intensive FDA interaction and guidance. If a product receives this designation,
then the FDA will work to expedite the development and review of that product.
Accelerated
Approval. Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval
upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or
on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an
effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the
condition and the availability or lack of alternative treatments. As a condition of accelerated approval, the FDA may require that a
sponsor perform adequate and well-controlled post-marketing clinical trials. In addition, the FDA currently requires pre-approval of
promotional materials as a condition for accelerated approval, which could adversely impact the timing of the commercial launch of the
product.
Even
if a product candidate qualifies for one or more of these programs, the standard for approval (i.e., safety and effectiveness) does not
change. We may explore one or more of these opportunities for Longeveron product candidates as appropriate, as the programs are not mutually
exclusive.
Marketing
Exclusivity
In
the case of biologic drugs, several types of marketing exclusivity may apply:
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Reference
product exclusivity; |
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Orphan
drug exclusivity; and |
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Pediatric
exclusivity. |
Reference
Product Exclusivity
We
believe that FDA will regulate Lomecel-B as a new biologic and will require submission and approval of a BLA under the PHS Act. The PHS
Act includes a framework for determining when a biologic is a “reference product” and therefore eligible for marketing exclusivity.
The reference product is the single biological product against which a biosimilar (a product that is highly similar to and has no clinically
meaningful differences from the reference product) or an interchangeable biosimilar (a product that is both biosimilar to, and will produce
the same clinical result as, the reference product) is evaluated.
FDA
must determine the date of “first licensure” (i.e., approval) of a biologic which will, in turn, determine whether that biologic
qualifies as a reference product that will be eligible for statutory exclusivity (and when such exclusivity will expire). Typically (but
not always) the date of approval is the date of first licensure. FDA will not approve a biosimilar or interchangeable biosimilar until
the date that is 12 years after the date on which the reference product was first approved. However, FDA may receive an application for
a biosimilar or interchangeable biosimilar four years after the date on which the reference product was first approved. These 12- and
four-year terms are each extended by six months if the product has been awarded pediatric exclusivity.
Legal
uncertainties remain about FDA’s application of the date of first licensure and statutory exclusivity provisions to cell therapy
products. At the appropriate time, we intend to provide information to FDA so that FDA can determine the date of first licensure of Lomecel-B
(or any other product candidate that will be regulated as a biologic) and the date from which statutory exclusivity will begin to run.
However, FDA may not make an immediate decision about the date of first licensure at the time it approves a new biologic. Furthermore,
there is currently no precedent showing how FDA will apply this statutory framework to a cell therapy product. The law in this area will
likely continue to evolve.
Orphan
Drug Designation and Exclusivity.
Congress
enacted the Orphan Drug Act in 1983 to spur development of drugs and biologics to treat diseases or conditions affecting few U.S. patients.
FDA may grant an orphan drug designation (ODD) for a drug or biologic drug being developed to treat a “rare disease or condition,”
defined as affecting fewer than 200,000 persons in the U.S., or affecting more than 200,000 persons in the U.S. but for which there is
no reasonable expectation that development costs will be recovered from U.S. sales of the product. A request for ODD must be submitted
to the FDA before a marketing application is submitted (i.e., BLA or NDA), but there is no assurance that FDA will award an ODD if requested.
In the fourth quarter of 2021, FDA granted ODD to Longeveron’s Lomecel-B for the treatment of HLHS.
An
ODD does not change the regulatory review standards of safety and effectiveness and does not shorten the length of the FDA review or
approval process. If an investigational product with an ODD subsequently receives the first FDA approval for the disease or
condition for which it has such designation, then the approved product may be eligible to receive orphan drug exclusivity (ODE) that prevents FDA from approving any other applications to market the same
drug or biologic for the same rare disease or indication for seven years, except in several specific circumstances including, among
others, demonstrating clinical superiority of a new product vs. the product with ODE because of greater safety, greater
effectiveness, or making a major contribution to patient care. Even if an investigational product has an ODD, there is no guarantee
that FDA will award ODE upon approval.
Competitors
may receive approval of either a different product for the same use or indication, or the same product for a different use or indication.
Approved drugs and biologics can also be used by physicians off-label, which is within the scope of their practice of medicine. Accordingly,
ODE is not an absolute protection against potentially competing products. Moreover, an ODE awarded to another sponsor could block FDA
approval of one of Longeveron’s product candidates for seven years. The law involving ODDs and ODEs, including FDA’s interpretation
of “same drug,” is continuing to evolve.
In
addition to the potential award of seven-year ODE upon product approval, the benefits of an ODD also include eligibility for certain
research tax credits and a waiver of the marketing application fee otherwise required under PDUFA. An application for a prescription
product with an ODD is not subject to an application fee unless the application also includes an indication for a non-rare disease or
condition as well. For fiscal year 2022, the application fee for a new drug or biologic requiring clinical studies is $3,117,218.
Pediatric
Exclusivity.
Pediatric
exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity (e.g., ODE) if a
sponsor conducts clinical trials in children in response to a written request from the FDA. The issuance of a written request does not
require the sponsor to undertake the described clinical trials.
Post-approval
Requirements.
Any
products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation, including,
among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling
and distribution, and advertising and promotion of the product. There also are continuing, annual program fees under PDUFA for any
marketed products. Establishment registration of drug and biologic drug manufacturers and their subcontractors with FDA and certain
state agencies subjects those entities to periodic unannounced inspections by the FDA for compliance with cGMPs, imposing certain
procedural and documentation requirements. Changes to the manufacturing process are strictly regulated, and, depending on the
significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and
correction of any deviations from cGMPs and impose reporting requirements upon us and any third-party manufacturers that we may
decide to use. Accordingly, manufacturers must continue to expend time, money and effort for production and quality control to
maintain compliance with cGMPs and other regulatory requirements.
The
FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product
reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity
or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved
labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition
of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:
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restrictions
on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; |
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fines,
warning letters, or untitled letters; |
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clinical
holds on clinical studies; |
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refusal
of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product approvals; |
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product
seizure or detention, or refusal to permit the import or export of products; |
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consent
decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; |
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mandated
modification of promotional materials and labeling and the issuance of corrective information; |
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the
issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other
safety information about the product; or |
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injunctions
or the imposition of civil or criminal penalties. |
The
FDA closely regulates the marketing, labeling, advertising and promotion of approved products. A company can make only those claims that
were approved by the FDA in the application for marketing approval and in accordance with the provisions of the approved labeling. The
FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with
these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil
and criminal penalties.
Physicians
may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the
product’s labeling and that differ from those tested by us and approved by the FDA. Physicians may believe that such off-label
uses are the best treatment for certain patients in varied circumstances. The FDA does not regulate the behavior of physicians in their
choice of approved treatments, as the practice of medicine is outside the scope of FDA’s authority. However, the FDA restricts
manufacturer’s communications on the subject of off-label use of their products. The federal government has levied large civil
and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label
promotion. The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions
under which specified promotional conduct is changed or curtailed. However, companies may share truthful and not misleading information
that is otherwise consistent with a product’s FDA-approved labeling.
Other
Healthcare Laws
Pharmaceutical
and medical device manufacturers are subject to additional healthcare regulation and enforcement by the federal government and by authorities
in the states and foreign jurisdictions in which they conduct their business. Such laws include, without limitation, U.S. federal anti-kickback,
fraud and abuse, false claims, consumer fraud, pricing reporting, data privacy and security, and transparency laws and regulations as
well as similar foreign laws in the jurisdictions outside the U.S. Similar state and local laws and regulations may also restrict business
practices in the pharmaceutical industry, such as state anti-kickback and false claims laws, which may apply to business practices, including
but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed
by non-governmental third-party payors, including private insurers, or by patients themselves; state laws that require pharmaceutical
companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated
by the federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;
state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information; state and local
laws which require tracking gifts and other remuneration and items of value provided to physicians, other healthcare providers and entities
or that require the registration of pharmaceutical sales representatives; and state and local laws that require the registration of pharmaceutical
sales representatives; and state and local laws governing the privacy and security of health information in some circumstances, many
of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts. Violation
of any of such laws or any other governmental regulations that apply may result in penalties, including, without limitation, significant
administrative, civil and criminal penalties, damages, fines, additional reporting obligations and oversight if we become subject to
a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, the curtailment or restructuring
of operations, exclusion from participation in governmental healthcare programs and imprisonment.
Japanese
Laws and Regulations
Under
the 2014 law passed by the Japanese government, two new Acts were added that regulate regenerative medicine development and offer two
pathways to market for regenerative medicine therapeutic candidates: The Act on the Safety of Regenerative Medicine (ASRM) and the Pharmaceutical
and Medical Devices Act (PMD Act).
Japan’s
Act on the Safety of Regenerative Medicine. The ASRM route is intended to allow physicians to provide cellular therapies to patients
through an application process that is regulated by the Japanese Ministry of Health, Labor and Welfare (MHLW). Manufacturers of cell
and gene therapy products wishing to utilize this pathway must identify and work with a partner clinic or hospital which enables the
clinic to act as the distributor, with the manufacturer receiving a fee or a royalty, for example. The ASRM route may require a clinical
trial or other clinical data in order to seek approval from the MHLW. Treatments under the ASRM route must be provided by a medical institution
for the purpose of either “medical research” or as a “medical treatment at one’s own expense.” Therapies
provided under this framework are not covered by Japan’s National Health Insurance.
Japan’s
Pharmaceutical & Medical Device Act. The PMD Act includes special treatment for regenerative medicine products and identifies
them as a stand-alone medical category with a novel “conditional approval” system. Sponsors seeking manufacturing approval
need to provide clinical data to show that the product does not have any major safety concerns, clinical data to demonstrate “probable”
efficacy, and satisfy established chemistry, manufacturing and controls criteria. A conditional approval can therefore occur after a
Phase 2 trial. The conditional approval period lasts for a maximum of seven years. Sponsors that receive conditional approval must re-apply,
with additional satisfactory safety and efficacy data, for a full unconditional approval within the timeframe provided to them under
the conditional approval. A conditional approval allows the product to be marketed and partially reimbursed through Japan’s National
Health Insurance.
Coverage
and Reimbursement
Sales
of any pharmaceutical product depend, in part, on the extent to which the product will be covered by third-party payors, such as federal,
state and foreign government healthcare programs, commercial insurance and managed healthcare organizations, and their level of reimbursement
for the product. Significant uncertainty exists as to the coverage and reimbursement status of any newly approved product. Decisions
regarding the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis. One third-party payor’s
decision to cover a particular product does not ensure that other payors will also provide coverage for the product. As a result, the
coverage determination process can require manufactures to provide scientific and clinical support for the use of a product to each payor
separately and can be time-consuming, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained
in the first instance. For products administered under the supervision of a physician, obtaining coverage and adequate reimbursement
may be particularly difficult because of the higher prices often associated with such drugs. Additionally, separate reimbursement for
the product itself or the treatment or procedure in which the product is used may not be available, which may impact physician utilization.
In addition, companion diagnostic tests require coverage and reimbursement separate and apart from the coverage and reimbursement for
their companion pharmaceutical or biological products. Similar challenges to obtaining coverage and reimbursement, applicable to pharmaceutical
or biological products, will apply to companion diagnostics.
In
addition, third-party payors are increasingly reducing reimbursements for pharmaceutical products and services. The U.S. government and
state legislatures have continued implementing cost-containment programs, including price controls, restrictions on coverage and reimbursement
and requirements for substitution of generic products. Third-party payors are more and more challenging the prices charged, examining
the medical necessity and reviewing the cost effectiveness of pharmaceutical products, in addition to questioning their safety and efficacy.
Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls
and measures, could further limit sales of any product. Decreases in third-party reimbursement for any product or a decision by a third-party
payor not to cover a product could reduce physician usage and patient demand for the product.
In
international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted
price ceilings on specific products and therapies. For example, the European Union provides options for its member states to restrict
the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of
medicinal products for human use. A member state may approve a specific price for the medicinal product or it may instead adopt a system
of direct or indirect controls on the profitability of the company placing the medicinal product on the market. Pharmaceutical products
may face competition from lower-priced products in foreign countries that have placed price controls on pharmaceutical products and may
also compete with imported foreign products. Furthermore, there is no assurance that a product will be considered medically reasonable
and necessary for a specific indication, will be considered cost-effective by third-party payors, that an adequate level of reimbursement
will be established even if coverage is available or that the third-party payors’ reimbursement policies will not adversely affect
the ability for manufacturers to sell products profitably.
Healthcare
Reform
In
the U.S. and certain foreign jurisdictions, there have been, and we expect there will continue to be, a number of legislative and regulatory
changes to the healthcare system. In March 2010, the ACA was signed into law, which substantially changed the way healthcare is financed
by both governmental and private insurers in the U.S. By way of example, the ACA increased the minimum level of Medicaid rebates payable
by manufacturers of brand name drugs from 15.1% to 23.1%; required collection of rebates for drugs paid by Medicaid managed care organizations;
imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell certain “branded prescription drugs”
to specified federal government programs, implemented a new methodology by which rebates owed by manufacturers under the Medicaid Drug
Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected; expanded eligibility criteria for
Medicaid programs; created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative
clinical effectiveness research, along with funding for such research; and established a Center for Medicare Innovation at CMS to test
innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.
Since
its enactment, there have been judicial and Congressional challenges to certain aspects of the ACA, and we expect there will be additional
challenges and amendments to the ACA in the future. Congress has considered legislation that would repeal or repeal and replace all or
part of the ACA. While Congress has not passed comprehensive repeal legislation, two bills affecting the implementation of certain taxes
under the ACA have passed. For example, in 2017, Congress enacted the Tax Act, which eliminated the tax-based shared responsibility payment
imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly
referred to as the “individual mandate.” In addition, the 2020 federal spending package permanently eliminated, effective
January 1, 2020, the ACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and,
effective January 1, 2021, also eliminates the health insurer tax. On December 14, 2018, a Texas U.S. District Court Judge ruled
that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed as part of the Tax
Act, the remaining provisions of the ACA were invalid as well. Additionally, on December 18, 2019, the U.S. Court of Appeals for
the 5th Circuit ruled that the individual mandate was unconstitutional and remanded the case back to the District Court to determine
whether the remaining provisions of the ACA are invalid as well. On June 17, 2021, the U.S. Supreme Court rejected that challenge to
the ACA, holding that plaintiffs in that case lacked standing to challenge the individual mandate or the remainder of the ACA, and that
the challenge to the ACA should be dismissed.
Other
legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to
providers of 2% per fiscal year and reduced payments to several types of Medicare providers, which will remain in effect through 2029
absent additional congressional action. Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers
set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed,
among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs
and reform government program reimbursement methodologies for pharmaceutical products.
Further,
on May 30, 2018, the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Beilina Right to Try Act of 2017, or the Right to
Try Act, was signed into law. The law, among other things, provides a federal framework for certain patients to access certain investigational
new product candidates that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval. Under certain
circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the
FDA expanded access program. There is no obligation for a drug manufacturer to make its products available to eligible patients as a
result of the Right to Try Act.
On
July 9, 2021, President Biden signed the “Executive Order on Promoting Competition in the American Economy,” which is focused
on increasing competition in several industries, including the pharmaceutical and biotechnology industries. Among other things, the Executive
Order directs the Health and Human Services Administration to increase support for generic and biosimilar drugs, to issue a comprehensive
plan to combat high prescription drug prices and price gouging, and to standardize plan options in the National Health Insurance Marketplace
so that consumers can compare plans more easily. The Executive Order also encourages the FTC to ban “pay for delay” and similar
agreements, in which brand-name drug manufacturers pay generic drug manufacturers to stay out of the market, resulting in an estimated
$3.5 billion increase in drug prices per year.
Human
Capital Management
As
of December 31, 2021, we had 18 full-time employees, two part-time employees and one full-time and part-time consultants. Among those,
four had M.D. or Ph.D. degrees, one has an M.B.A. degree, and one has a J.D. degree. Of these full-time employees and consultants, 12
are engaged in research and development activities. None of our employees are represented by a labor union or covered by a collective
bargaining agreement. We consider our relationship with our employees to be good.
Information
about our Executive Officers and other key employees is included in Part III, Item 10 of this 10-K, and incorporated by reference herein.
Available
Information
The
Company was formed as a Delaware limited liability company in October 2014 and converted into a Delaware corporation in February 2021
in connection with our IPO. Our principal executive offices are located at 1951 NW 7th Avenue, Suite 520 Miami, Florida 33136
and our telephone number is (305) 909-0840.
Our
Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and amendments to reports filed pursuant
to Sections 13(a) and 15(d) of the Exchange Act, are filed with the SEC. We are subject to the informational requirements of the
Exchange Act, and we file or furnish reports, proxy statements and other information with the SEC. Such reports and other
information we file with the SEC are available free of charge at our website www.longeveron.com when such reports are available on
the SEC’s website. The SEC maintains a website that contains reports, proxy and information statements, and other information
regarding issuers that file electronically with the SEC at www.sec.gov. Longeveron periodically provides other information for
investors on our corporate website, including press releases and other information about financial performance, information on
corporate governance and presentations. Our website address is www.longeveron.com, and we make our filings with the SEC available on
the Investor Relations page of our website. Our references to website URLs are intended to be inactive textual references only. The
information found on, or that can be accessed from or that is hyperlinked to, our website does not constitute part of, and is not
incorporated into, this Form 10-K. Our common stock is traded on the NASDAQ under the symbol “LGVN”.
Risk
Factors Summary
The
following is a summary of the principal risks that could adversely affect our business, operations and financial results. Please refer
to Item 1A “Risk Factors” of this Form 10-K below for additional discussion of the risks summarized in this Risk Factors
Summary.
Risks
Relating to our Business |
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We have limited operating history, liquidity and capital challenges; |
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The
novelty of our technologies, whether their potential will be realized, and challenges in obtaining regulatory acceptance; |
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Risks
relating to the materials used in our products, and our processing and storage facilities; |
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Future
competition for product sales; |
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We
face risks related to the current COVID-19 pandemic and other health epidemics and outbreaks; |
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We face risks, including inflation and supply shortages, resulting from adverse macroeconomic conditions resulting from various factors; and |
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The
use of our product candidates or future products in individuals may expose us to product liability claims, and we may not be able
to obtain adequate product liability insurance. |
Risks
Related to Intellectual Property |
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If
our trade secret and patent position does not adequately protect our products and uses, others could compete against us more directly; |
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If
certain license agreements are terminated, our ability to continue clinical trials and commercially market products could be adversely
affected; |
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We may be unable to sufficiently to protect the confidentiality of our proprietary information, trade secrets, and know-how; |
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Third-party
claims of intellectual property infringement may prevent or delay our product development efforts; |
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If
the Company’s intellectual property has not all been properly assigned to the Company, we may not be able to commercialize our technology and derive
revenue; |
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Intellectual
property rights do not necessarily address all potential threats to our competitive advantage; and |
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The
potential impact of intellectual property regulation, legislation and litigation on our ability to operate. |
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Risks
Related to Regulatory Approval and Other Governmental Regulations |
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We
may not be able to successfully develop or obtain the necessary regulatory approvals for our product candidates and obtain the necessary
regulatory approvals; |
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Failure
to get required regulatory approvals for conducting clinical trials, or final marketing approval; |
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We
may not be able to secure and retain research institutions to conduct our clinical trials; and |
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Producing
and marketing an approved drug or other medical product is subject to significant and costly post-approval regulation. |
Risks
Related to Our Dependence on Third Parties |
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We
face various risks relating to our reliance on third party suppliers, manufacturers and distributors; |
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The
successful commercialization of our current or future product candidates will depend on obtaining reimbursement from government and
third-party payors; |
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We
may enter into arrangements with third-party collaborators to help us develop our product candidates and commercialize our products,
and our ability to commercialize such products may be impaired or delayed if collaborations are unsuccessful; and |
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If
we engage in future acquisitions or strategic partnerships, this may increase our capital requirements, dilute our stockholders,
cause us to incur debt or assume contingent liabilities, and subject us to other risks. |
Risks
Related to the Discovery, Development and Commercialization of Our Product Candidates |
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Interim,
“topline” and preliminary data from our clinical trials that we announce or publish may change as more data become available
and are subject to audit and verification procedures that could result in material changes in the final data, and our later stage
or subsequent clinical trial results may not show efficacy, and may not support our earlier stage clinical safety and efficacy results
for any particular indication that we are studying or may study; |
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We
may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on other product candidates
or indications that may be more profitable or for which there is a greater likelihood of success; and |
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We
may face difficulties from changes to current regulations and future legislation, both in the U.S. as well as in other foreign jurisdictions
where we may be operating. |
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Risks
Related to Our Class A Common Stock and the Securities Market |
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We
face volatility for various reasons with respect to our Class A Common Stock; |
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We may be unable to access additional required capital, or be unable
to access additional capital on terms that we find acceptable, and may be limited in the amount of capital we may raise due to our size; |
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Raising
additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to
our product candidates on unfavorable terms to us; |
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We
are subject to securities litigation, which is expensive and could divert management attention; and |
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Provisions
in our certificate of incorporation and bylaws and Delaware law might discourage, delay or prevent a change in control of our company
or changes in our management and, therefore, depress the market price of our Class A Common Stock. |
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Risks
Related to Employee Matters, Managing Our Growth and Other Risks Related to Our Business |
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We
have never commercialized a product candidate before and may lack the necessary expertise, personnel and resources to successfully
commercialize any products on our own or together with suitable collaborators; and |
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In
order to successfully implement our plans and strategies, we will need to grow our organization, and we may experience difficulties
in managing this growth. |
Item
1A. Risk Factors
In
addition to the other information in this annual report on Form 10-K, the following risk factors should be considered carefully in
evaluating us. You should carefully consider the risks and uncertainties described below and the other information in this report,
including our financial statements and related notes appearing elsewhere in this report and in the section titled
“Management’s Discussion and Analysis of Financial Condition and Results of Operations,” before deciding whether
to invest in our Class A Common Stock or to maintain or change your investment. Our business, financial condition, results of
operations or prospects could be materially and adversely affected if any of these risks occurs, and as a result, the market price
of our Class A Common Stock could decline and you could lose all or part of your investment. This report also contains
forward-looking statements that involve risks and uncertainties. See “Cautionary Note Regarding Forward-Looking
Statements.” Our actual results could differ materially and adversely from those anticipated in these forward-looking
statements as a result of certain factors, including those set forth below. For a summary of these risk factors, please see
“Risk Factors Summary” beginning on page 31 of this report.
Risks
Related to our Business
We
have a limited operating history and have no products approved for commercial sale, which may make it difficult for you to evaluate our
current business and predict our future success and viability.
We
are a clinical stage biotechnology company with a limited operating history upon which you can evaluate our business and prospects. We
have no products approved for commercial sale and have not generated any material revenue from product sales. To date, we have devoted
substantially all of our resources and efforts to organizing and staffing our company, business planning, building and equipping our
research and development laboratories, building and equipping our manufacturing suites, raising capital, acquiring raw materials for
manufacturing, product candidate development and manufacturing, securing related intellectual property rights and conducting clinical
trials of Lomecel-B. We have not yet demonstrated our ability to obtain marketing approvals, manufacture a commercial-scale product or
arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization.
As a result, it may be more difficult for you to accurately predict our future success or viability than if we had a longer operating
history.
In
addition, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors and risks frequently
experienced by clinical stage biotechnology companies in rapidly evolving fields, including but not limited to changes in FDA or foreign
body regulatory oversight of products. We also may need to transition from a company with a research focus to a company capable of supporting
commercial activities. Such a transition may involve substantial additional capital requirements in order to launch and market a product,
changes in the use of proceeds, and significant adjustment to personnel, compared to a clinical-stage development company. If we do not
adequately address these risks and difficulties or successfully make such a transition, our business will suffer.
If
the potential of our product candidates to treat diseases is not realized, the value of our technology and our development programs could
be significantly reduced.
Our
team is currently exploring the potential of our product candidates to treat diseases. We have not yet proven in clinical trials that
our product candidates will be a safe and effective treatment for any disease or condition. Our product candidates are susceptible to
various risks, including undesirable and unintended side effects, unintended immune system responses, inadequate therapeutic efficacy,
or other characteristics that may prevent or limit their marketing approval or commercial use. We have not yet completed all of the testing
necessary to allow us to make a determination that serious unintended consequences will not occur. If the potential of our product candidates
to treat disease is not realized, the value of our technology and our development programs could be significantly reduced. Because our
product candidates are based on MSCs, any negative developments regarding the therapeutic potential or side effects of our MSCs, or regarding
scientific and medical knowledge about MSCs in general, could have a material adverse effect on our business, financial condition, results
of operations, and prospects.
Our
product development programs are based on novel technologies and are inherently risky.
We
are subject to the risks of failure inherent in the development of product candidates based on new technologies. The novel nature of
our product candidates creates significant challenges in regards to product development and optimization, manufacturing, government regulation,
third-party reimbursement, and market acceptance. For example, although the FDA has approved several cell therapy products, the FDA has
relatively limited experience with regulating these kinds of therapies, and its regulations and policies are still evolving. As a result,
the pathway to regulatory approval for our product candidates may be more complex and lengthier.
Additionally,
stem cells that are taken from one person and transplanted into a different individual may pose additional risks. For example, stem cells
that are not autologous (i.e., taken from, and given to, the same individual) but are instead allogeneic (i.e., taken from one individual
and given to a different person) are subject to donor-to-donor variability, which can make standardization more difficult. As a result
of these factors, the development and commercialization pathway for our therapies may be more complex and lengthier, and subject to increased
uncertainty, as compared to the pathway for new conventional (i.e., new chemical entity) drugs.
There
are no FDA-approved allogeneic, cell-based therapies for Aging Frailty, Alzheimer’s disease (AD), the Metabolic Syndrome or other
aging-related conditions, nor Hypoplastic Left Heart Syndrome, or other cardiac-related indications. This could complicate and delay
FDA approval of our product candidate for these indications, or other indications we study or will study.
Although
FDA has approved several cell therapy products, there are no allogeneic cell-based or stem cell therapies currently approved by the FDA
for the treatment of Aging Frailty or our other indications. There are also no conventional drugs or therapies currently approved by
the FDA with stated indications for Aging Frailty, Aging, or Frailty.
According
to the FDA, neither “Aging Frailty” or simply “Frailty,” nor the Metabolic Syndrome, presently have definitions
that are acceptable for characterizing the conditions for regulatory purposes, and there are no precedents for regulatory approvals in
these indications. This could prevent, complicate and/or delay regulatory approval of our product candidate for these indications.
The
FDA and the Japanese PMDA have both indicated that the concept of “Frailty” or the Metabolic Syndrome as an indication will
require additional clinical data and discussion before future pivotal trials and marketing authorization. Because the condition of Frailty
or the Metabolic Syndrome lacks consensus, there is no guarantee that PMDA, FDA or any regulatory agency will agree to an approvable
indication, that there will be consensus regarding the definition of the condition, or will agree on clinical endpoints that would be
considered acceptable for demonstrating clinically meaningful benefit. More specifically, our ability to begin Phase 3 (i.e., pivotal)
trials in a “Frailty” or “Aging Frailty” indication will depend on our Phase 2 clinical data and subsequent interactions
with FDA where we would discuss the size and scope of a Phase 3 program, the appropriate target patient population (i.e., defining the
indication), and agreement on one or more primary endpoints that demonstrate clinically meaningful outcome.
It
is possible that the FDA may never recognize “aging” as a disease, and may never agree to a definition of “Aging Frailty,”
“Frailty” or the Metabolic Syndrome, primarily due to a lack of consensus on the definitions amongst clinicians, researchers
and regulators, an insufficient understanding of the underlying pathophysiologic mechanisms that cause any or all of the manifestations,
or both. To obtain FDA approval for any indication for the disease states we are studying, we will have to demonstrate, among other things,
that our product candidates are safe and effective for that indication in the target population. The results of our clinical trials must
be statistically significant, meaning that there must be sufficient data to indicate that it is unlikely the outcome occurred by chance.
The FDA will also require us to demonstrate an appropriate dose (i.e., number of cells) and dosing interval for our product candidates,
and to identify and define treatment responders, which may require additional clinical trials. As a result, the clinical endpoints, the
criteria to measure the intended results of treatment, and the correct dosing for our cell-based therapeutic approaches for these indications
may be difficult to determine. These challenges may prevent us from developing and commercializing products on a timely or profitable
basis, or at all.
If
we are not able to recruit and retain qualified management and scientific personnel, we may fail in developing our technologies and product
candidates.
Our
future success depends to a significant extent on the skills, experience, and efforts of the principal members of our scientific and
management personnel. These members include Joshua M. Hare, M.D. and our staff of scientific consultants. Our co-founder, Dr. Hare,
remains employed by the University of Miami (UM), and provides services to us as a consultant on a limited basis. The loss of Dr. Hare
or any or all of these individuals could harm our business and might significantly delay or prevent the achievement of research, development
or business objectives. Competition for regulatory, clinical manufacturing and management personnel in the pharmaceutical industry is
intense. We may be unable to recruit or retain personnel with sufficient management skills in the area of cell therapeutics or attract
or integrate other qualified management and scientific personnel in the future.
Our
product candidates represent new classes of therapy that the marketplace may not understand or accept.
Even
if we successfully develop and obtain regulatory approval for our product candidates, the market may not understand or accept them. We
are developing product candidates that represent novel treatment approaches and will compete with a number of more conventional products
and therapies manufactured and marketed by others, including major pharmaceutical companies. The degree of market acceptance of any of
our future developed and potential products will depend on a number of factors, including:
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the
clinical safety and effectiveness of our products and their perceived advantage over alternative treatment methods; |
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our
ability to demonstrate that our cell-based products can have a clinically significant effect, initially for Aging Frailty, AD, HLHS,
the Metabolic Syndrome, ARDS and other disease states for which we may seek marketing approval; |
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our
ability to separate ourselves from the ethical controversies associated with cell product candidates derived from human embryonic
or fetal tissue; |
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ethical
controversies that may arise regarding the use of stem cells or human tissue of any kind, including adult stem cells, adult bone
marrow, and other adult tissues derived from donors; |
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adverse
events involving our product candidates or candidates of others that are cell based; |
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our
ability to supply a sufficient amount of our products to meet regular and repeated demand in order to develop a core group of medical
professionals familiar with and committed to the use of our products; and |
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the
cost of our products and the reimbursement policies of government and third-party payors. |
If
the health care community does not accept our product candidates or future approved products for any of the foregoing reasons, or for
any other reason, it could affect our sales or have a material adverse effect on our business, financial condition, results of operations,
and prospects.
Our
dependence upon a limited supply of bone marrow donors and biologic growth media may impact our ability to produce sufficient quantities
of our product candidates as needed to complete our clinical trials, and if our trials are successful, to meet product demand.
The
population of acceptable bone marrow donors is limited to volunteers between the ages of 18 and 45. In addition, potential donors are
prescreened for a variety of health conditions and are only allowed to donate bone marrow a total of six times in their lifetime, further
limiting the total number of potential donors. The amount of bone marrow donated may be insufficient for us to mass produce our product
candidates at a scale sufficient to meet our clinical trial needs or to produce a product to meet future commercial demand at an acceptable
cost. In addition, the expansion of MSCs through our proprietary manufacturing methods utilizes biologic growth media that may be in
limited supply. Our product candidates will be inherently more difficult to manufacture at commercial-scale than conventional pharmaceuticals,
which are manufactured using precise chemical formulations and operational methods. Cost-effective production at clinical trial or commercial
scale quantities may not be achievable.
Future
government regulation or health concerns, such as the ongoing COVID-19 pandemic, may also reduce the number of donors or otherwise limit
the amount of bone marrow available to us. If we cannot secure quantities of bone marrow or biologic growth media sufficient to meet
the manufacturing demands for our clinical trials, we might not be able to complete our clinical trials and obtain marketing approval
for our product candidates. Moreover, even if our clinical trials are successful and we obtain marketing approval for our product candidates,
our inability to secure enough bone marrow or biologic growth media to meet product demand could limit our potential revenues.
MSCs
are biological entities obtained from living humans that can pose risks to the recipient.
MSC
therapies require many manufacturing steps. Cells must be harvested from donor tissue, isolated, and expanded in cell culture to produce
a sufficient number of cells for use. Each step carries risks for contamination by other cells, microbes, or adventitious agents. The
transfer of cells into a recipient can also carry risks and complications associated with the procedure itself, and a recipient may reject
the transplanted cells.
Our
product candidates are derived from human bone marrow and therefore have the potential for disease transmission.
The
utilization of donated bone marrow creates the potential for transmission of cancer and communicable disease, including but not limited
to human immunodeficiency virus (HIV), viral hepatitis, syphilis, Creutzfeldt-Jakob disease, and other viral, fungal, or bacterial pathogens.
Although we and our suppliers are required to comply with federal and state regulations intended to prevent communicable disease transmission,
we or our suppliers may fail to comply with such regulations. Further, even with compliance, our products might nevertheless be viewed
by the public as being associated with transmission of disease, and a clinical trial subject or patient who contracts an infectious disease
might assert that the use of our product candidate or products resulted in disease transmission, even if the individual became infected
through another source.
Any
actual or alleged transmission of communicable disease could result in clinical trial subject or patient claims, litigation, distraction
of management’s attention, increased expenses, and adverse regulatory authority action. Further, any failure in screening, whether
by us or other manufacturers of similar products, could adversely affect our reputation, the support we receive from the medical community,
and overall demand for our products. As a result, such actions or claims, whether or not directed at us, could have a material adverse
effect on our reputation with our customers and our ability to market our products, which could have a material adverse effect on our
business, financial condition, results of operations, and prospects.
If
our processing and storage facility or our clinical manufacturing facilities are damaged or destroyed, our business and prospects could
be negatively affected.
Our
processing and storage facility is located in a region which experiences severe weather, notably hurricanes, from time to time. If this
facility in Miami, Florida or the equipment in the facility were to be significantly damaged or destroyed, we could suffer a loss of
some or all of the stored units of our product candidates and it could force us to halt our clinical trial processes. The risk of tropical
storm and hurricane activity historically rises on or about June 1st each year, and subsides on or about November 30th
each year. We have not undertaken a systematic analysis of the potential consequences to our business and financial results from
a major hurricane or tornado, flood, fire, earthquake, power loss, terrorist activity or other disasters and do not currently have a
recovery plan for such disasters. If we underestimate our insurance needs, we will not have sufficient insurance to cover losses above
and beyond the limits on our policies. In addition, we do not carry sufficient insurance to compensate us for actual losses from interruption
of our business that may occur, and any losses or damages incurred by us could harm our business. The occurrence of any of these business
disruptions could seriously harm our operations and financial condition and increase our costs and expenses.
Ethical
and other concerns surrounding the use of stem cell therapy or human tissue may negatively affect public perception of us or our future
products or product candidates, or may negatively affect regulatory approval of our future products or product candidates, thereby reducing
demand for our future products.
The
commercial success of our product candidates will depend in part on general public acceptance of the use of MSC therapy for the prevention
or treatment of human diseases. The use of embryonic cells and fetal tissue for research and MSC therapy has been the subject of substantial
national and international debate regarding related ethical, legal, and social issues. In the U.S., for example, until March 2009, federal
government funding of embryonic stem cell research was limited to specifically identified cell lines and was not otherwise available.
We do not use embryonic stem cells or fetal tissue, but the public may not be able to, or may fail to, differentiate our use of adult
MSCs from the use of embryonic stem cells or fetal tissue by others. This could result in a negative perception of our company or our
future products or product candidates, thereby reducing demand, which could have a material adverse effect on our business, financial
condition, results of operations, and prospects.
We
may obtain MSCs from volunteer adult bone marrow donors from non-profit organizations that collect and process tissue donations. Bone
marrow donors receive payment, but ethical concerns have been raised by some about the use of donated human tissue in a for-profit setting,
as we are doing. Future adverse events in the field of stem cell therapy, changes in public policy, or changes to the FDA’s regulatory
approval framework for these products could also result in greater governmental regulation of our product candidates or products, and
potential regulatory delays relating to their testing or approval.
We
may eventually compete for product sales with other companies, many of which will have greater resources or capabilities than we have,
or may succeed in developing better products or in developing products more quickly than we do, and we may not compete successfully with
them.
We
compete or may eventually compete with other companies and organizations that are marketing or developing therapies for our targeted
disease indications, based on traditional pharmaceutical, medical device, or other non-cellular therapy and technologies. In addition,
we have other potential competitors developing a variety of therapeutics, and in some cases, such as with Alzheimer’s disease,
there may be tens or hundreds of companies seeking to commercialize therapeutics.
We
also face competition in the cell therapy field from academic institutions and governmental agencies. Many of our current and potential
competitors have greater financial and human resources than we have, including more experience in research and development and more established
sales, marketing, and distribution capabilities.
We
anticipate that competition in our industry will increase. In addition, the health care industry is characterized by rapid technological
change, resulting in new product introductions and other technological advancements. Our competitors may develop and market products
that render product candidates under development by us now or in the future, or any products manufactured or marketed by us, non-competitive
or otherwise obsolete.
We
have ongoing challenges with respect to our liquidity and access to capital.
As
we advance the preclinical and clinical development of our programs, we expect to continue to incur significant expenses and operating
losses, for which we do not have offsetting revenue. We expect that our sales, research and development and general and administrative
costs will increase in connection with conducting additional preclinical studies and clinical trials for our current and future programs
and product candidates, contracting with contract research organizations (CROs) to support preclinical studies and clinical trials, expanding
our intellectual property portfolio, and providing general and administrative support for our operations. As a result, we will need additional
capital to fund our operations, which we may obtain from additional equity or debt financings, collaborations, licensing arrangements,
or other sources.
Since
2015, we have raised approximately $76.6 million in gross proceeds from the sale of shares of our equity securities (including the
$20.5 million raised on December 3, 2021 from a private placement of public equity (the “2021 PIPE Offering”), and
$26.6 million raised on February 12, 2021 and $2.5 million raised on March 15, 2021, from our IPO). As of December 31,
2021, we had $35.0 million in cash and cash equivalents and short-term investments. We had $0.5 million of indebtedness as of
December 31, 2020 from loans provided by the Small Business Administration (SBA) and the Paycheck Protection Program (PPP). However,
on March 4, 2021, $0.3 million of the indebtedness for PPP loan was forgiven and the remaining $0.2 million balance was paid in
full. According to the rules of the SBA, we are required to retain PPP Loan documentation for six years after the date the loan is
forgiven or repaid in full, and permit authorized representatives of the SBA, including representatives of its Office of Inspector
General, to access such files upon request. Should the SBA conduct such a review and reject all or some of our judgments pertaining
to satisfying PPP Loan eligibility or forgiveness conditions, we may be required to adjust previously reported amounts and
disclosures in the financial statements. To date, we have financed our operations primarily through public and private equity
financings, grant awards, and fees generated from clinical trial revenue and contract manufacturing services. There are no
assurances that we will be able to continue to finance operations through these means, and our inability to generate sufficient
revenue in the near term may have an adverse impact on our business, operations and prospects.
We
face risks related to the current COVID-19 pandemic and other health epidemics and outbreaks.
The
global outbreak of COVID-19 continues to impact countries, communities, supply chains and markets. The COVID-19 pandemic has impacted
and continues to impact our Bahamas Registry Trial business. It is also possible that the COVID-19 pandemic or other public health risks
could adversely affect our business, results of operations, financial condition or liquidity in the future. For example, they could impact
the timing and enrollment of our collaborators’ planned or ongoing clinical trials, delaying clinical site initiation, regulatory
review and the potential receipt of regulatory approvals, payment of milestones under our license agreements and commercialization of
one or more of our product candidates, if approved. The COVID-19 pandemic and other public health risks could also disrupt the production
capabilities of our contract manufacturing facility. Further, the outbreak of COVID-19 has heightened the risk that a significant portion
of our workforce will suffer illness or otherwise be unable to work. The impact of the COVID-19 pandemic is fluid and continues to evolve,
and therefore, we cannot currently predict the extent to which our business, clinical trials, results of operations, financial condition
or liquidity will ultimately be impacted. In addition, COVID-19 or other public health risks could materially and adversely impact our
operations due to, among other factors:
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general decline in business activity; |
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difficulty
accessing the capital and credit markets on favorable terms, or at all, and a severe disruption and instability in the global financial
markets, or deteriorations in credit and financing conditions which could affect our access to capital necessary to fund business
operations; |
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the
potential negative impact on the health of our employees, especially if a significant number of them or any of their family members
are impacted or if any of our senior leaders are impacted for an extended period of time; |
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the
potential negative impact on our ability to monitor the investigative sites participating in our clinical studies in person or even
remotely, which could result in a deviation from pre-pandemic protocols and/or site monitoring and data management plans, and delays
in our ability to perform data-related tasks dependent on communications with personnel at the investigative sites, such as resolution
of open data queries, the cumulative effects of which could lead to delayed or missed identification of non-compliance with GCP,
and/or unrecognized data errors; |
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potential
delays in the preparation and submission of applications for regulatory approval of our products, as well as potential delays in
FDA’s ability to review applications in a timely manner consistent with past practices; |
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potential
difficulty in adequately overseeing and/or evaluating the manufacturing process at the facilities that will manufacture future commercial
products; and |
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a
deterioration in our ability to ensure business continuity during a disruption. |
Adverse global conditions,
including macroeconomic uncertainty, may negatively impact our financial results.
Global conditions, dislocations
in the financial markets, or inflation could adversely impact our business. In addition, the global macroeconomic environment has been
and may continue to be negatively affected by, among other things, instability in global economic markets, increased U.S. trade tariffs
and trade disputes with other countries, instability in the global credit markets, supply chain weaknesses, instability in the geopolitical
environment as a result of the Russian invasion of the Ukraine, the withdrawal of the United Kingdom from the European Union, and other
political tensions, and foreign governmental debt concerns. Such challenges have caused, and may continue to cause, uncertainty and instability
in local economies and in global financial markets, which may adversely affect our business.
We
have a history of losses and may not be able to achieve profitability going forward.
We
have experienced significant losses since inception and, at December 31, 2021 and 2020, had an accumulated deficit of approximately $43.9
million and $26.9 million, respectively. We expect to incur additional losses in the future and expect the cumulative losses to increase.
We expect our operating expenses to increase and it is not likely that our grant revenues will fully fund our clinical programs. In such
event, we will not have sufficient cash flow to meet our obligations or make progress in our clinical programs, and will need to raise
additional capital.
We
have been funded in part by government and non-profit association grant awards, which is not a guaranteed source of future funding.
The
funding of government programs is dependent on budgetary limitations, congressional appropriations and administrative allotment of funds,
and changes in national health and welfare priorities, all of which are inherently uncertain and may be affected by changes in U.S. government
policies resulting from various political and military developments. Our continued receipt of government and non-profit association funding
is also dependent on the ability to adhere to the terms and provisions of the original grant and contract documents and other regulations.
We can provide no assurance that we will receive or continue to receive funding for the grants and contracts we have been awarded. The
loss of government funds or non-profit association grant awards, could have a material adverse effect on our clinical programs and on
our business, financial condition, and results of operations. For additional detail regarding the grant awards, we have received from
governmental and non-profit associations, see “Management’s Discussion and Analysis of Financial Condition and Results
of Operations- Grant Awards” on page 73 of this report.
The
use of our product candidates or future products in individuals may expose us to product liability claims, and we may not be able to
obtain adequate product liability insurance.
Because
of the nature of our products, we face an inherent risk of product liability claims. None of our product candidates have been widely
used over an extended period of time, and therefore our safety data are limited. We derive the raw materials for our product candidates
from human donor sources, the manufacturing process is complex, and the handling requirements are specific, all of which increase the
likelihood of quality failures and subsequent product liability claims. We will need to increase our insurance coverage if and when we
receive approval for and begin commercializing our product candidates. We may not be able to obtain or maintain product liability insurance
on acceptable terms with adequate coverage or at all. If we are unable to obtain insurance, or if claims against us substantially exceed
our coverage, then our business could be adversely impacted. Whether or not we are ultimately successful in any product liability litigation,
such litigation either before or after product approval and marketing could consume substantial amounts of our financial and managerial
resources and could result in, among other things:
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significant
awards against us; |
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substantial
litigation costs; |
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recall
of products or termination of clinical trials; |
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FDA
withdrawal of marketing approval of products or suspension or revocation of an IND for a product candidate; |
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injury
to our reputation; |
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withdrawal
of clinical trial participants; |
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withdrawal
of clinical trial sites or investigators; or |
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adverse
regulatory action. |
Any
of these results could have a material adverse effect on our business, financial condition, and results of operations.
Risks
Related to Intellectual Property
If
our trade secret and patent position does not adequately protect our product candidates and their uses, others could compete against
us more directly, which could harm our business and have a material adverse effect on our business, financial condition and results of
operations.
Our
success depends, in large part, on our ability to obtain and maintain intellectual property protection for our product candidates. The
patent position of biotechnology companies is generally highly uncertain, involves complex legal and factual questions, and continues
to be the subject of much litigation. Our trade secrets attempt to bridge the gap that threatens patent exclusivity for the protection
of products derived from MSCs. Our trade secrets also remain valid and enforceable without regard to limitations such as term restrictions
that are imposed on patents. Our trade secrets and know-how are the subject of various license agreements and confidentiality agreements
as further discussed below.
The
claims of existing U.S. and foreign patent applications and patents, and those patents that may issue in the future, or those to be licensed
to us, that are owned by the Company or under an obligation of assignment to the Company, may not confer on us significant commercial
protection against competing products. Furthermore, to the extent that the Company owns or is assigned or licenses patent rights covering
its business, third parties may challenge or design around those patent rights, such as by asserting that the patents are invalid or
arguing that the patent claims should be narrowly construed, and thereby avoid successful infringement actions.
Our
patent applications on MSC technology, in particular, include claims directed to therapeutic uses and kits comprising MSCs. Patents with
such claims tend to be more vulnerable to challenge by other parties than patents with extremely narrow claims. Also, our pending patent
applications may not issue, may issue with substantially narrower claims than currently pending claims, or we may not receive any additional
patents. Further, the laws of foreign countries may not protect our intellectual property rights to the same extent as do the laws of
the U.S. Our patents might not contain claims that are sufficiently broad to prevent others from practicing our technologies or from
competing with us with their own technology in the fields of interest to us.
Although
the Company has obligations of assignment and has been assigned patents and patent applications concerning stem cell products and their
uses, none of those patents or presently pending applications has granted claims or pending claims that, if granted, would prevent a
third party from commercializing their own allogeneic stem cell therapy for those indications that we are studying. Consequently, our
competitors may independently develop competing products that do not infringe our patents or other intellectual property.
Control
over patented technology requires the Company to obtain formal assignment of patents and applications from third parties. Although the
Company believes it has contracts requiring formal assignment of the patent properties in its patent portfolio, there is risk that the
inventors and research partners now of record as owning these patent properties will refuse to execute documents confirming assignment
of their rights to the Company or that litigation will be required to compel the execution of those documents. In the meantime, those
inventors and research partners may claim to be co-owners of some of the patent portfolio.
Because
of the extensive time required for development, testing, and regulatory review of a potential product, it is possible that, before any
of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization,
thereby reducing any advantages of the patent. To the extent our product candidates based on that technology are not commercialized ahead
of this patent expiration, to the extent we have no other patent protection on such products, or to the extent that regulatory or patent
extensions are not granted, those products might not have the robust protection we currently expect to enjoy. The background technologies
used in the development of our product candidates are known in the scientific community, and it may be possible to duplicate the methods
we use to create our product candidates, which makes us vulnerable to competition, without the ability to exclude others from potentially
commercializing a similar product.
If
certain license agreements are terminated, our ability to continue clinical trials and commercially market products could be adversely
affected.
We
are a party to various agreements that give us rights to use specified technologies applicable to research, development, and commercialization
of our product candidates. If these agreements are voided or terminated, our product development, research, and commercialization efforts
may be altered or delayed. Certain aspects of our technology rely on inventions developed using university or other third-party resources.
The universities or third parties may have certain rights, as defined by law or applicable agreements, and may choose to exercise such
rights. If we fail to comply with any terms or provisions of these agreements, our rights and our access to the universities’ or
third parties’ resources could be terminated. The Exclusive License Agreement with the University of Miami dated November 20, 2014,
as amended on December 11, 2017, and on March 3, 2021, requires the Company to pay fees and royalties and to make commercially reasonable
efforts to achieve milestones. The University of Miami may terminate the Exclusive License Agreement for material breach if the fees
and royalties are not paid, or if the milestones are not met and an extension to achieve the milestones is not agreed upon.
Some
of our employees, including but not limited to Dr. Hare, are employed by third party employers in addition to being employed or
engaged as a consultant by the Company. Such employees and consultants may owe obligations to the third-party employers related to that
employment. Those third-party employers may assert that they are entitled to assignment of some or all rights of new inventions made
by such employees or consultants. If we are unable to conclusively prove that we are entitled to assignment of those rights, we may be
required to negotiate co-ownership to or a license of those rights, if such an arrangement is available at all.
If
we are unable to protect the confidentiality of our proprietary information, trade secrets, and know-how, our competitive position could
be impaired and our business, financial condition, results of operations, and prospects could be adversely affected.
As
disclosed above, some aspects of our technology, especially regarding manufacturing processes, are unpatented and maintained by us as
trade secrets. In an effort to protect these trade secrets, we require our employees, consultants, collaborators, and advisors to execute
confidential disclosure agreements before the commencement of their relationships with us. These agreements require that all confidential
information developed by the individual or made known to the individual by us during the course of the individual’s relationship
with us be kept confidential and not disclosed to third parties. These agreements, however, may not provide us with adequate protection
against improper use or disclosure of confidential information, and these agreements may be breached. A breach of confidentiality could
affect our competitive position. In addition, in some situations, these agreements may conflict with, or be subject to, the rights of
third parties with whom our employees, consultants, collaborators, or advisors have previous employment or consulting relationships.
Also, others may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our
trade secrets.
Adequate
remedies may not exist in the event of unauthorized use or disclosure of our confidential information. The disclosure of our trade secrets
could impair our competitive position and could have a material adverse effect on our business, financial condition, results of operations,
and prospects.
Third-party
claims of intellectual property infringement may prevent or delay our product development efforts.
Our
commercial success depends in part on our avoiding infringement of the patents and proprietary rights of third parties. There is a substantial
amount of litigation involving patents and other intellectual property rights in the biotechnology and pharmaceutical industries. Numerous
U.S. and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are
developing our product candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases
that our product candidates, methods of making product candidates, and methods of using product candidates may give rise to claims of
infringement of the patent rights of others.
Third
parties may assert that we infringe their patents or are otherwise employing their proprietary technology without authorization and may
sue us. We are aware of several U.S. patents held by third parties covering potentially similar or related products and their manufacture
and use. Generally, conducting clinical trials and other acts relating to FDA approval are not considered acts of infringement in the
U.S. If and when Lomecel-B MSCs are approved by the FDA, third parties may seek to enforce their patents by filing a patent infringement
lawsuit against us. Patents issued in the U.S. by law enjoy a presumption of validity that can be rebutted only with evidence that is
“clear and convincing,” a heightened standard of proof. We may not be able to prove in litigation that any patent enforced
against us is invalid.
Additionally,
there may be third-party patents of which we are currently unaware with claims to materials, formulations, methods of manufacture or
methods for treatment related to the use or manufacture of our product candidates. Because patent applications can take many years to
issue, there may be currently pending patent applications which may later result in issued patents that our product candidates may infringe.
Some of those patent applications may not yet be available for public inspection. In addition, third parties may obtain patents in the
future and claim that use of our technologies infringes upon these patents. If any third-party patents were held by a court of competent
jurisdiction to cover the manufacturing process of our product candidates, constructs or molecules used in or formed during the manufacturing
process, or any final product itself, the holders of any such patents may be able to block our ability to commercialize the product candidates
unless we obtain a license under the applicable patents, or until such patents expire or they are finally determined to be held not infringed,
unpatentable, invalid or unenforceable. Similarly, if any third-party patent were held by a court of competent jurisdiction to cover
aspects of our formulations, processes for manufacture or methods of use, including combination therapy or patient selection methods,
the holders of any such patent may be able to block our ability to develop and commercialize the product candidate unless we obtained
a license or until such patent expires or is finally determined to be held not infringed, unpatentable, invalid or unenforceable. In
either case, such a license may not be available on commercially reasonable terms or at all. If we are unable to obtain a necessary license
to a third-party patent on commercially reasonable terms, or at all, our ability to commercialize our product candidates may be impaired
or delayed, which could in turn significantly harm our business.
Parties
making claims against us may seek and obtain injunctive or other equitable relief, which could effectively block our ability to further
develop and commercialize our product candidates. They might seek an exclusion order from the International Trade Commission to prevent
import of our product candidates. Defense of these claims, regardless of their merit, would involve substantial litigation expense and
would be a substantial diversion of employee resources from our business and may impact our reputation. In the event of a successful
claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful
infringement, obtain one or more licenses from third parties, pay royalties or redesign our infringing products, which may be impossible
or require substantial time and monetary expenditure. We cannot predict whether any such license would be available at all or whether
it would be available on commercially reasonable terms. Furthermore, even in the absence of litigation, we may need to obtain licenses
from third parties to advance our research or allow commercialization of our product candidates. We may fail to obtain any of these licenses
at a reasonable cost or on reasonable terms, if at all. In that event, we would be unable to further develop and commercialize our product
candidates, which could harm our business significantly.
We
may become involved in lawsuits to protect or enforce our patents or the patents of our collaborators or licensors, which could be expensive
and time consuming.
Litigation
may be necessary to enforce patents issued or licensed to us, to protect trade secrets or know-how, or to determine the scope and validity
of the proprietary rights. Litigation, opposition, or other patent office proceedings could result in substantial additional costs and
diversion of management focus. If we are ultimately unable to protect our technology, trade secrets, or know-how, we may be unable to
operate profitably. Competitors may infringe our patents or the patents of our collaborators or licensors. As a result, we may be required
to file infringement claims to protect our proprietary rights, which can be expensive and time-consuming, particularly for a company
of our size. In addition, in an infringement proceeding, a court may decide that a patent of ours is invalid or is unenforceable, or
may refuse to enjoin the other party from using the technology at issue. An adverse determination of any litigation or defense proceedings
could put one or more of our patents at risk of being invalidated or interpreted narrowly. Litigation or other patent office proceedings
may fail and, even if successful, may result in substantial costs and distraction to our management. We may not be able, alone or with
our collaborators and licensors, to prevent misappropriation of our proprietary rights, particularly in countries where the laws may
not protect such rights as fully as in the U.S.
Furthermore,
though we could seek protective orders where appropriate, because of the substantial amount of discovery required in connection with
intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during
this type of litigation. In addition, during the course of this kind of litigation, there could be public announcements of the results
of hearings, motions, or other interim proceedings or developments. If investors perceive these results to be negative, the market price
for our Class A Common Stock could be significantly harmed.
Our
industry is highly competitive and subject to significant or rapid technological change.
The
biotechnology industry, including our fields of therapeutic interest, is highly competitive and subject to significant and rapid technological
change. Accordingly, our success may depend, in part, on our ability to respond quickly to such change through the development and introduction
of new products. Our ability to compete successfully against currently existing and future alternatives to our product candidates and
systems and competitors who compete directly with us in the biopharmaceutical industry may depend, in part, on our ability to attract
and retain skilled scientific and research personnel, develop technologically superior products, develop competitively priced products,
obtain patent or other required regulatory approvals for our products, be an early entrant to the market and manufacture, market, and
sell our products, independently or through collaborations. If a third party were to commercialize a competitive product, there is no
assurance that we would have a basis for initiating patent infringement proceedings or that, if initiated, we would prevail in such proceedings.
If
our product candidates are approved by the FDA, then potential competitors who seek to introduce generic versions of our product candidates
may seek to take advantage of the abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with
our product candidates. The Biologics Price Competition and Innovation Act of 2009 might permit these potential competitors to enter
the market using a shorter and less costly development program for a biosimilar product that competes with our products.
If
all of the Company’s intellectual property has not been properly assigned to the Company, our business, financial condition, results
of operation, and prospects could be adversely affected.
While
the Company believes that each patent application or patent has already been assigned or, if it has not yet been formally assigned, is
under an obligation to be assigned to the Company either through direct employment agreements between the Company and the inventors,
or through research agreements with a third party and the Company, if such is not the case, our business, financial condition, results
of operations, and prospects could be adversely affected.
Intellectual
property rights do not necessarily address all potential threats to our competitive advantage.
The
degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations,
and may not adequately protect our business or permit us to maintain our competitive advantage. For example:
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others
may be able to develop products that are similar to our product candidates but that are not covered by the claims of the patents
that we own or license; |
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we
or our licensors might not have been the first to make the inventions covered by the issued patents or patent application that we
own or license; |
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we
or our licensors might not have been the first to file patent applications covering certain of our inventions; |
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others
may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our intellectual
property rights; |
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some
or all of our licensors’ pending patent applications may not lead to issued patents; |
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issued
patents that we own or license may be held invalid or unenforceable as a result of legal challenges by our competitors; |
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our
competitors might conduct research and development activities in countries where we do not have patent rights and then use the information
learned from such activities to develop competitive products for sale in our major commercial markets or in commercial markets where
we do not have patent rights; |
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we
may not develop additional proprietary technologies that are patentable; and |
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the
patents of others may have an adverse effect on our business. |
Should
any of these events occur, it could significantly harm our business, results of operations and prospects.
Intellectual
property litigation may lead to unfavorable publicity that harms our reputation and causes the market price of our common shares to decline.
During
the course of any intellectual property litigation, there could be public announcements of the initiation of the litigation as well as
results of hearings, rulings on motions, and other interim proceedings in the litigation. If securities analysts or investors regard
these announcements as negative, the perceived value of our existing products, programs or intellectual property could be diminished.
Accordingly, the market price of shares of our Class A Common Stock may decline. Such announcements could also harm our reputation or
the market for our future products, which could have a material adverse effect on our business, financial condition, results of operations,
and prospects.
Patent
reform legislation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement
or defense of our issued patents.
In
September 2011, the Leahy-Smith America Invents Act, or Leahy-Smith Act, was signed into law. The Leahy-Smith Act includes a number of
significant changes to U.S. patent law. These include provisions that affect the way patent applications are prosecuted and may also
affect patent litigation. In particular, under the Leahy-Smith Act, the U.S. transitioned in March 2013 to a “first inventor to
file” system in which, assuming that other requirements of patentability are met, the first inventor to file a patent application
will be entitled to the patent regardless of whether a third party was first to invent the claimed invention. A third party that files
a patent application in the USPTO after March 2013 but before us could therefore be awarded a patent covering an invention of that we
also made even if we had made the invention before the invention was made independently by such third party. This will require us to
be cognizant going forward of the time from invention to filing of a patent application. Furthermore, our ability to obtain and maintain
valid and enforceable patents depends on whether the differences between our technology and the prior art allow our technology to be
patentable over the prior art. Since patent applications in the U.S. and most other countries are confidential for a period of time after
filing or until issuance, we cannot be certain that we were the first to either (1) file any patent application related to our product
candidates or (2) invent any of the inventions claimed in our patents or patent applications.
The
Leahy-Smith Act also includes a number of significant changes that affect the way patent applications will be prosecuted and also may
affect patent litigation. These include allowing third-party submission of prior art to the USPTO during patent prosecution and additional
procedures to attack the validity of a patent by USPTO administered post-grant proceedings, including post-grant review (PGR), inter
partes review (IPR), and derivation proceedings. An adverse determination in any such submission or proceeding could reduce the scope
or enforceability of, or invalidate, our patent rights, which could adversely affect our competitive position.
Because
of a lower evidentiary standard necessary to invalidate a patent claim in USPTO proceedings compared to the evidentiary standard in U.S.
federal courts, a third party could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold a patent claim
invalid even though the same evidence would be insufficient to invalidate the claim if first presented in a district court action. Accordingly,
a third party may attempt to use the USPTO procedures to invalidate our patent claims that would not have been invalidated if first challenged
by the third party as a defendant in a district court action. Thus, the Leahy-Smith Act and its implementation could increase the uncertainties
and costs surrounding the prosecution of our or our licensors’ patent applications and the enforcement or defense of any resulting
issued patents, all of which could have a material adverse effect on our business, financial condition, results of operations, and prospects.
Changes
in U.S. patent law, or laws in other countries, could diminish the value of patents in general, thereby impairing our ability to protect
our product candidates.
As
is the case with other biopharmaceutical companies, our success is heavily dependent on intellectual property, particularly patents.
Obtaining and enforcing patents in the biopharmaceutical industry involve a high degree of technological and legal complexity. Therefore,
obtaining and enforcing biopharmaceutical patents is costly, time-consuming and inherently uncertain. Changes in either the patent laws
or in the interpretations of patent laws in the U.S. and other countries may diminish the value of our intellectual property and may
increase the uncertainties and costs surrounding the prosecution of patent applications and the enforcement or defense of issued patents.
We cannot predict the breadth of claims that may be allowed or enforced in our patents or in third-party patents. In addition, Congress
or other foreign legislative bodies may pass patent reform legislation that is unfavorable to us.
For
example, the U.S. Supreme Court has ruled on several patent cases in recent years, either narrowing the scope of patent protection available
in certain circumstances or weakening the rights of patent owners in certain situations. In addition to increasing uncertainty with regard
to our or our licensors’ ability to obtain patents in the future, this combination of events has created uncertainty with respect
to the value of patents, once obtained. Depending on decisions by the U.S. Congress, the U.S. federal courts, the USPTO, or similar authorities
in foreign jurisdictions, the laws and regulations governing patents could change in unpredictable ways that would weaken our or our
licensors’ ability to obtain new patents or to enforce our existing patents and patents we might obtain in the future.
Patent
terms may be inadequate to protect our competitive position on our product candidates for an adequate amount of time.
Patents
have a limited lifespan. In the U.S., if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years
from its earliest U.S. non-provisional filing date. Various extensions may be available, but the term of a patent, and the protection
it affords, are limited. Even if patents directed to our product candidates are obtained, once the patent term has expired, we may be
open to competition from competitive products. Given the amount of time required for the development, testing and regulatory review of
product candidates, patents directed to our product candidates might expire before or shortly after such candidates are commercialized.
As a result, our patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or
identical to ours.
If
we or our licensors do not obtain patent term extension for our product candidates and/or methods of their use, our business may be materially
harmed.
Depending
upon the timing, duration and specifics of FDA marketing approval of our product candidates and their methods of use, one or more of
our U.S. patents may be eligible for limited patent term restoration under the Drug Price Competition and Patent Term Restoration Act
of 1984, or the Hatch-Waxman Amendments, or the Biologics Price Competition and Innovation Act of 2009. These laws permit a patent restoration
term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process. A maximum
of one patent may be extended per FDA-approved product as compensation for the patent term lost during the FDA regulatory review process.
A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and
only those claims covering such approved drug product, a method for using it or a method for manufacturing it may be extended.
Patent
term extension may also be available in certain foreign countries upon regulatory approval of our product candidates. However, we or
our licensors may not be granted an extension because of, for example, failing to apply within applicable deadlines, failing to apply
prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements. Patent term extension may also not be
granted because the product candidates and/or methods of use are determined not to be the first permitted marketing or use of those drug
candidates in the jurisdiction in question, or patent term extension may not be granted because the product candidates and/or methods
of use are determined not to constitute an “active ingredient” or use of an “active ingredient” that is eligible
for patent term extension. Moreover, if patent term extension is granted then the additional time period or the scope of patent protection
afforded could be less than we request. If we or our licensors are unable to obtain patent term extension or restoration or the term
of any such extension is less than we request, our competitors may obtain approval of competing products following our patent expiration,
and our revenue could be reduced, possibly materially. Further, if this occurs, our competitors may take advantage of our investment
in development and trials by referencing our clinical and preclinical data and launch their product earlier than might otherwise be the
case.
We
may not be able to protect our intellectual property rights throughout the world.
Although
we have in-licensed issued patents and pending patent applications in the U.S. and certain other countries, filing, prosecuting and defending
patents in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries
outside the U.S. can be less extensive than those in the U.S. In addition, the laws of some foreign countries do not protect intellectual
property rights to the same extent as federal and state laws in the U.S. Consequently, we may not be able to prevent third parties from
practicing our in-licensed inventions in all countries outside the U.S. or from selling or importing products made using our in-licensed
inventions in and into the U.S. or other jurisdictions. Competitors may use our in-licensed technologies in jurisdictions where we have
not obtained patent protection to develop their own products and, further, may export otherwise infringing products to territories where
we or our licensors have patent protection but enforcement is not as strong as that in the U.S. These products may compete with our product
candidates, and our or our licensors patents or other intellectual property rights may not be effective or sufficient to prevent them
from competing.
Many
companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The
legal systems of many foreign countries do not favor the enforcement of patents and other intellectual property protection, which could
make it difficult for us to stop the infringement of our or our licensors’ patents or the marketing of competing products in violation
of our proprietary rights. Proceedings to enforce our or our licensors’ patent rights in foreign jurisdictions could result in
substantial costs and divert our efforts and attention from other aspects of our business, could put our or our licensors’ patents
at risk of being invalidated or interpreted narrowly and our or our licensors’ patent applications at risk of not issuing and could
provoke third parties to assert claims against us. We or our licensors may not prevail in any lawsuits that we or our licensors initiate,
and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our or our licensors’ efforts
to enforce or defend our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage
from the intellectual property that we develop or license.
Many
countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties. In addition,
many countries limit the enforceability of patents against government agencies or government contractors. In these countries, the patent
owner may have limited remedies, which could materially diminish the value of such patents. If we or our licensors are forced to grant
a license to third parties with respect to any patents relevant to our business, our competitive position may be impaired, and our business,
financial condition, results of operations and prospects may be adversely affected.
Obtaining
and maintaining our patent protection depends on compliance with various procedural, documentary, fee payment and other requirements
imposed by regulations and governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance
with these requirements.
Periodic
maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and/or applications will be due to the USPTO
and various foreign patent offices at various points over the lifetime of our patents and/or applications. We have systems in place to
remind us to pay these fees, and we rely on third parties to pay these fees when due. Additionally, the USPTO and various foreign patent
office’s require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent
application process and after a patent has been granted. We employ reputable law firms and other professionals to help us comply, and
in many cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with rules applicable to the
particular jurisdiction. However, there are situations in which noncompliance can result in abandonment or lapse of the patent or patent
application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. If such an event were to occur, it
could have a material adverse effect on our business, financial condition, and results of operations.
Risks
Related to Regulatory Approval and Other Government Regulations
If
we are not able to successfully develop and commercialize our product candidates and obtain the necessary regulatory approvals, we may
not generate sufficient revenues to continue our business operations.
To
generate sales revenue from our product candidates, we must conduct extensive preclinical studies and clinical trials to demonstrate
that our product candidates are safe and effective and we must obtain required regulatory approvals. Our early-stage product candidates
may fail to perform as we expect. Moreover, our product candidates in later stages of development may fail to show the required safety
and effectiveness for approval despite having progressed successfully through preclinical or initial clinical testing. We may need to
devote significant additional research and development, financial resources, and personnel to develop commercially viable products. If
our product candidates do not prove to be safe and efficacious in clinical trials, we will not obtain the required regulatory approvals.
If we fail to obtain such approvals, we may not generate sufficient revenues to continue our business operations.
Even
if we obtain regulatory approval of a product candidate, that approval may be subject to limitations on the indicated uses for which
it may be marketed. Even after granting regulatory approval, the FDA and regulatory agencies in other countries continue to review and
inspect marketed products, manufacturers, and manufacturing facilities, which may create additional regulatory burdens. Later discovery
of previously unknown problems with a product, manufacturer, or facility may result in restrictions on the product or manufacturer, including
a withdrawal of the product from the market or a withdrawal of the approved application by the FDA. Furthermore, FDA may require post-approval
studies or other post-approval commitments. Failure to comply with or meet those requirements or commitments could result in withdrawal
of the approved application by FDA. Regulatory agencies may also establish additional regulations, policies, or guidance that could prevent
or delay regulatory approval of our product candidates.
We
cannot market and sell our product candidates in the U.S. or in other countries if we fail to obtain the necessary regulatory approvals.
We
cannot sell our product candidates until regulatory agencies grant marketing approval. The process of obtaining regulatory approval is
lengthy, expensive, and uncertain, and the legal requirements for obtaining approval may change. It is likely to take several years to
obtain the required regulatory approvals for our lead signaling cell product candidates, or we may never gain the necessary approvals.
Any difficulties that we encounter in obtaining regulatory approval may have a substantial adverse impact on our operations. Moreover,
because our product candidates are all based on only three platform technologies, any adverse events in any of our clinical trials for
one of our product candidates could negatively impact the clinical trials and approval process for our other product candidates.
The
pathway to regulatory approval for MSCs may be more complex and lengthier than for approval of a new conventional drug. Similarly, to
obtain approval to market our cell products outside of the U.S., we, together with our collaborative partners, will need to file appropriate
applications and submit clinical data concerning our product candidates and receive regulatory approval from governmental agencies, which
in certain countries includes approval of the price we intend to charge for our product. We may encounter delays or rejections if changes
occur in regulatory agency regulations, policies or guidance during the period in which we develop a product candidate or during the
period required for review of any application for regulatory agency approval. If we are not able to obtain regulatory approvals for use
of our product candidates under development, we will not be able to commercialize such products, and therefore may not be able to generate
sufficient revenues to support our business.
If
we are not able to conduct our clinical trials properly and on schedule, marketing approval by FDA and other regulatory authorities may
be delayed or denied.
The
completion of our clinical trials may be delayed or terminated for many reasons, including, but not limited to, if:
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the
FDA does not grant INDs to test the product candidates in humans; |
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the
FDA does not grant, or suspends, permission to proceed and places a trial on clinical hold; |
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we
are not able to identify sufficient clinical trial sites and/or clinical trial investigators to begin or complete a trial; |
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subjects
do not enroll in our trials at the rate we expect; |
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subjects
experience an unacceptable rate or severity of adverse side effects; |
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third-party
clinical investigators do not perform our clinical trials on our anticipated schedule or consistent with the clinical trial protocol,
cGCP and regulatory requirements, or other third parties do not perform data collection and analysis in a timely or accurate manner; |
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inspections
by the FDA or IRBs of clinical trial sites at research institutions participating in our clinical trials find regulatory violations
that require us to undertake corrective action, suspend, or terminate one or more sites, or prohibit us from using some or all of
the data in support of our marketing applications; or |
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one
or more IRBs suspends or terminates the trial at an investigational site, precludes enrollment of additional subjects, or withdraws
its approval of the trial. |
Our
development costs will increase if we have material delays in our clinical trials, or if we are required to modify, suspend, terminate,
or repeat a clinical trial. If we are unable to conduct our clinical trials properly and on schedule, marketing approval may be delayed
or denied by the FDA.
Final
marketing approval of our product candidates by the FDA or other regulatory authorities for commercial use may be delayed, limited, or
denied, any of which could adversely affect our ability to generate operating revenues.
Final
marketing approval for our product candidates may be delayed, limited, or denied if, among other factors:
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we
are unable to satisfy the significant clinical testing required to demonstrate safety and effectiveness of our product candidates
before marketing applications can be filed with the FDA; |
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FDA
does not agree with our interpretation of data obtained from preclinical and nonclinical animal testing or human clinical trials,
even though the data can be interpreted in different ways; |
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we
fail at any stage of the development and testing of our product candidates, which may take years to complete; |
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we
receive negative or inconclusive results or reports of adverse side effects during a clinical trial; or |
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the
FDA requires us to expand the size and scope of the clinical trials. |
If
marketing approval for our product candidates is delayed, limited, or denied, our ability to market products, and our ability to generate
product sales, could be adversely affected.
There
has been very little success in gaining FDA approval for an Alzheimer’s disease drug, and we have not had success to date in developing
Alzheimer’s disease therapeutics.
Despite
billions of dollars invested by the biopharmaceutical industry in research programs to develop novel therapeutics for AD, there has only
been one FDA-approved treatment. Aduhelm (aducanumab), an amyloid beta-directed antibody, was approved by FDA in 2021 based upon the
drug’s effect on a surrogate endpoint. FDA has required confirmatory trials of clinical benefit, and there is ongoing public discussion
of the drug’s clinical benefit. Many new types and classes of drugs have been developed and tested in AD, including monoclonal
antibodies, g-secretase modulators and inhibitors, β-site amyloid precursor protein cleaving enzyme (BACE) inhibitors, receptor
for advanced glycation end-products (RAGE) inhibitors, nicotinic agonists, serotonin subtype receptor (5HT6) antagonists, and others.
The vast majority of these scientific programs have failed in clinical testing. Moreover, we have not had any success to date in developing
therapeutics for AD, and may never do so.
We
may not be able to secure and maintain research institutions to conduct our clinical trials.
We
rely on research institutions to conduct our clinical trials. Specifically, the limited number of bone marrow transplant centers further
heightens our dependence on such research institutions for our future Phase 3 clinical trials. Our reliance upon research institutions,
including hospitals and clinics, provides us with less control over the timing and cost of clinical trials and the ability to recruit
subjects. If we are unable to reach agreement with suitable research institutions on acceptable terms, or if any resulting agreement
is terminated, we may be unable to quickly replace the research institution with another qualified institution on acceptable terms. Even
if we do replace the institution, we may incur additional costs to conduct the trial at the new institution. We may not be able to secure
and maintain suitable research institutions to conduct our clinical trials.
Producing
and marketing an approved drug or other medical product is subject to significant and costly post-approval regulation.
Even
if approved for commercial sale, we may be required to conduct Phase 4 clinical trials or comply with other post-marketing requirements
or commitments for the products. Even if we obtain approval of a product, we can only market the product for the approved indications.
After granting marketing approval, the FDA and regulatory agencies in other countries continue to review and inspect marketed products,
manufacturers, and manufacturing facilities, creating additional regulatory burdens. Later discovery of previously unknown problems with
a product, manufacturer, or facility may result in restrictions on the product or manufacturer, including a withdrawal of the product
from the market. Further, regulatory agencies may establish different or additional regulations that could impact the post-marketing
status of our products.
Our
business involves the use of hazardous materials that could expose us to environmental and other liability.
We
have contract facilities in Florida that are subject to various local, state, and federal laws and regulations relating to safe working
conditions, laboratory and manufacturing practices, the experimental use of animals, and the use and disposal of hazardous or potentially
hazardous substances, including chemicals, micro-organisms, and various radioactive compounds used in connection with our research and
development activities. In the U.S., these laws include the Occupational Safety and Health Act, the Toxic Test Substances Control Act,
and the Resource Conservation and Recovery Act. We cannot guarantee that accidental contamination or injury to our employees and third
parties from hazardous materials will not occur. We do not have insurance to cover claims arising from our use and disposal of these
hazardous substances other than limited clean-up expense coverage for environmental contamination due to an otherwise insured peril,
such as fire.
Risks
Related to Our Dependence on Third Parties
We
rely on third parties to provide us with supplies to produce our product candidates. Any problems experienced by these third parties
could result in a delay or interruption in the supply of our product candidates for our clinical trials and future approved products
to our customers, which could have a material negative effect on our business.
We
rely on third parties to provide us with supplies to produce our product candidates. If the operations of these third parties are interrupted
or if they are unable to meet our delivery requirements due to capacity limitations or other constraints, we may be limited in our ability
to fulfill our supply of product candidates. Any prolonged disruption in the operations of third parties could have a significant negative
impact on our ability to produce our product candidates for pre-clinical and clinical trials or sell our future approved products, could
harm our reputation and could cause us to seek other third-party contracts, thereby increasing our anticipated development and commercialization
costs. In addition, if we are required to change third parties for any reason, we will be required to verify that the new third parties
maintain facilities and procedures that comply with quality standards required by the FDA and with all applicable regulations and guidelines.
The delays associated with the qualification of a new third party could negatively affect our ability to develop product candidates or
receive approval for any product candidates in a timely manner.
We
currently depend upon third parties for services and raw materials needed for the manufacture of our product candidates, and if these
products are successfully commercialized, we may become dependent upon third parties for product distribution. If any of these third
parties fail or are unable to perform in a timely manner, our ability to manufacture and deliver could be compromised.
To
produce our product candidates for use in clinical studies, and to produce any of our product candidates that may be approved for commercial
sale, we require biologic media, reagents, and other highly specialized materials in addition to the bone marrow aspirate used in the
manufacture of our product candidates. These items must be manufactured and supplied to us in sufficient quantities and in compliance
with the regulations governing cGMP and Current Good Tissue Practice (cGTP) promulgated by the FDA. To meet these requirements, we have
entered into supply agreements with firms that manufacture these components to meet cGMP and cGTP standards. Our requirements for these
items are expected to increase if and when we transition to the manufacture of commercial quantities of our product candidates.
In
addition, as we proceed with our clinical trial efforts, we must be able to demonstrate to the FDA that we can manufacture our product
candidates with consistent characteristics. While we currently produce our product candidates in our own facility, scaling up the manufacturing
process would require us to develop a larger facility, which could require significant time and capital investments to conform to applicable
manufacturing standards. Alternatively, we may be required to outsource some or all of our manufacturing, which would cause us to be
materially dependent on these suppliers for supply of cGMP- and cGTP-grade components of consistent quality. Our ability to complete
ongoing clinical trials may be negatively affected in the event that we are forced to seek and validate a replacement source for any
of these critical components. If we are not able to obtain adequate supplies of these items of consistent quality from our third-party
suppliers, it will also be more difficult to manufacture commercial quantities of our product candidates that are approved for commercial
sale.
In
addition, if one or more of our product candidates is approved for commercial sale, we intend to rely on third parties for their distribution.
Proper shipping and distribution require compliance with specific storage and shipment procedures (e.g., prevention of damage to shipping
materials and prevention of temperature excursions during shipment). Failure to comply with such procedures will necessitate return and
replacement, potentially resulting in additional cost and causing us to fail to meet supply requirements.
Use
of third-party manufacturers may increase the risk that we will not have adequate quantities of our product candidates.
We
may use a third-party manufacturer to supply our product candidates for clinical trials or other uses at some point. Reliance on third-party
manufacturers entails risks to which we would not be subject if we manufactured such components ourselves, including:
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reliance
on the third party for regulatory compliance and quality assurance; |
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the
possible breach of the manufacturing agreement by the third party; and |
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the
possible termination or nonrenewal of the agreement by the third party, based on its own business priorities, at a time that is costly
or inconvenient for us. |
Future
contract manufacturers are or will be subject to all of the risks and uncertainties that we would be subject to if we manufactured the
product candidates on our own. Similar to us, third-party manufacturers are subject to ongoing, periodic, and unannounced inspection
by the FDA and corresponding state and foreign agencies or their designees to ensure strict compliance with cGMP and cGTP regulations
and other governmental regulations and corresponding foreign standards. Although we do not control compliance by our contract manufacturers
with these regulations and standards, we—as the manufacturer—assume the liabilities for our contract manufacturers’
non-compliance. Our future contract manufacturers might not be able to comply with these regulatory requirements. If our third-party
manufacturers fail to comply with applicable regulations, the FDA or other regulatory authorities could impose penalties on us, including
fines, injunctions, civil penalties, consent decrees, compliance with FDA’s Application Integrity Policy, issuance of warning or
untitled letters, denial of marketing approval of our product candidates, delays, suspensions, or withdrawals of approvals, license revocation,
seizures or recalls of product candidates or our other products, operating restrictions, and criminal prosecutions. Any of these actions
could significantly and adversely affect supplies of our product candidates or other products and could have a material adverse effect
on our business, financial condition, and results of operations.
If
we decide to use third-party manufacturers in the future, they will likely be dependent upon their own third-party suppliers, making
us vulnerable to supply shortages and price fluctuations, which could harm our business.
The
operations of any future third-party manufacturers will likely be dependent upon their own third-party suppliers. A supply interruption
or an increase in demand beyond a supplier’s capabilities could harm the ability of any future manufacturers to manufacture our
product candidates or intended products until the manufacturer identifies and qualifies new sources of supply. Reliance on these third-party
manufacturers and their suppliers could subject us to a number of risks that could harm our business, including:
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interruption
of supply resulting from modifications to or discontinuation of a supplier’s operations; |
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failure
of third-party manufacturers or suppliers to comply with their own legal and regulatory requirements; |
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delays
in product shipments resulting from uncorrected defects, reliability issues, or a supplier’s variation in a component; |
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a
lack of long-term supply arrangements for key components with our suppliers; |
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inability
to obtain adequate supply in a timely manner, or to obtain adequate supply on commercially reasonable terms; |
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difficulty
and cost associated with locating and qualifying alternative suppliers for components in a timely manner; |
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production
delays related to the evaluation and testing of products from alternative suppliers, and corresponding regulatory qualifications; |
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delay
in delivery due to suppliers prioritizing other customer orders over ours or those of our third-party manufacturers; |
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damage
to our brand reputation caused by defective components produced by the suppliers; and |
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fluctuation
in delivery by the suppliers due to changes in demand from us, our third-party manufacturers or their other customers. |
Any
interruption in the supply of components of our product candidates or future products or materials, or our inability to obtain substitute
components or materials from alternate sources at acceptable prices in a timely manner, could impair our ability to meet the demands
of our clinical trials or of our future customers, which would have an adverse effect on our business.
We
will depend on third-party distributors in the future to market and sell our future products which will subject us to a number of risks.
We
will depend on third-party distributors to sell, market, and service our future products in our intended markets. We are subject to a
number of risks associated with reliance upon third-party distributors including:
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lack
of day-to-day control over the activities of third-party distributors; |
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failure
of the third-party distributors to comply with their own legal and regulatory requirements; |
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third-party
distributors may not commit the necessary resources to market and sell our future products to our level of expectations; |
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third-party
distributors may terminate their arrangements with us on limited or no notice or may change the terms of these arrangements in a
manner unfavorable to us; and |
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disagreements
with our future distributors could result in costly and time-consuming litigation or arbitration which we could be required to conduct
in jurisdictions with which we are not familiar. |
If
we fail to establish and maintain satisfactory relationships with our future third-party distributors, our revenues and market share
may not grow as anticipated, and we could be subject to unexpected costs which could harm our results of operations and financial condition.
The
successful commercialization of our current or future product candidates will depend on obtaining reimbursement from government and third-party
payors.
If
we successfully develop and obtain necessary regulatory approvals, we intend to sell our product candidates in countries such as the
U.S. and Japan. In the U.S., the market for any pharmaceutical product is affected by the availability of reimbursement from government
and third-party payors, such as government health administration authorities, private health insurers, health maintenance organizations,
and pharmacy benefit management companies. MSC therapies may be expensive compared with conventional pharmaceuticals, due to the higher
cost and complexity associated with the research, development, and production of product candidates, the small size and large geographic
diversity of the target patient population for some indications, and the complexity associated with distribution of signaling cell therapies
which require special handling, storage, and shipment procedures and protocols. This, in turn, may make it more difficult for us to obtain
adequate reimbursement from government and third-party payors, particularly if we cannot demonstrate a favorable cost-benefit relationship.
Government and third-party payors may also deny coverage or offer inadequate levels of reimbursement for our potential products if they
determine that the product has not received appropriate clearances from the FDA or other government regulators or is experimental, unnecessary
or inappropriate.
In
some other countries where we may seek to market our products, such as Japan, the pricing of prescription pharmaceutical products and
services and the level of government reimbursement are subject to governmental control. In these countries, pricing negotiations with
governmental authorities can take six to twelve months or longer after the receipt of marketing approval for a product. To obtain reimbursement
or pricing approval in some countries, we or our potential future collaborators may be required to conduct one or more clinical trials
that compare the cost effectiveness of our product candidates or products to other available therapies. Conducting one or more additional
clinical trials would be expensive and could result in delays in commercialization of our product candidates.
Managing
and reducing health care costs has been a general concern of federal and state governments in the U.S. and various foreign governments.
Although we do not believe that any recently enacted or presently proposed legislation in any jurisdictions in which we currently operate
should impact our business based on our current model, we might be subject to future regulations or other cost-control initiatives that
materially restrict the price we would receive for our products. In addition, government and third-party payors are increasingly challenging
the price and cost-effectiveness of medical products and services, and many limit reimbursements for newly approved health care products.
In particular, government and third-party payors may limit the indications for which they will reimburse patients who use any products
that we may develop. Cost control initiatives could decrease the price for products that we may develop, which could result in lower
product revenues to us.
We
may enter into arrangements with third-party collaborators to help us develop our product candidates and commercialize our products,
and our ability to commercialize such products may be impaired or delayed if collaborations are unsuccessful.
We
are parties to various collaborations with third parties, and may enter into additional collaborations in the future. We are dependent
upon the success of our current and any future collaborators in performing their responsibilities in connection with the relevant collaboration.
If we fail to maintain these collaborative relationships for any reason, we would need to perform the activities that we currently anticipate
would be performed by our collaborators on our own at our sole expense. This could substantially increase our capital needs, and we may
not have the capability or financial capacity to undertake these activities on our own, or we may not be able to find other collaborators
on acceptable terms, or at all. This may limit the programs we are able to pursue and result in significant delays in the development,
sale, and manufacture of our product candidates and products, and may have a material adverse effect on our business, financial condition,
and results of operations.
Our
dependence upon our current and potential future collaborations exposes us to a number of risks, including that our collaborators (i)
may fail to cooperate or perform their contractual obligations, including financial obligations, (ii) may choose to undertake differing
business strategies or pursue alternative technologies, or (iii) may take an opposing view regarding ownership of clinical trial results
or intellectual property.
Due
to these factors and other possible events, we could suffer delays in the research, development, or commercialization of our product
candidates and future products or we may become involved in litigation or arbitration, which could be time consuming and expensive. We
additionally may be compelled to split revenue with our collaborators, which could have a material adverse effect on our business, financial
condition, and results of operations.
If
we engage in future acquisitions or strategic partnerships, this may increase our capital requirements, dilute our stockholders, cause
us to incur debt or assume contingent liabilities, and subject us to other risks.
From
time to time, we may evaluate various acquisition opportunities and strategic partnerships, including licensing or acquiring complementary
products or product candidates, intellectual property rights, technologies or businesses. Any potential acquisition or strategic partnership
may entail numerous risks, including:
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operating expenses and cash requirements; |
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assumption of additional indebtedness or contingent liabilities; |
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the
issuance of our equity securities; |
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assimilation
of operations, intellectual property and products or product candidates of an acquired company, including difficulties associated
with integrating new personnel; |
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the
diversion of our management’s attention from our existing programs and initiatives in pursuing such a strategic merger or acquisition; |
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retention
of key employees, the loss of key personnel and uncertainties in our ability to maintain key business relationships; |
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risks
and uncertainties associated with the other party to such a transaction, including the prospects of that party to receive marketing
approvals for their existing products or product candidates; and |
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our
inability to generate revenue from acquired technology, product candidates and/or products sufficient to meet our objectives in undertaking
the acquisition or even to offset the associated acquisition and maintenance costs. |
In
addition, if we undertake acquisitions or pursue partnerships in the future, we may issue dilutive securities, assume or incur debt obligations,
incur large one-time expenses and acquire intangible assets that could result in significant future amortization expense. Moreover, we
may not be able to locate suitable acquisition opportunities, and this inability could impair our ability to grow or obtain access to
technology or products that may be important to the development of our business.
Risks
Related to the Discovery, Development and Commercialization of Our Product Candidates
Interim,
“topline” and preliminary data from our clinical trials that we announce or publish from time to time may change as more
data become available and are subject to audit and verification procedures that could result in material changes in the final data.
From
time to time, we may publicly disclose preliminary or topline data from our preclinical studies and clinical trials, which is based on
a preliminary analysis of then-available data. These results and related findings and conclusions are based on assumptions, estimations,
calculations and conclusions, and are subject to change following the generation of additional data or a more comprehensive review of
the data related to the particular study or trial. As a result, the topline or preliminary results that we report may differ from future
results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received
and fully evaluated. Topline data also remain subject to audit and verification procedures that may result in the final data being materially
different from the preliminary data we previously published. As a result, topline and preliminary data should be viewed with caution
until the final data are available.
From
time to time, we may also disclose interim data from our preclinical studies and clinical trials. For example, we have reported interim
data from our ongoing clinical trials elsewhere in this report. Interim data from clinical trials that we may complete are subject to
the risk that one or more of the clinical outcomes may materially change as subject enrollment continues and more subject data become
available or as subjects from our clinical trials continue other treatments for their disease. Adverse differences between preliminary
or interim data and final data could significantly harm our business prospects. Further, disclosure of interim data by us or by our competitors
could result in volatility in the price of our Class A Common Stock.
Further,
others, including regulatory agencies, may not accept or agree with our assumptions, estimates, calculations, conclusions or analyses
or may interpret or weigh the importance of data differently, which could impact the value of the particular program, the approvability
or commercialization of the particular product candidate or product and the value of our company in general. In addition, the information
we choose to publicly disclose regarding a particular study or clinical trial is based on what is typically extensive information, and
you or others may not agree with what we determine is material or otherwise appropriate information to include in our disclosure.
If
the interim, topline, or preliminary data that we report differ from actual results, or if others, including regulatory authorities,
disagree with the conclusions reached, our ability to obtain approval for, and commercialize, our product candidates may be harmed, which
could have a material adverse effect on our business, financial condition, and results of operations.
We
may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on other product candidates
or indications that may be more profitable or for which there is a greater likelihood of success.
Because
we have limited financial and managerial resources, we focus on research programs and product candidates that we identify for specific
indications. As a result, we may forego or delay pursuit of opportunities with other therapeutic platforms or product candidates or for
other indications that later prove to have greater commercial potential or a greater likelihood of success. Our resource allocation decisions
may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future
research and development programs, therapeutic platforms and product candidates for specific indications may not yield any commercially
viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may
relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which
it would have been more advantageous for us to retain sole development and commercialization rights.
The
U.S. FDA, Japanese PMDA and other comparable foreign regulatory authorities may not accept data from trials conducted in locations outside
of their jurisdiction.
We
are conducting several trials in the U.S., and we recently entered into a sponsored clinical research agreement with the National Center
for Geriatrics and Gerontology and Juntendo University Hospital in Japan to explore the safety and efficacy of Lomecel-B in older, frail
Japanese subjects. The acceptance of study data by the U.S. FDA, Japanese PMDA or other comparable foreign regulatory authority from
clinical trials conducted outside of their respective jurisdictions may be subject to certain conditions. In cases where data from foreign
clinical trials are intended to serve as the basis for marketing approval in the U.S., the FDA will generally not approve the application
on the basis of foreign data alone unless (1) the data are applicable to the U.S. population and U.S. medical practice; (2) the trials
are performed by clinical investigators of recognized competence and pursuant to cGCP requirements; and (3) the FDA is able to validate
the data through an on-site inspection or other appropriate means. The FDA may accept the use of some foreign data to support a marketing
approval if the clinical trial meets certain requirements. Additionally, the FDA’s clinical trial requirements, including the adequacy
of the subject population studied and statistical powering, must be met. Furthermore, such foreign trials would be subject to the applicable
local laws of the foreign jurisdictions where the trials are conducted. In Japan, the PMDA is requiring us to conduct our Japanese Phase
2 trial in a Japanese population in order to demonstrate safety and efficacy in Japanese subjects. There can be no assurance that the
FDA, PMDA or any applicable foreign regulatory authority will accept data from trials conducted outside of its respective jurisdiction.
If the FDA, PMDA or any applicable foreign regulatory authority does not accept such data, it would result in the need for additional
trials, which would be costly and time-consuming and delay aspects of our business plan, and which may result in our product candidates
not receiving approval for commercialization in the applicable jurisdiction.
Obtaining
and maintaining regulatory approval of a product in one jurisdiction does not mean that we will be successful in obtaining or maintaining
regulatory approval in other jurisdictions.
Obtaining
and maintaining regulatory approval of a product in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory
approval in any other jurisdiction. For example, even if the FDA or PMDA grants marketing approval of a product, comparable regulatory
authorities in foreign jurisdictions must also approve the manufacturing, marketing and promotion and reimbursement of the product in
those countries. However, a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory
approval process in others. Moreover, product types or regulatory classifications, as well as approval procedures, vary among jurisdictions
and can involve requirements and administrative review periods different from those in the U.S., including different or additional preclinical
studies or clinical trials, as clinical trials conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions.
In many jurisdictions outside the U.S., a product must be approved for reimbursement before it can be approved for sale in that jurisdiction.
In some cases, the price that we intend to charge for our products is also subject to approval.
Obtaining
foreign regulatory approvals and establishing and maintaining compliance with foreign regulatory requirements could result in significant
delays, difficulties and costs for us and could delay or prevent the introduction of our products in certain countries. If we or any
future collaborator fails to comply with the regulatory requirements in international markets or fails to receive applicable marketing
approvals, our target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed.
The
FDA and other regulatory agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses.
If
any of our product candidates are approved and we are found to have improperly promoted off-label uses of those products, we may become
subject to significant liability. The FDA and other regulatory agencies strictly regulate the promotional claims that may be made about
prescription products, such as our product candidates, if approved. In particular, an approved product may not be promoted for uses that
are not approved by the FDA or such other regulatory agencies as reflected in the product’s approved labeling. If we receive marketing
approval for a product candidate, physicians may nevertheless prescribe it to their patients in a manner that is inconsistent with the
approved label, which is within their purview as part of their practice of medicine. If we are found to have promoted such off-label
uses, however, we may become subject to significant liability. The U.S. federal government has levied large civil and criminal fines
against companies for alleged improper promotion of off-label use and has enjoined several companies from engaging in off-label promotion.
The FDA has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct
is changed or curtailed. The FDA may also issue a public warning letter or untitled letter to the company. If we cannot successfully
manage the promotion of our future approved products, we could become subject to significant liability, which would materially adversely
affect our business and financial condition.
If
we are required by the FDA to obtain approval of a companion diagnostic test in connection with approval of any of our product candidates,
and we do not obtain or face delays in obtaining FDA approval of a diagnostic test, we will not be able to commercialize such future
approved product and our ability to generate revenue will be materially impaired.
If
safe and effective use of any of our product candidates depends on the use of an in vitro diagnostic test that is not otherwise
commercially available, then the FDA generally will require approval or clearance of that diagnostic, known as a companion diagnostic,
at the same time that the FDA approves our product candidates if at all. According to FDA guidance, if the FDA determines that a companion
diagnostic is essential to the safe and effective use of a novel therapeutic product or indication, then the FDA generally will not approve
the therapeutic product or new therapeutic product indication if the companion diagnostic is not also approved or cleared for that indication.
If a satisfactory companion diagnostic is not commercially available, we may be required to create or obtain one that would be subject
to its own regulatory approval requirements. The process of obtaining or creating such a diagnostic is time consuming and costly.
Companion
diagnostics are developed in conjunction with clinical programs for the associated product and are subject to regulation as medical devices
by the FDA and comparable regulatory authorities. The approval of a companion diagnostic as part of the therapeutic product labeling
limits the use of the therapeutic product to only those patients who express the specific genetic alteration that the companion diagnostic
was developed to detect.
If
the FDA, PMDA or a comparable regulatory authority requires approval of a companion diagnostic for any of our product candidates, whether
before or after it obtains marketing approval, we, and/or future collaborators, may encounter difficulties in developing and obtaining
approval for such product candidate. Any delay or failure by us or third-party collaborators to develop or obtain regulatory approval
of a companion diagnostic could delay or prevent approval of a product candidate or continued marketing of an approved product.
We
may also experience delays in developing a sustainable, reproducible and scalable manufacturing process for the companion diagnostic
or in transferring that process to commercial partners or negotiating insurance reimbursement plans, all of which may prevent us from
completing our clinical trials of a product candidate or commercializing an approved product on a timely or profitable basis, if at all.
We
may attempt to secure approval from the FDA or comparable foreign regulatory authorities through an expedited review program, and if
we are unable to do so, then we could face increased expense to obtain, and delays in the receipt of, necessary marketing approvals.
We
may in the future seek approval for one or more of our product candidates under one of the FDA’s expedited review programs for
serious conditions. These programs are available to sponsors of therapies that address an unmet medical need to treat a serious condition.
The qualifying criteria and requirements vary for each expedited program. Prior to seeking review under one of these expedited programs
for any of our product candidates, we intend to seek feedback from the FDA and will otherwise evaluate our ability to seek and receive
marketing approval through an expedited review program.
There
can be no assurance that, after our evaluation of the FDA’s feedback and other factors, we will decide to pursue one or more of
these expedited review programs. Similarly, there can be no assurance that after subsequent FDA feedback we will continue to pursue one
or more of these expedited programs, even if we initially decide to do so. Furthermore, FDA could decide not to grant our request to
use one or more of the expedited review programs for a product candidate, even if the FDA’s initial feedback is that the product
candidate would qualify for such program(s). Moreover, FDA can decide to stop reviewing a product candidate under one or more of these
expedited review programs if, for example, the conditions that warranted expedited review no longer apply to that product candidate.
Some
of these expedited programs (e.g., accelerated approval) also require post-marketing clinical trials to be completed and, if any such
required trial fails, the FDA could withdraw the approval of the product. If one of our product candidates does not qualify for any expedited
review program, then this could result in a longer time period to approval and commercialization of such product candidate, could increase
the cost of development of such product candidate, and could harm our competitive position in the marketplace.
The
FDA’s Rare Pediatric Disease designation for Lomecel-B for HLHS does not guarantee that we will receive a priority review voucher
if the product is approved for this indication, nor does the receipt of Orphan Drug Designation for Lomecel-B for HLHS guarantee that
we will receive seven years of market exclusivity if the product is approved for this indication.
As
noted elsewhere in this report, FDA has granted both Rare Pediatric Disease designation and Orphan Drug Designation status for the use
of Lomecel-B to treat Hypoplastic Left Heart Syndrome (HLHS), a rare and life-threatening congenital heart defect in infants. These designations
were granted following our Phase 1 safety-focused ELPIS trial, where HLHS infants receiving Lomecel-B during Stage II cardiac reconstruction
surgery (bidirectional Glenn procedure) had 100% transplant-free survival between 2-3.5 years post-surgery (as of August 31, 2021). However,
even though FDA has granted Lomecel-B Rare Pediatric Disease designation for the treatment of HLHS, receipt of Rare Pediatric Disease
designation does not provide any guarantee that we would or will receive a priority review voucher upon approval for this indication.
If we do receive a priority review voucher upon approval of Lomecel-B for this indication, then that voucher permits a future application
to be treated as a priority review application by FDA. FDA does not guarantee that the future application will be reviewed in a particular
period of time. Vouchers may be transferred, including by sale; accordingly, there is a market for these vouchers at prices that have
historically fluctuated. If we receive a voucher, we cannot guarantee that we will use it or that there will be a market to transfer
or sell the voucher. Further, receipt of Orphan Drug Designation does not guarantee that we will receive seven years of market exclusivity
upon approval for this indication unless all appropriate statutory and regulatory criteria are met.
We
may face difficulties from changes to current regulations and future legislation, both in the U.S. as well as in other foreign jurisdictions
where we may be operating.
Existing
regulations and regulatory policies may change and additional government regulations may be enacted that could prevent, limit or delay
regulatory approval of our product candidates. We cannot predict the likelihood, nature or extent of government regulation that may arise
from future legislation or administrative action, either in the U.S. or abroad. If we are slow or unable to adapt to changes in existing
requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any
marketing approval that we may have obtained and we may not achieve or sustain profitability.
For
example, the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010,
or collectively the ACA, substantially changed the way healthcare is financed by both the government and private insurers, and significantly
impacted the U.S. pharmaceutical industry. Since its enactment, there have been judicial and Congressional challenges to certain aspects
of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.
Other
legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to
providers of 2% per fiscal year and reduced payments to several types of Medicare providers, which will remain in effect through 2029
absent additional congressional action. Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers
set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed,
among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs
and reform government program reimbursement methodologies for pharmaceutical products.
The
currently pending “Build Back Better Act,” if enacted, would make several significant changes to drug pricing, coverage,
and reimbursement that could materially impact our business. Among the key provisions related to drug pricing, Title XI of the Social
Security Act would be amended to direct the Secretary of the U.S. Department of Health and Human Services to establish a Drug Negotiation
Program to reduce spending on, and out-of-pocket costs for, prescription drugs. Each year, the Secretary would identify 100 brand-name
drugs lacking price competition and for which certain periods of time have elapsed since drug approval, and would select a proscribed
number of drugs on that list for price negotiations with manufacturers to establish a maximum fair price. Manufacturers that are noncompliant
with the fair price negotiation program would be subject to an excise tax during noncompliance periods. Other important drug pricing
provisions include a mandatory rebate for drug manufacturers of certain Medicare Part B and Part D drugs with prices increasing faster
than inflation beginning in 2023; cap setting on the costs for prescription drugs by setting annual out-of-pocket limits and lowering
beneficiary coinsurance in the initial coverage phase; and allowing cost-sharing for insulin products under Medicare Part D.
In
addition, other legislative changes have been proposed and adopted in the U.S. that could impact our future business and operations,
including those that may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse
effect on customers for our product candidates, if approved, and accordingly, our business, financial condition, and results of operations.
Moreover, there has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketed
products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among
other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs,
and reform government program reimbursement methodologies for drug products. At the state level, legislatures have increasingly passed
legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient
reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures,
and, in some cases, designed to encourage importation from other countries and bulk purchasing.
We
expect that the ACA, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage
criteria and in additional downward pressure on the price that we receive for any approved product. Any reduction in reimbursement from
Medicare or other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment
measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our product
candidates.
Legislative
and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for biotechnology
products. We cannot be sure whether additional legislative changes will be enacted, or whether FDA regulations, guidance or interpretations
will be changed, or what the impact of such changes on the marketing approvals of our product candidates, if any, may be. In addition,
increased scrutiny by Congress of the FDA’s approval process may significantly delay or prevent marketing approval, as well as
subject us to more stringent product labeling and post-marketing testing and other requirements.
Our
relationships with healthcare professionals, clinical investigators, CROs and third-party payors in connection with our current and future
business activities may be subject to federal and state healthcare fraud and abuse laws, false claims laws, transparency laws, government
price reporting, and health information privacy and security laws, which could expose us to, among other things, criminal sanctions,
civil penalties, contractual damages, exclusion from governmental healthcare programs, reputational harm, administrative burdens and
diminished profits and future earnings.
Healthcare
providers and third-party payors play a primary role in the recommendation and prescription of any product candidates for which we obtain
future marketing approval. Our current and future arrangements with healthcare professionals, clinical investigators, CROs, third-party
payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain
the business or financial arrangements and relationships through which we market, sell and distribute our products for which we obtain
marketing approval. Restrictions under applicable federal and state healthcare laws and regulations include the following:
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the
federal Anti-Kickback Statute prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering,
receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the
referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made under
a federal healthcare program such as Medicare and Medicaid. A person or entity does not need to have actual knowledge of the federal
Anti-Kickback Statute or specific intent to violate it in order to have committed a violation. In addition, the government may assert
that a claim including items or services resulting from a violation of the U.S. federal Anti-Kickback Statute constitutes a false
or fraudulent claim for purposes of the civil False Claims Act; |
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the
federal false claims and civil monetary penalties laws, including the civil False Claims Act, which can be enforced by private citizens
through civil whistleblower or qui tam actions, prohibit individuals or entities from, among other things, knowingly presenting,
or causing to be presented, to the federal government, claims for payment that are false or fraudulent or making a false statement
to avoid, decrease or conceal an obligation to pay money to the federal government; the federal Health Insurance Portability and
Accountability Act of 1996, or HIPAA, prohibits, among other things, executing or attempting to execute a scheme to defraud any healthcare
benefit program or making false statements relating to healthcare matters. Similar to the federal Anti-Kickback Statute, a person
or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation; |
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HIPAA,
as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, also imposes
obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually
identifiable health information; |
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the
federal Physician Payments Sunshine Act requires applicable manufacturers of covered drugs, devices, biologics and medical supplies
for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions,
to annually report to CMS starting in 2022 information regarding payments and other transfers of value to physicians, certain other
healthcare providers and teaching hospitals, as well as information regarding ownership and investment interests held by physicians
and their immediate family members. The information reported will be publicly available on a searchable website, with disclosure
required annually; and |
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analogous
state and foreign laws and regulations, such as state anti-kickback and false claims laws, may apply to sales or marketing arrangements
and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers. |
Some
state laws require biotechnology companies to comply with the biotechnology industry’s voluntary compliance guidelines and the
relevant compliance guidance promulgated by the federal government and may require drug manufacturers to report information related to
payments and other transfers of value to physicians and other healthcare providers or marketing expenditures. Some state laws require
biotechnology companies to report information on the pricing of certain drug products. State and foreign laws also govern the privacy
and security of health information in some circumstances, many of which differ from each other in significant ways and often are not
preempted by HIPAA, thus complicating compliance efforts. For instance, the collection and use of health data in the European Union is
governed by the General Data Protection Regulation, or the GDPR, which extends the geographical scope of European Union data protection
law to non-European Union entities under certain conditions, tightens existing European Union data protection principles, creates new
obligations for companies and new rights for individuals. Failure to comply with the GDPR may result in substantial fines and other administrative
penalties. In addition, on June 28, 2018, the State of California enacted the California Consumer Privacy Act, or CCPA, which took effect
on January 1, 2020. The CCPA creates individual privacy rights for California consumers and increases the privacy and security obligations
of entities handling certain personal information. The CCPA provides for civil penalties for violations, as well as a private right of
action for data breaches that is expected to increase data breach litigation. The CCPA may increase our compliance costs and potential
liability, and similar laws have been proposed at the federal level and in other states.
Efforts
to ensure that our current and future business arrangements with third parties will comply with applicable healthcare laws and regulations
will involve on-going substantial costs. It is possible that governmental authorities will conclude that our business practices may not
comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.
If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may
be subject to significant penalties, including civil, criminal and administrative penalties, damages, fines, disgorgement, individual
imprisonment, exclusion from participation in government funded healthcare programs, such as Medicare and Medicaid, integrity oversight
and reporting obligations, temporary or permanent debarment, contractual damages, reputational harm, diminished profits and future earnings
and the curtailment or restructuring of our operations. Defending against any such actions can be costly, time-consuming and may require
significant financial and personnel resources. Therefore, even if we are successful in defending against any such actions that may be
brought against us, our business may be impaired. Further, if any of the physicians or other healthcare providers or entities with whom
we expect to do business are found not to be in compliance with applicable laws, they may be subject to criminal, civil or administrative
sanctions, including exclusions from government funded healthcare programs.
Inadequate
funding for the FDA and other government agencies, future government shutdown or furlough of government employees, or public health
emergencies could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from
being reviewed or approved in a timely manner or otherwise prevent those agencies from performing normal business functions on which
the operation of our business may rely, which could negatively impact our business.
The
ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding
levels, ability to hire and retain key personnel, the availability of industry-paid user fees, and statutory, regulatory, and policy
changes. Average review times for product approvals at the FDA have fluctuated in recent years as a result. In addition, government funding
of other government agencies on which our operations may rely, including those that fund research and development activities, is subject
to the political process, which is inherently fluid and unpredictable.
Disruptions
at the FDA and other agencies, including those resulting from the ongoing COVID-19 global pandemic, may also slow the time necessary
for new products to be reviewed and/or approved by necessary government agencies, which would adversely affect our business. For example,
if a prolonged government shutdown and/or government employee furloughs were to occur, or if FDA’s response to a global pandemic
such as COVID-19 diverts FDA resources and attention to other regulatory efforts, then the ability of the FDA to timely review and process
our regulatory submissions, or inspect our or others’ manufacturing facilities, could be significantly impacted, which could have
a material adverse effect on our business, financial condition, and results of operations. Further, in our operations as a public company,
future government shutdowns, furloughs or public health emergencies could impact our ability to access the public markets and obtain
necessary capital in order to properly capitalize and continue our operations.
If
we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur
costs that could have a material adverse effect on our business, financial condition, and results of operations.
We
are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the
handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations involve the use of hazardous and flammable
materials, including chemicals and biological materials. Our operations also produce hazardous waste products. We generally contract
with third parties for the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these
materials. In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting
damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines
and penalties.
Although
we maintain workers’ compensation insurance to cover us for costs and expenses, we may incur due to injuries to our employees resulting
from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities. We do not maintain
insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal
of hazardous and flammable materials, including chemicals and biological materials.
In
addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations.
These current or future laws and regulations may impair our research, development or commercialization efforts. Failure to comply with
these laws and regulations also may result in substantial fines, penalties or other sanctions.
Our
research and development activities could be affected or delayed as a result of possible restrictions on animal testing.
Certain
laws and regulations require us to test our product candidates on animals before initiating clinical trials involving humans. Animal
testing activities have been the subject of controversy and adverse publicity. Animal rights groups and other organizations and individuals
have attempted to stop animal testing activities by pressing for legislation and regulation in these areas and by disrupting these activities
through protests and other means. To the extent the activities of these groups are successful, or if the laws and regulations regarding
animal testing otherwise change, our research and development activities may be interrupted, delayed or become more expensive.
Our
business activities may be subject to the U.S. Foreign Corrupt Practices Act, or the FCPA, and similar anti-bribery and anti-corruption
laws of other countries in which we operate, as well as U.S. and certain foreign export controls, trade sanctions, and import laws and
regulations. Compliance with these legal requirements could limit our ability to compete in foreign markets and subject us to liability
if we violate them.
If
we further expand our operations outside of the U.S., we must dedicate additional resources to comply with numerous laws and regulations
in each jurisdiction in which we plan to operate. Our business activities may be subject to the FCPA and similar anti-bribery or anti-corruption
laws, regulations or rules of other countries in which we operate. The FCPA generally prohibits companies and their employees and third-party
intermediaries from offering, promising, giving or authorizing the provision of anything of value, either directly or indirectly, to
a non-U.S. government official in order to influence official action or otherwise obtain or retain business. The FCPA also requires public
companies to make and keep books and records that accurately and fairly reflect the transactions of the corporation and to devise and
maintain an adequate system of internal accounting controls. Our business is heavily regulated and therefore involves significant interaction
with public officials, including officials of non-U.S. governments. Additionally, in many other countries, hospitals owned and operated
by the government, and doctors and other hospital employees would be considered foreign officials under the FCPA. Recently the Securities
and Exchange Commission (SEC) and Department of Justice (DOJ) have increased their FCPA enforcement activities with respect to biotechnology
and pharmaceutical companies. There is no certainty that all of our employees, agents or contractors, or those of our affiliates, will
comply with all applicable laws and regulations, particularly given the high level of complexity of these laws. Violations of these laws
and regulations could result in fines, criminal sanctions against us, our officers or our employees, disgorgement, and other sanctions
and remedial measures, and prohibitions on the conduct of our business. Any such violations could include prohibitions on our ability
to offer our products in one or more countries and could materially damage our reputation, our brand, our international activities, our
ability to attract and retain employees and our business, prospects, operating results and financial condition.
In
addition, our products and technology may be subject to U.S. and foreign export controls, trade sanctions and import laws and regulations.
Governmental regulation of the import or export of our products and technology, or our failure to obtain any required import or export
authorization for our products, when applicable, could harm our international sales and adversely affect our revenue. Compliance with
applicable regulatory requirements regarding the export of our products may create delays in the introduction of our products in international
markets or, in some cases, prevent the export of our products to some countries altogether. Furthermore, U.S. export control laws and
economic sanctions prohibit the shipment of certain products and services to countries, governments, and persons targeted by U.S. sanctions.
If we fail to comply with export and import regulations and such economic sanctions, penalties could be imposed, including fines and/or
denial of certain export privileges. Moreover, any new export or import restrictions, new legislation or shifting approaches in the enforcement
or scope of existing regulations, or in the countries, persons, or products targeted by such regulations, could result in decreased use
of our products by, or in our decreased ability to export our products to existing or potential customers with international operations.
Any decreased use of our products or limitation on our ability to export or sell access to our products would likely adversely affect
our business.
Risks
Related to Our Class A Common Stock and the Securities Market
The
price of our stock has been, and may continue to be, volatile, and you could lose all or part of your investment.
The
trading price of our Class A Common Stock has been, and may continue to be highly volatile and subject to wide fluctuations in response
to various factors, some of which we cannot control. The stock market in general, and pharmaceutical and biotechnology companies in particular,
have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance
of these companies.
Broad
market and industry factors may negatively affect the market price of our Class A Common Stock, regardless of our actual operating performance.
In addition to the factors discussed in this “Risk Factors” section and elsewhere in this report, these factors include:
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the
timing and results, or perception of the results, of preclinical studies and clinical trials of our product candidates or those of
our competitors; |
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the
success of competitive products or announcements by potential competitors of their product development efforts; |
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regulatory
actions with respect to our or our competitors’ product candidates or products; |
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actual
or anticipated changes in our growth rate relative to our competitors; |
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regulatory
or legal developments in the U.S. and other countries; |
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developments
or disputes concerning patent applications, issued patents or other proprietary rights; |
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the
recruitment or departure of key personnel; |
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announcements
by us or our competitors of significant acquisitions, strategic collaborations, joint ventures, or capital commitments; |
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actual
or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts; |
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fluctuations
in the valuation of companies perceived by investors to be comparable to us; |
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market
conditions in the pharmaceutical and biotechnology sector; |
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changes
in the structure of healthcare payment systems; |
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share
price and volume fluctuations attributable to inconsistent trading volume levels of our shares; |
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announcement
or expectation of additional financing efforts; |
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sales
of our Class A Common Stock by us, our insiders or our other stockholders; |
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expiration
of market stand-off or lock-up agreements; and |
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economic, industry and market conditions. |
The
realization of any of the above risks or any of a broad range of other risks, including those described in this “Risk Factors”
section, could have a dramatic and adverse impact on the market price of our Class A Common Stock.
Our ability to raise capital in the future
may be limited.
To date, our principal sources of capital used
to fund our programs and other operations have been grant funding and the net proceeds we received from sales of equity securities. We
have and will continue to use significant capital for the development and commercialization of our product candidates, and, as such, we
expect to seek additional capital from future issuance(s) of our securities, which may consist of issuances of equity and/or debt securities,
to fund our planned operations. Additional financing may not be available on favorable terms or at all. If adequate funds are not available
on acceptable terms, we may be unable to fund our capital requirements. Because our decision to issue securities in any future offering
will depend on market conditions and other factors beyond our control, we cannot predict or estimate the amount, timing or nature of our
future offerings. Thus, you bear the risk of our future securities offerings reducing the market price of our common stock and diluting
your interest.
In December 2021, we raised approximately $20.5
million in gross proceeds through the sale of our equity securities under a Form S-1 registration statement. As of February 14, 2022,
we are eligible to sell equity securities under a Form S-3 “shelf” registration statement. Using a shelf registration statement
to raise capital generally takes less time and is less expensive than other means, such as conducting an offering under a Form S-1 registration
statement. However, under current SEC rules and regulations, we must meet certain requirements to use a Form S-3 registration statement
to raise capital without restriction as to the amount of the market value of securities sold thereunder. One such requirement is that
we periodically evaluate the market value of our outstanding shares of common stock held by non-affiliates, or public float, and if, at
an evaluation date, our public float is less than $75.0 million, then the aggregate market value of securities sold by us or on our behalf
under the Form S-3 in any 12-month period is limited to an aggregate of one-third of our public float. Our public float is currently approximately
$30.0 million and therefore we are currently subject to the one-third of our public float limitation. If our ability to use our Form S-3
shelf registration statement for a primary offering of our securities is limited to one-third of our public float, we may conduct such
an offering pursuant to an exemption from registration under the Securities Act of 1933 or under a Form S-1 registration statement, and
we would expect either of those alternatives to increase the cost of raising additional capital relative to using our Form S-3 shelf registration
statement.
In addition, under current SEC rules and regulations,
our common stock must be listed and registered on a national securities exchange in order to use a Form S-3 registration statement (i)
for a primary offering, if our public float is not at least $75.0 million as of a date within 60 days prior to the date of filing the
Form S-3 or a re-evaluation date, whichever is later, and (ii) to register the resale of our securities by persons other than us (i.e.,
a resale offering). While currently our common stock is listed on the Nasdaq Capital Market, there can be no assurance that we will be
able to maintain such listing.
Our ability to timely raise sufficient additional
capital also may be limited by Nasdaq's stockholder approval requirements for transactions involving the issuance of our common stock
or securities convertible into our common stock in an offering other than a public offering (as defined in Nasdaq listing rules). For
instance, generally, stockholder approval is required prior to the issuance or potential issuance of common stock (or securities convertible
into or exercisable for common stock) which (together with sales by our officers, directors and substantial shareholders (as defined in
Nasdaq listing rules)) equals 20% or more of our common stock outstanding before the issuance at a price that is less than the lower of
the closing price of our common stock or the five trading day average closing price of our common stock, in each case, immediately preceding
the signing of the binding agreement (the "Minimum Price"). A public offering under Nasdaq rules typically involves broadly
announcing the proposed transaction, which often times has the effect of depressing the company's stock price. Accordingly, the price
at which we could sell our securities in a public offering may be less, and the dilution existing stockholders experience may in turn
be greater, than if we were able to raise capital through other means.
Raising
additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights to our
product candidates on unfavorable terms to us.
In
order to meet our operational goals, we will need to obtain additional capital, which we will likely obtain through a variety of
means, including through public or private equity financings, debt financings or other sources, including up-front payments and
milestone payments from strategic collaborations. To the extent that we raise additional capital through the sale of convertible
debt or equity securities, your ownership interest will be diluted, and the terms may include liquidation or other preferences that
adversely affect your rights as a stockholder. Any such financing may result in dilution to stockholders, imposition of debt
covenants, increased fixed payment obligations or other restrictions that may affect our business.
In addition, we currently have warrants issued that are subject
to downward exercise price adjustments that may be triggered in a future financing, and which, if exercised, would also result in
dilution. If we raise additional funds through up-front payments or milestone payments pursuant to strategic collaborations with
third parties, we may have to relinquish valuable rights to our product candidates, or grant licenses on terms that are not
favorable to us. In addition, we may seek additional capital due to favorable market conditions or strategic considerations even if
we believe we have sufficient funds for our current or future operating plans.
Information
available in public media that is published by third parties, including blogs, articles, message boards and social and other media may
include statements not attributable to the Company and may not be reliable or accurate.
We
are aware of a large volume of information being disseminated by third parties relating to our operations, including in blogs, message
boards and social and other media. Such information as reported by third parties may not be accurate, may lead to significant volatility
in our securities and may ultimately result in our common stock or other securities declining in value.
There
may not be sufficient liquidity in the market for our securities in order for investors to sell their shares.
We
are a small company that is relatively unknown to stock analysts, stock brokers, institutional investors and others in the investment
community that generate or influence sales volume, and even if we came to the attention of such persons, they tend to be risk-averse
and may be reluctant to follow an unproven company such as ours or purchase or recommend the purchase of our shares until such time as
we became more seasoned and viable. There may be periods of several days or more when trading activity in our shares is minimal as compared
to a mature issuer which has a large and steady volume of trading activity that will generally support continuous sales without an adverse
effect on share price. It is possible that a broader or more active public trading market for our common stock will not develop or be
sustained, or that trading levels will not continue. These factors may materially adversely affect the market price of our Class A Common
Stock, regardless of our performance. In addition, the public stock markets have experienced extreme price and trading volume volatility.
This volatility has significantly affected the market prices of securities of many companies for reasons frequently unrelated to the
operating performance of the specific companies. These broad market fluctuations may adversely affect the market price of our Class A
Common Stock.
The
dual class structure of our common stock may adversely affect the trading market for our Class A Common Stock.
We
cannot predict whether our dual class structure will result in a lower or more volatile market price of our Class A Common Stock or in
adverse publicity or other adverse consequences. For example, certain index providers have announced restrictions on including companies
with dual class or multi-class share structures in certain of their indexes. In July 2017, S&P Dow Jones and FTSE Russell announced
changes to their eligibility criteria for the inclusion of shares of public companies on certain indices, including the Russell 2000,
the S&P 500, the S&P MidCap 400 and the S&P SmallCap 600, to exclude companies with multiple classes of shares of common
stock from being added to these indices. Beginning in 2017, MSCI, a leading stock index provider, opened public consultations on their
treatment of no-vote and multi-class structures and temporarily barred new multi-class listings from certain of its indices. However,
in October 2018, MSCI announced its decision to include equity securities “with unequal voting structures” in its indices
and to launch a new index that specifically includes voting rights in its eligibility criteria. As a result, our dual class capital structure
would make us ineligible for inclusion in any of these indices, and mutual funds, exchange-traded funds and other investment vehicles
that attempt to passively track these indices will not be investing in our stock. These policies are still fairly new and it is as of
yet unclear what effect, if any, they will have on the valuations of publicly traded companies excluded from the indices, but it is possible
that they may depress these valuations compared to those of other similar companies that are included. Furthermore, we cannot assure
you that other stock indices will not take a similar approach to S&P Dow Jones or FTSE Russell in the future. Exclusion from indices
could make our Class A Common Stock less attractive to investors and, as a result, the market price of our Class A Common Stock could
be adversely affected.
If
securities or industry analysts do not publish research or reports, or if they publish adverse or misleading research or reports, regarding
us, our business or our market, our stock price and trading volume could decline.
The
trading market for our Class A Common Stock will be influenced by the research and reports that securities or industry analysts publish
about us, our business or our market. We do not currently have and may never obtain research coverage by securities or industry analysts.
If no or few securities or industry analysts commence coverage of us, the stock price would be negatively impacted. In the event we obtain
securities or industry analyst coverage, if any of the analysts who cover us issue adverse or misleading research or reports regarding
us, our business model, our intellectual property, our stock performance or our market, or if our operating results fail to meet the
expectations of analysts, our stock price would likely decline. If one or more of these analysts cease coverage of us or fail to publish
reports on us regularly, we could lose visibility in the financial markets, which in turn could cause our stock price or trading volume
to decline.
Our
quarterly operating results may fluctuate significantly or may fall below the expectations of investors or securities analysts, each
of which may cause our stock price to fluctuate or decline.
We
expect our operating results to be subject to quarterly fluctuations. Our net loss and other operating results will be affected by numerous
factors, including:
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variations
in the level of expense related to the ongoing development of our product candidates or future development programs; |
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results
of clinical trials, or the addition or termination of clinical trials or funding support by us or potential future partners; |
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our
execution of any collaboration, licensing or similar arrangements, and the timing of payments we may make or receive under potential
future arrangements or the termination or modification of any such potential future arrangements; |
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any
intellectual property infringement, misappropriation or violation lawsuit or opposition, interference or cancellation proceeding
in which we may become involved; |
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additions
and departures of key personnel; |
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strategic
decisions by us or our competitors, such as acquisitions, divestitures, spin-offs, joint ventures, strategic investments or changes
in business strategy; |
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if
any of our product candidates receives regulatory approval, the terms of such approval and market acceptance and demand for such
approved products; |
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regulatory
developments affecting our product candidates or future products, or those of our competitors; and |
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changes
in general market and economic conditions. |
If
our quarterly operating results fall below the expectations of investors or securities analysts, the price of our Class A Common Stock
could decline substantially. Furthermore, any quarterly fluctuations in our operating results may, in turn, cause the price of our stock
to fluctuate substantially. We believe that quarterly comparisons of our financial results are not necessarily meaningful and should
not be relied upon as an indication of our future performance.
Holders
of our Class B Common Stock will control the direction of our business and their ownership of our common stock will prevent you and other
stockholders from influencing significant decisions.
As
of December 31, 2021, two holders of our Class B Common Stock, Dr. Joshua Hare, our co-founder and Chief Scientific Officer, and
DS MED LLC, a limited liability company controlled by a member of our Board, Don Soffer, own approximately 93% of the combined voting
power of our Class A and Class B Common Stock. For so long as holders of Class B Common Stock continue to hold their shares, they will be able to significantly
influence or effectively control the composition of our board of directors and the approval of actions requiring stockholder approval
through their voting power. Accordingly, for such period of time, these holders will have significant influence with respect to our management,
business plans and policies. In particular, for so long as the Class B Common Stock remains outstanding, the holders may be able to cause
or prevent a change of control of our Company or a change in the composition of our board of directors, and could preclude any unsolicited
acquisition of our Company. The concentration of ownership could deprive you of an opportunity to receive a premium for your shares of
Class A Common Stock as part of a sale of our Company and ultimately might affect the market price of our Class A Common Stock.
If
we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our financial
results or prevent fraud. As a result, stockholders could lose confidence in our financial and other public reporting, which would harm
our business and the trading price of our Class A Common Stock.
Effective
internal controls over financial reporting are necessary for us to provide reliable financial reports and, together with adequate disclosure
controls and procedures, are designed to prevent fraud. Any failure to implement required new or improved controls, or difficulties encountered
in their implementation could cause us to fail to meet our reporting obligations. In addition, any testing by us conducted in connection
with Section 404, or any subsequent testing by our independent registered public accounting firm, may reveal deficiencies in our internal
controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to
our financial statements or identify other areas for further attention or improvement. Substandard internal controls could also cause
investors to lose confidence in our reported financial information, which could have a negative effect on the trading price of our stock.
We
are required to disclose changes made in our internal controls and procedures on a quarterly basis and our management is required to
assess the effectiveness of these controls annually. However, for as long as we are an emerging growth company, our independent registered
public accounting firm will not be required to attest to the effectiveness of our internal controls over financial reporting pursuant
to Section 404. We could be an emerging growth company for up to five years. An independent assessment of the effectiveness of our internal
controls over financial reporting could detect problems that our management’s assessment might not. Undetected material weaknesses
in our internal controls over financial reporting could lead to restatements of our financial statements, require us to incur the expense
of remediation, and result in a decline in the trading price of our stock.
We
are an “emerging growth company,” and we cannot be certain if the reduced reporting requirements applicable to emerging growth
companies will make our Class A Common Stock less attractive to investors.
We
are an “emerging growth company,” as defined in the JOBS Act. For as long as we continue to be an emerging growth company,
we intend to take advantage of exemptions from various reporting requirements that are applicable to other public companies that are
not emerging growth companies, including:
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being
permitted to provide only two years of audited financial statements, in addition to any required unaudited interim financial statements,
with correspondingly reduced “Management’s Discussion and Analysis of Financial Condition and Results of Operations”
disclosure in this report; |
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not
being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act; |
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not
being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory
audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial
statements; |
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reduced
disclosure obligations regarding executive compensation in this report and our periodic reports and proxy statements; |
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exemptions
from the requirements of holding nonbinding advisory stockholder votes on executive compensation and stockholder approval of any
golden parachute payments not previously approved; and |
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extended transition period for complying with new or revised financial accounting standards. |
We
cannot predict if investors will find our Class A Common Stock less attractive because we may rely on these exemptions. If some investors
find our Class A Common Stock less attractive as a result, there may be a less active trading market for our Class A Common Stock and
our stock price may be more volatile.
We
will remain an emerging growth company until the earliest to occur of: (1) the last day of the fiscal year in which we have more than
$1.07 billion in annual revenue; (2) the date we qualify as a “large accelerated filer,” with at least $700 million of equity
securities held by non-affiliates; (3) the date on which we have issued more than $1.0 billion in non-convertible debt securities during
the prior three-year period; and (4) the last day of the fiscal year ending after the fifth anniversary of our IPO.
Under
the JOBS Act, emerging growth companies can also delay adopting new or revised accounting standards until such time as those standards
apply to private companies. We have elected to take advantage of the extended transition period for complying with new or revised accounting
standards and, therefore, our financial statements may not be comparable to other public companies that comply with public company effective
dates. As a result, changes in rules of U.S. generally accepted accounting principles or their interpretation, the adoption of new guidance
or the application of existing guidance to changes in our business could significantly affect our financial position and results of operations.
The
requirements of being a public company may strain our resources, result in more litigation and divert management’s attention.
As
a public company, we are subject to the reporting requirements of the Exchange Act, the Sarbanes-Oxley Act, the Dodd-Frank Wall Street
Reform and Consumer Protection Act, or the Dodd-Frank Act, the listing requirements of Nasdaq and other applicable securities rules and
regulations. Complying with these rules and regulations results in legal and financial compliance costs, makes some activities more difficult,
time consuming or costly and increases demand on our systems and resources, including management. In order to maintain and, if required,
improve our disclosure controls and procedures and internal control over financial reporting to meet this standard, significant resources
and management oversight may be required. As a result, management’s attention may be diverted from other business concerns, which
could adversely affect our business and operating results. We may also need to hire additional employees or engage outside consultants
to comply with these requirements, which will increase our costs and expenses.
In
addition, changing laws, regulations and standards relating to corporate governance and public disclosure are creating uncertainty for
public companies, increasing legal and financial compliance costs and making some activities more time consuming. These laws, regulations
and standards are subject to varying interpretations, in many cases due to their lack of specificity and, as a result, their application
in practice may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty
regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices. We intend to
invest resources to comply with evolving laws, regulations and standards, and this investment may result in increased general and administrative
expenses and a diversion of management’s time and attention from revenue-generating activities to compliance activities. If our
efforts to comply with new laws, regulations and standards differ from the activities intended by regulatory or governing bodies due
to ambiguities related to their application and practice, regulatory authorities may initiate legal proceedings against us and our business
may be adversely affected.
These
new rules and regulations may make it more expensive for us to obtain director and officer liability insurance and, in the future, we
may be required to accept reduced coverage or incur substantially higher costs to obtain coverage. These factors could also make it more
difficult for us to attract and retain qualified members of our board of directors, particularly to serve on our audit committee and
compensation committee, and qualified executive officers.
By
disclosing information in this report and in future filings required of a public company, our business and financial condition will become
more visible, which we believe may result in threatened or actual litigation, including by competitors and other third parties. If those
claims are successful, our business could be seriously harmed. Even if the claims do not result in litigation or are resolved in our
favor, the time and resources needed to resolve them could divert our management’s resources and seriously harm our business.
We
are subject to securities litigation, which is expensive and could divert management attention.
The
market price of our Class A Common Stock may be volatile, and such volatility has made, and may continue to make, us subject to securities
class action litigation. We have been the target of this type of litigation to date, and may also be in the future. Additional securities
litigation against us could result in substantial costs and divert our management’s attention from other business concerns, which
could seriously harm our business.
We
do not currently intend to pay dividends on our Class A Common Stock and, consequently, your ability to achieve a return on your investment
will depend on appreciation of the value of our Class A Common Stock.
We
have never declared or paid any cash dividends on our equity securities. We currently anticipate that we will retain future earnings
for the development, operation and expansion of our business and do not anticipate declaring or paying any cash dividends for the foreseeable
future. Any return to stockholders will therefore be limited to any appreciation in the value of our Class A Common Stock, which is not
certain.
Provisions
in our certificate of incorporation and bylaws and Delaware law might discourage, delay or prevent a change in control of our company
or changes in our management and, therefore, depress the market price of our Class A Common Stock.
Our
certificate of incorporation and bylaws contain provisions that could depress the market price of our Class A Common Stock by acting
to discourage, delay or prevent a change in control of our company or changes in our management that the stockholders of our company
may deem advantageous. These provisions, among other things:
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establish
a classified board of directors so that not all members of our board are elected at one time; |
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permit
only the board of directors to establish the number of directors and fill vacancies on the board; |
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provide
that directors may only be removed “for cause” and only with the approval of two-thirds of our stockholders; |
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provide
for a dual class common stock structure, which provides certain affiliates of ours, including our co-founder and members of our Board,
individually or together, with the ability to significantly influence the outcome of matters requiring stockholder approval, even
if they own significantly less than a majority of the shares of our outstanding Class A Common Stock and Class B Common Stock; |
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authorize
the issuance of “blank check” preferred stock that our Board could use to implement a stockholder rights plan (also known
as a “poison pill”); |
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eliminate
the ability of our stockholders to call special meetings of stockholders; |
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prohibit
stockholder action by written consent, which requires all stockholder actions to be taken at a meeting of our stockholders; |
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prohibit
cumulative voting; |
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authorize
our Board to amend our bylaws; |
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establish
advance notice requirements for nominations for election to our board or for proposing matters that can be acted upon by stockholders
at annual stockholder meetings; and |
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require
a super-majority vote of stockholders to amend some of the provisions described above. |
In
addition, Section 203 of the General Corporation Law of the State of Delaware, or the DGCL, prohibits a publicly-held Delaware corporation
from engaging in a business combination with an interested stockholder, generally a person which together with its affiliates owns, or
within the last three years has owned, 15% of our voting stock, for a period of three years after the date of the transaction in which
the person became an interested stockholder, unless the business combination is approved in a prescribed manner.
Any
provision of our certificate of incorporation, bylaws or Delaware law that has the effect of delaying or preventing a change in control
could limit the opportunity for our stockholders to receive a premium for their shares of our capital stock and could also affect the
price that some investors are willing to pay for our Class A Common Stock.
Our
certificate of incorporation provides that the Court of Chancery of the State of Delaware and the federal district courts of the U.S. will be the exclusive forums for substantially all disputes between us and our stockholders, which could limit our stockholders’
ability to obtain a favorable judicial forum for disputes with us or our directors, officers or employees.
Our
certificate of incorporation provides that the Court of Chancery of the State of Delaware is the exclusive forum for:
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any
derivative action or proceeding brought on our behalf; |
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any
action asserting a claim of breach of fiduciary duty; |
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any
action asserting a claim against us arising under the DGCL, or as to which the DGCL confers jurisdiction on the Court of Chancery
of the State of Delaware; |
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any
action to interpret, apply, enforce or determine the validity of our certificate of incorporation or bylaws; and |
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any
action asserting a claim against us that is governed by the internal-affairs doctrine. |
Our
certificate of incorporation further provides that the federal district courts of the U.S. will be the exclusive forum for
resolving any complaint asserting a cause of action arising under the Securities Act. These exclusive-forum provisions may limit a stockholder’s
ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers or other employees,
which may discourage lawsuits against us and our directors, officers and other employees. Any person or entity purchasing or otherwise
acquiring any interest in any of our securities shall be deemed to have notice of and consented to this provision. If a court were to
find these exclusive-forum provisions in our bylaws to be inapplicable or unenforceable in an action, we may incur additional costs associated
with resolving the dispute in other jurisdictions, which could seriously harm our business. Nothing in our certificate of incorporation
precludes stockholders that assert claims under the Securities Act or the Exchange Act from bringing such claims in state or federal
court, subject to applicable law.
Risks
Related to Employee Matters, Managing Our Growth and Other Risks Related to Our Business
We
have never commercialized a product candidate before and may lack the necessary expertise, personnel and resources to successfully commercialize
any products on our own or together with suitable collaborators.
We
have never commercialized a product candidate, and we currently have no sales force, marketing or distribution capabilities, nor do any
of our current employees have any experience in commercializing a regulated product. To achieve commercial success for our product candidates,
which we may license to others, we will rely on the assistance and guidance of those collaborators. For product candidates for which
we retain commercialization rights, we will have to develop our own sales, marketing and supply organization or outsource these activities
to a third party.
Factors
that may affect our ability to commercialize our future approved products on our own include recruiting and retaining adequate numbers
of effective sales and marketing personnel, obtaining access to or persuading adequate numbers of physicians to prescribe our products
and other unforeseen costs associated with creating an independent sales and marketing organization. Developing a sales and marketing
organization will be expensive and time-consuming and could delay the launch of our future approved products. We may not be able to build
an effective sales and marketing organization. If we are unable to build our own distribution and marketing capabilities or to find suitable
partners for the commercialization of our future approved products, we may not generate revenues from them or be able to reach or sustain
profitability.
In
order to successfully implement our plans and strategies, we will need to grow our organization, and we may experience difficulties in
managing this growth.
In
order to successfully implement our development and commercialization plans and strategies, and as we transition into operating as a
public company, we expect to need additional managerial, operational, sales, marketing, financial and other personnel. Future growth
would impose significant added responsibilities on members of management, including:
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identifying,
recruiting, integrating, maintaining and motivating additional employees; |
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managing
our internal development efforts effectively, including preclinical and clinical studies and investigations, as well as FDA, PMDA
and other comparable foreign regulatory agencies’ review process for any current or future product candidates, while complying
with any contractual obligations to contractors and other third parties we may have; and |
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improving
our operational, financial and management controls, reporting systems and procedures. |
Our
future financial performance and our ability to successfully develop and, if approved, commercialize, any current or future product candidates
will depend, in part, on our ability to effectively manage any future growth, and our management may also have to divert a disproportionate
amount of its attention away from day-to-day activities in order to devote a substantial amount of time to managing these growth activities.
We
currently rely, and for the foreseeable future will continue to rely, in substantial part on certain independent organizations, advisors
and consultants to provide certain services, including key aspects of clinical development and manufacturing. We cannot assure you that
the services of independent organizations, advisors and consultants will continue to be available to us on a timely basis when needed,
or that we can find qualified replacements. In addition, if we are unable to effectively manage our outsourced activities or if the quality
or accuracy of the services provided by third party service providers is compromised for any reason, our clinical trials may be extended,
delayed or terminated, and we may not be able to obtain marketing approval of our current and future product candidates or otherwise
advance our business. We cannot assure you that we will be able to manage our existing third-party service providers or find other competent
outside contractors and consultants on economically reasonable terms, or at all.
If
we are not able to effectively expand our organization by hiring new employees and/or engaging additional third-party service providers,
we may not be able to successfully implement the tasks necessary to further develop and commercialize our current and future product
candidates and, accordingly, may not achieve our research, development and commercialization goals.
Our
internal computer systems, or those of any of our CROs, manufacturers, other contractors, consultants, collaborators or potential future
collaborators, may fail or suffer security or data privacy breaches or other unauthorized or improper access to, use of, or destruction
of our proprietary or confidential data, employee data, or personal data, which could result in additional costs, loss of revenue, significant
liabilities, harm to our brand and material disruption of our operations.
Despite
the implementation of security measures, our internal computer systems and those of our current and any future CROs and other contractors,
consultants, collaborators and third-party service providers, are vulnerable to damage from computer viruses, cybersecurity threats,
unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failure. If such an event were to occur and
cause interruptions in our operations or result in the unauthorized acquisition of or access to personally identifiable information or
individually identifiable health information (violating certain privacy laws such as HIPAA, Health Information Technology for Economic
and Clinical Health Act and GDPR), it could result in a material disruption of our drug discovery and development programs and our business
operations, whether due to a loss of our trade secrets or other similar disruptions. Some of the federal, state and foreign government
requirements include obligations of companies to notify individuals of security breaches involving particular personally identifiable
information, which could result from breaches experienced by us or by our vendors, contractors, or organizations with which we have formed
strategic relationships. Notifications and follow-up actions related to a security breach could impact our reputation, cause us to incur
significant costs, including legal expenses and remediation costs. For example, the loss of clinical trial data from completed or future
clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce
the lost data. We also rely on third parties to manufacture our product candidates, and similar events relating to their computer systems
could also have a material adverse effect on our business. To the extent that any disruption or security breach were to result in a loss
of, or damage to, our data, or inappropriate disclosure of confidential or proprietary information, we could be exposed to litigation
and governmental investigations, the further development and commercialization of our product candidates could be delayed, and we could
be subject to significant fines or penalties for any noncompliance with certain state, federal and/or international privacy and security
laws.
Our
insurance policies may not be adequate to compensate us for the potential losses arising from any such disruption, failure or security
breach. In addition, such insurance may not be available to us in the future on economically reasonable terms, or at all. Further, our
insurance may not cover all claims made against us and could have high deductibles in any event, and defending a suit, regardless of
its merit, could be costly and divert management attention.
Our
ability to utilize our net operating loss carryforwards and certain other tax attributes may be limited.
Although
our first year incurring NOLs will be for the tax year ended 2021, the net operating loss carryforwards, or NOLs, could expire
unused and be unavailable to offset future income tax liabilities because of their limited duration or because of restrictions under
U.S. tax law. Under the current Tax Act, federal NOLs generated in tax years ending after December 31, 2017 may be carried
forward indefinitely. It is uncertain if and to what extent various states will conform to the Tax Act.
In
addition, under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, if a corporation undergoes an “ownership
change” (generally defined as a cumulative change in our ownership by “5-percent shareholders” that exceeds 50 percentage
points over a rolling three-year period), the corporation’s ability to use its pre-change NOLs and certain other pre-change tax
attributes to offset its post-change income and taxes may be limited. Similar rules may apply under state tax laws. We may have experienced
such ownership changes in the past, and we may experience ownership changes in the future as a result of subsequent shifts in our stock
ownership, some of which are outside our control. We have not conducted any studies to determine annual limitations, if any, that could
result from such changes in the ownership. Our ability to utilize those NOLs could be limited by an “ownership change” as
described above and consequently, we may not be able to utilize a material portion of our NOLs and certain other tax attributes, which
could have a material adverse effect on our cash flows and results of operations.
A
variety of risks associated with marketing our product candidates internationally could materially adversely affect our business.
We
plan to seek regulatory approval of our product candidates outside of the U.S., including specifically in Japan, and, accordingly, we
expect that we will be subject to additional risks related to operating in foreign countries if we obtain the necessary approvals, including:
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differing
regulatory requirements and reimbursement regimes in foreign countries; |
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unexpected
changes in tariffs, trade barriers, price and exchange controls and other regulatory requirements; |
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economic
weakness, including inflation, or political instability in particular foreign economies and markets; |
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compliance
with tax, employment, immigration and labor laws for employees living or traveling abroad; |
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foreign
taxes, including withholding of payroll taxes; |
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foreign
currency fluctuations, which could result in increased operating expenses and reduced revenue, and other obligations incident to
doing business in another country; |
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difficulties
staffing and managing foreign operations; |
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workforce
uncertainty in countries where labor unrest is more common than in the U.S.; |
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potential
liability under the FCPA or comparable foreign regulations; |
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challenges
enforcing our contractual and intellectual property rights, especially in those foreign countries that do not respect and protect
intellectual property rights to the same extent as the U.S.; |
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production
shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and |
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business
interruptions resulting from geo-political actions, including war and terrorism. |
These
and other risks associated with our international operations may materially adversely affect our ability to attain or maintain profitable
operations.