On February 17,
2021, we entered into a License Agreement with Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd. (“Huadong”), a wholly-owned
subsidiary of Huadong Medicine Co., Ltd. (the “Huadong License Agreement”), pursuant to which we granted Huadong exclusive
rights for the purpose of developing and commercializing PRV-3279, a DART® (bispecific antibody-based molecule) targeting
the B cell surface proteins CD32B and CD79B, in Greater China (mainland China, Hong Kong, Macau and Taiwan). We will retain exclusive
worldwide rights to develop PRV-3279 for combination uses to reduce the immunogenicity of biotherapeutics, but Huadong will
have the exclusive right to distribute PRV-3279 in that field in Greater China. In consideration of the license and other
rights granted as part of the Huadong License Agreement, we will receive and upfront payment of $6.0 million and up to
$11.5 million in research, development and manufacturing funding over the next three years. If Huadong successfully
develops, obtains regulatory approval for, and commercializes PRV-3279 in Greater China, we are eligible to receive up
to $37.0 million in regulatory milestones and up to $135.0 million in commercial milestones based on aggregate net
sales in a calendar year in Greater China. If commercialized, we would also be eligible to receive low double-digit royalties
on net sales of PRV-3279 by Huadong in Greater China. The License Agreement may be terminated by either party upon a material
breach or bankruptcy of the other party, by Huadong without cause upon at least 12 months prior notice to us and by us in the
event Huadong challenges a licensed patent or in the event that our upstream license terminates. We may also terminate the License
Agreement if Huadong ceases commercialization of PRV-3279 for a consecutive period of six months after first commercial sale.
We are generally responsible for the manufacturing of PRV-3279 at least through regulatory approval in
Greater China and Huadong will exclusively purchase all clinical and commercial supply requirements of PRV-3279 from us
until Huadong exercises its option to assume manufacturing responsibilities, which may be triggered
after regulatory approval in China. We will retain all rights to PRV-3279 in the rest of the world. We plan to begin a Phase 2a
trial of PRV-3279 in systemic lupus erythematosus in the second half of 2021 and expect a portion of such trial to be conducted
in Hong Kong.
T1D
Background Information
T1D
is the end result of immune-mediated destruction of the insulin-producing beta cells of the pancreas and is one of the most common
and serious chronic conditions occurring in childhood. T1D patients require life-long dependence on insulin products delivered
through multiple daily injections or continuous infusion pumps. While the disease presents in children and adults, the vast majority
of T1D is diagnosed in children, with more than half of T1D patients diagnosed before the age of 14 years. The life-expectancy
of individuals with younger-onset disease is on average 16 years shorter than non-diabetic individuals. Individuals diagnosed
before the age of 10 years have a 30-times greater risk of serious cardiovascular outcomes than the general population resulting
in decreased life expectancy, compared to healthy individuals. It is believed the loss of beta cells, which is more severe and
rapid in younger individuals leading to increased glycemic load, is the cause of increased cardiovascular-related deaths. The
disease is believed to occur in genetically susceptible individuals upon exposure to environmental triggers. In addition, because
of a similar genetic predisposition, patients with T1D are at high risk of developing celiac disease. Celiac disease is characterized
by autoimmunity in the gut and other organs triggered by consumption of gluten and can lead to malnutrition and other complications
including a form of cancer called lymphoma. There is no approved therapy for celiac disease.
Lack
of insulin secretory capacity has serious consequences, even when patients receive insulin replacement therapy. The complications
of T1D include eye disease, nerve damage, kidney disease and heart disease. Diabetic retinopathy has a prevalence of approximately
80% among patients with T1D and is the leading cause of vision impairment and blindness among adults. Moreover, about 60% to 70%
of people with diabetes present some form of neuropathy that can induce numbness, weakness and blood pressure dysregulation. In
addition, diabetic nephropathy is the leading cause of chronic kidney disease and affects about 30% of T1D patients. Diabetes
can also cause severe heart complications and adults with diabetes are two to four times more likely to die from heart disease
than adults without diabetes.
In
summary, people with T1D experience substantial morbidity and mortality owing to chronic complications.
Current
T1D Treatment Options and Their Limitations
So
far, no disease-modifying or curative treatment exists for T1D. Patients with T1D still need to use daily insulin injections to
manage blood sugar to within a normal range. However, it is estimated that fewer than one-third of people with T1D in the United
States achieve target blood glucose levels and insulin injections often cause hypoglycemia (low blood sugar). While insulin injections
or infusion allow a person with T1D to stay alive, they do not cure the disease, nor do they necessarily reduce the risk of serious
effects and long-term complications of T1D.
While
pancreatic and islet cell transplantation offer the ability to normalize glucose levels and remove the dependence on insulin products,
there are significant risks, resulting in a modest number of such transplants being conducted every year. There is risk associated
with mandatory immunosuppression, which commonly results in the development of infections that may be life-threatening. Furthermore,
pancreas transplantation may be associated with technical complications (vascular thrombosis, pancreatitis, infection, fistulas)
as well as acute and chronic organ rejection. Islet cell transplantation can provide better glycemic control and protect patients
from hypoglycemic episodes, but only approximately 50% of patients are insulin-free after three years of follow-up.
New
approaches are still required and could significantly enhance patient care. In particular, there is a strong need for new preventive
or curative treatments. Among the different possible strategies, primary prevention through vaccination and secondary prevention
(interception) with a disease-modifying non-chronic immune modulator seem to be the best candidates considering the potential
efficacy and safety balance that needs to be achieved.
Overview
of T1D Biology and teplizumab Mechanism of Action
T1D
is an autoimmune disease which occurs in genetically-predisposed individuals. Specialized white blood cells of our immune system,
known as self-reactive T cells (also called auto-reactive), are triggered, presumably by CVB viral infection of the beta cells
in at least 50% of cases, to attack and destroy beta cells of the pancreas, thus causing a decline in the natural production of
insulin. Simultaneously, another type of T cell, Tregs, which normally suppress the activity of self-reactive T cells, fail to
do so effectively.
The
clinical progression of T1D is relatively well understood and predictable, as it is a continuum marked by clinically-relevant
biomarkers which identify stages of the disease. In an individual with genetic risk (primarily driven by human leukocyte antigen
(“HLA”) haplotypes), the natural evolution of T1D has been described in stages (see figure below).
●
|
Stage
1: emergence of T1D-related autoantibodies which reflect the initiation of the autoimmune process; this stage is associated
with normoglycemia.
|
●
|
Stage
2: persistence T1D-related autoantibodies, but with further loss of beta cell function and development of dysglycemia.
|
●
|
Stage
3: symptomatic or clinical T1D, when remaining beta cell capacity is insufficient to maintain glucose metabolism.
|
Stages
of Type 1 Diabetes
It
is important to note that once subjects develop two or more T1D-related autoantibodies (Stage 1), the progression to clinical
T1D (Stage 3) is not a matter of “if” but “when” as greater than 95 percent of the Stage 1 subjects and
virtually all of the Stage 2 subjects will progress to Stage 3 necessitating insulin dependence. The progression of Stage 1 to
Stage 3 is 44% in five years, and of Stage 2 to Stage 3 is 75% in four to five years.
Current
Clinical Development Program
At-Risk
Individuals (Stage 2)
Phase
2 Clinical Trial of teplizumab in At Risk Relatives who develop T1D (At-Risk TN-10 Study)
In
June 2020, we announced that new data from the “At-Risk” TN-10 Study, presented by TrialNet at the 2020 American Diabetes
Association Scientific Sessions on June 15, 2020, which demonstrated that a single 14-day course of our lead drug candidate, teplizumab,
delayed the median onset of clinical T1D, as compared to placebo, by approximately three years in at-risk individuals. These
new data from the “At-Risk” TN-10 Study added approximately one year to the two-year median delay that was previously
observed.
The
“At-Risk” TN-10 Study, a pivotal Phase 2 clinical trial, conducted at TrialNet sites and sponsored by National Institute
of Diabetes and Digestive and Kidney Diseases (“NIDDK”), part of the National Institute of Health (“NIH”),
evaluated teplizumab for the delay of clinical T1D in at-risk individuals. At-risk was defined by the presence of two or more
T1D-related autoantibodies and dysglycemia (abnormal glucose metabolism). Seventy-six subjects were enrolled, ages eight to 49,
with 72 percent under the age of 18, and randomized to receive a single course of either teplizumab or placebo. Subjects were
followed in a blinded fashion until a minimum 40 subjects developed clinical T1D which triggered the analysis of the primary endpoint,
and then indefinitely in other TrialNet studies after this time. Those who developed clinical T1D after the primary analysis was
completed are eligible to enroll in a Provention trial which we initiated in March 2020, described below.
The
trial results showed the median time to clinical
diagnosis of T1D after one course of teplizumab was approximately five years (59.6 months) (an improvement of 12 months from previously
published data) compared to approximately two years (27.1 months) for the placebo group (24.9 months in previously published data).
Nearly half of those treated with teplizumab are estimated to be free of clinical T1D at five years. The hazard ratio was 0.457
or a 54 percent reduction in risk of developing clinical T1D (p=0.01).
In
addition, teplizumab treatment was associated with a greater on-study C-peptide (p=0.009), a measure of a persons’ own insulin
production, compared to placebo. For both groups, C-peptide area under the curve (“AUC”) mean slopes preceding study
entry were similar and declining. In the placebo group, this decline continued over the six months after study entry. By contrast,
the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.02 relative to study entry).
Mechanistically,
the association between the induction of partially exhausted CD8 T cells and the delay of clinical T1D conferred by teplizumab,
previously described in newly diagnosed T1D patients, was also confirmed in subjects at-risk. C-peptide levels at three, six and
18 months post-teplizumab administration correlated with the levels of exhausted CD8+ T cells in the peripheral blood (p=0.01
vs placebo). Subjects with the highest increase (top quartile) in exhausted CD8 T cells had no progression to clinical T1D in
the period of observation of the study (p=0.005 vs placebo). Finally, inflammatory cytokines IFN-gamma and TNF-alpha were lower
in the exhausted CD8 T cells in teplizumab vs placebo-treated subjects (p<0.0001).
In
summary, while no additional safety signals have been noted, the results showed that teplizumab’s effect on delaying the
onset of clinical T1D was not only consistent from previous analyses, but was durable and now extended to a median of approximately
three years (32.5 months). See below for further analysis.
Breakthrough
Therapy Designation (United States)
In
August 2019, the FDA granted breakthrough therapy designation to teplizumab for the delay or prevention of clinical T1D
in individuals at-risk of developing the disease. Breakthrough therapy designation is an FDA program designed to expedite
the development and review of therapeutic candidates intended to treat serious or life-threatening diseases.
PRIME
Eligibility (European Union)
In October 2019, the
EMA granted PRIority MEdicines (“PRIME”) eligibility to teplizumab for the prevention or delay of clinical T1D in individuals
at-risk of developing the disease. The PRIME initiative is designed to expedite the development and review of promising therapies
that target an unmet need and show potential clinical benefit so the medicine can reach patients earlier. The designation offers
the opportunity for enhanced interaction and dialogue with the EMA to optimize development, as well as the potential for accelerated
assessment at the time of application for a marketing authorization.
Phase
2 Clinical Trial of teplizumab in At Risk Relatives who develop T1D (TN-10 Extension)
We
initiated an open-label Phase 2 study in March 2020 to evaluate the safety of teplizumab in participants who were in the TN-10
trial and have subsequently developed clinical T1D after the conclusion of that trial. Eligible subjects will receive teplizumab
treatment within one year of their clinical T1D diagnosis. Participants will have a follow-up period of up to 78 weeks (18 months)
from the first dose of treatment. The study may enroll up to 30 participants and is currently enrolling.
Newly-Diagnosed
Patients (Stage 3)
Phase
3 Clinical Trial of teplizumab in Pediatric Patients Newly-Diagnosed T1D (PROTECT Study)
The
PROTECT study (PROvention T1D trial Evaluating C-peptide with Teplizumab) is a randomized,
double-blind, placebo-controlled, multicenter Phase 3 clinical trial in pediatric and adolescent patients (aged eight to 17 years)
that are newly-diagnosed with clinical T1D. Patients with minimum beta-cell cell function (C-peptide >0.2 pmol/mL) and within
six weeks of T1D diagnosis will receive two courses of teplizumab, six months apart. Each course will consist of 12 days of teplizumab
administered intravenously. The primary endpoint is the change in C-peptide at 18 months. Secondary endpoints including insulin
use, HbA1C levels, hypoglycemic events and safety will also be evaluated. The study is expected to enroll approximately 300 patients
with 2:1 randomization (200 active: 100 placebo) and enrollment commenced in the second quarter of 2019. We expect to complete
enrollment in the second half of 2021 and report top line results for the Phase 3 PROTECT study in mid-2023, subject to change
for any potential COVID-19 related or other interruptions.
In
March 2020, we announced a temporary pause in the randomization of patients with newly diagnosed T1D into our global Phase 3 PROTECT
study of teplizumab. This pause was taken to protect patients, caregivers, clinical site staff, company employees and contractors
as part of the collective global efforts to combat the COVID-19 pandemic. Patients that were undergoing study therapy were allowed
to complete their course, as recommended by the PROTECT study’s Data Safety Monitoring Board, which was expanded to include
infectious disease expertise. In June 2020, we resumed enrollment on a country by country, site by site basis based upon review
of local COVID-19 infection rates and the site’s ability to maintain the safety of participants.
We
are also conducting an extension study of the PROTECT trial, PROTECT Extension. The purpose of this study is to evaluate the long-term
safety profile of PROTECT study patients who received a 12-day course of teplizumab treatment upon T1D diagnosis and a second
12-day course of teplizumab treatment approximately six months later. The extension study will provide a total of 5-year safety
data from the initiation of treatment for the participants in the PROTECT Study.
We
believe that combination therapy may enhance the potential therapeutic benefit of teplizumab by increasing efficacy, enhancing
the durability of response, or restoring insulin production by beta cells. Combination therapies may include beta-cell transplant
and beta cell antigens, tolerogenic cytokines, other immune modulators which could enhance the removal of self-reactive lymphocytes
or increase the function of Tregs, or metabolic agents that could further improve or preserve beta cell function or mass. We are
collaborating with Precigen (formerly Intrexon) and its subsidiary, ActoBio Therapeutics, to explore the combination of teplizumab
and the oral administration of a Lactococcus lactis strain genetically engineered to secrete human proinsulin and human
interleukin-10, an anti-inflammatory cytokine. We plan to explore other combination therapies as the Phase 3 program progresses.
Prior
Clinical Evaluation of teplizumab
To
date, clinical development of teplizumab has included both academic and biopharmaceutical sponsors. Approximately 1,100
subjects have been enrolled in teplizumab clinical trials, with over 800 subjects receiving teplizumab. These studies
represent various doses, formulations, and indications and includes earlier smaller investigator-sponsored studies. The majority
of patients were enrolled in T1D studies (>1,000), and the rest in renal or renal-pancreatic allograft rejection, pancreatic
islet transplant, psoriatic arthritis or plaque psoriasis trials.
In
T1D patients, ten studies have been conducted, of which nine involved intravenous dosing (two Phase 1, three Phase 2, two Phase
3 and a Phase 3 extension study) and one subcutaneous dosing (Phase 1).
Among
the T1D studies of teplizumab:
|
●
|
In
Stage 2, the At-Risk study enrolled Stage 2 individuals who were characterized as having at least two T1D autoantibodies and
evidence of hyperglycemia
|
|
●
|
In
Stage 3, five studies (Study 1, Study 2, Study 3, Study 4 “AbATE”, and Study 5 “Delay”) were completed
under the direction of Dr. Kevan Herold (currently at Yale University) and collaborators. Studies 2, 3 and 4 were sponsored
by the Immune Tolerance Network. Four additional studies were conducted by MacroGenics: three with intravenous administration
(“Protégé”, “Protégé Extension”, and “Protégé Encore”)
and one with subcutaneous administration (SUBCUE) of teplizumab. Among these studies, “Protégé”
and “Protégé Encore” were Phase 3 studies. Protégé was the largest completed study
for treatment of T1D, which enrolled 516 patients (aged eight to 35 years and T1D diagnosis within 12 weeks of study entry)
and randomized into three teplizumab dosing regimens compared to placebo. Teplizumab showed promising immunological
and clinical activities in these studies and was well tolerated. In particular, teplizumab treatment showed promising
data on the preservation of C-peptide levels and the reduction of exogenous insulin use.
|
Stage
2 Program
Stage
2: At-Risk TN-10 Study
The
At-Risk TN-10 study was developed and conducted by Type 1 Diabetes TrialNet, funded by the National Institutes of Health, the
American Diabetes Association, or the ADA, and the Juvenile Diabetes Research Foundation. The objective of the study was to determine
whether treatment of at-risk subjects with teplizumab results in a delay or prevention of clinical T1D in patients at-risk, i.e.,
with pre-symptomatic Stage 2 T1D. The primary endpoint was completed in 2018. The study was conducted in 18 sites in the United
States, Canada and Germany.
Participants
over eight years of age with Stage 2 T1D (presence of at least two T1D autoantibodies and dysglycemia, who were non-diabetic relatives
of T1D individuals) were randomized 1:1 to receive teplizumab or placebo. Dysglycemia was defined on oral glucose tolerance test
(“OGTT”) as: (a) Fasting plasma glucose ≥ 110mg/dL, and <126mgdL, or (b) 2-hour plasma glucose ≥140mg/dL,
and <200mg/dL, or (c) 30, 60, or 90-minute value on OGTT ≥200mg/dL.
The
primary endpoint was the time from randomization to the clinical diagnosis of diabetes, using ADA criteria. Criteria for clinical
T1D diagnosis are based on glucose testing, or the presence of unequivocal hyperglycemia with acute metabolic decompensation (diabetic
ketoacidosis). One of the following criteria must be met on two occasions as soon as possible but no less than one day apart for
diabetes to be defined:
|
●
|
Symptoms
of diabetes plus casual plasma glucose concentration > 200 mg/dL (11.1 mmol/l). Casual is defined as any time of day without
regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.
|
|
●
|
Fasting
plasma glucose ≥ 126 mg/dL (7 mmol/l). Fasting is defined as no caloric intake for at least eight hours.
|
|
●
|
2-hour
plasma glucose ≥ 200 mg/dL (11.1 mmol/l). The test should be performed using a glucose load containing the equivalent of
1.75g/kg body weight to a maximum of 75 g anhydrous glucose dissolved in water.
|
Teplizumab
was administered over a 14-day course: 51 μg/m2, 103 μg/m2, 207 μg/m2, and 413 μg/m2 on study days 0–3, respectively,
and 826 μg/m2 on each of study days four through 13. A total of 112 participants were screened and 76 were randomized, 44 to
teplizumab and 32 to placebo. The baseline characteristics were balanced for age (median ~13-14 years of age), relationship to
the relative with T1D, type of T1D autoantibodies and HbA1c.
At-Risk
TN-10 Study– Primary Data Readout in June 2019
Treatment
with a single course of teplizumab delayed the time to T1D (see figure below): 19 of the 44 (43%) teplizumab-treated and 23 of
the 32 (72%) placebo-treated participants were diagnosed with T1D. The annualized rates of T1D development were 14.9% and 35.9%
per year, for the teplizumab and placebo groups, respectively. The median time to T1D was 24.4 months in the placebo and 48.4
months in the teplizumab groups (hazard ratio = 0.412 (95% CI: 0.216, 0.783) p=0.006 (2-sided)).
Time
to T1D
In
pre-specified analyses, the effects of teplizumab on the primary outcome based on baseline characteristics were evaluated. Although
subgroup analyses had small sample sizes and need to be taken with caution, participants without anti-ZnT8 antibodies showed a
greater effect size compared to those who did not have the antibody. The presence of HLA-DR4 and absence of HLA-DR3
were also associated with greater effect size, as was a below median C-peptide response to the OGTT at baseline (1.75 nmol/L).
These larger effect sizes are attributed to more rapid progression of the disease in these subgroups, rather than clinically-actionable
baseline characteristics able to predict response to teplizumab. We believe all patients with Stage 2 T1D can benefit from teplizumab
as long as they have beta cells to be protected.
Teplizumab
treatment was associated with few adverse events, described in the table below. Similar to previous studies with teplizumab in
newly-diagnosed T1D patients, the lymphocyte count declined to a nadir on day five by 72.3% (IQR 82.1, 68.4%) (p<0.0001). The
transient lymphopenia is believed to be the mechanistic consequence of margination (adhesion to the blood vessel wall) rather
than depletion. Fifteen (34.1%) of the grade 3 events in the teplizumab group involved lymphopenia during the first 30 days after
study drug administration. The lymphocyte counts recovered quickly: Lymphopenia resolved in all participants by day 45 except
in one, whose counts returned on day 105. A spontaneously resolving rash, as previously noted, occurred in 36% of drug treated
participants. The rates of infection were similar in the two treatment arms. The adverse events below were determined to be possibly,
probably or definitely related to the study drug.
Adverse
Events
Adverse
Effect Category
|
|
Teplizumab
|
|
Placebo
|
|
|
No.
of Events
|
|
No.
of Subjects (%)
|
|
No.
of Events
|
|
No.
of Subjects (%)
|
Blood/Bone
Marrow***
|
|
45
|
|
33
(75)
|
|
2
|
|
2
(6.2)
|
Dermatology/Skin***
|
|
17
|
|
16
(36.4)
|
|
1
|
|
1
(3.1)
|
Pain
|
|
11
|
|
5
(11.4)
|
|
5
|
|
3
(9.4)
|
Infection
|
|
8
|
|
5
(11.4)
|
|
5
|
|
3
(9.4)
|
Gastrointestinal
|
|
5
|
|
4
(9.1)
|
|
3
|
|
3
(9.4)
|
Metabolic/Laboratory
|
|
7
|
|
4
(9.1)
|
|
2
|
|
2
(6.2)
|
Pulmonary/Upper
Respiratory
|
|
6
|
|
4
(9.1
|
|
0
|
|
0
(0)
|
Constitutional
Symptoms
|
|
3
|
|
2
(4.5)
|
|
0
|
|
0
(0)
|
Allergy/Immunology
|
|
2
|
|
2
(4.5)
|
|
0
|
|
0
(0)
|
Cardiac
General
|
|
1
|
|
1
(2.3)
|
|
1
|
|
1
(3.1)
|
Endocrine
|
|
0
|
|
0
(0)
|
|
2
|
|
2
(6.2)
|
Vascular
|
|
1
|
|
1
(2.3)
|
|
1
|
|
1
(3.1)
|
Neurology
|
|
1
|
|
1
(2.3)
|
|
0
|
|
0
(0)
|
Ocular/Visual
|
|
1
|
|
1
(2.3)
|
|
0
|
|
0
(0)
|
Musculoskeletal/Soft
Tissue
|
|
2
|
|
1
(2.3)
|
|
0
|
|
0
(0)
|
Hepatobiliary/Pancreas
|
|
0
|
|
0
(0)
|
|
1
|
|
1
(3.1)
|
Syndromes
|
|
1
|
|
1
(2.3)
|
|
0
|
|
0
(0)
|
Hemorrhage/Bleeding
|
|
1
|
|
1
(2.3)
|
|
0
|
|
0
(0)
|
Total
Events and Subjects
|
|
112
|
|
44
(100)
|
|
23
|
|
32
(100)
|
***
p < 0.001 Teplizumab vs placebo
Other
anti-CD3 mAb experimental treatments, such as otelixizumab, have been associated with Epstein Barr virus (“EBV”),
clinical reactivation in patients with latent infection. At entry, 30 participants (39%) (16 teplizumab and 14 placebo) had antibodies
against EBV in TN-10. At weeks 3-6 after study drug treatment, there was quantifiable EBV DNA in whole blood in eight of the seropositive
participants – all in the teplizumab group, one of whom had symptoms of pharyngitis, rhinorrhea, and cough on day 38. In
these participants, the EBV DNA levels were below the level of quantification between day 43 and 134 (average 77 days). At entry,
17 participants (ten teplizumab and seven placebo) had antibodies against cytomegalovirus (“CMV”). One teplizumab
participant, who was CMV seropositive, had detectable levels of CMV DNA at day 20 that was undetectable by day 42. These results
show that, while viral reactivation may be observed during the first weeks post-teplizumab administration, these are typically
asymptomatic and that immune competence is maintained that results in the resolution of viremia.
The
TN-10 trial results demonstrate that a single course of teplizumab significantly delayed the progression to clinical T1D in high-risk
Stage 2 relatives who had at least two autoantibodies and dysglycemia. The median delay in the diagnosis of diabetes was approximately
two years, and at the conclusion of the trial, the frequency of diabetes-free subjects was double in the drug (57%) vs placebo-treated
subjects (28%). The relatively rapid rate of progression to clinical diabetes in the placebo group, consistent with the previously
reported natural history, reflects the very high risk of these individuals and reflects the inevitability of progression from
Stage 2 to Stage 3 disease, consistent with observations of high rates of beta cell killing in these subjects. The rapid development
of clinical T1D may also reflect the enrichment of pediatric participants (72.4%) in whom the rate of progression is rapid. The
safety profile was consistent with previous experience and teplizumab was well-tolerated.
At-Risk
TN-10 Study – June 2020 Data Update
After
the primary readout in the TN-10 study, patients were followed indefinitely in other TrialNet observational studies. On June 15,
2020, we announced that new data from the TN-10 study was presented on that date by TrialNet at the 2020 American Diabetes Association
Annual meeting. These follow-up data demonstrated that the single 14-day course of teplizumab had delayed the onset of clinical
T1D, as compared to placebo, by a median of approximately three years in at-risk individuals. In other words, the follow-up data
from the TN-10 added approximately one year to the two-year median delay that was previously observed and reported in the primary
analysis. The median time to clinical diagnosis of T1D after one course of teplizumab was approximately five years compared to
approximately two years for the placebo group (unchanged from previously published data). Nearly half of those treated with teplizumab
are estimated to be free of clinical T1D at five years. The hazard ratio was 0.457 or a 54 percent reduction in risk of developing
clinical T1D (p=0.01).
In
addition, teplizumab treatment was associated with a greater on-study C-peptide (p=0.009), a measure of a persons’ own insulin
production, compared to placebo. For both groups, C-peptide AUC mean slopes preceding study
entry were similar and declining. In the placebo group, this decline continued over the six months after study entry. By contrast,
the teplizumab-treated group showed an increased C-peptide AUC over this period (p=0.02 relative to study entry).
Note:
Adapted from presentation 277-OR at ADA 2020 (Sims et al, June 15, 2020).
Mechanistically,
the association between the expansion of partially exhausted CD8 T cells and the delay of clinical T1D conferred by teplizumab,
previously described in newly diagnosed T1D patients, was also confirmed in subjects at-risk. C-peptide levels at three, six and
18 months post-teplizumab administration correlated with the levels of exhausted CD8+ T cells in the circulation (p=0.01 vs placebo).
Subjects with the highest increase (top quartile) in exhausted CD8 T cells at 3 months post-teplizumab had no progression to clinical
T1D in the period of observation of the study (p=0.005 vs placebo). Finally, inflammatory cytokines IFN-gamma and TNF-alpha were
lower in the exhausted CD8 T cells in teplizumab vs placebo-treated subjects (p<0.0001).
In
summary, the follow-up results showed that teplizumab’s effect on delaying the onset of clinical T1D was not only consistent
from previous analyses, but was durable and now extended the median delay to approximately three years, without any additional
safety signals noted.
Stage
3 Program
Protégé
Study
Protégé
was a randomized, controlled Phase 3 clinical trial conducted in 83 centers in North America (U.S., Canada, Mexico), India, Israel,
and Europe (Czech Republic, Estonia, Germany, Latvia, Poland, Romania, Spain, Sweden, Ukraine) completed between 2007 and 2011.
Patients aged eight to 35 years with recently diagnosed T1D (≤12 weeks) were followed for 12 months (Protégé)
and continued to 24 months (Protégé Extension). Three dose regimens of teplizumab were administered to 417
patients as intravenous infusions for six to 14 days; 99 patients received placebo. At 12 months, the primary efficacy endpoint,
the proportion of patients with insulin use <0.5 U/kg per day and HbA1c <6.5%, ranged from 13.7% to 20.8% patients in the
teplizumab groups, depending on dosing regimen, and 20.4% in the placebo group. The difference between teplizumab-treated
patients and placebo-treated patients was not significant. The change in HbA1c from baseline also did not show a significant
difference between teplizumab and placebo. However, subgroup analyses indicated the following findings:
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We
believe that the primary endpoint could have been achieved if cut-offs were changed to insulin use of <0.25 U/kg per day
and HbA1c <7.0%, not only at 12 months but also at 24 months (figure below).
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C-peptide
levels significantly improved in the teplizumab group compared with placebo group
in all patients, and further analyses indicated that this difference was more pronounced
in younger patients (aged eight to 11 years) and patients enrolled in United States sites.
These findings are consistent with other clinical trials, showing a stronger effect in
T1D patients who are younger (<17 years), more recently diagnosed (<10 weeks),
and with higher C-peptide levels at baseline.
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Protégé
Encore Study
Protégé
Encore was a randomized, controlled Phase 3 clinical trial conducted in 125 centers in 16 countries completed between 2009 and
2012. Patients aged eight to 35 years with recently diagnosed T1D were to be followed for 24 months. Three dose regimens of teplizumab,
given as intravenous infusions for six to 14 days, were compared with placebo. The primary endpoint, the proportion of patients
with insulin use <0.5 U/kg per day and HbA1c <6.5% at 12 months, was not met. Study enrollment was stopped at 254 patients
(400 planned) when the Protégé study showed that the primary endpoint was not met. Efficacy analyses were not conducted
in this study.
A
summary of the C-peptide data in the completed Phase 2 clinical trials and Phase 3 Protégé study are shown in the
table below. All these studies have shown consistent and significant C-peptide benefit. Furthermore, subgroup analysis of the
Protégé data indicated that younger patients (aged eight to 17 years) with minimum baseline beta cell function (C-peptide
>0.2 pmol/mL) along with even more robust data in newly-diagnosed T1D (diagnosis under six weeks, Study 1), informed the inclusion
criteria that will be applied in our planned Phase 3 study, PROTECT.
*
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Full
9.0 mg/m2/course 14-Day regimen was explored in 205 treated patients and 98 placebos;
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Delay
study based on 12-month time-point. All other studies based on 24-month time-points
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SUBCUE
Study
SUBCUE
was a randomized, controlled Phase 1 clinical trial to evaluate the safety and tolerability, pharmacokinetic (“PK”),
and pharmacodynamics (“PD”) of subcutaneously injected teplizumab conducted between 2010 and 2011. Patients
aged 18 to 35 years who were diagnosed with T1D within 12 months were to be given three dosing regimens of teplizumab or
placebo. Patients were to be followed for 91 days. However, the study was stopped after one subject was enrolled, upon the Protégé
study results.
Safety
Data
Teplizumab safety
data in T1D subjects have been analyzed from five clinical studies with similar study characteristics including a randomized controlled
design and testing the proposed cumulative dose of 9034 µg/m2 (~9.0 mg/m2) per treatment course. Four
of these studies enrolled subjects with newly diagnosed Stage 3 clinical T1D (two Phase 2 studies, AbATE and Delay,
and two Phase 3 studies, Protégé and Encore). One of these trials enrolled Stage 2 subjects in
the At-risk (TN-10) study. The safety summary provided below pools data from the four Stage 3 clinical studies and a separate
summary for the Stage 2, At-risk study (TN-10).
In
Stage 3 teplizumab and placebo subjects, there were no major differences in the overall adverse events (“AEs”)
(99.6% and 99.1%), and serious adverse events (“SAEs”) (12.2% (91 of 729 subjects), and 8.9% (19 out of 213 subjects),
although there were more severe AEs in teplizumab subjects (59% and 25%). In At-risk Stage 2 subjects, there was a higher
incidence of AEs, SAEs, and severe AEs in the teplizumab subjects compared with placebo (AEs: 97.7% and 68.8%, SAEs: 15.9%
(7 of 44 subjects) and 3.1% (1 of 32 subjects), and severe AEs: 59.1% and 9.4%).
The most common AEs were
related to decreases in white blood cells (lymphopenia, leukopenia and neutropenia) as well as rash. Lymphopenia was expected
based on the mechanism of action of teplizumab and was observed in approximately 80% of Stage 3 and 73% of Stage 2 T1D
subjects who received teplizumab compared with approximately 18% of Stage 3 and 6% of Stage 2 subjects who received placebo.
Lymphopenia was commonly mild to moderate and resolved within 14 days. In Stage 3 T1D subjects, approximately 36% and 12% of teplizumab
- and placebo-treated subjects, respectively, reported rash. In Stage 2 TID subjects, approximately 14% and 0% of teplizumab-
and placebo-treated subjects, respectively, reported rash. In teplizumab-treated patients, the rash was predominantly mild
to moderate and usually resolved within one to two weeks. Laboratory abnormalities were also reported as AEs. The main differences
in incidence in teplizumab and placebo subjects were related to liver function tests. For example, increased alanine aminotransferase
occurred in 27.8% and 12.7% of Stage 3 teplizumab and placebo subjects and 4.5% and 3.1% of Stage 2 teplizumab and
placebo subjects. These transaminase elevations were likely due to cytokine effects on the liver, usually resolved within 14 days
of dose completion, and did not cause significant or lasting clinical concern. Cytokine release syndrome, which may include symptoms
of rash, headache, nausea, vomiting, and chills/fever, occurred in 6% and 1.4% of teplizumab- and placebo-treated Stage
3 subjects and 2.3% and 0% of teplizumab- and placebo-treated Stage 2 subjects. Cytokine release syndrome was predominantly
mild to moderate in severity, and in the majority of subjects (~80%), the treatment course was completed.
In both Stage 3 and Stage
2 subjects, a total of 118 subjects (98 teplizumab (12.4%), 20 control (8.2%)) experienced 1 or more SAEs for a
total of 167 SAEs. The majority, 76.7%, (128 out of 167) of SAEs were not considered treatment-related, while 23.4% (39 out of
167) were deemed related.
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In
Stage 3 subjects, 110 of 729 total participants (91 teplizumab (12.2%), 19 control
(8.8%)) reported at total of 158 SAEs. The most common SAEs were related to diabetes
control including diabetic ketoacidosis, hypoglycemic seizures/unconsciousness, hyperglycemia,
hypoglycemia (consistent with the underlying disorder) and were reported in 4.9% and
2.3% of Stage 3 teplizumab and placebo subjects, respectively. These events did
not occur in any Stage 2 subjects.
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In
Stage 2 subjects, 8 of 76 total participants (7 of 44 teplizumab (15.9%), 1 of
32 controls (3.1%)) reported a total of 9 SAEs during the study. Of the 8 SAEs
reported in teplizumab subjects, 4 were infections (pneumonia, cellulitis, wound
infection, and gastroenteritis). Two of the 8 SAEs reported in teplizumab subjects
were considered by the investigators to be related to study treatment and included serum
sickness and pneumonia.
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Three
deaths were observed in Stage 3 subjects and categorized by the principal investigator (in accordance with International Conference
on Harmonisation/Good Clinical Practice guidelines) and included in the Investigator Brochure for teplizumab filed with
the FDA. The relationship between each death and teplizumab is listed in the Investigator Brochure as follows: one death,
“none”; one death “not related”; and one death “unlikely.” The specific causes of deaths were
(1) unknown for subject with gastrointestinal symptoms which the relationship was listed as “none” in the Investigator
Brochure, (2) anterior myocardial infarction with ventricular tachycardia and cardio-respiratory arrest for which the relationship
was listed as “not related” in the Investigator Brochure and (3) diabetic ketoacidosis for which the relationship
was listed as “unlikely” in the Investigator Brochure. No deaths were reported in Stage 2 subjects.
The most common severe
AE occurring in at least 10% of Stage 3 subjects was lymphopenia observed in 43.6% (326 out of 729 subjects) and 5.2% (11 out
of 213 subjects) of teplizumab and placebo subjects, respectively. In Stage 2 subjects, lymphopenia was also the most frequently
observed severe AE, occurring in 47.5% (21of 44 subjects) teplizumab-treated subjects but none of the placebo subjects.
This AE is consistent with the mechanism of action of teplizumab.
Overall,
in both Stage 3 and Stage 2 subjects, infections were reported in comparable rates between teplizumab and controls (53.0% vs 52.7%)
with the most common infections reported involving upper respiratory infections (19.0% vs 17.6%), nasopharyngitis (11.1% vs 9.4%)
and pharyngitis (5.1% vs 4.5%). The rate of primary EBV infections does not appear to be increased with teplizumab (1.9% vs 3.6%).
While there were more cases of EBV reactivation with teplizumab (3.9% vs 1.2%), they were asymptomatic in the majority
of subjects and were associated with transient viremia.
The
safety profile of teplizumab in the at-risk population (Stage 2 T1D), appeared to be comparable with those of newly diagnosed
patients (Stage 3 T1D). No new safety signals were identified. The majority of the adverse events were mild to moderate and were
transient and manageable.
Phase
2 Clinical Trial of teplizumab in combination with AG019 in newly diagnosed T1D patients
This
is a Phase 1b/2a clinical trial being conducted in collaboration with Precigen exploring the combination of teplizumab with Precigen’s
AG019 in participants with recent-onset T1D. AG019 is a capsule consisting of engineered Lactococcus lactis specifically modified
to deliver human proinsulin and the tolerance-enhancing cytokine human interleukin-10 to the mucosal lining of the gastro-intestinal
tissues. The primary objective of the study is to assess the safety and tolerability of different doses of AG019 alone as well
as AG019 in association with teplizumab. The secondary objectives of this study are: to obtain PD data of AG019 alone as well
as AG019 in association with teplizumab; and PK data to determine the potential presence of AG019 in systemic circulation (safety
- systemic exposure) and the presence of L. lactis bacteria in fecal excretion (local exposure). The study will enroll 48 participants
and will be conducted in two phases:
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Phase
1b: open-label part of the study which will investigate the safety and tolerability of two different doses of AG019 in two
age groups (18 to 40 years of age and 12 to 17 years of age).
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Phase
2a: randomized, double-blind part of the study which will investigate the safety and tolerability of AG019, in association
with teplizumab, in two age groups (18 to 40 years of age and 12 to 17 years of age).
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The
study commenced in October 2018 and is currently enrolling the Phase 2a. In January 2021, Precigen presented the following positive
interim data from the Phase 1b (monotherapy) and Phase 2a (combination) arms of the study:
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AG019
monotherapy as well as the combination of AG019 and teplizumab were well-tolerated and safe.
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58%
(7/12) and 70% (7/10) adult showed insulin C-peptide stabilization at 6-months in monotherapy and combination arms, respectively.
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Increase
in pre-proinsulin (PPI) - specific Type 1 regulatory (Tr1) cells in both monotherapy and combination arms.
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Significant
decrease in PPI-specific CD8+ T cells in both monotherapy and combination arms.
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PRV-101
(CVB Vaccine) for Acute Infection and T1D
PRV-101
is a polyvalent (more than one strain) prophylactic CVB vaccine intended to prevent acute CVB infection and the development of
CVB-induced T1D and celiac autoimmunity. Based on epidemiological and pre-clinical study data to date, we believe that, if successful,
PRV-101 may prevent up to 50% of T1D cases and up to 20% of celiac cases. Preclinical studies completed to date by Vactech and
replicated independently by us demonstrate that CVB triggers diabetes in animal models of T1D and that vaccination against CVB
protects mice from acute infection as well as prevents the onset of diabetes triggered by CVB infection.
Current
Clinical Development Program
First
in Human Phase 1 Clinical Trial of PRV-101 (PROVENT Study)
In
December 2020, we announced the initiation of the PROVENT (PROtocol for coxsackievirus VaccinE in healthy voluNTeers) study, a
first-in-human study of PRV-101 for the prevention of acute CVB infection and the potential delay or prevention of T1D and celiac disease.
PROVENT
is a placebo-controlled, double-blind, randomized first-in-human study being conducted at the Clinical Research Services Turku
- CRST Oy, a clinical trial unit in Turku, Finland. The study’s primary endpoint is the safety of two dose levels of PRV-101
in healthy adult volunteers provided three administrations with 4-week intervals. Tolerability and immunogenicity will also be
evaluated. The primary objective of this first-in-human (“FIH”) clinical trial is to evaluate the safety and tolerability
of multiple doses of PRV-101 administered at two different dose levels. A secondary objective is to evaluate the immunogenicity
of PRV-101 (ability to elicit antibodies, including neutralizing antibodies, against CVB). Results of PROVENT are expected in
the fourth quarter of 2021.
CVB
Infection Market
Enteroviruses
are responsible for an estimated ten to 15 million symptomatic infections in the United States annually. CVB contributes to a
major part of the healthcare costs of enteroviruses as they cause the most serious complications and are among the most frequently
reported enteroviral infections according to the CDC. Acute CVB infection is usually asymptomatic or causes common cold-type symptoms.
It often also leads to a febrile illness associated by rash, hand-foot-mouth disease and/or mild GI distress. However, CVB infections
also cause more severe manifestations including pericarditis, myocarditis, meningitis and pancreatitis.
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Myocarditis:
CVB is the most common etiologic agents for myocarditis in the Western world, responsible for up to 33% of cases of
myocarditis. Myocarditis is an important cause of sudden unexpected death: the prevalence of myocarditis in children and adolescents
leading to sudden unexpected death has been reported to be as high as 8% to 42%. In certain individuals, acute myocarditis
progresses to chronic myocarditis and dilated cardiomyopathy, which is a severe life-threatening condition.
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Otitis
media: otitis media (middle ear inflammation) may develop in patients with upper respiratory disease caused by enterovirus.
Otitis media constitutes 18% of physician visits in the United States (largest single reason in children). The costs of otitis
media treatment in the United States were estimated to be approximately $3 billion in 2014.
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Meningitis:
CVB is a common cause of enteroviral meningitis. Meningitis beyond the neonatal period is characterized by the sudden
onset of fever of 38-40°C. Headache and photophobia are almost universally reported in these patients. Reports on the
incidence of viral meningitis vary from approximately 50,000 hospitalized cases to over 2 million cases of aseptic meningitis
per year. Based on 300,000 annual cases of aseptic meningitis in the United States (of which enteroviruses, and coxsackie
viruses in particular, are the most common cause), the economic impact is estimated to be $1.5 billion in direct costs alone.
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Overview
of CVB Infection of the Pancreas, T1D and PRV-101’s Mechanism of Action
Longitudinal
studies of more than 200,000 children studied for up to two decades in Finland by our technology licensor, Vactech, and its collaborators
(“DIPP Study”), identified CVB infection as a likely environmental trigger in the onset of T1D autoimmunity and T1D-associated
celiac disease (“CD”) autoimmunity. Subsequent full-virome analysis of the TEDDY Study (400,000 children international
study) confirmed that CVB is the only virus whose persistent infection is associated with the development of T1D and celiac disease
autoimmunity (T1D-associated and also independent of T1D).
CVB
infection is very common and is responsible for various symptoms and complications ranging from mild respiratory disease, gastrointestinal
disturbances and hand-foot-mouth disease to life-threatening cardiomyopathy and meningitis. However, in patients with a certain
genetic background, CVB appears responsible for the development of autoimmunity. The T1D association with CVB infection has been
observed in independent cohorts in 15 countries, including in North America, Europe and Australasia. These epidemiological observations
have been substantiated by biological experimentation. Insulin-producing beta cells in the pancreas express specialized receptors
associated with the transport, storage and release of insulin. These receptors appear to be used by CVB to preferentially infect
these cells and polymorphism in these receptors are associated with development of T1D autoimmunity. Infection by enteroviruses
can be detected in the pancreatic beta cells of approximately 60% of T1D patients and in the gut of most patients with T1D-associated
CD. Importantly, if mothers have anti-CVB immunity at the time of the pregnancy, a 50% reduction in the onset of T1D autoimmunity
(T1D-associated auto-antibodies) has been observed in their offspring, presumably due to protection by maternal antibodies passed
on to the fetus. This observation strongly suggests the potential efficacy of CVB vaccination for children and/or mothers, resulting
in the development of protective antibodies potentially capable of preventing or delaying the onset of T1D.
An
analysis of stool samples collected from these individuals identified enterovirus infections prior to the first detection of T1D
auto-antibodies. Enterovirus RNA was also detected in stool samples. Examination of antibodies present in DIPP children who developed
at least two islet cell auto-antibodies (sign of incipient T1D) and/or progressed to T1D confirmed that among all enteroviruses,
only CVB was significantly associated with initiation of beta cell autoimmunity.
Enterovirus
RNA in Blood is Linked to the Development of T1D
OR:
odd ratio; CI: confidence interval; EV: enterovirus
Preclinical
Evaluation PRV-101
Preclinical
Data for PRV-101
The
mechanism of action and efficacy of PRV-101 is supported by the results of several in vivo studies. Inactivated CVB-based viral
vaccines efficiently protect mice from CVB infections and from viral spread to the pancreas, as seen for CVB1 and CVB3 vaccines.
Similar experiments conducted with a vaccine covering all six CVB serotypes demonstrated that it can induce a strong neutralizing
anti-CVB response in mice and protect the animals against multiple CVB infections from the corresponding live viruses. Independent
experiments confirm that CVB infection can accelerate T1D onset in T1D susceptible NOD (Non-obese diabetic) or SOCS-1-Tg (suppressor
of cytokine signaling 1 transgenic) mice, suggesting that protection from CVB infection would therefore protect against T1D development.
This hypothesis has been confirmed in experiments conducted by the Karolinska Institute (Sweden) and the University of Tampere
(Finland), demonstrating that CVB1 and CVB3 vaccines produced by Provention indeed protected SOCS-1-Tg mice against T1D induced
by CVB1 and CVB3, respectively. These mice develop T1D after CVB infection as a consequence of a direct infection of insulin-producing
beta cells in the pancreas and the subsequent immune response against the beta cells, mimicking human T1D. A three-injection vaccination
course induced robust neutralizing antibody responses against CVB1/CVB3 and protected mice from both CVB1/CVB3 infection and CVB1/CVB3-driven
T1D. CVB1/CVB3 infection led to a loss of insulin-producing cells in unvaccinated mice, which also was prevented by the vaccine.
These data strongly supported the development of PRV-101 for the prevention of T1D in humans.
Formalin-Inactivated
CVB1 Vaccine is effective against CVB1-Induced T1D in a Mouse Model.
As
seen in the left panel below, CVB1 infection led to loss of insulin-producing cells, and this pathology was completely prevented
by the CVB1 vaccine (right panel). In this experiment, while 50% of unvaccinated mice develop T1D as a consequence of CVB1 infection,
all vaccinated mice were protected (not shown).
Important
from a safety point of view, the formalin-inactivated CVB1 vaccines did not cause any undesirable effects in the pancreas. There
was no vaccine-induced pancreatic pathological change, islet autoimmunity or diabetes in the vaccinated mice. Similar results
were obtained for Provention-manufactured CVB1 and CVB3 vaccines (not shown).
Finally,
maternal CVB infection during gestation in mice protects the offspring from CVB infection and subsequent T1D development, presumably
through transfer of specific antibodies from the mother to the fetus, corroborating previous findings in humans in the DIPP study
and further supporting the use of a prophylactic vaccine to protect against CVB-associated-T1D.
CTA-Enabling
Program to Support FIH Study
The
CVB vaccine toxicology program to date has consisted of Good Laboratory Practices (“GLP”) and non-GLP safety and immunogenicity
studies conducted in mice. These studies were designed to identify and characterize potential toxicities associated with PRV-101
treatment, including those arising from the immune responses induced by the product. They mirrored the administration regimen
that is now used in the PROVENT FIH study, and by the same route of administration.
Pharmacology
studies have also been conducted to determine the desired composition of the vaccine, leading to successful GMP manufacturing
of the final polyvalent vaccine for clinical trials.
PRV-3279
(Humanized CD32B x CD79B Dual Affinity Biologic for SLE and Other Autoimmune Diseases)
PRV-3279
is a humanized CD32B x CD79B dual affinity biologic in a new class of bispecific scaffold antibody-like molecules called DARTs.
It is designed to simultaneously bind to CD32B and CD79B on B cells. The simultaneous binding of both CD32B and CD79B triggers
CD32B-coupled immunoreceptor tyrosine-based inhibitory motif signaling, which leads to the suppression of B cells activated to
produce auto-antibodies, while not causing broad B cell depletion.
We
believe PRV-3279 may intercept the pathophysiology of SLE by preventing the production of auto-antibodies by abnormally active
B cells.
Current
Clinical/Preclinical Development Program
Phase
1b/2a clinical trial of PRV-3279 in Healthy Volunteers and Patients with Lupus
We
are conducting a two-part study in SLE, the PREVAIL (PRV-3279 EVAluation In Lupus) study. PREVAIL
is a randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to evaluate the safety, tolerability, PK, PD, and
immunogenicity of multiple ascending doses of PRV-3279 in 16 healthy adult volunteers (Part 1) and the efficacy of PRV-3279 in
patients with lupus (Part 2).
On
March 12, 2020, we announced positive top-line results from the Phase 1b portion of the PREVAIL study. PRV-3279 was well-tolerated,
with no serious adverse events, and as expected, did not deplete B cells and demonstrated profound and sustained binding to circulating
B lymphocytes, with reduction of circulating immunoglobulin M levels in a dose-proportional manner. While anti-drug antibody production
was observed at both dose levels tested, immunogenicity was found not to affect exposure, safety or pharmacodynamic parameters.
Data from PREVAIL-1 was presented at the American College of Rheumatology (ACR) conference in November 2020.
Based
on these results, we plan to commence the Phase 2a portion of the PREVAIL study in lupus patients in the second half of 2021.
Our
ultimate goal is to determine if PRV-3279 can intercept the pathophysiology of SLE by preventing the production of auto-antibodies
by abnormally active B cells. Part 2 will have a planned treatment duration of six months and endpoints will include lupus clinical
assessments and biomarker measurements. Clinical endpoints will include the Systemic Lupus Erythematosus Disease Activity Index
2000 (SLEDAI-2K), the British Isles Lupus Assessment Group score, urine protein to creatinine ratio, and daily glucocorticoid
use. Additional biomarkers will include urinary/renal markers (e.g., serum creatinine, estimated glomerular filtration rate) and
blood/circulating markers (e.g., auto-antibodies, complement (C3 and C4), B cell function/phenotype, including CD32B expression/response
relationship).
In
support of the clinical evaluation of PRV-3279 in lupus in PREVAIL-2, we and our partner, MacroGenics, studied the effect of PRV-3279
on B cells from lupus patients ex vivo. PRV-3279 was able to reduce the activation of these B cells similarly to its effects
on healthy volunteer B cells, regardless of the activity level of the lupus patients. These data were presented at the ACR conference
in November 2020.
Current
Preclinical Development Program
Preclinical
Studies for the Prevention of the Immunogenicity of Biotherapeutics Including Gene Therapy
We
believe that PRV-3279 has the potential to prevent or reduce the immunogenicity of biotherapeutics, including but not limited
to gene therapy vectors and transgenes (new proteins expressed as a result of the gene therapy).
As
the field of gene therapy advances, patients’ immune responses to the viral vectors and the transgene products remain a
key challenge negatively impacting the safety, efficacy and ability to deliver additional courses systemically. One of the current
mitigation strategies to overcome these immune responses is pharmacological modulation of the patients’ antibody immune
responses with the B cell depleting agent rituximab in combination with the immune-suppressive agent sirolimus. Prolonged use
of rituximab has been associated with certain adverse events. The use of PRV-3279, as a non-depleting B cell inhibitor, is a potential
strategy to address this unmet need in serious genetic diseases.
PRV-3279
has been shown to reduce B cell responses to viral antigens using an experimental vaccine challenge in Phase 1. In January 2021,
we announced positive pre-clinical data in a mouse model of gene therapy for Pompe disease. A PRV-3279 mouse surrogate was tested
in mice transgenic for human CD32B, which received gene therapy with an AAV vector AAV9 encoding for the enzyme GAA gene. Errors
in the GAA gene cause the serious human glycogen storage disease type II (Pompe disease).
In
the study, the PRV-3279 surrogate reduced anti-AAV9 vector antibody levels in a dose-dependent fashion. Anti-AAV9 antibodies have
been linked to reduced efficacy, safety concerns and the inability to re-dose patients, and thus, based on these and other study
data, we believe PRV-3279 co-administration with gene therapy products has the potential to improve the safety and efficacy of
this therapeutic modality. The PRV-3279 surrogate in combination with sirolimus increased skeletal muscle levels of GAA enzyme
expression. Consistent with prior results from clinical trials in healthy human subjects, the PRV-3279 surrogate decreased IgM
production and was well tolerated.
Based
on these data, we plan to look for opportunities to work with academic and industry experts to combine PRV-3279 with gene therapy
and other biotherapeutic products to further our mission of preventing and intercepting devastating immune-mediated conditions.
SLE
Market and Other Opportunities for PRV-3279
Sales
of therapies to treat SLE are expected to climb to nearly $3 billion by 2025-2027, approximately 7-8% annual growth from 2019.
This growth is driven primarily by treatments that target B cells belimumab, with a new indication in lupus nephritis in 2020,
and off-label use of rituximab - and the approval of new mechanisms (voclosporin for lupus nephritis, approved in January 2021,
and the expected approval of novel mechanisms such as Type I interferon inhibitors for SLE). The uptake of belimumab has been
driven largely by safety rather than substantial efficacy, supporting the unmet need and potential for novel and safe non-depleting
B cell therapies with greater efficacy.
In
addition to SLE, PRV-3279 has the potential to treat other B cell- and auto-antibody-driven autoimmune diseases. Such diseases
include multiple sclerosis and RA, where B cell therapies rituximab and recently approved ocrelizumab (Ocrevus) have sales in
excess of $1 billion. Several niche/orphan indications may also be explored, including T1D (potentially in combination with teplizumab),
Sjogren’s syndrome, vasculitis (e.g., polymyalgia rheumatica, giant cell arteritis, Behçets disease), myasthenia
gravis, pemphigus, neuromyelitis optica, anti-NMDA receptor encephalitis, Guillain-Barré syndrome, chronic inflammatory
demyelinating polyneuropathy, Grave’s ophthalmopathy, IgG4-related disease, and idiopathic thrombocytopenic purpura.
SLE
Background Information
SLE
is a chronic autoimmune disorder that can affect nearly every major organ system, causing inflammation, tissue injury, organ damage,
and in some patients, organ failure. The prognosis of SLE is highly variable in individual patients, often waxing and waning throughout
their lifetime. The natural history of SLE ranges from relatively benign disease to rapidly progressive and even fatal disease.
Comorbidities, such as infections, malignancies, hypertension, lipid disorders and diabetes increase the risk of disability and
death in patients with SLE. Organ systems commonly affected by SLE include the central nervous system, kidneys, gastrointestinal
system, mucous membranes, heart, skin, hematologic system, musculoskeletal system and lungs, with specific organ involvement defining
subsets of the disease (e.g., lupus nephritis). According to the Lupus Foundation of America, at least 1.5 million Americans are
afflicted by SLE and more than 16,000 new cases of lupus are reported annually. It is estimated that five million people throughout
the world suffer from some form of lupus. Lupus affects primarily women of childbearing age (15 to 44 years). However, men, children,
and teenagers can also develop lupus.
The
pathogenesis of SLE is characterized by an abnormal overactivation of B cells and subsequent pathologic production of auto-antibodies
(antibodies that attack one’s own cells and tissues). Uncontrolled activation of B cells is normally terminated when the
activating stimulus is exhausted and when a negative feedback loop is triggered by the engagement of an inhibitory Fc receptor
(“FcR”), known as FcgammaRIIb (“CD32B”). Mutations in the CD32B gene in humans are associated with an
increased likelihood of SLE, and reduced expression of CD32B is apparent in B cells from SLE patients. It is thought that activation
of this inhibitory pathway could ameliorate the overactive B cell-driven pathology of SLE and other autoimmune diseases. In addition,
the excess auto-antibodies produced bind to target antigens and form immune complexes.
When
the B cell receptor (“BCR”) (which is the “Y” shaped molecule, resembling an antibody in the figure below)
is bound and activated by an antigen, it initiates a cascade of biochemical changes necessary for the activation of the CD32B
inhibitory pathway, thus triggering the negative feedback loop. CD79B is a subunit of the BCR that plays a key role in this process
when it is close to CD32B. Therefore, if a pharmacologic treatment is to activate the CD32B inhibitory pathway, it also has to
simultaneously bind to CD79B. PRV-3279 (formerly MGD010), is a humanized CD32B x CD79B DART protein developed originally by MacroGenics
as a bi-specific therapy with these properties, and thus a potential treatment for SLE and other similar diseases. It is designed
to simultaneously bind to CD32B and CD79B on B cells.
PRV-3279
and related molecules have shown inhibitory effects on BCR-induced B cell proliferation and antibody secretion (including B cells
obtained from SLE patients) as well as beneficial effects in mouse models of autoimmunity. PRV-3279 is expected to boost the negative
feedback loop on B cells by robustly engaging the available CD32B and CD79B.
PRV-3279
has been studied in humans and was shown to be well tolerated. Proof of mechanism and PRV-3279’s inhibitory effect on antibody
immune responses were demonstrated in a Phase 1a single ascending dose study in healthy volunteers, including a cohort demonstrating
inhibition of the immunogenicity of the hepatitis A vaccine. Immunogenicity of PRV-3279 was also observed, but had no impact on
mechanistic effects, safety or pharmacokinetics, and decreased with increasing doses of PRV-3279, possibly a reflection of its
mechanism of action.
Our
ultimate goal is to determine if PRV-3279 can intercept the pathophysiology of SLE by preventing the production of auto-antibodies
by abnormally active B cells.
Current
Treatment Options for SLE and Their Limitations
The
treatment and management of SLE depends on disease severity and disease manifestations. Hydroxychloroquine plays a central role
in the long-term treatment of SLE and is the cornerstone of SLE therapy. Corticosteroids, nonsteroidal anti-inflammatory drugs
(NSAIDs), and immunosuppressive agents (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate, and mycophenolate mofetil)
have also been used in the treatment and management of SLE. These treatments are only modestly effective and present safety and/or
immune suppression concerns with prolonged use. The B cell-depleting antibody rituximab (Rituxan), while not approved for treatment
of SLE, appears to be beneficial in certain subsets of patients.
In
2011, the FDA approved belimumab (Benlysta), an antibody that targets B lymphocyte stimulator, for the treatment of mild to moderate
SLE in combination with standard therapy, providing additional clinical validation of the therapeutic benefit of B cell-targeted
therapy for autoimmune diseases. However, the modest therapeutic benefit of belimumab and delayed onset of disease intervention
indicate the need for additional therapeutic strategies to inhibit overactive B cells. We believe PRV-3279 can fulfill that requirement
and is uniquely differentiated to allow for rapid inhibition of activated B cells (potentially more effective than belimumab),
while sparing non-activated B cells from depletion or inactivation (potentially safer than rituximab).
In
December 2020 and January 2021, the FDA approved belimumab and voclosporin, respectively, for the treatment of lupus nephritis.
We will focus development of PRV-3279 in SLE.
Overview
of CD32B Biology and Relevance in Lupus
CD32B
is expressed widely on the surface of human B cells. In addition to its expression on B cells, CD32B is also expressed on other
immune cells such as dendritic cells, macrophages, neutrophils, and mast cells. It is a single-chain protein with a portion that
sits outside of the cell membrane, which can be bound by chemical signals.
CD32B
is the only known inhibitory FcR in the immune system. It plays an important role not only for innate and adaptive immune responses,
but also in the maintenance of immune tolerance and controlling autoimmunity. Mice deficient in CD32B have increased antibody
responses due in part to chronic B cell activation, and as a result, develop autoimmune disease similar to human SLE. In contrast,
B cell-specific overexpression of CD32B and cross-linking of CD32B with antibodies ameliorate the incidence and severity of lupus
in mouse lupus models. In humans, mutations and decreased expression of the CD32B gene are associated with an increased likelihood
of SLE. These results underscore the important role of CD32B in regulating the antibody immune response and suggest that drug-mediated
engagement of CD32B could provide therapeutic benefit in autoimmune diseases by dampening the effects of chronically activated
B cells and reducing the production of auto-antibodies. In particular, preventing the production of auto-antibodies could intercept
the disease course in lupus nephritis, a subtype of lupus driven by accumulation of auto-antibodies and immune complexes (a mass
of antibodies and other molecules) in the kidneys.
Consistently,
a monoclonal antibody anti-CD19 which binds CD32B with high affinity, XmAb5871 (Xencor), was shown in 2018 to be efficacious -albeit
missing the primary endpoint- in a Phase 2 lupus trial, particularly in patients with B cell biomarker signatures, providing indirect
validation for the potential of PRV-3279 in lupus. XmAb5871, which has shown thrombocytopenia (unlike PRV-3279, XmAb5871 binds
to CD32A, which is expressed on platelets), has not moved forward in development to date.
Mechanism
of Action of PRV-3279
PRV-3279
is in a new class of bispecific scaffold antibody-like molecules called DARTs. It is designed to simultaneously bind to CD32B
and CD79B on B cells. The simultaneous binding of both CD32B and CD79B triggers CD32B-coupled immunoreceptor tyrosine-based inhibitory
motif signaling, which leads to the suppression of B cells activated to produce auto-antibodies, while not causing broad B cell
depletion.
To
prolong its half-life in the body, PRV-3279 contains a human IgG1 Fc region (a specific antibody fragment) that is manipulated
to eliminate its effector function. As a molecule designed to inhibit immune responses, PRV-3279 does not activate any part of
the immune system either in the body or in laboratory tests. PRV-3279 also does not bind to platelets, a unique feature compared
to competing molecules targeting CD32B that are associated with toxicity due to binding to platelets (e.g., XmAb5871, an anti-CD19
mAb which binds to CD32 via the Fc fragment).
Prior
Preclinical Evaluation of PRV-3279
The
only nonhuman species that PRV-3279 binds to is chimpanzees. An initial non-GLP study with PRV-3279 in chimpanzees demonstrated
it to be well tolerated at all doses, with an assigned no observed-adverse-effect level (“NOAEL”), of 10 mg/kg.
Due
to the lack of target binding, chronic four-week and three-month repeat-dose GLP toxicology studies were performed using a surrogate
DART molecule similar to PRV-3279 that was designed to target human CD32B and mouse CD79B in a transgenic mouse line that expresses
human CD32B. A NOAEL at the highest dose of 50 mg/kg was assigned in the three-month study. We believe these studies, and our
regulatory interactions, support the advancement of PRV-3279 in long-term efficacy studies in humans, such as PREVAIL-2.
Prior
Clinical Evaluation and Proof of Mechanism for PRV-3279
To
date, there have been two clinical trials completed with PRV-3279. The first study was conducted at a single site in the U.S.,
from February 2015 to February 2017 and was a FIH, double-blind, placebo-controlled Phase 1a clinical trial to evaluate the safety,
tolerability, PK, PD, and immunogenicity of PRV-3279 in healthy adult volunteers.
A
total of 49 subjects were randomized; 12 received placebo and 37 received PRV-3279 intravenously at escalating doses from 0.1
mg/kg to 10 mg/kg in six cohorts. PRV-3279 was well tolerated over the range of doses, with only mild adverse events that resolved
quickly, including headache, somnolence (sleepiness), upper respiratory tract infection, folliculitis and night sweats. Target
binding and proof of mechanism were demonstrated by measuring functional B cell inhibition at doses of 1 mg/kg or higher, without
broader B cell activation or depletion observed.
Subsequently,
proof of mechanism was further confirmed in a dose escalation extension of the study in which single doses of PRV-3279 at 3 mg/kg
and 10 mg/kg (16 subjects) were compared with placebo (eight subjects) for the ability to affect B cell responses to a hepatitis
A vaccine, which was administered to participants who had no previous hepatitis A immunity, on day two of the study. At both doses,
PRV-3279 reduced the proportion of volunteers who generated an immune response against the vaccine, as well as the amount of antibody
they produced, in both cases as compared to placebo.
PRV-3279
exhibited an approximate half-life of seven days after a single dose. A majority (~86%) of study participants developed antibodies
against PRV-3279 (i.e., immunogenicity) after receiving the 3 mg/kg dose, but no detrimental effect was observed on the pharmacokinetics
of PRV-3279. The proportion of participants developing antibodies against PRV-3279 decreased with increasing dose (29% in the
10 mg/kg dose) and such antibodies did not occur in the multiple dose chimpanzee study, suggesting that PRV-3279 may limit its
own immunogenicity at therapeutic doses, which is consistent with its mechanism of action.
The
second study was the Phase 1b portion of the PREVAIL study, which was a double-blind, placebo-controlled, multiple ascending dose
study in 16 health volunteers described above.
PRV-015
(human anti-interleukin 15 mAb) for Non-Responsive Celiac Disease (NCRD)
PRV-015
is a fully human immunoglobulin (“IgG1
) mAb that binds to and inhibits pro-inflammatory cytokine interleukin
(IL-15), which has been identified as a major mediator in the pathophysiology of celiac disease. PRV-015 has emerged as a leading
candidate for the treatment of nonresponsive celiac disease, in which patients continue to have disease activity despite ongoing
gluten free diet (“GFD”).
PRV-015
has undergone clinical testing in approximately 250 subjects who have received PRV-015 across two Phase 1 (healthy volunteers
and psoriasis, rheumatoid arthritis (“RA”) and three Phase 2 clinical trials (celiac disease, RCD-II, RA).
No serious adverse events deemed related to PRV-015 were observed that would preclude further clinical development. Proof of mechanism
and/or proof of concept was demonstrated in RA, celiac disease and refractory celiac disease Type II. The effect of PRV-015 in
celiac disease was evidenced by reduction in inflammation and symptoms after a controlled gluten challenge in a Phase 2a clinical
trials with 63 celiac patients.
Celiac
Disease Market
There
is no approved drug for CD. The annual healthcare utilization by NRCD patients in 2013 was $18,206, for $4,796 in matched controls
due to the extra costs of uncontrolled CD investigations and treatment of complications. Given the large prevalence (15 to 20
million patients world-wide, 1% of the population in the Western world and 0.5% in Asia), and the unmet need (50% of patients
on GFD continue to suffer from disease activity due to contaminating gluten in the diet), NRCD is considered a substantial opportunity
for pharmaceutical development of an effective and well-tolerated adjunctive treatment to the GFD.
Current
Clinical Development Program
Phase
2b Clinical Trial of PRV-015 in Celiac Disease (PROACTIVE Study)
We
and our partner Amgen conducted chronic toxicology studies in 2019 and early 2020. In August 2020, we initiated the PROACTIVE
study (PROvention Amgen Celiac ProtecTIVE Study), a randomized, double-blind, placebo-controlled, parallel-group, multicenter
Phase 2 clinical trial in adult patients with NRCD. PRV-015 will be administered every two weeks via subcutaneous route for six
months. The hypothesis of this study is that PRV-015 will be superior to the GFD at intercepting the effects of contaminating
gluten exposure in celiac patients following a GFD, as measured by symptoms and objective signs of intestinal inflammation after
24 weeks of treatment. Approximately 220 subjects are planned to be enrolled. We expect to report top line results for the Phase
2b PROACTIVE study in 2022.
Celiac
Disease Background Information
Celiac
disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals. Approximately
1% of the western population is affected by celiac disease. This prevalence has been reported to be doubling every 20 years. Gluten
is ubiquitous in food and elicits autoimmune responses in celiac patients, with damage to the mucosal lining of the small intestine.
Celiac disease causes debilitating symptoms and serious medical complications, as the small bowel damage can lead to nutrient
malabsorption and results in a range of subsequent intestinal and extra-intestinal clinical manifestations. The stimulation of
intestinal lymphocytes for decades can lead to the development of lymphoma, with increased mortality.
Gluten
is the main protein present in some of the most common cereals (wheat, barley, rye). Modern diets are increasingly enriched with
gluten and it is also used as an additive in processed foods, cosmetics and oral medications. Gluten is also present in trace
amounts in foods labeled as “gluten-free”, as a tableting excipient, and in products such as toothpaste and lipstick.
As little as 50mg/day of gluten triggers the disease. A normal diet contains >10 g/day, 200 times the amount that causes damage
and intestinal histological abnormalities. As such, celiac patients face enormous challenges to follow a strict GFD.
The
pathophysiology of celiac disease is characterized by an abnormal immune response to gluten. Humans lack enzymes to fully digest
gluten, which against the right genetic background triggers inflammation and autoimmunity in the intestine and in other organs.
An adaptive immune response is triggered when gluten peptides are deamidated in the extracellular space, by the enzyme tissue
transglutaminase, normally an intracellular enzyme that is released by damaged cells. This deamidation renders gluten peptides
high-avidity binders to HLA-DQ2 and HLA-DQ8, which present these peptides to intestinal CD4+ T cells, thereby activating these
T cells and initiating the inflammatory cascade. The innate immune system’s intraepithelial lymphocytes (“IELs”),
primarily CD8+, are able to directly lyse and destroy intestinal epithelial cells, damaging the mucosal lining of the small intestine,
in response to IL-15 release stimulated by gluten peptides. In healthy individuals, the activated T cells are controlled by Tregs,
but this does not happen in celiac disease as IL-15 confers the effector CD4+ T cells resistance to suppression by Tregs.
Celiac
disease causes debilitating symptoms and serious medical complications. In many patients, gastrointestinal symptoms derived from
intestinal mucosal damage dominate the patient reported symptoms at diagnosis. The normal villi (absorptive finger-like prolongations)
present in the gut of healthy individuals are lost in active celiac disease as a result of mucosal atrophy and crypt enlargement.
Small bowel damage often leads to nutrient malabsorption that can result in a range of further clinical manifestations (anemia,
osteopenia, failure to thrive in children). In addition, extra-intestinal symptoms and systemic manifestations are often present,
such as dermatitis, infertility, or neurological and skeletal disorders. Mortality is increased in subjects with persistent intestinal
mucosal damage.
The
most serious complication of celiac disease is the development of an in situ small bowel T cell lymphoma after many years of exposure,
voluntary or inadvertent, to gluten. This malignant complication of celiac disease, which appears to be independent of gluten
and unresponsive to a strict GFD, is termed RCD-II when the percentage of aberrant IELs is >20% and Type I refractory celiac
disease when the percentage is <20%. In RCD-II, aberrant IELs proliferate in what represents a slow-growing non-Hodgkin lymphoma
localized (in situ) in the small bowel, primarily in the epithelial compartment. RCD-II affects approximately 0.5% of celiac patients
and can lead to overt and systemic enteropathy-associated T cell lymphoma, with very poor prognosis and >80% mortality in five
years.
Current
Treatment Options and Their Limitations
Celiac
disease is the only common autoimmune disorder with no approved medication. The only current available strategy for the management
of celiac disease is a lifelong total avoidance of gluten. While simple in theory, the ubiquity of gluten in foodstuffs, medications,
household substances, cosmetics, and gluten-free items makes total avoidance of gluten difficult, if not impossible.
The
main challenge to the successful maintenance of a GFD is that cereal flours are widely used in the food industry and are present
in numerous food products either naturally or as additives. Although gluten-free products can be purchased, commercially manufactured
gluten-free products may be difficult to find, tend to be less flavorful and are more expensive than regular gluten containing
foods. In addition, labeling of food products is deficient in many countries. Even in countries with superior labeling guidelines
foods labeled “gluten-free” may nevertheless contain gluten. For example, in northern European countries amounts of
up to 100 parts per million are permitted in gluten-free products designated apt for celiac sufferers.
For
these reasons, celiac sufferers are regularly exposed to gluten contamination in the food and beverages they consume. This exposure
to gluten contamination and the associated physiological and psychological consequences results in a self-limitation of social
activities and/or a reduction in the variety of foods consumed. Thus, the only currently available management option of a GFD
presents both a considerable challenge and substantial burden for patients. A study by Shah and collaborators (2014) found the
burden of celiac disease and GFD on patient quality of life to be very high, second only to end-stage renal disease – a
condition that requires multiple, weekly dialysis treatments.
As
a result of the difficulty in maintaining total avoidance of gluten while on a GFD, gluten contamination causes 50% or more of
all diagnosed celiac patients on a GFD to continue to experience disease activity. Patients who continue to have symptoms despite
attempting to maintain a GFD are deemed to have NRCD. NRCD has been defined as “persistent
symptoms, signs or laboratory abnormalities typical of celiac disease despite 6–12 months of dietary gluten avoidance”.
As requested by patient support groups and experts, alternative treatment options that can be administered independently or in
combination with a GFD, as well as treatments for refractory celiac disease, are required in order to improve the quality of life
for celiac patients.
Overview
of IL-15 Biology and PRV-015 Mechanism of Action
IL-15
is a pro-inflammatory cytokine that serves as a potent growth, survival, and activation factor for T cells, particularly IELs,
and for natural killer (“NK”), cells. Increased expression of IL-15 has been demonstrated in a variety of inflammatory
conditions, including celiac disease, RA, and psoriasis. IL-15 is considered a central regulator of celiac disease immunopathology
and a non-redundant driver of lymphomagenesis in RCD-II.
Substantial
evidence suggests a pathophysiological role for IL-15 in celiac disease:
Innate
immunity:
|
●
|
IL-15
is an essential, non-redundant growth and activation factor for the IELs which destroy the intestinal mucosa;
|
|
●
|
The
expression of IL-15 in the intestinal epithelium is necessary for villous atrophy; and
|
|
●
|
In
some patients, IL-15 drives progression towards lymphomagenesis and potentially fatal RCD-II.
|
Adaptive
immunity:
|
●
|
IL-15
enhances the presentation of deamidated gluten peptides by APCs;
|
|
●
|
IL-15
renders the activated CD4+ T cells resistant to inhibition by Tregs; and
|
|
●
|
IL-15
has been proven to be a key factor in the loss of tolerance to food antigens.
|
By
activating the IELs, IL-15 is believed to be the main mediator in the mucosal damage that ensues in response to gluten exposure
in celiac disease. The expression of IL-15 in the intestinal epithelium is necessary for villous atrophy in animal models of celiac
disease and circumstantial evidence suggests this to be the case in humans, as well. In addition, IL-15 renders effector T cells
resistant to inhibition by Tregs, promoting loss of tolerance to food antigens.
One
of the studied mouse models of celiac disease is an IL-15-transgenic mouse, in which IL-15 overexpression by gut epithelial cells
leads to celiac-like disease, including T and B cell-mediated pathology. IEL apoptosis has been observed in this animal model
after treatment with anti-IL-15 or anti-IL-15-receptor monoclonal antibodies.
Figure
1. Multiple actions of IL-15 in the pathophysiology of celiac and refractory celiac disease
PRV-015
(formerly AMG 714 and HuMax-IL15), is a fully human immunoglobulin (IgG
) mAb which binds to and inhibits the function
of IL-15 in all its forms (cis, trans, soluble IL-15 bound to IL-15R
). PRV-015 inhibits IL-15-induced T cell proliferation
and shows a dose-dependent inhibition of IL-15-induced TNF-
production. PRV-015 underwent preclinical testing and
was subsequently evaluated in a Phase 1 and Phase 2 study in subjects with RA, in a Phase 1 study in healthy volunteers and in
patients with psoriasis, and in two Phase 2a studies in celiac disease and refractory celiac disease Type-II.
Pre-clinical
Evaluation of PRV-015
The
nonclinical development of PRV-015 consisted of a series of in vitro studies demonstrating the binding properties of PRV-015
against human IL-15; in vitro and in vivo studies providing proof-of-concept for the benefit of blocking the IL-15
pathway in celiac disease; and a series of GLP studies evaluating the nonclinical safety profile of Hu714MuXHu, the PRV-015 surrogate
molecule which is active in macaques.
Pharmacology
PRV-015
was found to be efficacious in a mouse model of celiac disease triggered by the transgenic expression of human IL-15 in the gut
epithelium. In this model, PRV-015 prevented IEL activation and proliferation, as well as histological abnormalities. In addition,
PRV-015 was able to induce apoptosis of human IELs in ex vivo culture of small intestinal explants from active celiac disease
and RCD-II patients. In this culture experiment, PRV-015 resulted in a suppression of IL-15-driven anti-apoptotic signaling via
JAK3 and STAT5.
Toxicology
In
vitro studies demonstrated that PRV-015 had high binding affinity for human IL-15, but lower affinity for macaque IL-15. Additionally,
PRV-015 neutralized human IL-15 but did not efficiently neutralize macaque IL-15. To enable preclinical and toxicology studies
in macaques, a surrogate antibody, Hu714MuXHu, was developed by Amgen by fusing the F(ab) portion of a mouse anti-human IL-15
mAb known to neutralize macaque IL-15, M111, with human IgG1 Fc. Hu714MuXHu was shown to neutralize macaque IL-15 with approximately
the same potency as PRV-015 neutralizes human IL-15.
There
was a decrease in NK cell counts and NK cell activity following administration of Hu714MuXHu to monkeys, reflecting a PD response
to IL-15 blockade in this species, given the known role of IL-15 in NK cell biology in animal models (rodents and non-human primates).
Of note, no changes in absolute or relative numbers of NK cells were observed in any of the human studies. This difference between
observations in preclinical studies and clinical trials appears related to a differential sensitivity of human versus cynomolgus
monkey NK cells to IL-15 deprivation. Human NK cells are not dependent on IL-15 for their survival, possibly due to the redundant
role of IL-2 on human NK cells.
Pharmacokinetics
of PRV-015
The
PK of PRV-015 was consistent with a typical human immunoglobulin G1 antibody with no apparent target-mediated disposition within
the investigated dosing range. The mean half-life in human studies has been 20 to 22 days, potentially enabling monthly dosing.
There
was no development of anti-drug antibodies to PRV-015 in healthy volunteers, patients with psoriasis or patients with refractory
celiac disease. Only one RA patient in the phase 2b study was positive for anti-drug antibodies. Approximately 14% of patients
with celiac disease developed anti-drug antibodies in the Phase 2a clinical trial, with an additional 10% presenting pre-existing
anti-drug antibodies, a reflection of the abnormal antibody responses which characterize celiac disease. The anti-drug antibodies
were not associated with injection reactions or adverse events, and they were non-neutralizing, with no impact on PK.
Proof
of Mechanism for PRV-015 and Prior Clinical Evaluation
PRV-015
was initially developed for RA in two small Phase 1 and 2 studies with approximately 200 patients with moderate-to-severe
disease. Although PRV-015 missed the primary endpoint in the Phase 2 study at week 14, the results were significant at weeks 12
and 16, establishing proof-of-concept. Approximately 60% of patients with active RA in both Phase 1 and Phase 2 studies
versus approximately 30% of patients in the placebo groups demonstrated a response to treatment as measured by the American College
of Rheumatology 20% improvement score (ACR 20) at 8 and 12 weeks, respectively. PRV-015 also led to decreases in RA inflammatory
biomarkers such as C-reactive protein and erythrocyte sedimentation rate. PRV-015 was not effective in psoriasis in a small Phase
1 study, suggesting PRV-015’s action is selective, unlike that of broad systemic immune suppressants.
Upon
gluten challenge in a Phase 2 clinical trial in celiac disease (CELIM-NRCD-001), PRV-015 did not prevent gluten-induced architectural
mucosal injury, and thus missed the primary endpoint, yet the high dose of PRV-015, 300 mg, showed statistically significant attenuation
of gluten’s effects on the change from baseline in intestinal inflammation, in patient-reported symptom questionnaires (the
Celiac Disease Patient Reported Endpoint, CeD PRO, a registrational endpoint in NRCD) and in diarrhea, compared with placebo.
The totality of the results from the patients who had gluten challenge indicate that 300 mg PRV-015 (formerly AMG 714) given every
two weeks can ameliorate the inflammation and symptoms caused by substantial gluten exposure, the first demonstration of such
dual benefit in intestinal inflammation and symptoms for any experimental medication for celiac disease. The results suggest that
PRV-015 can be a potential adjunctive treatment for NRCD to the GFD to ameliorate or resolve persistent inflammation seen in the
majority of celiac patients already on GFD.
In
the Phase 2a clinical trial in RCD-II (CELIM-RCD-002), the primary endpoint (reduction in intestinal IELs) was not achieved, yet
PRV-015 showed statistically significant benefit over placebo in reducing T cell receptor clonality (no increase in clonality
with PRV-015) and symptoms (diarrhea). Other endpoints, such as histology, did not reach statistically significant differences
between groups, but the results consistently favored PRV-015 numerically. PRV-015 was generally well tolerated, with no observed
immunogenicity.
Summary
data of the Phase 2a clinical trial as presented at Digestive Disease Week in June 2018 is shown below:
The
CELIM-NRCD-001 study included 62 randomized celiac patients on a gluten-free diet, of which 49 patients underwent a substantial
gluten challenge of 2.5 grams per day for 10 weeks in order to assess the ability of PRV-015 to ameliorate the effects of gluten.
Upon gluten challenge, PRV-015 did not prevent gluten-induced architectural mucosal changes, the primary endpoint in the study.
However, in secondary efficacy assessments, the PRV-015 300 mg dose consistently attenuated the effects of gluten in intestinal
inflammation (intraepithelial lymphocyte density, p=0.03), and in gastrointestinal symptoms as measured by three independent endpoints:
the Celiac Disease Patient Reported Endpoint (CeD-PRO, p=0.02), the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD-GSRS,
p=0.07) and the Bristol Stool Form Scale (BSFS/diarrhea, p=0.0002). The CeD-PRO is a validated endpoint acceptable for registrational
trials. In addition, patients in the PRV-015 300 mg arm had a significantly improved Physician Global Assessment of disease
(PGA, p=0.03). The totality of the results demonstrated proof-of-concept for PRV-015 300 mg given subcutaneously every two
weeks in the amelioration of inflammation and symptoms caused by the consumption of gluten by celiac patients. Importantly, PRV-015
was well tolerated, and only 14% of patients developed anti-drug antibodies, which were non-neutralizing and not correlated with
impact of efficacy or safety. The PK profile was consistent with a monoclonal antibody, and potentially enables future monthly
dosing.
Summary
of clinical trials
Study
Number (Phase; Sponsor)
|
|
Key
Design Features
|
|
Dose
Route, Duration
|
|
Study
Population
|
Hx-IL15-001
(Phase
1;
Genmab)
|
|
Double-blind,
placebo-controlled, single SC infusion, dose escalation, study with open-label, repeat-dose (4 weekly doses) follow-up
|
|
Initial
single dose: 0 or 0.15 to 8 mg/kg SC infusion
Repeated
dose: 0.5 to 4 mg/kg SC infusion once weekly for four weeks. five doses over eight weeks
|
|
30
subjects with RA
|
|
|
|
|
|
|
|
20030210
(Phase
2;
Genmab/
Amgen)
|
|
Double-blind,
placebo-controlled, multiple SC infusion, parallel-group, multicenter study
|
|
0
or 40 to 280 mg SC infusion dose every two weeks for 12 weeks with initial 200% loading dose
|
|
180
subjects with RA
|
|
|
|
|
|
|
|
20050193
(Phase
1;
Amgen)
|
|
Double-blind,
placebo-controlled, single SC or IV doses, dose-escalation study
|
|
SC
doses: 0, 30, 100, 300 or 700 mg (cohorts 1 to 4) IV dose: 0 or 100 mg (cohort 5)
|
|
40
healthy subjects
|
|
|
|
|
|
|
|
20060349
(Phase
1b/2a; Amgen)
|
|
Double-blind,
placebo-controlled, multiple SC doses, dose-escalating study
|
|
0
or 150 mg SC (cohort 1)
0
or 300 mg SC (cohort 2)
Every
two weeks for 12 weeks
|
|
22
subjects with moderate to severe psoriasis
|
|
|
|
|
|
|
|
CELIM-NRCD-001
(Phase 2a; Celimmune)
|
|
Double-blind,
placebo- controlled, SC, parallel group, multicenter study
|
|
0,
150 mg or 300 mg PRV-015 once every two weeks for six consecutive doses over ten weeks
|
|
63
subjects with NRCD
|
|
|
|
|
|
|
|
CELIM-RCD-002
(Phase 2a; Celimmune)
|
|
Double-blind,
placebo controlled IV infusion, parallel group, multicenter study
|
|
0
or 8 mg/kg IV, a total of seven times over ten weeks
|
|
24
subjects with Type II refractory celiac disease
|
Safety
of PRV-015
Approximately
250 subjects have been exposed to PRV-015 to date, including approximately 200 subjects for 12 weeks of biweekly dosing. In all
studies to date, PRV-015 was generally well tolerated by healthy volunteers, patients with active RA, and patients with celiac
disease or RCD-II. While PRV-015 has the potential, to increase susceptibility to infections as is the case with immune modulators,
PRV-015 has not demonstrated this effect in the six clinical trials completed to date. No deaths or clinically significant changes
in laboratory parameters were observed, including no NK cell depletion.
The
only adverse events clearly increased in PRV-015-treated patients have been injection site reactions, which were more commonly
reported in subjects exposed to PRV-015, in a dose-dependent fashion (up to ~52% on PRV-015 vs ~26% in placebo in the celiac Phase
2a clinical trial), and nasopharyngitis (most cases with suspected allergic origin at a single site in RCD-II). In the population
which will be studied in Phase 2b, celiac disease, there were no SAEs in the Phase 2a clinical trial, while there were six SAEs
(five on PRV-015 and one on placebo) in the RCD-II, a much sicker patient population with immune suppression at baseline. Of the
five SAE on PRV-015 in RCD-II patients, two were infections (both resolved while on PRV-015). There was one mild balance disorder
(considered unlikely to be related to PRV-015 and resolved while on the drug). Another patient had mild cerebellar syndrome which
lead to discontinuation from the study.
PRV-6527
(Small Molecule CSF-1R Inhibitor) for Crohn’s Disease
PRV-6527
(previously known as JNJ-40346527) is a highly potent and selective small-molecule oral inhibitor of CSF-1R, which we acquired
the rights to for irritable bowel diseases (“IBDs”), including Crohn’s disease, in April 2017. It was developed
by Janssen and has undergone clinical testing in 178 subjects to date, across Phase 1 (healthy volunteers; 94 received single
dose up to 600 mg or two doses of 450 mg) and two Phase 2 clinical trials (RA 63 patients received 200 mg/day for 12 weeks; and
21 Hodgkin’s lymphoma (“HL”), patients received 150 mg/day to 650 mg/day for at least three weeks). No serious
adverse events deemed related to PRV-6527 were observed that would preclude further clinical development and proof of mechanism
was demonstrated based on inhibition of CSF-1R signaling and myeloid cell counts in blood. While clinical data in the RA study
was inconclusive and did not demonstrate efficacy in this disease, PRV-6527 ameliorates Crohn’s-like disease in mouse models,
and CSF-1R and its pathway are upregulated in CD.
We
conducted a Phase 2a proof of concept clinical trial, referred to as the PRINCE study, in approximately 80 patients with CD to
assess a clinical and histologic/tissue (gut mucosa) anti-inflammatory effects after 12 weeks of treatment with PRV-6527. This
study evaluated doses and dosing duration that were previously tested by Janssen. The primary efficacy endpoint of the study was
the change in the Crohn’s Disease Activity Index (CDAI) score at week 12. While PRV-6527 demonstrated a substantial improvement
in this symptom driven score at week 12, it did not differentiate from placebo. This high placebo response was deemed to be possibly
related to the standard of care and/or background medication used (~85%) in the study’s predominantly biologic-naïve
population. PRV-6527 was associated with improvements in several key secondary objective endpoints in the steroid-free population
(75% of study subjects), including mucosal endoscopy (as assessed by the Simple Endoscopic Score for Crohn’s Disease, SES-CD)
and tissue histology (as measured by the Global Histological Activity Score, GHAS). Analysis of exploratory serum and tissue biomarkers
showed that patients treated with PRV-6527 had significant reductions in circulatory inflammatory monocytes, as well as macrophages,
dendritic cells and the CSF1 gene signature in colonic tissue, providing proof of mechanism in the interception of inflammatory
myeloid cells. PRV-6527 was found to be generally well tolerated, with no drug-related serious adverse events. In December 2019,
Janssen declined to exercise its right to buy back PRV-6527 from us for a one-time payment of $50.0 million and single-digit royalties
on future net sales in inflammatory bowel disease indications. We retain the rights and are free to sublicense the program on
a worldwide basis to another partner in the field of inflammatory bowel disease.
Significant
Contracts and Agreements Related to Research and Development Activities
License
and Acquisition Agreements
MacroGenics
Asset Purchase Agreement
In
May 2018, we entered into the MacroGenics Asset Purchase Agreement with MacroGenics pursuant to which we acquired
MacroGenics’ interest in teplizumab (renamed PRV-031), a humanized mAb for the treatment of T1D. As partial
consideration for the MacroGenics Asset Purchase Agreement, we granted MacroGenics a warrant to purchase 2,162,389 shares of
our common stock at an exercise price of $2.50 per share. In July 2019, these warrants were exercised by MacroGenics on a
cashless basis. We are obligated to pay MacroGenics contingent milestone payments totaling $170.0 million upon the
achievement of certain regulatory approval milestones, including $60.0 million payable within 90 days of an approval of a BLA
for a first indication in the United States. In addition, we are obligated to make contingent milestone payments to
MacroGenics totaling $225.0 million upon the achievement of certain sales milestones. We have also agreed to pay MacroGenics
a single-digit royalty on net sales of the product. We have also agreed to pay third-party obligations, including low
single-digit royalties, a portion of which is creditable against royalties payable to MacroGenics, aggregate milestone
payments of up to approximately $0.7 million and other consideration, for certain third-party intellectual property under
agreements we assumed pursuant to the Asset Purchase Agreement. Further, we are required to pay MacroGenics a low
double-digit percentage of certain consideration to the extent it is received in connection with a future grant of rights to teplizumab
by us to a third party. We are obligated to use reasonable commercial efforts to develop and seek regulatory approval for teplizumab.
Vactech
License
In
April 2017, we entered into a License Agreement with Vactech, pursuant to which Vactech granted us exclusive global rights for
the purpose of developing and commercializing the CVB vaccine platform technology. In consideration of the licenses and other
rights granted by Vactech, we issued two million shares of our common stock to Vactech. We paid Vactech a total of approximately
$0.5 million for transition and advisory services during the first 18 months of the term of the agreement. Vactech is obligated
to transition its intellectual property, provide reference samples, assist with the technology transfer to a third-party contract
manufacturer, and participate on our scientific advisory board. In addition, we may be obligated to make a series of contingent
milestone payments to Vactech totaling up to an additional $24.5 million upon the achievement of certain clinical development
and regulatory filing milestones, of which, $0.5 million became payable to Vactech in January 2021 upon the dosing of the first
patient in the Phase 1 PROVENT study. In addition, we have agreed to pay Vactech tiered single-digit royalties on net sales of
any approved product based on the CVB platform technology and three additional payments totaling $19.0 million upon the achievement
of certain annual net sales levels. The Vactech Agreement may be terminated by us on a country by country basis without cause
(in which case the exclusive global rights to the technology will transfer back to Vactech) and by either party upon a material
breach or insolvency of the other party. If we terminate the agreement with respect to two or more specified European countries,
the agreement will be deemed terminated with respect to all of the European Union, and if we terminate the agreement with respect
to the United States, the agreement will be deemed terminated with respect to all of North America and expires upon the expiration
of our last obligation to make royalty payments to Vactech.
MacroGenics
License Agreement
In
May 2018, we entered into a License Agreement with MacroGenics, pursuant to which MacroGenics granted us exclusive global rights
for the purpose of developing and commercializing MGD010 (renamed PRV-3279), a humanized protein and a potential treatment for
SLE and other similar diseases. As partial consideration for the MacroGenics License Agreement, we granted MacroGenics a warrant
to purchase 270,299 shares of our common stock at an exercise price of $2.50 per share. In July 2019, these warrants were exercised
by MacroGenics on a cashless basis. We are obligated to make contingent milestone payments to MacroGenics totaling $42.5 million
upon the achievement of certain developmental and approval milestones for the first indication, and an additional $22.5 million
upon the achievement of certain regulatory approvals for a second indication. In addition, we are obligated to make contingent
milestone payments to MacroGenics totaling $225.0 million upon the achievement of certain sales milestones. We have also agreed
to pay MacroGenics a single-digit royalty on net sales of the product. Further, we are required to pay MacroGenics a low double-digit
percentage of certain consideration to the extent received in connection with a future grant of rights to PRV-3279 by us to a
third party. We are obligated to use commercially reasonable efforts to develop and seek regulatory approval for PRV-3279. The
license agreement may be terminated by either party upon a material breach or bankruptcy of the other party, by us without cause
upon prior notice to MacroGenics, and by MacroGenics in the event that we challenge the validity of any licensed patent under
the agreement, but only with respect to the challenged patent.
Amgen
License and Collaboration Agreement
In
November 2018, we entered into a License and Collaboration Agreement (the “Amgen Agreement”) with Amgen, Inc. (“Amgen”)
for PRV-015 (formerly AMG 714), a novel anti-IL-15 monoclonal antibody being developed for the treatment of gluten-free diet NRCD.
Under the terms of the agreement, we will conduct and fund a Phase 2b trial in NRCD and lead the development and regulatory activities
for the program. Amgen agreed to make an equity investment of up to $20.0 million in us, which was completed in September 2019
through the purchase of 2,500,000 shares of our common stock. Amgen is also responsible for the manufacturing of PRV-015. Upon
completion of the Phase 2b trial, a $150.0 million milestone payment is due from Amgen to us, plus an additional regulatory milestone
payment, and single digit royalties on future sales; provided, however, that Amgen has the right to elect not to pay the $150.0
million milestone, in which case we will have an option to negotiate for the transfer to us of rights to AMG 714 pursuant to a
termination license agreement between Amgen and us. The material terms of the termination license agreement have been negotiated
and agreed and form part of the Amgen Agreement. Under the terms of the termination license agreement, we would be obligated to
make certain contingent milestone payments to Amgen and other third parties totaling up to $70.0 million upon the achievement
of certain clinical and regulatory milestones and a low double-digit royalty on net sales of any approved product based on the
IL-15 technology. The agreement may be terminated by either party upon a material breach or upon an insolvency event and by Amgen
if we are not able to fund our clinical development obligations (among other termination triggers). The agreement expires upon
the expiration of Amgen’s last obligation to make royalty payments to us.
Intravacc
Development Services Agreement
In
March 2018, we entered into a Development Services Agreement with The Institute of Translational Vaccinology (“Intravacc”),
pursuant to which Intravacc will provide services related to process development, Good Manufacturing Practice (“GMP”),
and non-GMP manufacturing of our polyvalent CVB vaccine, including providing proprietary technology for manufacturing purposes.
We will pay Intravacc approximately 10.0 million euros for their services over the development and manufacturing period. Each
party retains its existing intellectual property and will share newly developed intellectual property via a fully-paid non-exclusive
license between the parties for all development work through phase 1 clinical trials. Any future use, including commercial use,
of Intravacc’s technology will be subject to a separate nonexclusive license agreement. The Intravacc Development Services
Agreement may be terminated by us with ninety days’ notice without cause and by either party upon a material breach or insolvency
of the other party.
AGC
Biologics Agreement
In
February 2019, we entered into services agreement with AGC Biologics (“AGC”), to manufacture and supply teplizumab
for our anticipated clinical and commercial supply needs. We may terminate the agreement or any stage of services thereunder with
90 days’ prior written notice. If we provide less than 12 months’ notice of termination for the termination of a scheduled
batch, we may incur a cancellation fee. The amount of the cancellation fee would depend on the timing of such notice. Each party
also has the right to terminate the agreement for other customary reasons such as material breach and bankruptcy. The agreement
contains provisions relating to compliance by AGC with current GMP, cooperation by AGC in connection with potential marketing
applications for teplizumab, indemnification, confidentiality, dispute resolution and other customary matters for an agreement
of this kind.
Parexel
Services Agreement
In
February 2019, we entered into a services agreement with Parexel (the “Parexel Services Agreement”), pursuant to which
we retained Parexel to perform implementation and management services in connection with the PROTECT study of teplizumab.
We may terminate the services agreement or any work order for any reason and without cause with 90 days’ written notice.
Either party may terminate the agreement in the event of a material breach or, bankruptcy petition by the other party or, if any
approval from a regulatory authority is revoked, suspended or expires without renewal.
Intellectual
Property
We
believe that our current patent applications and any future patents and other proprietary rights that we own, or control through
licensing, are and will be essential to our business. We believe that these intellectual property rights will affect our ability
to compete effectively with others. We also rely and will rely on trade secrets, know-how, continuing technological innovations
and licensing opportunities to develop, maintain and strengthen our competitive position. We seek to protect these, in part, through
confidentiality agreements with certain employees, consultants, advisors and other parties. Our success will depend in part on
our ability, and the ability of our licensor, to obtain, maintain (including making periodic filings and payments) and enforce
patent protection for our/their intellectual property, including those patent applications to which we have secured exclusive
rights.
We
plan to spend considerable resources and focus in the future on obtaining United States and foreign patents. We have and will
continue to actively protect our intellectual property. No assurances can be given that any of our patent applications will result
in the issuance of a patent or that the examination process will not require us to narrow our claims. In addition, any issued
patents may be contested, circumvented, found unenforceable or invalid, and we may not be able to successfully enforce our patent
rights against third parties. No assurance can be given that others will not independently develop a similar or competing technology
or design around any patents that may be issued to us. We intend to expand our international operations in the future and our
patent portfolio, copyright, trademark and trade secret protections may not be available or may be limited in foreign countries.
PRV-031
(teplizumab anti-CD3 antibody)
Through
our agreement with MacroGenics, we have acquired a patent portfolio that includes seven issued patents, including two United States
patents and five ex-United States patents in Australia, Israel, Mexico and Singapore. The issued patents are set to expire no
earlier than dates ranging from 2026 and 2028, subject to any disclaimers, patent term adjustments or extensions available under
the law. These issued patents cover use of certain humanized antibodies that bind to CD3 in the treatment of autoimmune disorders,
including T1D and RA.
We have additionally
filed one PCT international patent application, one United States non-provisional patent application, one United States provisional
patent application, and one Taiwanese patent application directed to various new uses of anti-CD3 antibodies, including
teplizumab for the prevention or delay of clinical T1D. If issued, patents claiming priority to these applications will expire
no earlier than 2040, subject to any disclaimers, patent term adjustments or extensions available under the law.
PRV-101
(CVB/T1D)
Through
our agreement with Vactech, we have a licensed patent portfolio that includes three issued United States patents, one pending
United States patent application, and 14 patents in various European countries (i.e., one granted European patent
validated in 14 European Patent Convention member states). The issued United States patents, pending United States patent
application and the European country patents disclose use of a CVB vaccine composition in the prevention or treatment of T1D.
The
patents issued in the United States and various European countries generally have terms of 20 years from their respective priority
filing dates, subject to available extensions, and are thus set to expire no earlier than 2032, subject to any disclaimers, patent
term adjustments or extensions available under the law.
PRV-3279
(CD32B/CD79B diabody)
Through
our agreement with MacroGenics, we have licensed a patent portfolio that includes: i) 187 issued patents, including 12 United
States patents, 110 patents in European countries, and 65 patents in other ex-United States jurisdictions; and ii) 38 pending
patent applications, including seven pending United States patent applications, four pending European patent applications, and
27 pending patent applications in other ex-United States jurisdictions.
The
patents and patent applications disclose a platform technology for making diabodies, specific anti-CD32B antibodies, specific
anti-CD79B antibodies, specific diabodies that co-ligate both CD32B and CD79B, as well as use of these antibodies and diabodies
in treating various disorders, including cancer, autoimmune disorder, inflammatory disorder, and IgE-mediated allergic disorder.
The
issued patents in the United States and various ex-United States countries generally have terms of 20 years from their respective
priority filing dates, subject to available extensions, and are thus set to expire no earlier than dates ranging from 2032 and
2034, subject to any disclaimers, patent term adjustments or extensions available under the law. In the event that the pending
patent applications issue as patents, although there can be no assurance that the patent applications will issue, the patents
would be set to expire no earlier than dates ranging from 2032 and 2037, subject to any disclaimers, patent term adjustments or
extensions available under the law.
We have additionally
filed one PCT international patent application, two United States non-provisional patent applications, and one United
States provisional patent application directed to new use of B cell inhibitors and the prevention of immunogenicity associated
with gene therapy, including PRV-3279. If issued, patents claiming priority to these applications will expire no earlier than
2040, subject to any disclaimers, patent term adjustments or extensions available under the law.
PRV-015
(IL-15)
Through
our agreement with Amgen, we have licensed a patent portfolio that includes: i) 79 issued patents, including eight United States
patents, 42 patents in European countries, and 29 patents in other ex-United States jurisdictions; and ii) 19 pending patent applications,
including two pending United States patent applications, one pending European patent application, and 16 pending patent applications
in other ex-United States jurisdictions.
The
patents and patent applications disclose anti-IL-15 antibodies, methods of using the same, manufacturing conditions and dosages
of the same.
The
issued patents are set to expire no earlier than dates ranging from 2022 and 2027, subject to any disclaimers or extensions under
the law. In the event that the pending patent applications issue as patents, although there can be no assurance that the patent
applications will issue, the patents would be set to expire no earlier than dates ranging from 2026 and 2037, subject to any disclaimers,
patent term adjustments of extensions available under the law.
PRV-6527
(CSF-1R)
Through
our agreement with Janssen Pharmaceutica NV, we have licensed a patent portfolio that includes: i) 73 issued patents, including
one United States patent, one patent in European countries, and 71 patents in other ex-United States jurisdictions; and ii) three
pending patent applications, including one pending United States patent application, one pending European patent application,
and one pending patent applications in other ex-United States jurisdictions. The issued patents are set to expire no earlier than
dates ranging from 2027 and 2030, subject to any disclaimers, patent term adjustments or extensions under the law. In the event
that the pending patent applications issue as patents, although there can be no assurance that the patent applications will issue,
the patents would be set to expire no earlier than dates ranging from 2027 and 2030, subject to any disclaimers, patent term adjustments
or extensions under the law.
Sales
and Marketing
We
are a clinical stage company without a history of revenue or marketing experience. We intend to commercialize teplizumab ourselves
in the U.S., however, because commercialization is expensive and time consuming, we intend to explore multiple commercialization
strategies outside the U.S., including:
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exploring
strategic partners for commercialization in markets outside the United States;
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developing
drug candidates through the earlier stages of clinical development with the objectives of rapid, cost effective risk reduction
and value creation and then establishing strategic partnership for late stage clinical development and subsequent commercialization;
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developing
a robust pipeline of promising drug candidates at various stages of the development process to establish optionality and regular
value inflection opportunities and revenue(s);
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strategically
entering into co-development partnership(s) to retain potential for commercialization rights on selected drug candidate(s)
and market opportunities; and
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partnering
with industry participants to incorporate our technology into new and existing drugs.
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We
expect that partnering with pharmaceutical or biotherapeutic companies may accelerate product acceptance into target market areas
outside the United States and gain the sales and marketing advantages of the partner’s distribution infrastructure. We intend
to continue to strengthen our market position and solidify our leadership position in immunotherapy by continuing to improve our
technology, broadening our clinical and therapeutic applications, identifying new clinical and therapeutic applications and forming
strategic relationships with our licensors.
Manufacturing
We
do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of any of our
product candidates. Although we rely and intend to continue to rely upon third–party contract manufacturers to produce our
products and product candidates, we have recruited personnel and consultants with experience to manage these third–party
contract manufacturers. In certain cases, our collaboration partners for each respective program are responsible for providing
clinical drug supply or drug product for those program’s clinical trials. In other cases, we have engaged third-party manufacturers
to provide services related to process development, non-GMP and GMP manufacturing and other related services.
The
table below lists the third-party responsible for manufacturing drug supply for each of our programs:
Product
Candidate
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Supplier
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Party
Responsible for Costs
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PRV-031
(teplizumab)
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AGC
Biologics
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Provention
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PRV-101
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Intravacc
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Provention
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PRV-3279
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Existing
drug supply – MacroGenics
Future
drug supply – vendors being evaluated
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MacroGenics
Provention
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PRV-015
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Amgen
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Amgen
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We
have historically relied upon an existing supply of teplizumab produced by MacroGenics for use in our clinical trials of
teplizumab. This existing supply is insufficient to fully supply the ongoing PROTECT study to completion or our potential
commercialization need. In February 2019, we entered into an agreement with AGC Biologics to manufacture teplizumab
for our anticipated clinical trial needs as well as for potential commercialization of teplizumab.
Supplies
of teplizumab sufficient to supply the PROTECT study have been manufactured by our CMO’s and are in the process of
being released by Provention for clinical use.
In
order to obtain regulatory approval for teplizumab, third-party manufacturers have been required to consistently produce
teplizumab in commercial quantities and of specified quality on a repeated basis and document their ability to do so. The
required number of batches of teplizumab have been manufactured at our CMO’s by the processes we intend to use for
commercialization. The quality and consistency of these lots, along with their comparability to teplizumab manufactured
for clinical studies, is now under review by the FDA.
If
the FDA finds that the teplizumab manufactured by the current third-parties is not of sufficient quality, or is not comparable
to drug product used in the TN-10 study, delays in FDA acceptance of our BLA submission may occur. Such delays would, in
turn, delay the potential marketing and commercialization of teplizumab, which would materially and adversely affect our
business.
Competition
We
face substantial competition from well-established large pharmaceutical companies, as well as innovative new entrants. Nevertheless,
we believe our strategic intent is sufficiently differentiated in that we are focusing on intercepting or potentially preventing
the onset and progression of immune-mediated and inflammatory diseases by selecting and developing product candidates that are
aimed at relevant and predominantly upstream pathophysiological targets.
The
symptomatic treatment of T1D is a highly competitive market with large incumbents such as Sanofi, Novo Nordisk and Eli Lilly providing
insulin and Medtronic, Abbott, and Dexcom providing blood glucose monitoring products and many working on new ways to manage the
disease. Our goal is to delay or prevent the onset of T1D and spare patients the need to live with blood glucose monitoring and
daily insulin injections and this therapy’s many complications and clinically relevant shortfalls. We believe our enteroviral
vaccine approach is unique in that it aims to prevent the onset of T1D prior to the rise of immune cells and auto-antibodies programmed
to attack insulin producing beta cells. We are aware of competitive vaccine technologies in development that are attempting to
alter the autoimmune cycle once these auto-antibodies have been detected. However, we believe our vaccine approach may intercept
the process prior to this cycle being initiated (primary prevention).
We
believe our secondary prevention (i.e., interception) approach with teplizumab is more advanced and differentiated from other
immunomodulation therapies which have shown preservation of beta cell function in early phase studies of newly diagnosed onset
T1D including anti-thymocyte globulin (ATG), CTLA4-Ig (costimulatory blocker), anti-CD20 (Rituxan) and LFA3-Ig (alefacept). All
of these Phase 2 studies were conducted by the academic community or by T1D networks and do not appear to be in active Phase 3
development by industry sponsors. The most recent data were reported with Thymoglobulin which is an approved anti-thymocyte globulin
obtained by immunization of rabbits with human thymocytes and is indicated for the treatment of renal transplant acute rejection
in conjunction with concomitant immunosuppression and for induction in adult renal transplant recipients. Low dose ATG was administered
intravenously for 2 days in early onset T1D (within 100 days of diagnosis). While C-peptide preservation was observed, due to
the risk of serum sickness, ATG was administered during a 2-3 day hospitalization and required pre-medication, including intravenous
corticosteroids. In January 2020, a Phase 3 trial in newly diagnosed T1D patients with ladarixin (Dompe) an interleukin-8 inhibitor,
was announced on the basis of post-hoc results in a subset of patients after the drug failed to improve C-peptide in Phase 2a.
Importantly, teplizumab is the only experimental drug with positive data in Stage 2, in the prevention/delay of clinical T1D,
and no other pivotal studies are on-going in this indication.
PRV-015
has the potential to be the first drug ever approved for CD since it is the only medication which has shown simultaneous improvement
in gluten-induced symptoms and gut inflammation to date, and since most clinical-stage products are early in development and have
not established proof-of-concept. Competition includes experimental medications in development by 9 Meters (larazotide acetate,
Phase 2b study completed in 2014; Phase 3 started in 2019 as a symptomatic relief, not disease-modifying agent), ImmunogenX (IMGX-003/latiglutenase,
Phase 2b study completed in 2016 missed primary endpoint, new phase 2a started in 2019), Zedira/Dr. Falk (ZED1227, phase 2a on-going),
Cour (NP-GLI, Phase 1/2 completed in 2019) and PvP Biologics (KumaMax, Phase 1 completed in 2019).
The
market for lupus is currently led by large pharmaceutical companies commercializing older, off-patent products such as steroids,
immunosuppressive agents including azathioprine, cyclosphosphamide, cyclosporine and mycophenolate. In addition, Glaxo SmithKline
(GSK) and Roche offer recently approved B cell-targeted agents. GSK received approval for belimumab (Benlysta) in 2011, the first
drug approval in lupus in 50 years. Despite modest efficacy and slow onset of effect, belimumab’s annual sales are currently
approximately $800 million and are expected to grow with the December 2020 approval in lupus nephritis. Roche’s rituximab
(Rituxan), a blockbuster drug, is used off-label in lupus despite not having been approved in SLE. The lupus field is competitive
and new experimental drugs are being tested in late-stage trials by large pharmaceutical companies and early to mid-stage biotech
companies and include the anti-interferon alpha receptor anifrolumab (Astra Zeneca), which posted a positive Phase 3 trial in
late 2019. The calcineurin inhibitor voclosporin (Aurinia Pharmaceuticals) was approved for lupus nephritis in January 2021. We
expect that PRV-3279 will be differentiated from the competition because of greater and faster-onset efficacy, better safety (PRV-3279
does not deplete B cells and is not expected to be immune-suppressive), and less side effects (since PRV-3279 is a highly specific
mAb with likely minimal off-target side effects). There are no drugs approved for the prevention of the immunogenicity of biotherapeutics,
and rituximab is occasionally used off-label.
Government
Regulation
Our
business activities, including the manufacturing, research, development and marketing of our product candidates, are subject to
extensive regulation by numerous governmental authorities in the United States and other countries. Before marketing in the United
States, any new drug developed by us or our collaborators must undergo rigorous preclinical testing, clinical trials and an extensive
regulatory clearance process implemented by the FDA. The process for obtaining regulatory approval and compliance with applicable
federal, state and local laws and regulations requires the expenditure of substantial time and financial resources. Moreover,
government coverage and reimbursement policies will both directly and indirectly impact our ability to successfully commercialize
any future approved products, and such coverage and reimbursement policies will be impacted by enacted and any applicable future
healthcare reform and drug pricing measures. In addition, we are subject to state and federal laws, including, among others, anti-kickback
laws, false claims laws, data privacy and security laws, and transparency laws that restrict certain business practices in the
pharmaceutical industry.
US
Regulation of Drugs and Biologics
In
the United States, the FDA regulates human drugs under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and
in the case of biologics, also under the Public Health Service Act (“PHSA”) and their implementing regulations. The
FDA regulates, among other things, the development, testing, manufacture, safety, efficacy, record keeping, packaging, labeling,
storage, approval, advertising, promotion, import, export, sale and distribution of biopharmaceutical products.
The
process required by the FDA before a drug or biologic may be marketed in the United States generally involves the following:
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completion
of preclinical laboratory tests, animal studies and formulation studies according to Good Laboratory Practices (“GLP”)
regulations or other applicable regulations;
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submission
to the FDA of an Investigational New Drug Application (“IND”), which must become effective before human clinical
trials may begin;
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approval
by an independent institutional review board (“IRB”) or ethics committee at each clinical trial site before each
clinical trial may be initiated;
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performance
of adequate and well-controlled human clinical trials in accordance with applicable IND regulations, good clinical practices
(“GCPs”), and other clinical-trial related regulations to evaluate the safety and efficacy of the investigational
product for each proposed indication;
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preparation
and submission to the FDA of a New Drug Application (“NDA”) or BLA requesting marketing approval for one or more
proposed indications, including payment of application user fees;
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review
of the NDA or BLA by an FDA advisory committee, where applicable;
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satisfactory
completion of one or more FDA inspections of the manufacturing facility or facilities at which the drug or biologic is produced
to assess compliance with GMP requirements to assure that the facilities, methods and controls are adequate to preserve the
product’s identity, strength, quality and purity;
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satisfactory
completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCPs and the integrity
of the clinical data submitted in support of the NDA or BLA; and
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FDA
review and approval of the NDA or BLA, which may be subject to additional post-approval requirements, including the potential
requirement to implement a Risk Evaluation and Mitigation Strategy (“REMS”), and any post-approval studies required
by the FDA.
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Preclinical
and Clinical Development
Before
testing any drug product candidates in humans, the product candidate intended for human use must undergo rigorous laboratory and
animal testing until adequate proof of safety is established. This preclinical testing generally involves laboratory evaluations
of drug chemistry, formulation and stability, as well as in vitro and animal studies, to assess the potential for adverse events
and in some cases to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations
and requirements, including GLP regulations for safety and toxicology studies. The sponsor must submit the results of the preclinical
studies, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical
protocol, to the FDA as part of the IND, An IND is a request for authorization from the FDA to administer an investigational product
to humans and must become effective before human clinical trials may begin. An IND automatically becomes effective 30 days after
receipt by the FDA, unless before that time, the FDA raises concerns or questions related to one or more proposed clinical trials
and places the trial on clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before
the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.
The
clinical stage of development involves the administration of the investigational product to healthy volunteers or patients under
the supervision of qualified investigators, in accordance with GCP requirements, which include the requirement that all patients
provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing
the objectives of the study, inclusion and exclusion criteria, the parameters to be used in monitoring the safety and effectiveness
criteria to be evaluated. Each protocol, as well as any subsequent amendments, must be submitted to the FDA as part of the IND.
Additionally, each clinical trial and its related documentation, including the trial protocol and informed consent form, must
be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks
to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. Some
clinical trials are also overseen by an independent group of qualified experts organized by the clinical trial sponsor, known
as a data safety monitoring board or committee. This group may recommend continuation of the study as planned, changes in study
conduct, or cessation of the study at designated checkpoints based on access to certain data from the study.
Clinical
trials for new product candidates are then typically conducted in humans in three sequential phases that may overlap. Phase 1
trials involve the initial introduction of the product candidate into a small number of healthy human volunteers or disease-affected
patients who are initially exposed to a single dose and then multiple doses of the product candidate. The emphasis of Phase 1
trials is on testing for safety or adverse events, dosage, tolerance, metabolism, distribution, excretion and clinical pharmacology.
Phase 2 involves studies in a limited patient population to determine the initial efficacy of the compound for specific targeted
indications, to determine dosage tolerance and optimal dosage, and to identify possible adverse side effects and safety risks.
Once a compound shows evidence of effectiveness and is found to have an acceptable safety profile in Phase 2 evaluations, Phase
3 trials are undertaken to more fully evaluate clinical outcomes. Phase 3 clinical trials generally involve a large number of
patients at multiple sites and are designed to provide the data necessary to demonstrate the effectiveness of the product for
its intended use, its safety in use and to establish the overall benefit/risk relationship of the product and provide an adequate
basis for product labeling. Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial
marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic
indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of
an NDA or BLA. Failure to exhibit due diligence with regard to conducting mandatory Phase 4 clinical trials could result in withdrawal
of approval for products.
During
the development of a new drug or biological product, sponsors have the opportunity to meet with the FDA at certain points, including
prior to submission of an IND, at the end of phase 2, and before submission of an NDA or BLA. These meetings can 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. Regulatory authorities, IRBs and Data Monitoring Committees may require
additional data before allowing clinical trials to commence, continue or proceed from one phase to another, and could demand that
studies be discontinued or suspended at any time if there are significant safety issues. Progress reports detailing the results
of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur. The
FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research
subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of
a clinical trial at its institution if the clinical trial is not being conducted in accordance with the clinical protocol, GCP,
or other IRB requirements or if the drug has been associated with unexpected serious harm to patients.
Information
about certain clinical trials, including details of the protocol and eventually study results, also must be submitted within specific
time frames to the National Institutes of Health for public dissemination on the Clinicaltrials.gov data registry.
Concurrent
with clinical trials, companies usually complete additional animal studies and must also develop additional information about
the physical characteristics of the drug or biologic and finalize a process for manufacturing the product in commercial quantities
in accordance with GMP requirements. The manufacturing process must be capable of consistently producing quality batches of the
product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality,
potency and purity of the final drug or biological product. For biological products in particular, the PHSA emphasizes the importance
of manufacturing control for products whose attributes cannot be precisely defined in order to help reduce the risk of the introduction
of adventitious agents. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted
to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
Generating
the required data and information for regulatory approval takes many years and requires the expenditure of substantial resources.
Following completion of the required testing, the results of the preclinical studies and clinical trials, along with information
relating to the product’s chemistry, manufacturing, and controls and proposed labeling, are submitted to the FDA as part
of an NDA or BLA requesting approval to market the product for one or more indications. To support marketing approval, the data
submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product in the
proposed patient population to the satisfaction of the FDA. Under the PDUFA, each NDA or BLA must be accompanied by a user fee,
which for federal fiscal year 2021 is $2,875,842 for an application requiring clinical data. The sponsor of an approved NDA or
BLA is also subject to an annual program fee, which for fiscal year 2021 is $336,432. The FDA adjusts the PDUFA user fees on an
annual basis, but fee waivers or reductions are available in certain circumstances.
Under
applicable laws and FDA regulations, each NDA or BLA submitted for FDA approval is given an internal administrative review within
60 days following submission of the NDA or BLA. If deemed sufficiently complete to permit a substantive review, the FDA will accept
the NDA or BLA for filing. The FDA can refuse to file any NDA and BLA that it deems incomplete or not properly reviewable. Once
the submission is accepted for filing, the FDA begins an in-depth review of the NDA or BLA. The FDA has established internal goals
of eight months from submission for priority review of NDAs or BLAs that cover product candidates that offer major advances in
treatment or provide a treatment where no adequate therapy exists, and 12 months from submission for the standard review of NDAs
and BLAs. However, the FDA is not legally required to complete its review within these periods, these performance goals may change
over time and the review is often extended by FDA requests for additional information or clarification.
Before
approving an NDA or BLA, the FDA will typically conduct pre-approval inspections of the facilities at which the product is manufactured
to determine whether the manufacturing processes and facilities are in compliance with GMP requirements and adequate to assure
consistent production of the product within required specifications. The FDA may also audit the clinical trial sponsor and one
or more sites at which clinical trials have been conducted to determine compliance with GCPs and data integrity. Additionally,
the FDA may refer any NDA or BLA, including applications for novel product candidates which present difficult questions of safety
or efficacy, to an advisory committee. Typically, an advisory committee is a panel of independent experts, including clinicians
and other scientific experts that reviews, evaluates and provides a recommendation as to whether the application should be approved
and under what conditions. The FDA is not bound by the recommendation of an advisory committee, but it considers such recommendations
when making final decisions on approval. The FDA likely will re-analyze the clinical trial data, which could result in extensive
discussions between the FDA and the applicant during the review process.
Before
receiving FDA approval to market a potential product, we or our collaborators must demonstrate through adequate and well-controlled
clinical trials that the potential product is safe and effective in the patient population that will be treated. In addition,
under the Pediatric Research Equity Act (“PREA”), an NDA or BLA or supplement thereto must contain data to assess
the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing
and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for
submission of pediatric data or full or partial waivers of the requirement to provide data from pediatric studies.
After
the FDA evaluates an NDA or BLA, it will issue an approval letter or a Complete Response Letter. An approval letter authorizes
commercial marketing of the drug or biologic with specific prescribing information for specific indications. A Complete Response
Letter indicates that the review cycle of the application is complete and the application will not be approved in its present
form. A Complete Response Letter usually describes all of the specific deficiencies in the NDA or BLA identified by the FDA. The
Complete Response Letter may require additional clinical data and/or other significant and time-consuming requirements related
to clinical trials, preclinical studies or manufacturing. If a Complete Response Letter is issued, the applicant may either resubmit
the NDA or BLA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and
information are submitted, the FDA may decide that the NDA or BLA does not satisfy the criteria for approval. Data obtained from
clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data. In addition,
delays or rejections may be encountered based upon changes in regulatory policy, regulations or statutes governing product approval
during the period of product development and regulatory agency review.
If
regulatory approval of a potential product is granted, this approval will be limited to those disease states and conditions for
which the product is approved. Marketing or promoting a drug for an unapproved indication is generally prohibited. Furthermore,
FDA approval may require that contraindications, warnings or precautions be included in the product labeling and entail ongoing
requirements for risk management, including post-marketing, or Phase 4, studies, testing and surveillance programs, and distribution
restrictions. Following approval, many types of changes to the approved product, such as adding new indications, manufacturing
changes and additional labeling claims, are subject to further testing requirements and FDA review and approval and may require
the development of additional data or preclinical studies and clinical trials.
Any
drug is likely to produce some toxicities or undesirable side effects in animals and in humans when administered at sufficiently
high doses and/or for sufficiently long periods of time. Unacceptable toxicities or side effects may occur at any dose level at
any time in the course of studies in animals designed to identify unacceptable effects of a product candidate, known as toxicological
studies, or during clinical trials of our potential products. The appearance of any unacceptable toxicity or side effect could
cause us or regulatory authorities to interrupt, limit, delay or abort the development of any of our product candidates. Further,
such unacceptable toxicity or side effects could ultimately prevent a potential product’s approval by the FDA or foreign
regulatory authorities for any or all targeted indications or limit any labeling claims and market acceptance, even if the product
is approved.
In
addition, as a condition of approval, the FDA may require an applicant to develop a REMS. A REMS uses risk minimization strategies
beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks. To determine whether
a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected
benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product
is a new molecular entity. REMS can include medication guides, physician communication plans for healthcare professionals, and
elements to assure safe use (“ETASU”). ETASU may include, but are not limited to, special training or certification
for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries.
The FDA may require a REMS before approval or post-approval if it becomes aware of a serious risk associated with use of the product.
The requirement for a REMS can materially affect the potential market and profitability of a product.
Any
trade name that we intend to use for a potential product must be approved by the FDA irrespective of whether we have secured a
formal trademark registration from the United States Patent and Trademark Office. The FDA conducts a rigorous review of proposed
product names and may reject a product name if it believes that the name inappropriately implies medical claims or if it poses
the potential for confusion with other product names. The FDA will not approve a trade name until the NDA or BLA for a product
is approved. If the FDA determines that the trade names of other products that are approved prior to the approval of our potential
products may present a risk of confusion with our proposed trade name, the FDA may elect to not approve our proposed trade name.
If our trade name is rejected, we will lose the benefit of any brand equity that may already have been developed for this trade
name, as well as the benefit of our existing trademark applications for this trade name.
We
and our collaborators and contract manufacturers also are required to comply with the applicable FDA GMP regulations. GMP regulations
include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and
documentation. Manufacturing facilities are subject to inspection by the FDA. These facilities must be approved before we can
use them in commercial manufacturing of our potential products and must maintain ongoing compliance for commercial product manufacture.
Manufacturers and other entities involved in the manufacture and distribution of approved drugs or biologics are required to register
their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and
certain state agencies for compliance with GMPs and other laws. Accordingly, manufacturers must continue to expend time, money
and effort in the area of production and quality control to maintain GMP compliance. Future inspections by the FDA and other regulatory
agencies may identify compliance issues at the facilities of our contract manufacturers that may disrupt production or distribution
or require substantial resources to correct. In addition, the discovery of conditions that violate these rules, including failure
to conform to GMPs, could result in enforcement actions, and the discovery of problems with a product after approval may result
in restrictions on a product, manufacturer or holder of an approved NDA or BLA, including voluntary recall and regulatory sanctions.
If
a product is approved, we must also comply with post-marketing requirements, including, but not limited to, compliance with advertising
and promotion requirements, which include restrictions on promoting products for unapproved uses or patient populations (known
as ‘‘off-label use’’), monitoring and record-keeping activities, reporting of adverse events, product
sampling and distribution restrictions, and limitations on industry sponsored scientific and educational activities. Although
physicians may prescribe legally available products for off-label uses, manufacturers may not market or promote such uses. The
FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that
is found to have improperly promoted off-label uses may be subject to significant liability. If there are any modifications to
the product, including changes in indications, labeling or manufacturing processes or facilities, we may be required to submit
and obtain FDA approval of a new NDA or BLA or an NDA or BLA supplement, which may require us to develop additional data or conduct
additional pre-clinical studies and clinical trials.
FDA
may withdraw approval of an NDA or BLA 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 mandatory revisions to the approved labeling to add new safety information; imposition of post-market or clinical trials
to assess new safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences
include, among other things: restrictions on the marketing or manufacturing of the product; complete withdrawal of the product
from the market or product recalls; fines, warning letters or other enforcement-related letters or clinical holds on post-approval
clinical trials; refusal of the FDA to approve pending NDAs or BLAs or supplements to approved NDAs or BLAs, or suspension or
revocation of product approvals; product seizure or detention, or refusal to permit the import or export of products; injunctions
or the imposition of civil or criminal penalties; and consent decrees, corporate integrity agreements, debarment, or exclusion
from federal health care programs; or mandated modification of promotional materials and labeling and the issuance of corrective
information.
In
addition to FDA requirements, we must also comply with federal and state anti-fraud and abuse laws, including anti-kickback and
false claims laws, healthcare information privacy and security laws, post-marketing safety surveillance, and disclosure of payments
or other transfers of value to healthcare professionals and entities. In addition, we are subject to other federal and state regulation
including, for example, the implementation of corporate compliance programs.
If
we elect to distribute our products commercially, we must comply with state laws that require the registration of manufacturers
and wholesale distributors of pharmaceutical products in a state, including, in certain states, manufacturers and distributors
who ship products into the state even if such manufacturers or distributors have no place of business within the state. Some states
also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution,
including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as
it moves through the distribution chain.
Outside
of the United States, our ability to market a product is contingent upon receiving a marketing authorization from the appropriate
regulatory authorities, including the EMA. The requirements governing the conduct of clinical trials, marketing authorization,
pricing and reimbursement vary widely from country to country. At present, foreign marketing authorizations are applied for at
a national level, although within the European Community, centralized registration procedures are available to companies wishing
to market a product in more than one European Community member state. If the regulatory authority is satisfied that adequate evidence
of safety, quality and efficacy has been presented, marketing authorization will be granted. This foreign regulatory development
and approval process involves all of the risks associated with achieving FDA marketing approval in the United States as discussed
above. In addition, foreign regulations may include applicable post-marketing requirements, including safety surveillance, anti-fraud
and abuse laws, and implementation of corporate compliance programs and reporting of payments or other transfers of value to healthcare
professionals and entities.
Expedited
development and review programs
The
FDA is authorized to designate certain products for expedited development or review if they are intended to address an unmet medical
need in the treatment of a serious or life-threatening disease or condition. These programs include fast track designation, breakthrough
therapy designation, priority review designation, and accelerated approval pathway.
The
FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that
meet certain criteria. Specifically, new drugs and biologics are eligible for fast track designation if they are intended to treat
a serious or life-threatening condition and preclinical or clinical data demonstrate the potential to address unmet medical needs
for the condition. Fast track designation applies to both the product and the specific indication for which it is being studied.
Fast track designation provides opportunities for more frequent interactions with the FDA review team to expedite development
and review of the product. The sponsor of a drug or biologic can request the FDA to designate the product for fast track status
any time before receiving NDA or BLA approval. Fast track designation may be withdrawn by the sponsor or rescinded by the FDA
if the designation is no longer supported by data emerging from the clinical trial process.
Additionally,
a drug or biologic may be eligible for designation as a breakthrough therapy if the product is intended, alone or in combination
with one or more other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence
indicates that the product may demonstrate substantial improvement over existing currently approved therapies on one or more clinically
significant endpoints. The benefits of breakthrough therapy designation include the same benefits as fast track designation, plus
intensive guidance from the FDA to ensure an efficient drug development program. Drugs or biologics designated as breakthrough
therapies are also eligible for accelerated approval of their respective marketing applications.
A
product may also be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides
a meaningful advantage over available therapies. In addition, it must demonstrate 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
(“IMM”) that is reasonably likely to predict an effect on IMM or other clinical benefit. As a condition of approval,
the FDA may require that a sponsor of a drug or biologic receiving accelerated approval perform adequate and well-controlled post-marketing
clinical trials. If the FDA concludes that a drug or biologic shown to be effective can be safely used only if distribution or
use is restricted, it will require such post-marketing restrictions as it deems necessary to assure safe use of the product. If
the FDA determines that the conditions of approval are not being met, such as the required post-marketing confirmatory trial does
not demonstrate a clinical benefit, the FDA can withdraw its accelerated approval for such drug or biologic. In addition, unless
otherwise informed by the FDA, the FDA currently requires, as a condition for accelerated approval, that all advertising and promotional
materials that are intended for dissemination or publication be submitted to the agency in advance for review.
Finally,
the FDA may designate a product for priority review if it is a drug or biologic that treats a serious condition and, if approved,
would provide a significant improvement in safety or effectiveness. The FDA determines at the time that the marketing application
is submitted, on a case-by-case basis, whether the proposed drug represents a significant improvement in treatment, prevention
or diagnosis of disease when compared with other available therapies. Significant improvement may be illustrated by evidence of
increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting drug reaction,
documented enhancement of patient compliance that may lead to improvement in serious outcomes, or evidence of safety and effectiveness
in a new subpopulation. A priority review designation is intended to direct overall attention and resources to the evaluation
of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six
months for an original BLA or NDA from the date of filing.
Even
if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions
for qualification or decide that the time period for FDA review or approval will not be shortened. Furthermore, fast track designation,
priority review, accelerated approval and breakthrough therapy designation, do not change the standards for approval and may not
ultimately expedite the development or approval process.
Orphan
drug designation and exclusivity
Orphan
drug designation in the United States is designed to encourage sponsors to develop products intended for the treatment of rare
diseases or conditions. In the United States, a rare disease or condition is statutorily defined as a condition that affects fewer
than 200,000 individuals in the United States or that affects more than 200,000 individuals in the United States and for which
there is no reasonable expectation that the cost of developing and making the product available for the disease or condition will
be recovered from sales of the product in the United States.
Orphan
drug designation qualifies a company for certain tax credits. In addition, if a drug candidate that has orphan drug designation
subsequently receives the first FDA approval for that drug for the disease for which it has such designation, the product is entitled
to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same
indication for seven years following product approval unless the subsequent product candidate is demonstrated to be clinically
superior. Absent a showing of clinical superiority, FDA cannot approve the same product made by another manufacturer for the same
indication during the market exclusivity period unless it has the consent of the sponsor or the sponsor is unable to provide sufficient
quantities.
A
sponsor may request orphan drug designation of a previously unapproved product or new orphan indication for an already marketed
product. In addition, a sponsor of a product that is otherwise the same product as an already approved orphan drug may seek and
obtain orphan drug designation for the subsequent product for the same rare disease or condition if it can present a plausible
hypothesis that its product may be clinically superior to the first drug. More than one sponsor may receive orphan drug designation
for the same product for the same rare disease or condition, but each sponsor seeking orphan drug designation must file a complete
request for designation. To qualify for orphan exclusivity, however, the drug must be clinically superior to the previously approved
product that is the same drug for the same condition. If a product designated as an orphan drug ultimately receives marketing
approval for an indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.
Regulation
of companion diagnostic tests
Although
we do not believe that a companion diagnostic test will be required for the safe and effective use of our product candidates,
FDA may disagree and require use of a companion diagnostic to identify appropriate patient populations for our products. Under
the FDCA, in vitro diagnostics, including companion diagnostics, are regulated as medical devices. In the United States, the FDCA
and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device
design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing,
labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance. Unless
an exemption applies, diagnostic tests require marketing clearance or approval from the FDA prior to commercial distribution.
In August 2014, the FDA issued final guidance clarifying the requirements that will apply to approval of therapeutic products
and in vitro companion diagnostics. According to the guidance, for novel drugs, a companion diagnostic device and its corresponding
therapeutic should be approved or cleared contemporaneously by FDA for the use indicated in the therapeutic product’s labeling.
Approval or clearance of the companion diagnostic device will ensure that the device has been adequately evaluated and has adequate
performance characteristics in the intended population.
Reimbursement
Potential
sales of any of our product candidates, if approved, will depend, at least in part, on the extent to which such products will
be covered by third-party payors, such as government health care programs, commercial insurance and managed healthcare organizations.
These third-party payors are increasingly managing access and using restrictive measures to contain costs. If a third-party payor
decides to provide coverage for an approved drug product, patient access and reimbursement is not certain. Further, one payor’s
determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug
product. Decreases in third-party reimbursement or a decision by a third-party payor to not cover a product candidate, if approved,
could reduce utilization of our products, and have a material adverse effect on our sales, results of operations and financial
condition. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize
an appropriate return on our investment in product development.
In
addition, the United States government, state legislatures and foreign governments have continued implementing cost-containment
programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption
of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls
and measures, could further limit our future revenues and results of operations.
Healthcare
Laws and Regulations
Sales
of our product candidates, if approved, or any other future product candidate will be subject to healthcare regulation and enforcement
by the federal government and the states and foreign governments in which we might conduct our business. The healthcare laws and
regulations that may affect our ability to operate include the following:
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The
federal anti-kickback statute makes it illegal for any person or entity to knowingly and willfully, directly or indirectly,
solicit, receive, offer, or pay any remuneration that is in exchange for or to induce the referral of business, including
the purchase, order, lease of any good, facility, item or service for which payment may be made under a federal healthcare
program, such as Medicare or Medicaid. The term “remuneration” has been broadly interpreted to include anything
of value.
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Federal
false claims and false statement laws, including the federal civil False Claims Act, prohibits, among other things, any person
or entity from knowingly presenting, or causing to be presented, for payment to, or approval by, federal programs, including
Medicare and Medicaid, claims for items or services, including drugs, that are false or fraudulent.
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The
United States federal Health Insurance Portability and Accountability Act of 1996, as amended (“HIPAA”), which
prohibits executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters
and which also imposes certain requirements relating to the privacy, security and transmission of individually identifiable
health information on certain types of entities, which include many healthcare providers and health plans with which we interact.
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The
Federal Food, Drug, and Cosmetic Act, which among other things, strictly regulates drug product and medical device marketing,
prohibits manufacturers from marketing such products prior to approval or for unapproved indications and regulates the distribution
of samples.
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Federal
laws, including the Medicaid Drug Rebate Program, that require pharmaceutical manufacturers to report certain calculated product
prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a
condition of reimbursement under government healthcare programs.
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The
so-called “federal sunshine” law, which requires pharmaceutical and medical device companies to monitor and report
certain financial interactions with physicians and teaching hospitals (and additional categories of healthcare practitioners
beginning with reports submitted in 2022) to the federal government for re-disclosure to the public.
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Also,
many states have similar laws and regulations, such as anti-kickback and false claims laws that may be broader in scope and may
apply to claims reimbursed by private payors as well as government programs or regardless of reimbursement. Additionally, we may
be subject to state laws that require pharmaceutical companies to comply with the federal government’s and/or pharmaceutical
industry’s voluntary compliance guidelines, impose specific restrictions on interactions between pharmaceutical companies
and healthcare providers or require pharmaceutical companies to report information related to payments and other transfers of
value to physicians and other healthcare providers or marketing expenditures, as well as state laws governing the privacy and
security of health information, many of which differ from each other in significant ways and often are not preempted by HIPAA.
Many of these laws and regulations also contain ambiguous requirements or require administrative guidance for implementation.
Additionally,
to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws.
Segments
and Geographic Information
Operating
segments are defined as components of an enterprise about which separate discrete information is available for evaluation by the
chief operating decision maker, or decision-making group, in deciding how to allocate resources and in assessing performance.
We view our operations and manage our business in one operating and reporting segment.
Employees
As
of February 22, 2020, we had 59 full-time employees which are located throughout the United States. While we lease office
space for our principal executive offices in Red Bank, NJ, our employees work remotely. None of our employees are represented
by a labor union or covered by a collective bargaining agreement, and we believe our relationship with our employees is good.
Additionally, we utilize independent contractors and other third parties to assist with various aspects of our drug and product
development.
We
provide salaries and benefits that are competitive based on compensation information from independent compensation consultant.
A portion of the compensation for almost all of our employees is performance-based. Performance-based compensation takes into
account both individual and Company-wide performance. In addition, a portion of performance-based compensation consists of equity
incentives. The split between base salary and performance-based compensation is tailored to each employee’s job function
and level. In addition, we provide nationally competitive benefits, including healthcare, a 401(k) program and a technology allowance.
We
are committed to the well-being of our employees and recognize that a remote workforce especially values the ability to balance
work with other aspects of their lives. As a virtual company, we embrace variable work schedules for our employees. We also allow
part-time arrangements and flexible work schedules.
In
addition, we seek to provide a collaborative and inclusive workplace where all employees feel empowered to do their best work
and contribute to our mission. We are an equal opportunity employer and strictly prohibit and do not tolerate discrimination against
employees, including based on race, creed, color, religion, national origin, citizenship status, age, gender, military and veteran
status and sexual orientation. We also prohibit any form of harassment or abuse in the workplace.
We
strive to hire qualified candidates from diverse backgrounds, cultures, and ethnicities. At December 31, 2020, 33% of our C-suite
team was female.
We
also provide professional development and advancement opportunities for our employees that includes internal training, skills
building and opportunities for internal advancement.
Our
Corporate Information
We
are a Delaware corporation formed on October 4, 2016. Our principal executive offices are located at 55 Broad Street, 2nd Floor,
Red Bank, New Jersey 07701. Our phone number is (908) 336-0360 and our web address is http://www.proventionbio.com. Information
contained in or accessible through our web site is not, and should not be deemed to be, incorporated by reference in, or considered
part of, this prospectus supplement.
Available
Information
We
make available free of charge through our website our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports
on Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act. We make
these reports available through our website as soon as reasonably practicable after we electronically file such reports with,
or furnish such reports to, the SEC. You can review our electronically filed reports and other information that we file with the
SEC on the SEC’s web site at http://www.sec.gov. We also make available, free of charge on our website, the reports filed
with the SEC by our executive officers, directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as
reasonably practicable after copies of those filings are provided to us by those persons. The information contained on, or that
can be accessed through, our website is not a part of or incorporated by reference in this Annual Report on Form 10-K.