PART I
This Annual Report on Form 10-K contains forward-looking statements, within the meaning of the Securities Exchange Act
of 1934 and the Securities Act of 1933, that involve risks and uncertainties. Forward-looking statements convey our current expectations or forecasts of future events. All statements contained in this
Annual Report other than statements of historical fact are forward-looking statements. Forward-looking statements include statements regarding our future financial position, business strategy,
budgets, projected costs, plans and objectives of management for future operations. The words "may," "continue," "estimate," "intend," "plan," "will," "believe," "project," "expect," "seek,"
"anticipate," "should," "could," "would," "potential," or the negative of those terms and similar expressions may identify forward-looking statements, but the absence of these words does not
necessarily mean that a statement is not forward-looking. You should not place undue reliance on these forward-looking statements, which speak only as of the date of this report. All of these
forward-looking statements are based on information available to us at this time, and we assume no obligation to update any of these statements. Actual results could differ from those projected in
these forward-looking statements as a result of many factors, including those identified in "Business," "Risk Factors," "Management's Discussion and Analysis of Financial Condition and Results of
Operations" and elsewhere. We urge you to review and consider the various disclosures made by us in this report, and those detailed from time to time in our filings with the Securities and Exchange
Commission, that attempt to advise you of the risks and factors that may affect our future results.
ITEM 1. BUSINESS.
Overview
We are a specialty pharmaceutical company focused on developing and commercializing products for the treatment of central nervous system, or CNS,
diseases. Our extensive expertise in product development has been built over the past 23 years: initially as a standalone development organization, then as a U.S. subsidiary of Shire plc
and, upon our acquisition of substantially all the assets of Shire Laboratories Inc. in late 2005, as Supernus Pharmaceuticals. We launched Oxtellar XR (extended release oxcarbazepine), our
first epilepsy product, in the first quarter of 2013 and launched our second epilepsy product, Trokendi XR (extended release topiramate), in the third quarter of 2013. We are also developing multiple
product candidates in psychiatry to address the large market opportunity in the treatment of attention deficit hyperactivity disorder, or ADHD, including ADHD patients with impulsive aggression. We
market our products in the United States through our own focused sales force targeting specialty physicians and seek strategic collaborations with other pharmaceutical companies to license our
products outside the United States.
Our
neurology portfolio consists of Oxtellar XR and Trokendi XR which are the first and only once-daily extended release oxcarbazepine and topiramate products, respectively, indicated for epilepsy in
the U.S. market. The products are differentiated compared to the immediate release products by offering convenient once-daily dosing and unique pharmacokinetic profiles that can be very important for
patients with epilepsy. A once-daily dosing regimen has been shown to improve compliance allowing patients to benefit from their medications, and the unique smooth and steady pharmacokinetic profiles
of once-daily dosing avoid the blood level fluctuations that are typically associated with immediate release products and their side effects.
Oxtellar
XR is indicated for adjunctive therapy of partial seizures in adults and in children 6 years to 17 years of age and Trokendi XR is indicated for initial monotherapy in patients
10 years of age and older with partial onset or primary generalized tonic-clonic seizures, and as adjunctive therapy in patients 6 years of age and older with partial onset or primary
generalized tonic-clonic seizures or with seizures associated with Lennox-Gastaut syndrome. Since launching both products in 2013, we have grown Oxtellar XR and Trokendi XR to a combined 8,270
prescriptions in the month of December 2013.
Our
psychiatry product candidates include SPN-810 (molindone hydrochloride), which received positive topline results from its Phase IIb study for the treatment of impulsive aggression in ADHD
patients. As a result of a September 2013 scientific meeting with the Food and Drug Administration, or FDA the
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Company
is now designing a Phase III protocol which will undergo a Special Protocol Assessment, or SPA. We expect patient dosing to commence during 2015. SPN-812 is being developed as a
non-stimulant treatment for ADHD. SPN-812 completed a Phase IIa proof of concept trial in 2011 and we have completed the development of several extended release formulations that will be tested
in a future Phase IIb trial. We held a pre investigational new drug application, or IND, meeting with the FDA for the extended release program in June 2013. The Company expects to conduct a
multi-dose steady state pharmacokinetic study in 2014 to select the final product formulation for a Phase IIb trial.
We
have several additional product candidates in various stages of development, including SPN-809 for which we hold an active IND. SPN-809 represents a novel mechanism of action for the U.S.
anti-depressant market. We believe our broad and diversified portfolio of product candidates provides us with multiple opportunities to achieve our goal of becoming a leading specialty pharmaceutical
company focused on CNS diseases.
The
table below summarizes our current portfolio of novel products and product candidates.
|
|
|
|
|
Product
|
|
Indication
|
|
Status
|
Oxtellar XR
|
|
Adjunctive therapy for epilepsy
|
|
Launched
|
Trokendi XR
|
|
Epilepsy
|
|
Launched
|
SPN-810
|
|
Impulsive aggression in ADHD
|
|
Phase IIb completed
|
SPN-812
|
|
ADHD
|
|
Phase IIa completed
|
SPN-809
|
|
Depression
|
|
Active IND
|
We
have a successful track record of developing novel products by applying proprietary technologies to known drugs to improve existing therapies and enable the treatment of new indications. We have a
broad portfolio of drug development technologies consisting of six platforms that include the following: Microtrol (multiparticulate delivery platform), Solutrol (matrix delivery platform) and
EnSoTrol (osmotic delivery system). In addition to Oxtellar XR and Trokendi XR, our proprietary technologies have been used in the following approved products: Carbatrol (carbamazepine), Adderall XR
(mixed amphetamine salts), and Intuniv (guanfacine), marketed by Shire; Equetro (carbamazepine), marketed by Validus Pharmaceuticals Inc.; Sanctura XR (trospium chloride), marketed by
Allergan, Inc.; Oracea (doxycycline), marketed by Galderma Laboratories, L.P.; and Orenitram (treprostinil diethanolamine) that is expected to be launched by United Therapeutics
Corporation, or United Therapeutics, in 2014. We are continuing to expand our intellectual property portfolio to provide additional protection for our technologies, products, and product candidates.
We have three U.S. patents issued covering Oxtellar XR and three U.S. patents issued covering Trokendi XR. Throughout our 23 year history, we have continued our commitment to innovation with a
focus for the past eight years on successfully developing and commercializing our own products in neurology and psychiatry.
Our Strategy
Our goal is to be a leading specialty pharmaceutical company developing and commercializing new medicines in neurology and psychiatry. Key elements
of our strategy to achieve this goal are to:
-
-
Expand our in-house sales and marketing capabilities, focused on specialty markets in the United
States, to promote Oxtellar XR and Trokendi XR.
We have built our sales and marketing capabilities in the United States to launch Oxtellar XR and Trokendi XR. We expanded our
sales and marketing capabilities throughout 2013 to approximately 110 sales representatives and are further expanding these capabilities to more than 150 sales representatives by mid-2014.
-
-
Continue to advance our product candidates in our psychiatry portfolio, including SPN-810 and
SPN-812.
As part of our longer term strategy, we intend to further develop our product candidates in our psychiatry portfolio to enable further diversification of our pipeline
and future growth. SPN-810 (molindone hydrochloride) is being developed as a treatment for impulsive
2
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aggression
in patients with ADHD. The Company successfully completed a Phase IIb trial in 2012. As a result of a September 2013 scientific meeting with the FDA, the Company is now designing a
Phase III protocol which will undergo a SPA with patient dosing planned to begin in 2015. SPN-812 is being developed as a non-stimulant treatment for ADHD. SPN-812 completed a Phase IIa
proof of concept trial in 2011 and we have developed several extended release formulations. We held a pre-IND meeting with the FDA for the extended release program in June 2013. The Company expects to
conduct a multi-dose steady state pharmacokinetic study in 2014 to select the final product formulation for a Phase IIb trial.
-
-
Continue to develop differentiated products by applying our technologies to known drug
compounds.
We intend to continue our development activities on known drug compounds and compounds with established mechanisms of action thereby reducing the risks, costs and
time typically associated with pharmaceutical product development. We intend to leverage our proprietary and in-licensed technologies, to expand our patent portfolio and further develop and protect
our diverse pipeline of product candidates.
-
-
Establish strategic partnerships to accelerate and maximize the potential of our product
candidates worldwide.
We intend to continue to seek strategic collaborations with other pharmaceutical companies to commercialize our products outside the United States. We
believe that we are an attractive collaborator for pharmaceutical companies due to our broad portfolio of proprietary technologies and our proven product development track record. We may seek to
in-license products which would be sold through our sales force.
-
-
Leverage our management team's expertise to develop and commercialize our broad portfolio of
product candidates.
We intend to leverage the expertise of our executive management team in developing and commercializing innovative therapeutic products. We plan to continue
to evaluate and develop additional CNS product candidates that we believe have significant commercial potential through our internal research and development efforts or, wherever appropriate, external
collaborations.
Epilepsy
Overview
Epilepsy is a complex neurological disorder characterized by spontaneous recurrence of unprovoked seizures, which are sudden surges of electrical
activity in the brain that impair a person's mental and/or physical abilities. Epilepsy, which is typically diagnosed by a neurologist, is estimated to affect 50 million people worldwide(1) and
2 million people in the United States.(2) According to IMS Health, U.S. sales of anti-epileptic drugs, or AEDs, were approximately $4.6 billion in 2013.
-
(1)
-
Bialer,
M.,
Key factors in the discovery and development of new antiepileptic drugs
, published January 2010
in
Nature
.
-
(2)
-
U.S.
Centers for Disease Control and Prevention,
Epilepsy Self-Management Tools
(citing DiIorio, C.,
The Prevention Research Centers' Managing Epilepsy Well
Network
, published September 2010 in
Epilepsy &
Behavior
).
3
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Epileptic
seizures can cause a person to experience severe muscle jerking, to lose consciousness and fall, or to suffer from distorted vision, all potentially leading to physical injuries or
hospitalization. Until reliable seizure control has been achieved, patients are forced to adjust their lifestyles to avoid activities that a seizure can significantly disrupt or render life
threatening. A breakthrough seizure is a sudden, unexpected seizure experienced by a patient who previously had achieved reliable seizure control. Even when no physical injury occurs, breakthrough
seizures often result in significant social, legal and developmental consequences for patients such as loss of driver's license, loss of employment, disruption of school attendance, academic
underachievement, and disruption of social networks. In addition, a single breakthrough seizure can lead to permanent loss or reduction in overall seizure control. Data suggest that a significant
proportion of patients who experience a breakthrough seizure have a lower chance of achieving reliable seizure control.(3) In certain cases, a single breakthrough seizure can develop into
status epilepticus
, a prolonged seizure or series of repeated seizures, and eventually result in brain damage or death. Data indicate that the risk of
sudden unexpected death in epilepsy was 23 times higher in patients who had at least one breakthrough seizure compared to patients who had achieved seizure control.(4)
Current Treatment Options
Once a patient is diagnosed with epilepsy, the goal of the neurologist is to find the particular drug or combination of drugs, and appropriate
dosing, that will lead the patient to reliable seizure control while minimizing side effects. There are currently over 15 approved AEDs marketed in the United States. Side effects play a major role in
altering treatment in epilepsy as they can limit the usefulness of AEDs. AEDs are generally associated with the incidence of numerous side effects that can adversely impact the quality of life for
patients with epilepsy. Such side effects may include dizziness, paresthesia, headaches, cognitive deficiencies such as memory loss and speech impediment, digestive problems, somnolence, double
vision, gingival enlargement, nausea, weight gain, and fatigue. To address these side effects and help patients better tolerate their AEDs, neurologists typically initiate treatment with a single AED
as monotherapy at a low dose and then increase the dose(titration) until the patient reaches the most efficacious dose with an acceptable tolerance of side effects.
Many
patients develop refractory epilepsy, which refers to inadequate control of seizures despite treatment, thereby requiring treatment with multiple AEDs. Patients taking more than one AED at a time
are susceptible to side effects associated with each of the multiple drugs and with drug interactions. Despite the introduction of new AEDs in the past few years, drug therapy remains ineffective for
seizure control in up to 30% of patients with epilepsy.(5) Many patients fail drug therapy either because the drugs do not control their seizures or because they cannot tolerate the side effects.
-
(3)
-
Citizen
Petition of UCB, Inc. to U.S. Food and Drug Administration, submitted October 3, 2006 (citing Schmidt, D.,
Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of
current clinical experience
, published
December 2005 in
Epilepsia
).
-
(4)
-
Citizen
Petition of UCB, Inc. to U.S. Food and Drug Administration, submitted October 3, 2006 (citing Tomson, T.,
Sudden unexpected death in epilepsy: a review of incidence and risk factors
, published
May 2005 in
Acta Neurologica
Scandinavia
).
-
(5)
-
World
Health Organization,
Epilepsy: aetiogy, epidemiology and prognosis
, Fact Sheet No. 165, revised
February 2001.
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Dynamics of the Epilepsy Market
There are several important dynamics that play a major role in the treatment of epilepsy and that differentiate epilepsy from many other
diseases:
-
-
Compliance is Critical to the Reduction in Breakthrough Seizures
Compliance
with drug treatment regimens is critically important to achieving effective therapy for patients with epilepsy where the consequences of non-compliance can be life threatening. Patient
non-compliance with AED therapy is a serious issue and remains one of the most common causes of breakthrough seizures. Not only is taking all prescribed doses critical for epileptic patients, but the
timing of when patients take their prescribed doses is also important. Typically, non-compliance is caused by frequent or multiple dosing, serious side effects, or a lack of tolerability. A 2002
survey undertaken by neurologists in the United States found that, at least once per month, 71% of patients with epilepsy forgot to take their AED, and it was evident that the chances of a patient
missing a dose increased with the number of tablets prescribed.(6) Of patients that missed a dose, 45% reported a breakthrough seizure. Patients taking a larger number of tablets/capsules further
increased their odds of having a breakthrough seizure by 43% after a missed dose. Other studies also have shown reduced rates in breakthrough seizures as a result of improved compliance with AED
treatment regimens. In addition, a non-compliant patient can cost the healthcare system approximately $16,300 per year when compared to a compliant patient.(7)
-
-
Immediate Release Products Have Serious Side Effects and Lack of
Tolerability
The
FDA has recognized AEDs as being "critical dose drugs," or drugs in which a comparatively small difference in dose or concentration may lead to serious therapeutic failures and/or serious side
effects. Immediate release formulations of AEDs necessitate frequent administration to maintain appropriate plasma concentrations. However, these immediate release formulations cause wide fluctuations
of blood levels of the active drug during the day, with peak concentrations when the drug is released and potentially sub-therapeutic concentrations thereafter. At least one study has shown that
complaints of side effects typically occur when blood levels exceed certain concentrations, particularly at high doses, and the risk of breakthrough seizures can occur when blood levels are below
certain minimum effective levels, as indicated in the chart below.
-
(6)
-
Cramer,
J.A.,
The relationship between poor medication compliance and seizures
, published August 2002 in
Epilepsy & Behavior
.
-
(7)
-
Faught,
R.E., Weiner, J.R., Guérin, A. et al.,
Impact of nonadherence to antiepileptic drugs on healthcare
utilization and costs: Findings from RANSOM study
, published March 2009
Epilepsia
; 50:501-9.
5
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Simulated Plasma Concentration-Time Curve at Steady State of Immediate Release
Anti-Epileptic Drug Administered Over Two Days
Source:
Pellock, JM et al, Epilepsy & Behavior 5 (2004), 302
-
-
Generic Substitution May Cause an Increase in Breakthrough Seizures
Patients
today are most typically switched from branded drugs to generics, or from one generic drug to another, mainly to reduce cost. In most states, unless a physician explicitly writes "dispense as
written" or "no substitution," pharmacists can switch a patient to a lower-cost generic drug without the consent of either the patient or the physician. Epilepsy patients are particularly sensitive to
changes in their drugs or formulations because slight variations in the blood concentrations of these drugs could lead to the occurrence of breakthrough seizures. Accordingly, despite existing
regulatory criteria to ensure the bioequivalence of generic drugs, the "switch-back" rates of AEDs (that is, the frequency of an individual being returned to his or her previous branded product under
a physician's guidance) is much
higher than for many other drug products. For example, the rates of patients switching back from generics to branded drugs because of adverse events, or AEs, were found to be 20.8% to 44.1% for AEDs
compared to 7.7% to 9.1% for non-AEDs.(7)
A
number of epilepsy advocacy groups such as the Epilepsy Foundation of America, the American Academy of Neurology, the Centers for Medicare and Medicaid Services and several regulatory agencies
around the world, including the UK National Institute for Health and Clinical Excellence, or NICE, Sweden's Medical Products Agency, or MPA, and other European agencies, have all acknowledged that AED
generic substitutions for non-therapeutic reasons can be harmful and should either be limited or not permitted, and have issued guidelines, recommendations or taken affirmative steps to limit such
substitutions. Additionally, approximately 88% of physicians indicate that they are concerned with the increase in breakthrough seizures resulting from switching from branded drugs to generics.(8)
While we are not aware of any well-controlled studies conducted to establish unequivocal scientific evidence that generic substitutions cause increased incidence of breakthrough seizures, the FDA is
currently considering stricter standards of bioequivalence for generics and its Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted 11-2 that the current bioequivalence standards
are insufficient for critical dose drugs such as AEDs.
-
(7)
-
J.
LeLorier,
Clinical consequences of generic substitution of lamotrigine for patients with epilepsy
,
published October 2008 in
Neurology
.
-
(8)
-
Dalia
Buffery, MA, ABD,
Switching to Generics Antiepileptic Drugs: Growing Concerns
, published September
2008 in
American Health & Drug Benefits.
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-
-
Physicians are Reluctant to Switch to New Chemical Entities
In
the epilepsy market, new chemical entities, or NCEs, generally lack the same appeal that would typically be associated with a new drug for other indications. Based on IMS Health prescription data
from 1994 to 2005 for NCE launches for seizure disorders, such NCEs, on average, experienced slow market penetration, characterized by a 0.58% to 1.1% market share point gain on an annual basis. We
believe this is because physicians are often reluctant to change a stable patient's existing therapy and risk a breakthrough seizure in the patient. Despite the introduction of several NCEs over the
past decade, a significant number of epileptic patients continue to lack reliable seizure control. Many NCEs continue to be associated with several side effects. Therefore, many older and existing
drugs continue to be prescribed and their prescription levels have either been maintained since their peak or declined very slowly.
Benefits of Extended Release Products in the Epilepsy Market
-
-
Extended Release Products May Improve Compliance and Reduce Breakthrough
Seizures
Achieving
reliable seizure control for patients and avoiding the serious health and life dangers that can be associated with breakthrough seizures depends on patients being compliant and diligent in
taking their medications. Frequent and multiple dosing, side effects and lack of tolerability of the immediate release products can significantly contribute to patients forgetting doses or
intentionally skipping them.
Even taking a second or third dose later than the scheduled time may place a patient at an increased risk of a breakthrough seizure because the drug level in the patient's blood could drop below the
minimum effective therapeutic level that prevents such seizures. We believe increased patient compliance can be achieved with extended release products that offer once-daily dosing, reduced side
effects and improved tolerability. We believe physicians understand that the release profiles of extended release products can produce more consistent and steadier blood levels as compared to
immediate release products, resulting in fewer side effects and better tolerability that further help patients to be compliant, have fewer breakthrough seizures and, correspondingly, enjoy a better
quality of life.
-
-
Extended Release Products Reduce Side Effects and Improve Tolerability
When
extended release formulations are used appropriately, drug levels remain within the patient's therapeutic zone, thereby reducing patient exposure to fluctuating drug levels which may exacerbate
side effects or induce frequency of breakthrough seizures. Because extended release formulations can reduce peak concentrations, it may also be possible to adjust doses upward to a more efficacious
level without exacerbating side effects associated with peak concentrations. Extended release formulations can also reduce the frequency and the extent of the troughs, or lower concentrations of the
drug in the blood, thereby avoiding concentrations below the minimum effective concentrations that can increase the risk of breakthrough seizures.
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Simulated Plasma Concentration-Time Curve at Steady State of Immediate Release and
Extended Release Anti-Epileptic Drug Administered Over Two Days
Source:
Pellock, JM et al, Epilepsy & Behavior 5 (2004), 302
The
enhanced safety profile of extended release products as compared to similar immediate release products has been supported by several studies. For example, in a 2004 published trial conducted by
physicians at Johns Hopkins, Carbatrol, an anti-epileptic extended release carbamazepine product that uses our Microtrol technology, and Tegretol XR, another extended release carbamazepine product,
demonstrated better tolerability and side effect profiles than comparable immediate release products. The trial reported that 49% of patients had side effects during treatment with immediate release
carbamazepine such as sedation, double-vision, confusion, ataxia, dizziness or poor coordination, whereas with extended release carbamazepine treatments, only 20% of patients reported these side
effects.
Reduction in CNS Side Effects Following Conversion to Carbamazepine Extended Release
from Immediate Release Preparation
Source:
Miller AD et al., Acta Neurol. Scand 2004: 109: 374-377
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Equally
as important, the patients in the trial tolerated high doses of extended release carbamazepine significantly better than high doses of immediate release carbamazepine. Specifically, 63% of
patients treated with 1200 mg or more per day of immediate release carbamazepine developed side effects, yet only 12% of patients experienced side effects while taking similar doses of extended
release carbamazepine. The investigators surmised that the improved tolerability of extended release
carbamazepine at high doses may provide a treatment option for patients previously discontinuing immediate release carbamazepine because of dose-limiting side effects.
Other
products where reductions in side effects were reported by patients when switching from immediate release to extended release formulations include Depakote ER (divalproex sodium extended
release) and Keppra XR (levetiracetam extended release).
-
-
Managed Care Does Not Limit Success of Extended Release Products
Given
the serious nature of epilepsy and the key dynamics in the epilepsy market, we believe managed care plans acknowledge the important benefits of extended release AED products and, therefore, have
not limited the success of such products even when lower cost generic immediate release products are available. For example, according to industry data, the commercial launches of extended release
products Keppra XR and Lamictal XR have enjoyed acceptance rates by managed care plans that are similar to those of the corresponding immediate release products. Most managed care plans also
acknowledge the position of several patient advocacy groups and the American Academy of Neurology regarding the risks of generic substitution of AEDs, including potential for breakthrough seizures.
Although switching to a low-cost generic AED may initially offer some cost savings, we believe they also recognize that the risk and cost of one breakthrough seizure outweighs the potential savings
from generics. For example, the healthcare costs associated with the treatment of patients who experience breakthrough seizures, which may run in excess of $26,000 per patient on an annual basis, is
significantly greater than any cost savings per patient that may be achieved through switching to a low-cost generic AED. According to a 2009 survey, the total healthcare costs for patients using
branded topiramate products were approximately 20% lower than for patients using multiple generic topiramate products.(9)
-
-
Extended Release Products Perform Well in the Market
Extended
release products have generally been commercially successful in the epilepsy market, even in the face of immediate release generic products. Moreover, IMS Health prescription data for seizure
disorder drugs from 1994 to 2005 shows that extended release products perform better than NCEs during the first five years of their commercial launch. Currently, there are five extended release AEDs
on the market (Tegretol XR, Carbatrol, Depakote ER, Lamictal XR, Keppra XR), as reflected in the chart below, with Depakote ER gaining almost 40% of all divalproex prescriptions, including immediate
release versions of Depakote and generic divalproex, in its fifth year after commercial launch. We believe that the modest conversion of the corresponding molecule prescriptions of the recent
commercial launches of Keppra XR and Lamictal XR are due to limited promotional support behind both products.
-
(9)
-
Duh,
M.S.,
The risks and costs of multiple-generic substitution of topiramate
, published June 2009 in
Neurology
.
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Comparison of Molecule Conversion of Extended Release Anti-Epilepsy Drugs
(measured as percentage of total prescriptions for each individual molecule)
Source:
IMS Health
Our Neurology Portfolio
Oxtellar XR and Trokendi XR are novel extended release formulations of two well known and approved AEDs, oxcarbazepine and topiramate, respectively.
Both formulations are designed to offer epilepsy patients effective therapy, reduced side effects and improved compliance with once-per-day dosing. We believe that by delivering more consistent and
steady maintenance of blood level concentrations of oxcarbazepine and topiramate, respectively, Oxtellar XR and Trokendi XR can potentially reduce adverse side effects and improve tolerability of the
drugs, which can improve compliance and enable patients to benefit from better seizure control and fewer breakthrough seizures as compared to similar immediate release products. Given that Oxtellar XR
and Trokendi XR are based on different drug compounds and different mechanisms of action, they target different market segments and patient populations within the epilepsy market.
Oxtellar XR (extended release oxcarbazepine)
Oxtellar XR is a novel oral once-daily extended release formulation of oxcarbazepine, which we launched on February 4, 2013. The product was
approved by the FDA as adjunctive therapy of partial seizures in adults and in children 6 years to 17 years of age and has three years of marketing exclusivity through October 2015.
Three
U.S. patents have been issued covering Oxtellar XR providing patent protection through 2027.
Novartis
markets oxcarbazepine as an immediate release formulation, under the brand name Trileptal. It is also available in a generic form. Trileptal was initially developed and approved in the United
States in 2000. Trileptal is indicated for monotherapy and adjunctive therapy of epilepsy. Like many
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AED's
it is also prescribed by physicians for nonapproved indications. It reached peak worldwide sales of $721 million in 2006 before generic products entered the U.S. market in October
2007.(10)
Oxcarbazepine
represents approximately 2.8% of total AED prescriptions, according to data from IMS Health. Oxcarbazepine is an active voltage-dependent sodium channel blocker that, despite its
effectiveness in treating epilepsy, is associated with many side effects that tend to limit its use. The side effects associated with taking oxcarbazepine include, among others, dizziness, double
vision, somnolence, nausea, fatigue and vomiting. Oxtellar XR has been designed to reduce side effects, resulting in improved patient compliance and tolerability.
With
its novel pharmacokinetic profile that delivers lower peak plasma concentrations, slower rate of input and smoother and more consistent blood levels compared to immediate release products such as
Trileptal, we believe Oxtellar XR has the potential of improving the tolerability of oxcarbazepine by reducing the side effects experienced by patients. This could enable more patients to effectively
tolerate higher doses of oxcarbazepine, which would permit them to benefit from the resulting efficacy and greater seizure control that have been previously reported in patients at higher doses. In
addition, Oxtellar XR once-per-day dosing is designed to improve patient compliance compared to the current immediate release products that are taken multiple times per day.
Commercialization Strategy
Oxtellar XR is the only once-daily oxcarbazepine product indicated for the treatment of epilepsy in the U.S. as an adjunctive therapy and competes
against the existing immediate release oxcarbazepine products on the market. We believe that Oxtellar XR could, over time, capture a significant share of the oxcarbazepine prescription market,
consistent with the performance of similar extended release products that have been introduced in the U.S. epilepsy market over the past 15 years. We launched the product on February 4,
2013 with a small specialty sales force of approximately 75 representatives. As of December 31, 2013, we had a sales force of more than 110 sales representatives promoting Oxtellar XR for
adjunctive therapy of partial seizures in adults and in children 6 years to 17 years of age in the United States. Our commercial effort includes our sales force calling on healthcare
providers to educate them on the treatment benefits of Oxtellar XR in epilepsy. Three US patents have been issued covering Oxtellar XR and providing patent protection expiring no earlier than 2027.
The
results of the Phase III pivotal trial for Oxtellar XR appeared in the March 2014 issue of
Acta Neurologica Scandinavica
. The publication
entitled "Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR) as adjunctive therapy in patients with refractory
partial-onset seizures: a randomized controlled trial," can be found in
Acta Neurologica Scandinavica
, Volume 129, Issue 3, pages 143-153 and is
available online at http://onlinelibrary.wiley.com/doi/10.1111/ane.12207/abstract. These results indicate the effectiveness of Oxtellar XR in the treatment of patients with refactory partial onset
seizures.
-
(10)
-
Based
on sales data as reported in Novartis AG's Annual Report on Form 20-F for the fiscal year ended December 31, 2006 and in a media
release issued by Novartis International AG on January 21, 2008.
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Trokendi XR (extended release topiramate)
Trokendi XR is a novel oral once-daily extended release topiramate product for the treatment of epilepsy, which we launched on August 26,
2013. Trokendi XR is the first once-daily topiramate product approved in the U.S., as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized
tonic-clonic seizures, and as adjunctive therapy in patients 6 years of age and older with partial onset or primary generalized tonic-clonic seizures or with seizures associated with
Lennox-Gastaut syndrome.
Topiramate
is marketed by Johnson & Johnson under the brand name Topamax and is also available in generic forms. Topiramate is currently available only in immediate release form and is
indicated for monotherapy and adjunctive therapy in epilepsy and for the treatment of migraine. Like many AED's it is also prescribed by physicians for nonapproved indications. Topamax reached peak
worldwide sales of $2.7 billion in 2008, before generic products entered the U.S. market in March 2009.(11) With approximately 11.7 million total topiramate prescriptions in the U.S. in
2013, topiramate represents approximately 8.7% of total AED prescriptions, according to data from IMS Health. Topiramate is believed to work in epilepsy through various mechanisms. It enhances the
inhibitory effect of the GABA (gamma-aminobutyric acid) neurotransmitter that regulates neuronal excitability throughout the nervous system, blocks the excitatory effect of the glutamate
neurotransmitter, blocks the sodium
channel and inhibits the carbonic anhydrase enzyme. The side effects associated with taking topiramate, which have tended to limit its use, include, among others, dizziness, fatigue, somnolence and
slowing of certain cognitive functions.
Trokendi
XR is designed to improve patient compliance and to have a better tolerability profile compared to the current immediate release products that are taken multiple times per day. Trokendi XR's
pharmacokinetic profile delivers lower peak plasma concentrations and slower input rate over an extended time period resulting in smoother and more consistent blood levels of topiramate during the day
compared to immediate release Topamax. We believe such a profile mitigates blood level fluctuations that are typically associated with many of the side effects or breakthrough seizures that patients
can suffer when taking immediate release products. Side effects can lead patients to skipping doses, and such non-compliance could place them at higher risk for breakthrough seizures.
Commercialization Strategy
We believe that the side effects associated with immediate release topirate create an opportunity for us to offer patients Trokendi XR as an
alternative therapy with an improved once-per-day profile. We believe that Trokendi XR could, over time, capture a significant share of the topiramate prescriptions, consistent with the performance of
similar extended release products that have been introduced in the U.S. epilepsy market over the past 15 years. As of December 31, 2013, we had a sales force of more than 110 sales
representatives promoting Trokendi XR to healthcare providers for the treatment of epilepsy in the United States. Three U.S. patents have been issued covering the product and providing patent
protection expiring no earlier than 2027.
Clinical
data was released at the American Epilepsy Society Meeting in December 2013 in Washington DC. You may find this data and scientific posters included in Exhibit 99.2 of Form 8-K
filed on December 13, 2013. In total, Supernus had twelve presentations/scientific posters highlighting data that were generated on Trokendi XR and Oxtellar XR.
-
(11)
-
Based
on sales data as reported in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 3, 2010.
12
Table of Contents
ADHD
Overview
ADHD is a common CNS disorder characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity. ADHD affects an
estimated 6% to 9% of all school-age children and 3% to 5% of adults in the United States.(12) An estimated 50% of children with ADHD continue to meet criteria for ADHD into adolescence.(13) For the
12 months ending July 2013, according to data from IMS Health, the U.S. market for ADHD prescription drugs was $8.6 billion with 58.2 million prescriptions. Diagnosis of ADHD
requires a comprehensive clinical evaluation based on identifying patients who exhibit the core symptoms of inattention, hyperactivity, and impulsivity. Generally, behavior is sufficiently severe and
persistent to cause functional impairment. Although many children may be inattentive, hyperactive or impulsive, the level of severity and degree of functional impairment, as well as considerations of
what may be behind the underlying symptoms, determine which children meet the diagnosis and are treated for ADHD. It is estimated that the annual societal cost of illness for ADHD is more than
$36 billion.(14)
Current Treatment Options
Since Ritalin was introduced, stimulant therapies have grown to become the most common form of treatment for ADHD. Studies indicate that
approximately 80% of ADHD patients respond to stimulants.(15) A key difference between older and newer oral stimulants is the duration of action. Most of the older stimulants, representing
approximately 35% of total oral stimulant prescriptions based on IMS Health data, are immediate release products that last approximately four hours, requiring multiple administrations throughout the
day. In contrast, most of the recently launched products, representing approximately 65% of total oral stimulant prescriptions based on IMS Health data, are extended release formulations that last up
to twelve hours or more.
While
stimulant treatments calm and improve the concentration of ADHD patients, these drugs have been shown to have various side effects including loss of appetite, insomnia and, to a lesser degree,
cardiovascular effects. Stimulant treatments are controlled substances and can be associated with social stigma and the potential for abuse. Approximately 30% of patients with ADHD are non-responsive
to or non-tolerant of treatment with stimulants.(16) Non-stimulants offer physicians an alternative ADHD therapy, including for patients who have coexisting conditions, such as conduct disorder, major
depressive disorder, or bipolar disorder, that are contraindicated for stimulant use based on the risk for stimulant abuse.
-
(12)
-
Dopheide,
J.A.,
Attention-Deficit-Hyperactivity Disorder: An Update
, published June 2009 in
Pharmacotherapy
.
-
(13)
-
Floet, A.M.W.,
Attention-Deficit/Hyperactivity Disorder
, published February 2010 in
Pediatrics in
Review
.
-
(14)
-
Pelham,
W.E.,
The Economic Impact of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents
,
published July 2007 in
Journal of Pediatric Psychology
.
-
(15)
-
Swanson,
J.M.,
Attention-deficit hyperactivity disorder and hyperkinetic disorder
, published February 1998
in
The Lancet
and Budur, K.,
Non-Stimulant Treatment for Attention Deficit Hyperactivity Disorder
,
published July 2005 in
Psychiatry
.
-
(16)
-
Wigal,
S.B.,
Efficacy and Safety Limitations of Attention-Deficit Hyperactivity Disorder Pharmacotherapy in Children and
Adults
, published August 2009 in
CNS Drugs
and Budur, K.,
Non-Stimulant Treatment for Attention Deficit
Hyperactivity Disorder
, published July 2005 in
Psychiatry
.
13
Table of Contents
Coexisting Conditions
Studies show that as many as 67% of children who have ADHD may have coexisting conditions such as oppositional defiant disorder, conduct disorder,
anxiety disorder and depression.(17) In addition, it has been estimated that approximately 25% of children with ADHD also exhibit persistent conduct problems, such as impulsive aggression.(18)
Untreated, these serious conduct problems can place patients at risk of persistent aggressive and anti-social behavior, such as knowingly destroying property, physically attacking people and bullying.
These patients also face an increased risk of suicidal behavior, and are at high risk of entering the juvenile justice system and developing substance abuse problems later in adulthood.
Aggression
is usually divided into two subtypes: predatory (i.e., "cold") aggression, which can be described as goal-oriented, controlled and/or planned, and impulsive or affective
(i.e., "hot") aggression, which can be described as reactive, unplanned and/or uncontrolled. Patients with ADHD who exhibit aggression commonly demonstrate the "hot," or impulsive, type of
aggression. For these patients, this "hot" aggression is generally recurrent, occurs outside of a justifiable social context, has intensity, frequency, duration or severity that is disproportionate to
its triggers and causes distress and impairment to the patient. Impulsive aggression represents a broad category of maladaptive, aggressive behaviors that can complicate the management of ADHD,
autism, bipolar disorder, post-traumatic stress disorder and other psychiatric disorders.
Current Treatments for Impulsive Aggression in Patients with ADHD
Currently, there are no approved medications for treating impulsive aggression in patients with ADHD. The current treatment options for impulsive
aggression in patients with ADHD include psychosocial interventions, such as school-or family-based behavioral therapies, which are usually not wholly effective. In the large, multisite Multimodal
Treatment Study of Children with ADHD,(19) a seminal clinical trial designed by experts from key stakeholder communities such as the National Institute of Mental Health, researchers observed that
after 14 months of either ADHD medication-only or a regimen that combined ADHD medication with behavioral interventions, 44% of those children with ADHD (or 26% of the total sample size in the
trial) who exhibited initial aggression still had what can be described as impulsive aggression at the end of the trial, demonstrating that psychosocial interventions may not work for a large
percentage of children with ADHD who exhibit aggressive behaviors.
In
response, doctors have also tried to treat this group with off-label use of prescription medicines, such as mood stabilizers, stimulants and anti-psychotic drugs. Results have varied, but
anti-psychotic drugs appear to have the best therapeutic potential. Unfortunately, many of these agents are associated
with adverse effects including obesity, dyskinesia, lipid abnormalities, and diabetes, which is of particular concern when treating pediatric populations.
-
(17)
-
Floet, A.M.W.,
Attention-Deficit/Hyperactivity Disorder
, published February 2010 in
Pediatrics in Review
.
-
(18)
-
Jensen,
P.S.,
Consensus Report on Impulsive Aggression as a Symptom Across Diagnostic Categories in Child Psychiatry: Implications
for Medication Studies
, published March 2007 in
Journal of the American Academy of Child and Adolescent Psychiatry
.
-
(19)
-
The
MTA Cooperative Group,
A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity
disorder
, published December 1999 in
Archives of General Psychiatry
.
14
Table of Contents
Our Psychiatry Portfolio
Our psychiatry portfolio includes three product candidates for the treatment of impulsive aggression in patients with ADHD, ADHD or its coexisting
conditions and one product candidate for depression, each of which is designed to bring important advancements in therapy.
SPN-810 (molindone hydrochloride)
We are developing SPN-810 (molindone hydrochloride extended release formulation) as a novel treatment for impulsive aggression in patients with ADHD.
We initiated a Phase IIb trial of SPN-810 in the United States in June 2011, from which we received preliminary results in November 2012. The study accomplished its objectives of establishing a
dose range at which the drug is effective and confirmed the efficacy of SPN-810 in the treatment of impulsive aggression in some ADHD patients. Based on the efficacy demonstrated by the low and medium
doses in this study across several measures in these patients, we have decided to advance the program into later stage development. We are continuing our discussions with the FDA to advance the
development program and the design and protocol for Phase III clinical trials of SPN-810. If approved by the FDA, SPN-810 could be the first product available to address this serious, unmet
medical need.
Molindone
hydrochloride was previously marketed in the United States as an anti-psychotic to treat schizophrenia under the trade name Moban. Molindone hydrochloride is unusual among anti-psychotics in
that it is less likely to be associated with weight gain. In addition, we believe the lower doses tested for the proposed indication of impulsive aggression should be more easily tolerated than the
higher doses approved to treat schizophrenia. SPN-810's low potential to cause weight gain leads us to believe that SPN-810 could be an attractive candidate among the anti-psychotic drugs for the
effective treatment of impulsive aggression in patients with ADHD. Although initially we are developing SPN-810 as a treatment of impulsive aggression in patients with ADHD, if we are successful in
demonstrating the effectiveness of SPN-810, we may then look to develop the product candidate for the treatment of other patient populations that are characterized by impulsive aggression, including
patients with autism, schizophrenia, some forms of dementia, and bipolar disorder. We are developing an intellectual property position around the novel synthesis process for this product candidate,
its novel use in impulsive aggression in ADHD and its novel delivery with extended release.
SPN-810 Development Program
We have conducted several clinical trials for SPN-810, including a Phase IIb trial that was successfully completed in 2012. As a result of a
September 2013 scientific meeting with the FDA, the Company is now designing a Phase III protocol which will undergo a SPA with patient dosing planned to begin in 2015. In 2014, the Company
will focus on preparations for this Phase III trial. Such preparations include scaling up the active ingredient and formulation manufacturing to a commercial scale to produce adequate supplies
for pivotal Phase III trials.
In
2012, we completed a Phase IIb multicenter, randomized, double-blind, placebo-controlled trial in the United States in pediatric subjects 6 to 12 years of age diagnosed with ADHD and
impulsive aggression that is not controlled by optimal stimulant and behavioral therapy. The primary objective of the study was to assess the effectiveness of SPN-810, extended release, at three
different doses in reducing impulsive aggression after at least three weeks of treatment. The primary endpoints were the effect in reducing impulsive aggression as measured by change in the score of
the RetrospectiveModified Overt Aggression Scale, or R-MOAS, and the rate of remission of impulsive aggression. Secondary endpoints include measurement of the effectiveness of SPN-810 on
Clinical Global Impression, or CGI, and ADHD scales as well as evaluation of the safety and tolerability of the drug. In addition, we are exploring the potential added advantages of an
extended-release formulation, such as greater compliance and, therefore, effectiveness in school-age children and lower unwanted side
15
Table of Contents
effects
or interpatient variability. Patients who completed the study were offered the opportunity to continue into an open-label phase of six months duration. We received preliminary results from
this trial in November 2012.
For all patients
, low and medium doses of SPN-810 met the efficacy endpoint of rate of remission of aggression and showed statistical significance
versus placebo with p-values of 0.009 and 0.043 and percent of patients with R-MOAS remission of 51.9% and 40.0%, respectively. Although statistical significance was not reached, the low and medium
doses also showed a reduction in score for the R-MOAS of 62.6% and 57.9%, respectively, with p-values of 0.071 and 0.115.
For patients of 30 kg or more in weight
, the low and medium doses of SPN-810 showed statistical significance versus placebo on the change in R-MOAS
primary endpoint with p-values of 0.024 and
0.049, and high percent reduction in the R-MOAS scores of 80.9% and 75.2%, respectively. In addition, both doses resulted in remission of aggression with statistical significance versus placebo
(p-values of 0.004 and 0.021), and percentages of patients with R-MOAS remission of 66.7% and 53.3%, respectively. The low dose also met the secondary endpoints of Clinical Global Impression for
Severity and Improvement, and of the Swanson, Nolan and Pelham Rating Scale, or SNAP-IV, rating for Oppositional Defiant Disorder, or ODD, with statistical significance versus placebo with p-values of
0.007, 0.017 and 0.039, respectively, and improvements of 41.3%, 34.5% and 49.3%. The high dose did not show statistically significant efficacy across any of these measures.
For patients under 30 kg in weight
, while the low and medium doses showed improvements over placebo in the primary endpoints and the SNAP-IV rating for
ODD, the studied doses did not show statistical significance versus placebo on efficacy measures. Coupled with the fact that the high dose did not show efficacy with statistical significance, this
unexpected result leads us to believe that the most effective doses are those that achieve certain plasma concentrations (related to body weight) that do not exceed a level beyond which a saturation
threshold is reached.
Efficacy in Patients
³
30 kg on Low to Medium Doses
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Primary Efficacy Endpoints
(Treatment vs. placebo in ITT population)
|
|
Placebo
|
|
Low Dose
|
|
Medium Dose
|
|
High Dose
|
|
R-MOAS Change Overall (% improvement)
|
|
|
(38.5
|
)
|
|
(62.6
|
)
|
|
(57.9
|
)
|
|
(39.7
|
)
|
Patients (<30kg)
|
|
|
(35.3
|
)
|
|
(42.3
|
)
|
|
(44.4
|
)
|
|
(33.7
|
)
|
Patients (
³
30kg)
|
|
|
(41.5
|
)
|
|
(80.9
|
)
|
|
(75.2
|
)
|
|
(44.4
|
)
|
R-MOAS Remission Overall (% of patients)
|
|
|
(20.0
|
)
|
|
(51.9
|
)
|
|
(40.0
|
)
|
|
(32.3
|
)
|
Patients (<30kg)
|
|
|
(25.0
|
)
|
|
(33.3
|
)
|
|
(26.7
|
)
|
|
(21.4
|
)
|
Patients (
³
30kg)
|
|
|
(16.7
|
)
|
|
(66.7
|
)
|
|
(53.3
|
)
|
|
(41.2
|
)
|
R-MOAS=Retrospective-Modified
Overt Aggression Scale; R-MOAS Change=from Baseline (Visit 5) to Endpoint (Visit 10); R-MOAS Remission=Score of
£
10 (LOCF=Last Observation Carried Forward) at Endpoint (Visit 10)
Efficacy in Patients
³
30 kg on Low to Medium Doses
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Primary Efficacy Endpoints
(Treatment vs. placebo in ITT population)
|
|
Placebo
|
|
Low Dose
|
|
Medium Dose
|
|
High Dose
|
|
R-MOAS Change Overall (% improvement)
|
|
|
(38.5
|
)
|
|
(62.6
|
)
|
|
(57.9
|
)
|
|
(39.7
|
)
|
Patients (<30kg)
|
|
|
(35.3
|
)
|
|
(42.3
|
)
|
|
(44.4
|
)
|
|
(33.7
|
)
|
Patients (
³
30kg)
|
|
|
(41.5
|
)
|
|
(80.9
|
)
|
|
(75.2
|
)
|
|
(44.4
|
)
|
R-MOAS Remission Overall (% of patients)
|
|
|
(20.0
|
)
|
|
(51.9
|
)
|
|
(40.0
|
)
|
|
(32.3
|
)
|
Patients (<30kg)
|
|
|
(25.0
|
)
|
|
(33.3
|
)
|
|
(26.7
|
)
|
|
(21.4
|
)
|
Patients (
³
30kg)
|
|
|
(16.7
|
)
|
|
(66.7
|
)
|
|
(53.3
|
)
|
|
(41.2
|
)
|
16
Table of Contents
R-MOAS=Retrospective-Modified Overt Aggression Scale; R-MOAS Change=from Baseline (Visit 5) to Endpoint (Visit 10); R-MOAS Remission=Score of
£
10 (LOCF=Last Observation Carried Forward) at Endpoint (Visit 10)
Statistical Significance in Patients
³
30 kg on Low Dose
|
|
|
|
|
|
|
|
|
|
|
Secondary Efficacy Endpoints
(Treatment vs. placebo in ITT population)
|
|
Low Dose
P-value
|
|
Medium Dose
P-value
|
|
High Dose
P-value
|
|
CGI-Severity Overall
|
|
|
0.133
|
|
|
0.308
|
|
|
0.245
|
|
Patients (<30kg)
|
|
|
0.420
|
|
|
0.839
|
|
|
0.946
|
|
Patients (
³
30kg)
|
|
|
0.007
|
|
|
0.117
|
|
|
0.125
|
|
CGI-Improvement Overall
|
|
|
0.175
|
|
|
0.061
|
|
|
0.888
|
|
Patients (<30kg)
|
|
|
0.494
|
|
|
0.664
|
|
|
0.756
|
|
Patients (
³
30kg)
|
|
|
0.017
|
|
|
0.028
|
|
|
0.654
|
|
SNAP-IVODD Subscale Overall
|
|
|
0.061
|
|
|
0.122
|
|
|
0.661
|
|
Patients (<30kg)
|
|
|
0.639
|
|
|
0.173
|
|
|
0.607
|
|
Patients (
³
30kg)
|
|
|
0.039
|
|
|
0.179
|
|
|
0.861
|
|
CGI=Clinical
Global Impression; SNAP-IV=Swanson, Nolan and Pelham, ADHD Rating Scale; ODD=Oppositional Defiant Disorder
Efficacy in Patients
³
30 kg on Low Doses
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Secondary Efficacy Endpoints
(Treatment vs. placebo in ITT population)
|
|
Placebo
|
|
Low Dose
|
|
Medium Dose
|
|
High Dose
|
|
CGI-Severity Overall (% improvement)
|
|
|
19.6
|
|
|
28.2
|
|
|
25.5
|
|
|
26.7
|
|
Patients (<30kg)
|
|
|
22.9
|
|
|
17.0
|
|
|
22.4
|
|
|
23.9
|
|
Patients (
³
30kg)
|
|
|
15.9
|
|
|
41.3
|
|
|
31.1
|
|
|
29.5
|
|
CGI-Improvement Overall (% improvement)
|
|
|
15.1
|
|
|
20.0
|
|
|
28.1
|
|
|
18.2
|
|
Patients (<30kg)
|
|
|
15.1
|
|
|
6.2
|
|
|
23.5
|
|
|
12.5
|
|
Patients (
³
30kg)
|
|
|
15.1
|
|
|
34.5
|
|
|
35.5
|
|
|
21.2
|
|
SNAP-IVODD Subscale Overall (% improvement)
|
|
|
18.0
|
|
|
34.4
|
|
|
30.3
|
|
|
21.4
|
|
Patients (<30kg)
|
|
|
12.8
|
|
|
17.4
|
|
|
23.2
|
|
|
17.9
|
|
Patients (
³
30kg)
|
|
|
21.5
|
|
|
49.3
|
|
|
39.3
|
|
|
24.2
|
|
CGI=Clinical
Global Impression; SNAP-IV=Swanson, Nolan and Pelham, ADHD Rating Scale; ODD=Oppositional Defiant Disorder
SPN-810
was well tolerated throughout the study across all doses. The two serious AEs that occurred were not drug related; one of those occurred prior to administration of study medication. One
patient in the low dose arm and two patients in the medium dose arm had severe AEs that were considered either possibly or definitely related to the drug. Six patients in total discontinued the study
because of AEs in the active treatment arms: one in low dose; two in medium dose; and three in high dose. SPN-810 did not appear to have any notable or systematic effects on laboratory assessments,
vital signs or ECG assessments and exhibited a good safety and tolerability profile.
17
Table of Contents
Safe and Well Tolerated
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Number (%) of Patients with:
|
|
Placebo
|
|
Low Dose
|
|
Medium Dose
|
|
High Dose
|
|
Any adverse event (AE)
|
|
|
18 (58.1
|
)
|
|
11 (37.9
|
)
|
|
18 (60.0
|
)
|
|
21 (67.7
|
)
|
Adverse reaction
|
|
|
7 (22.6
|
)
|
|
6 (20.7
|
)
|
|
11 (36.7
|
)
|
|
13 (41.9
|
)
|
Severe AEs
|
|
|
0 (0.0
|
)
|
|
1 (3.4
|
)
|
|
4 (13.3
|
)
|
|
1 (3.2
|
)
|
Severe Adverse Reaction
|
|
|
0 (0.0
|
)
|
|
1 (3.4
|
)
|
|
2 (6.7
|
)
|
|
0 (0.0
|
)
|
Any serious AE (SAE)
|
|
|
0 (0.0
|
)
|
|
0 (0.0
|
)
|
|
0 (0.0
|
)
|
|
1 (3.2
|
)
|
Serious Adverse Reaction
|
|
|
0 (0.0
|
)
|
|
0 (0.0
|
)
|
|
0 (0.0
|
)
|
|
0 (0.0
|
)
|
AEs leading to discontinuation
|
|
|
1 (3.2
|
)
|
|
1 (3.4
|
)
|
|
2 (6.7
|
)
|
|
3 (9.7
|
)
|
Adverse
Reaction=those AEs considered possibly or definitely study drug related, according to investigator
Safe and Well Tolerated
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Adverse Reaction (%) of Patients
|
|
Placebo
|
|
Low
|
|
Medium
|
|
High
|
|
Decreased appetite
|
|
|
0
|
|
|
0
|
|
|
3.3
|
|
|
6.5
|
|
Increased appetite
|
|
|
3.2
|
|
|
6.9
|
|
|
6.7
|
|
|
6.5
|
|
Sedation
|
|
|
6.5
|
|
|
6.9
|
|
|
6.7
|
|
|
6.5
|
|
Somnolence
|
|
|
3.2
|
|
|
0
|
|
|
0
|
|
|
6.5
|
|
Fatigue
|
|
|
0
|
|
|
0
|
|
|
0
|
|
|
9.7
|
|
Dystonia
|
|
|
0
|
|
|
0
|
|
|
6.7
|
|
|
0
|
|
Adverse
Reactions in
³
5% of patients across Titration and Maintenance Periods
SPN-812
We are developing SPN-812, which is currently in Phase II development, as a novel non-stimulant treatment for ADHD. SPN-812 is a selective
norepinephrine reuptake inhibitor that we believe could be more effective and have a better side effect profile than other non-stimulant treatments for ADHD. The active ingredient in SPN-812 has an
extensive safety record in Europe, where it was previously marketed for many years as an anti-depressant. SPN-812 has not been developed and marketed in the United States and, therefore, it would be
considered and reviewed by the FDA as an NCE. Supernus currently holds an active IND for the immediate-release formulation SPN-812. We anticipate we will commence a trial to select the final
extended-release formulation for SPN-812 in the second half of 2014.
SPN-812
would provide an additional option to the few non-stimulant therapies currently available. We believe that SPN-812 could be more effective than other non-stimulant therapies due to its
different pharmacological profile. Due to its demonstrated efficacy as an anti-depressant, SPN-812, if studied in that specific patient population and shown to be effective, may exhibit increased
benefit in up to an estimated 40% of ADHD patients who also suffer from major depression.(20) We are developing an intellectual property position around the novel synthesis process for this product
candidate, its novel use in ADHD and its novel delivery with extended release.
-
(20)
-
Biederman,
J.,
New Insights Into the Comorbidity Between ADHD and Major Depression in Adolescent and Young Adult
Females
, published in April 2008 in
Journal of the American Academy of Child and Adolescent Psychiatry
and Report of CME
Institute of Physicians Postgraduate Press, Inc., published in August 2008 in
Journal of Clinical Psychiatry
.
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SPN-812 Development Program
We completed a proof-of-concept Phase IIa U.S. clinical trial of SPN-812 in adults for the treatment of ADHD in 2011, in which SPN-812 was
well tolerated and demonstrated a statistically significant improvement over placebo as a treatment for ADHD. The trial met the primary endpoints of safety and tolerability, and showed statistically
significant median reduction versus placebo in both investigator-rated and patient-rated ADHD symptom scores. The trial was a randomized, double-blind, placebo-controlled trial in 52 adults with a
current diagnosis of ADHD (26 subjects per treatment group).
Patients
in the active arm were administered SPN-812 at a single dose level three times a day over five weeks, after a one-week titration phase. The primary endpoint was safety, and SPN-812 was shown
to be safe and well tolerated by patients. The secondary endpoints included: the efficacy of SPN-812 as measured by Total ADHD Symptom Score on the Conners' Adult ADHD Rating Scale, or CAARS, a
commonly-used measurement for ADHD in adults, as rated by each of the investigators and the patients, and the effectiveness of SPN-812 when compared to placebo as determined by changes in the
CGIImprovement, or CGI-I, score. Patients in the active group achieved overall significant median reductions from baseline in investigator-rated CAARS total ADHD symptom scores by study
end, of 11.5 points versus 6.0 points for placebo (p=0.0414) and in self-rated CAARS total symptom scores by study end, of 10.5 points versus 1.0 for placebo (p=0.0349). With respect to the other
secondary endpoint of CGI-I scores, patients exhibited a trend, although not statistically significant, toward larger median reductions in scores from baseline versus placebo.
Given
the positive results of this Phase IIa trial, we have focused on developing an extended release formulation for optimum clinical outcome. The Company will be completing a clinical trial
of the pharmacokinetics of extended release formulations in the first half of 2014 to select the final formulation that will later enter a Phase IIb trial.
SPN-809
We are developing SPN-809 as a novel once-daily product candidate for the treatment of depression. SPN-809 is based on the same active ingredient as
SPN-812. We currently have an open IND for SPN-809 as a treatment of depression, the indication for which the active ingredient in SPN-809 was approved and marketed in Europe for many years.
Depression is a serious and common disease affecting approximately 121 million people worldwide.(21) Based on IMS Health data, the worldwide market for anti-depressants is approximately
$12 billion.
SPN-809
is a norepinepherine reuptake inhibitor that represents an opportunity to offer a differentiated treatment option for patients suffering from depression in the United States. Initial market
research suggests that psychiatrists would like to have such a once-daily option at their disposal to treat various patients. Because SPN-809 contains the same active ingredient as SPN-812, we expect
that many of our activities related to the development of SPN-812 will also benefit the development of SPN-809. Supernus holds an active IND for the SPN-809 product candidate.
Our Proprietary Technology Platforms
We have a successful track record of developing novel products by applying proprietary technologies to known drugs to improve existing therapies and
enable the treatment of new indications. Our key proprietary technology platforms include: Microtrol, Solutrol and EnSoTrol. These technologies create novel customized product profiles designed to
meet efficacy needs, more convenient and less frequent dosing, enhanced patient compliance, and improved tolerability in certain specific applications. We have
-
(21)
-
World
Health Organization,
Epilepsy: aetiogy, epidemiology and prognosis
, Fact Sheet No. 165,
revised February 2001.
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employed
our technologies in the development of our legacy products, as well as in our current product portfolio.
Microtrol (multiparticulate delivery platform)
Microtrol is based on the use of coated and uncoated multi-particulates that can be filled into capsules, administered as a sprinkle, or compressed
into tablets as varying ratios to achieve novel customized release profiles. The following approved and marketed products incorporate our Microtrol
technology:
-
-
Sanctura XR (trospium chloride), a treatment for overactive bladder;
-
-
Oracea (doxycycline), a treatment for inflammatory lesions of rosacea;
-
-
Carbatrol (carbamazepine), an anti-epilepsy treatment;
-
-
Equetro (carbamazepine), a treatment for bipolar disorder; and
-
-
Adderall XR (mixed amphetamine salts), a stimulant ADHD treatment.
These
products will not contribute to our future financial results.
Solutrol (matrix delivery platform)
Solutrol is a matrix delivery system that can deliver poorly soluble, highly soluble, and pH dependent compounds in a reproducible and complete
manner. Solutrol has been incorporated into Intuniv (guanfacine), a nonstimulant ADHD treatment, which is currently licensed to and marketed by Shire plc. In April 2009, this license became
fully paid up when we sold to Shire the right to receive royalties and milestone payments owed to us for $36.9 million, which we primarily reinvested into our research and development
activities.
EnSoTrol (osmotic delivery system)
EnSoTrol is comprised of a solubility enabled core and other agents surrounded by a semi-permeable membrane with a laser-drilled hole. When EnSoTrol
is introduced to the contents of the gastrointestinal tract, it will induce solubilization of the core contents via fluid intake across the membrane coating. The solubilized core contents are then
released through the laser-drilled hole along the osmotic gradient, thus yielding a surface-area controlled constant release
profile. EnSoTrol has been tested in several clinical trials, including Phase III trials conducted by United Therapeutics for an oral formulation of treprostinil diethanolamine, or treprostinil
which received FDA approval in December 2013.
In
June 2006, we entered into a license agreement with United Therapeutics, for the worldwide development and commercialization of an oral formulation of treprostinil, which utilizes EnSoTrol for the
treatment of pulmonary arterial hypertension, or PAH, as well as for other indications. Under the terms of the license agreement, we have received pre-commercial milestone payments of
$1.5 million. Remaining milestone payments to us could total up to approximately $6.0 million, which includes milestone payments that could total $2.0 million based on the
satisfaction of development milestones of oral treprostinil in PAH and up to approximately $4.0 million for the development of additional treprostinil products for a second indication. We are
also entitled to receive royalties in the low to mid single digits based on net sales worldwide of the oral formulation of treprostinil. On December 23, 2013, the FDA approved the product and
at that time United Therapeutics indicated that it will launch the product in 2014. Our license agreement with United Therapeutics will expire, on a country-by-country and product-by-product basis,
12.5 years from the first commercial sale of each product in such country. United Therapeutics may terminate, at its option, the agreement for a technical, strategic or market-related cause
after giving us a reasonable opportunity to cure. We may terminate the agreement if, after having launched a product in a country, United Therapeutics or its
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sublicensee
discontinues the sale of such product for a prolonged period of time for reasons unrelated to force majeure, regulatory or safety issues. In addition, either party may terminate the
agreement for the material, uncured breach by the other party and in certain events of bankruptcy or insolvency of the other party.
Sales and Marketing
We have built our sales and marketing capabilities in the United States to launch Oxtellar XR and Trokendi XR. Additionally, there are plans to
further expand our sales and marketing capabilities to more than 150 sales representatives by mid-2014. Promoting two epilepsy products to the same physician audience allows us to leverage our
commercial infrastructure with these prescribers. Once we have obtained approval for any of our product candidates in our psychiatry portfolio, we anticipate adding additional sales force members who
will be dedicated to marketing our psychiatry products.
Manufacturing
We do not own or operate manufacturing facilities for the production of any of our product candidates beyond Phase II clinical trials, nor do
we have plans to develop our own manufacturing operations for Phase III clinical materials or commercial products in the foreseeable future. We currently depend on third-party Commercial
Manufacturing Organizations, or CMOs, for all of our required raw materials and drug substance for our preclinical research and clinical trials. We do not have contractual relationships for the
commercial manufacture of all our product candidates. For Trokendi XR, Oxtellar XR and our product candidates, we currently rely on single third-party suppliers for raw materials including drug
substance and single manufacturers for the final commercial products. We currently employ internal resources and as needed third-party consultants to manage our manufacturing contractors.
We
have entered into agreements with Patheon Pharmaceuticals Inc. and Catalent Pharma Solutions, leading CMOs headquartered in North America, for the manufacture of the final commercial
products Oxtellar XR and Trokendi XR, respectively. These CMOs offer a comprehensive range of contract manufacturing and packaging services and have successfully handled the scale up of Oxtellar XR
and Trokendi XR to a commercial production scale.
Competition
The biotechnology and pharmaceutical industries are highly competitive. A number of multinational pharmaceutical companies as well as large
biotechnology companies are pursuing the development of or are currently marketing pharmaceutical products in the anti-epilepsy and ADHD markets on which we are focusing.
Epilepsy
There are currently over 15 branded products, as well as their generic counterparts, on the U.S. market indicated to treat some form of epilepsy.
Several NCEs have entered the epilepsy market including Potiga, Vimpat and Banzel. Another NCE, Aptiom, was recently approved and could enter the market in early 2014. Based on IMS Health prescription
data from 1994 to 2005 for NCE launches for seizure disorders, such NCEs, on average, experienced slow market penetration ranging from 0.58% to 1.1% market share point gain on an annual basis. We
believe this is because physicians are often reluctant to change a stable patient's existing therapy and risk a breakthrough seizure in their patients.
Oxtellar
XR competes with all immediate release oxcarbazepine products including Trileptal and related generic products. We believe that Oxtellar XR's once-daily formulation solves a drug delivery
challenge specific to oxcarbazepine that must be overcome by all potential competitors. We are aware of companies who have modified-release oxcarbazepine products that are marketed outside of the
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United
States but, to our knowledge, such products are not being pursued for the U.S. market. These modified-release oxcarbazepine products include Apydan, which is developed by Desitin
Arzneimittel GmbH, and requires twice-daily administration.
Trokendi
XR competes with all immediate release topiramate products including Topamax and related generic products. We are aware that Upsher-Smith Laboratories, Inc., or Upsher-Smith, has an
extended release topiramate product, which it has described as an internally developed program for the management of epilepsy in adults using its proprietary formulation technology. This product
received FDA approval on March 11, 2014, and is expected to be launched by Upsher-Smith under the brand name Qudexy XR sometime before the end of the second quarter of 2014.
ADHD
Competition in the U.S. ADHD market has increased with the commercial launch of several products in recent years, including the launch of generic
versions of branded drugs, such as Adderall XR. Shire plc is one of the leaders in the U.S. ADHD market with three products: Adderall XR, an extended release stimulant treatment designed to
provide once-daily dosing; Vyvanse, a stimulant prodrug product launched in 2007; and Intuniv, a non-stimulant treatment launched in November 2009. Other stimulant products for the treatment of ADHD
in the U.S. market include the following once-daily formulations: Concerta; Metadate CD; Ritalin LA; Focalin XR; and Daytrana. Other non-stimulants are Strattera and Kapvay. We are also aware of
clinical development efforts by several large and small pharmaceutical companies including Eli Lilly, Otsuka America, Inc., BMS, AstraZeneca plc, Abbott Laboratories and Alcobra to
develop additional treatment options for ADHD.
Intellectual Property and Exclusivity
Overview
We have been building and continue to build our intellectual property portfolio relating to our products and product candidates, including Oxtellar
XR and Trokendi XR. We seek patent protection, where appropriate, in the United States and internationally for our products and product candidates. Our policy is to actively seek to protect our
proprietary position by, among other things, filing patent applications in the United States and abroad (including Europe, Canada and certain other countries when appropriate) relating to proprietary
technologies that are important to the development of our business. We also rely on trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain
our proprietary position. We cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future,
nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our technology.
Our
success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for the technologies and products we consider important to our business, defend our
patents, preserve the confidentiality of our trade secrets and operate our business without infringing the patents and proprietary rights of third parties.
We
have established and continue to build proprietary positions for Oxtellar XR, Trokendi XR, our pipeline product candidates and technologies in the United States and abroad.
Patent Portfolio
Our extended release oxcarbazepine patent portfolio currently includes five U.S. patents, three of which cover Oxtellar XR. We have also obtained two
patents for extended release oxcarbazepine in Europe, one patent each in Canada. Japan, Australia, and Mexico. In addition, we have certain pending U.S. and foreign patent applications that are
directed to various extended release formulations containing
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oxcarbazepine.
The three issued U.S. patents covering Oxtellar XR will expire in 2027. We own all of the issued patents and the pending applications.
In
addition to the patents and patent applications relating to Oxtellar XR, we currently have three U.S. patents that cover Trokendi XR. We have one patent each issued in Europe and Australia for
extended release topiramate and have certain pending U.S. and foreign patent applications in Canada and other countries that relate to the U.S. patents directed to various extended release
formulations containing topiramate. Two of the issued U.S. patents will expire in 2027 and the third patent will expire in 2029. We own all of the issued patents and pending applications.
Our
patent portfolio also contains patent applications relating to our other pipeline products. We have four families of pending U.S. non-provisional and foreign counterpart patent applications
relating to our SPN-810 product candidate. Patents, if issued, from the applications could have terms expiring from 2029 to 2033. We own all of the issued patents and the pending applications.
With
regard to our SPN-812 product candidate, we have three families of pending U.S. non-provisional and foreign counterpart patent applications. Patents, if issued, from the applications could expire
from 2029 to 2033. We have one patent each issued in Europe and Canada in one of these families, covering a method of treating ADHD using viloxazine. We own all of the issued patents and the pending
applications.
The
U.S. patent system permits the filing of provisional and non-provisional patent applications. A non-provisional patent application is examined by the U.S. Patent and Trademark Office, or USPTO,
and can mature into a patent once the USPTO determines that the claimed invention meets the standards for patentability. A provisional patent application is not examined for patentability, and
automatically expires 12 months after its filing date. As a result, a provisional patent application cannot mature into a patent. The requirements for filing a provisional patent application
are not as strict as those for filing a non-provisional patent application. Provisional applications are often used, among other things, to establish an early filing date for a subsequent
non-provisional patent application. The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the
patent term is 20 years from the earliest date of filing a non-provisional patent application. In the United States, a patent's term may be lengthened by patent term adjustment, or PTA, which
compensates a patentee for administrative delays by the USPTO in granting a patent. In view of a recent court decision, the USPTO is under greater scrutiny regarding its calculations where the USPTO
erred in calculating the PTA for the patents in question denying the patentee a portion of the patent term to which it was entitled. Alternatively, a patent's term may be shortened if a patent is
terminally disclaimed over another patent.
The
filing date of a non-provisional patent application is used by the USPTO to determine what information is prior art when it considers the patentability of a claimed invention. If certain
requirements are satisfied, a non-provisional patent application can claim the benefit of the filing date of an earlier filed provisional patent application. As a result, the filing date accorded by
the provisional patent application may supersede information that otherwise could preclude the patentability of an invention.
The
term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, or PTE, which permits patent term restoration as compensation for the patent term lost during the
FDA regulatory review process. The Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Amendments, permits a PTE of up to five years beyond the expiration of the
patent. The length of the PTE is related to the length of time the drug is under regulatory review. Patent extension cannot extend the remaining term of a patent beyond a total of 14 years from
the date of product approval and only one patent applicable to an approved drug may be extended. Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a
patent that covers an approved drug. In the future, if and when our pharmaceutical products receive FDA or other
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regulatory
approval, we may be able to apply for PTEs on patents covering those products. Depending upon the timing, duration and specifics of FDA approval of our SPN-810 and SPN-812 product
candidates and issuance of a U.S. patent covering them based on a U.S. patent application in our portfolio, we may obtain a U.S. patent that is eligible for limited patent term restoration.
Other Intellectual Property Rights
We seek trademark protection in the United States and internationally where available and when appropriate. We have filed for trademark protection
for several marks, which we use in connection with our pharmaceutical research and development collaborations as well as products. We are the owner of various U.S. federal trademark registrations
(®) and registration applications (), including the following marks referred to in this Annual Report on Form 10-K pursuant to applicable U.S. intellectual property
laws: "Supernus®," "Microtrol®," "Solutrol®," "Trokendi XR," "Oxtellar XR®," and the registered Supernus Pharmaceuticals logo.
From
time to time, we may find it necessary or prudent to obtain licenses from third party intellectual property holders. Where licenses are readily available at reasonable cost, such licenses are
considered a
normal cost of doing business. In other instances, however, we may use the results of freedom-to-operate inquiries and internal analyses to guide our early-stage research away from areas where we are
likely to encounter obstacles in the form of third party intellectual property. For example, where a third party holds relevant intellectual property and is a direct competitor, a license might not be
available on commercially reasonable terms or available at all. We strive to identify potential third party intellectual property issues in the early stages of our research programs, in order to
minimize the cost and disruption of resolving such issues.
To
protect our competitive position, it may be necessary to enforce our patent rights through litigation against infringing third parties. Litigation to enforce our own patent rights is subject to
uncertainties that cannot be quantified in advance. In the case of an adverse outcome in litigation, we could be prevented from commercializing a product or using certain aspects of our technology
platforms as a result of patent infringement claims asserted against us. This could have a material adverse effect on our business. In addition, litigation involving our patents carries the risk that
one or more of our patents will be held invalid (in whole or in part, on a claim-by-claim basis) or held unenforceable. Such an adverse court ruling could allow third parties to commercialize products
or use technologies that are similar to ours, and then compete directly with us, without payment to us. See "Risk FactorsIf we are sued for infringing intellectual property rights of
third parties, it will be costly and time consuming, and an unfavorable outcome in that litigation would have a material adverse effect on our business."
In-Licensing Arrangements
Afecta Pharmaceuticals, Inc.
We have entered into two license agreements with Afecta Pharmaceuticals, Inc., or Afecta, pursuant to which we obtained an exclusive option to
evaluate Afecta's CNS pipeline and to obtain exclusive worldwide rights to selected product candidates, including an exclusive license to SPN-810. Under the terms of the license agreements, we have
paid Afecta $550,000 in license fees and milestone payments and may pay up to an additional $300,000 upon the achievement of certain milestones. If a product candidate is successfully developed and
commercialized, we will be obligated to pay royalties to Afecta based on net sales worldwide in the low-single digits. Unless terminated by us or Afecta for material breach or bankruptcy, by Afecta
for our discontinuation of development and commercialization activities, or by us for convenience, the license agreements will continue in full force and effect on a country-by-country basis until six
months from the discontinuation of the commercial sale and collection of revenues for the Afecta product.
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Rune Healthcare Limited
In June 2006, we entered into a purchase and sale agreement with Rune Healthcare Limited, or Rune, where we obtained the exclusive worldwide rights
to a product concept from Rune for SPN-809. Under the terms of the agreement, we have paid Rune a £25,000 up-front fee. If we receive approval to market and sell any products based on the
Rune product concept, we will be obligated to pay royalties to Rune based on net sales worldwide in the low-single digits. Unless terminated by us or Rune for material breach, by Rune for our
discontinuation of development or commercialization activities relating to a product based on the Rune product concept, we will be obligated to pay royalties to Rune on a country-by-country basis
until the earlier of (a) ten years from the date of first commercial sale of a product based on the Rune product concept, or (b) the market entry in such country of any product utilizing
the Rune product by any entity other than us, our affiliates or our licensees.
Confidential Information and Inventions Assignment Agreements
We require our employees, temporary employees and consultants to execute confidentiality agreements upon the commencement of employment, consulting
or collaborative relationships with us. These agreements provide that all confidential information developed or made known during the course of the relationship with us be kept confidential and not
disclosed to third parties except in specific circumstances. The agreements provide that all inventions resulting from work performed for us or relating to our business and conceived or completed by
the individual during employment or assignment, as applicable, shall be our exclusive property to the extent permitted by applicable law.
We
seek to protect our products, product candidates and our technologies through a combination of patents, trade secrets, proprietary know-how, FDA exclusivity and contractual restrictions on
disclosure.
Government Regulation
Product Approval
Government authorities in the United States at the federal, state and local level, and other countries, extensively regulate, among other things, the
research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, recordkeeping, promotion, advertising, distribution, marketing, export and import of products such
as those we are developing. Our product candidates must receive final approval from the FDA before they may be marketed legally in the United States.
U.S. Drug Development Process
In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and through implementation of regulations. The
process of obtaining regulatory approvals and ensuring compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial
resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process, or after approval, may subject an applicant to administrative
or judicial sanctions. These sanctions could include the FDA's refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls, product seizures,
product detention, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.
The
process required by the FDA before a drug may be marketed in the United States generally involves the following:
-
-
completion of preclinical laboratory tests, animal studies and formulation studies according to Good Laboratory Practices
regulations;
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-
-
submission to the FDA of an IND, which must become effective before human clinical trials may begin;
-
-
performance of adequate and well-controlled human clinical trials according to Good Clinical Practices, or GCP, to
establish the safety and efficacy of the proposed drug for its intended use;
-
-
submission to the FDA of an NDA for a new drug;
-
-
satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to
assess compliance with current Good Manufacturing Practices, or cGMP; and
-
-
FDA review and approval of the NDA.
The
testing and approval process require substantial time, effort and financial resources and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if
at all.
Once
a pharmaceutical product candidate is identified for development, it enters the preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, toxicity,
carcinogenicity, formulation and stability, as well as animal studies. An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data and any
available clinical data or literature, to the FDA as part of the IND. The sponsor must also include a protocol detailing, among other things, the objectives of the initial clinical trial, the
parameters to be used in monitoring safety and the effectiveness criteria to be evaluated if the initial clinical trial lends itself to an efficacy evaluation. Some preclinical testing may continue
even after the IND is submitted. The IND
automatically becomes effective 30 days after receipt by the FDA, unless the FDA places the clinical trial on a clinical hold within that 30-day time period. In such a case, the IND sponsor and
the FDA must resolve any outstanding concerns before the clinical trial can begin. Clinical holds also may be imposed by the FDA at any time before or during trials due to safety concerns or
non-compliance.
All
clinical trials must be conducted under the supervision of one or more qualified investigators in accordance with GCP regulations. These regulations include the requirement that all research
subjects provide informed consent. Further, an institutional review board, or IRB, must review and approve the plan for any clinical trial before it commences at any institution. An IRB considers,
among other things, whether the risks to individuals participating in the trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the information regarding
the clinical trial and the consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.
Once
an IND is in effect, each new clinical protocol and any amendments to the protocol must be submitted to the IND for FDA review, and to the IRBs for approval. Protocols detail, among other things,
the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety.
Human
clinical trials for product candidates are typically conducted in three sequential phases that may overlap or be combined:
-
-
Phase I.
The product is initially introduced into
healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion. In the case of some products for severe or life-threatening diseases, especially
when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing may be conducted in patients.
-
-
Phase II.
Phase II trials involve
investigations in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to
determine dosage tolerance and optimal dosage and schedule.
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-
-
Phase III.
In Phase III, clinical trials are
undertaken to further evaluate dosage, clinical efficacy and safety in an expanded patient population at geographically dispersed clinical trial sites. These trials are intended to establish the
overall risk/benefit ratio of the product and provide an adequate basis for regulatory approval and product labeling.
Phase I,
Phase II and Phase III testing may not be completed successfully within any specified period, if at all. Progress reports detailing the results of the clinical trials
must be submitted at least annually to the FDA and safety reports must be submitted to the FDA and the investigators for serious and unexpected side effects. 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 IRB's requirements or if the drug has been associated with unexpected
serious harm to patients.
Concurrent
with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product
candidate and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP 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 and purity of the final product. 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.
During
the development of a new drug, a sponsor may be able to request a SPA the purpose of which is to reach agreement with the FDA on the Phase III clinical trial protocol design and analysis
that will form the primary basis of an efficacy claim. An SPA is intended to provide assurance that if the agreed upon clinical trial protocol is followed, the clinical trial endpoints are achieved,
and there is a favorable risk-benefit profile, the data may serve as the primary basis for an efficacy claim in support of an NDA. However, SPA agreements are not a guarantee of an approval of a
product candidate or any permissible claims about the product candidate. In particular, SPAs are not binding on the FDA if previously unrecognized public health concerns arise during the performance
of the clinical trial, other new scientific concerns regarding the product candidate's safety or efficacy arise, or if the sponsoring company fails to comply with the agreed upon clinical trial
protocol.
U.S. Review and Approval Processes
The results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests
conducted on the drug, proposed
labeling and other relevant information, are submitted to the FDA as part of an NDA for a new drug, requesting approval to market the product.
As
an alternate path to FDA approval, particularly for modifications to drug products previously approved by the FDA, an applicant may submit an NDA under Section 505(b)(2) of the FDCA.
Section 505(b)(2) was enacted as part of the Hatch-Waxman Amendments, and permits the submission of an NDA where at least some of the information required for approval comes from clinical
trials not conducted by or for the applicant and for which the applicant has not obtained a right of reference. The FDA interprets Section 505(b)(2) of the FDCA to permit the applicant to rely
upon the FDA's previous findings of safety and effectiveness for an approved product. The FDA requires submission of information needed to support any changes to a previously approved drug, such as
published data or new studies conducted by the applicant, including bioavailability or bioequivalence studies, or clinical trials demonstrating safety and effectiveness. The FDA may then approve the
new product candidate for all or some of the label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant.
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The submission of an NDA is subject to the payment of a substantial user fee; a waiver of such fee may be obtained under certain limited circumstances. For example, the agency
will waive the application fee for the first human drug application that a small business or its affiliate submits for review.
In
addition, under the Pediatric Research Equity Act of 2003, or PREA, which was reauthorized under the Food and Drug Administration Safety and Innovation Act of 2012, an NDA or supplement to an NDA
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 data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply
to any drug for an indication for which orphan designation has been granted. Pursuant to the FDA's approval of Oxtellar XR, we must conduct four pediatric post-marketing studies; however, the FDA
granted a waiver for the pediatric study requirements for ages birth to one month and a deferral for submission of post-marketing assessments for children 1 month to 6 years of age.
Pursuant to the FDA's approval of Trokendi XR, the FDA granted a deferral for submission of post-marketing pediatric studies in the following categories 1) adjunctive therapy in POS for
children 1 month to less than 6 years of age, 2) initial monotherapy in POS and PGTC for children 2 years to less than 10 years of age, and 3) adjunctive
therapy in PGTC and adjunctive therapy in Lennox-Gastaut Syndrom from 2 years to less than 6 years of age. We expect to need a total of four pediatric studies to fulfill these deferred
pediatric commitments for Trokendi XR.
Section 505(b)(2) New Drug Applications
To the extent that a Section 505(b)(2) NDA relies on clinical trials conducted for a previously approved drug product or the FDA's prior
findings of safety and effectiveness for a previously approved drug product, the Section 505(b)(2) applicant must submit patent certifications in its Section 505(b)(2) application with
respect to any patents for the approved product on which the application relies that are listed in the FDA's publication, Approved Drug Products with Therapeutic Equivalence Evaluations, commonly
referred to as the Orange Book. Specifically, the applicant must certify for each listed patent that (1) the required patent information has not been filed; (2) the listed patent has
expired; (3) the listed patent has not expired, but will expire on a particular date and approval is not sought until after patent expiration; or (4) the listed patent is invalid,
unenforceable or will not be infringed by the proposed new product. A certification that the new product will not infringe the previously approved product's listed patent or that such patent is
invalid or unenforceable is known as a Paragraph IV certification. If the applicant does not challenge one or more listed patents through a Paragraph IV certification, the FDA will not
approve the Section 505(b)(2) NDA application until all the listed patents claiming the referenced product have expired. Further, the FDA will also not approve, as applicable, a
Section 505(b)(2) NDA application until any non-patent exclusivity, such as, for example, five-year exclusivity for obtaining approval of an NCE, three year exclusivity for an approval based on
new clinical trials, or pediatric exclusivity, listed in the Orange Book for the referenced product, has expired.
If
the Section 505(b)(2) NDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the owner of
the referenced NDA for the previously approved product and relevant patent holders within 20 days after the Section 505(b)(2) NDA has been accepted for filing by the FDA. The NDA and
patent holders may then initiate a patent infringement suit against the Section 505(b)(2) applicant. Under the FDCA, the filing of a patent infringement lawsuit within 45 days of receipt
of the notification regarding a Paragraph IV certification automatically prevents the FDA from approving the Section 505(b)(2) NDA for 30 months beginning on the date the patent
holder receives notice, or until a court deems the patent unenforceable, invalid or not infringed, whichever is earlier. Moreover, in cases where a
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ITEM 1A. RISK FACTORS.
Investing in our common stock involves a high degree of risk. Before making an investment decision, you should carefully
consider the risks described below with all of the other information we include in this report and the additional information in the other reports we file with the Securities and Exchange Commission
(the "SEC" or the "Commission"). These risks may result in material harm to our business and our financial condition and results of operations. In this event, the market price of our common stock may
decline and you could lose part or all of your investment.
Risks Related to Our Business and Industry
We are dependent on the commercial success of Oxtellar XR and Trokendi XR.
Prior to the commercialization of Oxtellar XR and Trokendi XR, we expended significant time, resources and effort on the development of these product
candidates while a substantial majority of our resources are now focused on continuing the commercialization in the United States of our approved products, Oxtellar XR, which commenced on
February 4, 2013, and Trokendi XR, which commenced on August 26, 2013. We expect to continue to expend significant time, resources and effort on the development of our other product
candidates. All of our other product candidates are in earlier stages of development and subject to the risks of failure inherent in developing drug products.
Our
ability to successfully commercialize Oxtellar XR and Trokendi XR will depend on, among other things, our ability to:
-
-
maintain commercial manufacturing arrangements with third-party manufacturers for Oxtellar XR and Trokendi XR;
-
-
produce, through a validated process, sufficiently large quantities and inventory of our products to meet demand;
-
-
build and maintain a wide variety of internal sales, distribution and marketing capabilities sufficient to build
commercial sales of our products;
-
-
secure widespread acceptance of our products from physicians, health care payors, patients and the medical community;
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-
properly price and obtain adequate coverage and reimbursement of the product by governmental authorities, private health
insurers, managed care organizations and other third-party payors;
-
-
maintain compliance with ongoing FDA labeling, packaging, storage, advertising, promotion, recordkeeping, safety and other
post-market requirements;
-
-
manage our growth and spending as costs and expenses increase due to commercialization; and
-
-
establish collaborations with third parties for the commercialization of our products in countries outside the United
States, and such collaborators' ability to obtain regulatory and reimbursement approvals in such countries.
There
are no guarantees that we will be successful in completing these tasks. Successful commercialization will also depend on whether we can adequately protect against and effectively respond to any
claims by holders of patents and other intellectual property rights that our products infringe their rights, whether any unanticipated adverse effects or unfavorable publicity develops in respect of
our products, as well as the emergence of new or existing products as competition, which may be proven to be more clinically effective and cost-effective.
In
addition, we have begun, and will need to continue, investing substantial financial and management resources to build out our commercial infrastructure and to recruit and train sufficient
additional qualified marketing, sales and other personnel in support of our sales of Oxtellar XR and Trokendi
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XR.
In addition, we have certain revenue expectations with respect to the sale of Oxtellar XR and Trokendi XR. If we cannot successfully commercialize and achieve those revenue expectations with
respect to Oxtellar XR and Trokendi XR, this would result in a material adverse impact on our anticipated revenues and liquidity.
The
continued commercial success of Oxtellar XR and Trokendi XR will be largely dependent on the ability of third-party manufacturers and collaborators. They may not deploy the resources we would like
them to, and our revenue would then suffer. In addition, we could become embroiled in disputes with these parties regarding the terms of any agreements, their performance or intellectual property
rights. Any dispute could disrupt the sales of our products and adversely affect our reputation and revenue. In addition, if any of our manufacturing or collaboration partners fail to effectively
perform under our
arrangements for any reason, we may not be able to find a suitable replacement partner on a timely basis, or at all, or on acceptable terms.
Continued increase in sales of Oxtellar XR or Trokendi XR may be slow or limited for a variety of reasons including competing branded and generic therapies or safety issues.
If either Oxtellar XR or Trokendi XR is not successful in gaining broad commercial acceptance, our business would be harmed.
Any increase in sales of Oxtellar XR and Trokendi XR will be dependent on several factors including our ability to educate and increase physician
awareness of the benefits and cost-effectiveness of our products relative to competing therapies. The degree of market acceptance of any of our products or approved product candidates among
physicians, patients, health care payors and the medical community will depend on a number of factors, including:
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-
acceptable evidence of safety and efficacy;
-
-
relative convenience and ease of administration;
-
-
the prevalence and severity of any adverse side effects;
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-
availability of alternative treatments;
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-
pricing and cost effectiveness;
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-
the effectiveness of our sales and marketing capability and strategies; and
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-
ability to obtain sufficient third-party coverage or reimbursement.
In
addition, Oxtellar XR and Trokendi XR will be subject to continual review by the FDA, and we cannot assure you that newly discovered or developed safety issues will not arise. With the use of any
newly marketed drug by a wider patient population, serious AEs may occur from time to time that initially do not appear to relate to the drug itself. Any safety issues could cause us to suspend or
cease marketing of our approved products, cause us to modify how we market our approved products, subject us to substantial liabilities and adversely affect our revenues and financial condition. In
the event of a withdrawal of either Oxtellar XR or Trokendi XR from the market, our revenues would decline significantly and our business would be seriously harmed and could fail.
We have rapidly expanded our operations and will continue to do so to support increased commercialization of Oxtellar XR and Trokendi XR, which has significantly increased
our costs, and until we achieve economies of scale, we will incur negative margins on sales of Oxtellar XR and Trokendi XR.
We have and expect to continue to significantly increase our investment in commercial infrastructure. We will need to effectively manage the
expansion of our operations and facilities and continue to grow our infrastructure to fully commercialize Oxtellar XR and Trokendi XR. We must effectively manage our supply chain and distribution
network, all of which requires strict planning in order to meet production timelines. As of December 31, 2013, we employed approximately 110 sales representatives.
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We
continue to add marketing and sales personnel, and personnel in all other areas of our operations, which strain our existing managerial, operational, financial and other resources. As a result of
the scaling of our commercial operations, we expect to incur negative margins on any sales of Oxtellar XR and Trokendi XR until we are able to generate significant sales volume. We will also need to
maintain our commercial manufacturing arrangements with third parties for any approved product to avoid the loss of revenue from potential sales of such product, and adversely impact its market
acceptance. If we fail to manage the growth in our systems and personnel appropriately and successfully in order to achieve our commercialization plans for Oxtellar XR and Trokendi XR, our revenues
could suffer and our business could be harmed.
We are dependent on the success of our products being successfully commercialized and our product candidates, which may never receive regulatory approval.
Prior to the commercialization of Oxtellar XR and Trokendi XR, we expended significant time, resources and effort on the development of these product
candidates. While a substantial majority of our resources are now focused on the commercialization of our products Oxtellar XR and Trokendi XR in the United States, we expect to continue to expend
significant time, resources and effort on the development of our other product candidates. All of our product candidates are in earlier stages of development and subject to the risks of failure
inherent in developing drug products. Accordingly, our ability to generate significant product revenues in the near term will depend almost entirely on our ability to successfully commercialize
Oxtellar XR and Trokendi XR.
Our
ability to successfully commercialize any of our product candidates will depend on, among other things, our ability to:
-
-
receive marketing approvals from the FDA and similar foreign regulatory authorities;
-
-
produce, through a validated process, sufficiently large quantities of our product candidates to permit successful
commercialization;
-
-
establish commercial manufacturing arrangements with third-party manufacturers;
-
-
build and maintain strong sales, distribution and marketing capabilities sufficient to launch commercial sales of our
product candidates;
-
-
establish collaborations with third parties for the commercialization of our product candidates in countries outside the
United States, and such collaborators' ability to obtain regulatory and reimbursement approvals in such countries;
-
-
secure acceptance of our product candidates from physicians, health care payors, pharmacies, wholesalers, patients and the
medical community;
-
-
successfully complete our clinical trials; and
-
-
manage our spending as costs and expenses increase due to commercialization and clinical trials.
There
are no guarantees that we will be successful in completing these tasks. If we are unable to successfully complete these tasks, we may not be able to commercialize any of our other product
candidates in a timely manner, or at all, in which case we may be unable to maximize our revenues to increase the growth of our business. In addition, if we experience unanticipated delays or
problems, development costs could substantially increase and our business, financial condition and results of operations will be adversely affected.
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We have limited sales and marketing experience and resources, and we may not be able to effectively market and sell our products or product candidates, if approved, in the
United States.
We have built our sales and marketing capabilities in the United States to launch Oxtellar XR and Trokendi XR. Additionally, there are plans to
further expand our sales and marketing capabilities later in 2014. We have limited sales and marketing experience and have been building such capabilities by investing significant amounts of financial
and management resources. We have committed and will commit additional resources to develop internal sales and marketing capabilities. Further, we could face a number of additional risks in
establishing internal sales and marketing capabilities, including:
-
-
we may not be able to attract talented and qualified personnel to build an effective marketing or sales force capability;
-
-
the cost of establishing a marketing and sales force capability may not be justifiable in light of the revenues generated
by Oxtellar XR, Trokendi XR, or any of our product candidates if approved by the FDA; and
-
-
our direct sales and marketing efforts may not be successful.
If
we are unable to establish adequate sales and marketing capabilities or are unable to do so in a timely manner, we may not be able to generate product revenues and may never become profitable.
The commercial success of our products and product candidates, once approved, depends upon attaining market acceptance by physicians, patients, third-party payors and the
medical community.
Physicians may not prescribe Oxtellar XR, Trokendi XR or any of our product candidates if approved by the FDA at the levels which we anticipate, in
which case we would not generate the revenues we anticipate. Market acceptance of any of our products or product candidates by physicians, patients, third-party payors and the medical community
depends on, among other things:
-
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our ability to provide acceptable evidence of safety and efficacy;
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acceptance by physicians and patients of each product or product candidate as a safe and effective treatment;
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-
perceived advantages of our products or product candidates over alternative treatments;
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relative convenience and ease of administration of our products or product candidates compared to existing treatments;
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any labeling restrictions placed upon each product or product candidate in connection with its approval;
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-
the prevalence and severity of the adverse side effects of each of our products or product candidates;
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-
the clinical indications for which each of our products or product candidates are approved, including any potential
additional restrictions placed upon each product or product candidate in connection with its approval;
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-
prevalence of the disease or condition for which each product or product candidate is approved;
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the cost of treatment in relation to alternative treatments, including generic products;
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the extent to which each product or product candidate is approved for inclusion on formularies of hospitals and managed
care organizations and the level of reimbursement;
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any negative publicity related to our or our competitors' products or product candidates, including as a result of any
related adverse side effects;
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-
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the effectiveness of our or any current or future collaborators' sales, marketing and distribution strategies;
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pricing and cost effectiveness; and
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the availability of adequate reimbursement by third parties.
For
example, new AEDs that were introduced in the market as NCEs historically have not quickly gained significant market share against existing molecules in the epilepsy market because physicians are
often reluctant to change a stable patient's existing therapy (even for an NCE) and risk a breakthrough seizure or tolerability issues in their patients. Although Oxtellar XR and Trokendi XR are not
NCEs, they are subject to the risk that they will not be able to gain significant market share against existing AEDs. If our products or product candidates do not achieve an adequate level of
acceptance by physicians, third-party payors and patients, we may not generate sufficient revenues from these products or product candidates to become or remain profitable on a timely basis, if at
all.
Final marketing approval of any of our product candidates by the FDA or other regulatory authorities may be delayed, limited, or denied, any of which would adversely affect
our ability to generate operating revenues.
Our business depends on the successful development and commercialization of our products and product candidates. We are not permitted to market any
of our product candidates in the United States until we receive approval of an NDA from the FDA, or in any foreign jurisdiction until we receive the requisite approvals from such jurisdiction.
Satisfaction of regulatory requirements typically takes many years, is dependent upon the type, complexity and novelty of the product and requires the expenditure of substantial resources. We cannot
predict whether or when we will obtain regulatory approval to commercialize our remaining product candidates and we cannot, therefore, predict the timing of any future revenues from these product
candidates, if any.
The
FDA has substantial discretion in the drug approval process, including the ability to delay, limit or deny approval of a product candidate for many reasons. For example, the
FDA:
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-
could determine that we cannot rely on Section 505(b)(2) for our product candidates;
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-
could determine that the information provided by us was inadequate, contained clinical deficiencies or otherwise failed to
demonstrate the safety and effectiveness of any of our product candidates for any indication;
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-
may not find the data from bioequivalence studies and/or clinical trials sufficient to support the submission of an NDA or
to obtain marketing approval in the United States, including any findings that the clinical and other benefits of our product candidates outweigh their safety risks;
-
-
may disagree with our trial design or our interpretation of data from preclinical studies, bioequivalence studies and/or
clinical trials, or may change the requirements for approval even after it has reviewed and commented on the design for our trials;
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-
may determine that we have identified the wrong reference listed drug or drugs or that approval of our
Section 505(b)(2) application of our other product candidates, is blocked by patent or non-patent exclusivity of the reference listed drug or drugs;
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-
may identify deficiencies in the manufacturing processes or facilities of third-party manufacturers with which we enter
into agreements for the supply of the API used in our product candidates;
-
-
may identify deficiencies in the manufacturing processes or facilities of third-party manufacturers with which we enter
into agreements for the manufacturing of our product candidates;
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-
may approve our product candidates for fewer or more limited indications than we request, or may grant approval contingent
on the performance of costly post-approval clinical trials;
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-
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may change its approval policies or adopt new regulations; or
-
-
may not approve the labeling claims that we believe are necessary or desirable for the successful commercialization of our
product candidates.
Notwithstanding
the approval of many products by the FDA pursuant to Section 505(b)(2), over the last few years, some pharmaceutical companies and others have objected to the FDA's
interpretation of Section 505(b)(2). If the FDA changes its interpretation of Section 505(b)(2), or if the FDA's interpretation is successfully challenged in court, this could delay or
even prevent the FDA from approving any Section 505(b)(2) application that we submit. Any failure to obtain regulatory approval of our product candidates would significantly limit our ability
to generate revenues, and any failure to obtain such approval for all of the indications and labeling claims we deem desirable could reduce our potential revenues.
Our trials may fail to demonstrate acceptable levels of safety, efficacy or any other requirements of our product candidates, which could prevent or significantly delay
regulatory approval.
We may be unable to sufficiently demonstrate the safety and efficacy of our product candidates to obtain regulatory approval. We must demonstrate
with substantial evidence gathered in well-controlled studies, and to the satisfaction of the FDA with respect to approval in the
United States (and to the satisfaction of similar regulatory authorities in other jurisdictions with respect to approval in those jurisdictions), that each product candidate is safe and effective for
use in the target indication. The FDA may require us to conduct or perform additional studies or trials to adequately demonstrate safety and efficacy, which could prevent or significantly delay our
receipt of regulatory approval and, ultimately, the commercialization of that product candidate.
In
addition, the results from the trials that we have completed for our product candidates may not be replicated in future trials, or we may be unable to demonstrate sufficient safety and efficacy to
obtain the requisite regulatory approvals for our product candidates. A number of companies in the pharmaceutical industry have suffered significant setbacks in advanced development, even after
promising results in earlier trials. If our product candidates are not shown to be safe and effective, our clinical development programs could be delayed or might be terminated.
Our products and product candidates may cause undesirable side effects or have other properties that limit their commercial potential or delay or prevent their regulatory
approval.
Undesirable side effects caused by any of our product candidates could cause us or regulatory authorities to interrupt, delay or halt development and
could result in the denial of regulatory approval by the FDA or other regulatory authorities, and potential products liability claims. Undesirable side effects caused by any of our products could
cause regulatory authorities to temporarily or permanently halt sales of the products. Undesirable side effects that are caused by any of our products or product candidates could have a material
adverse effect on our business as a whole.
Immediate
release oxcarbazepine and topiramate, drug compounds upon which Oxtellar XR and Trokendi XR are based, respectively, are known to cause various side effects, including but not limited to
dizziness, paresthesia, headaches, cognitive deficiencies such as memory loss and speech impediment, digestive problems, somnolence, double vision, gingival enlargement, nausea, weight gain, and
fatigue. The use of Oxtellar XR and Trokendi XR may cause similar side effects as compared to their reference products, or may cause additional or different side effects.
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If
these products cause side effects or if any of our product candidates receive marketing approval, and we or others later identify undesirable side effects caused by the product candidate, a number
of potentially significant negative consequences could result, including:
-
-
regulatory authorities may withdraw approvals of the product candidate or otherwise require us to take the approved
product off the market;
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-
regulatory authorities may require additional warnings, or a narrowing of the indication, on the product label;
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-
we may be required to create a medication guide outlining the risks of such side effects for distribution to patients;
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-
we may be required to modify the product in some way;
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-
the FDA may require us to conduct additional clinical trials or costly post-marketing testing and surveillance to monitor
the safety or efficacy of the product;
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-
sales of approved products may decrease significantly;
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-
we could be sued and held liable for harm caused to patients; and
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-
our reputation may suffer.
Any
of these events could prevent us from achieving or maintaining the commercial success of our products and product candidates and could substantially increase commercialization costs.
If other versions of extended or controlled release oxcarbazepine or topiramate are approved and successfully commercialized , then our business would be materially harmed.
Other third parties may seek approval to manufacture and market their own versions of extended release oxcarbazepine or topiramate anti-epileptic
drugs in the United States. For example, we are aware that Upsher-Smith's Qudexy XR (extended release topiramate) received FDA approval in March 2014 and will compete with Trokendi XR
when launched commercially. As Trokendi XR was not granted any marketing exclusivity by the FDA, other than under circumstances in which third parties may infringe or are infringing our patents, we
may not be able to prevent the submission or approval of another full NDA for any competitor's extended or controlled release topiramate product candidate, including Qudexy XR. In addition, we
are aware of companies who are marketing modified-release oxcarbazepine products outside of the United States, such as Apydan, which is developed by Desitin Arzneimittel GmbH and requires
twice-daily administration. If companies with modified-release oxcarbazepine products outside of the United States pursue or obtain approval of their products within the United States, such competing
products may limit the potential success of Oxtellar XR in the United States, and our business and growth prospects would be materially impaired. Accordingly, if any third party is successful in
obtaining approval to manufacture and market their own versions of extended release oxcarbazepine or topiramate in the United States, we may not be able to recover expenses incurred in connection with
the development of or realize revenues from Oxtellar XR or Trokendi XR.
If we do not obtain marketing exclusivity for our product candidates, our business may suffer.
Under the Hatch-Waxman Amendments, three years of marketing exclusivity may be granted for the approval of new and supplemental NDAs, including
Section 505(b)(2) applications, for, among other things, new indications, dosage forms, routes of administration, or strengths of an existing drug, or for a new use, if new clinical
investigations that were conducted or sponsored by the applicant are determined by the FDA to be essential to the approval of the application. This exclusivity, which is sometimes referred to as
clinical investigation exclusivity, prevents the FDA from approving an
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application
under Section 505(b)(2) for the same conditions of use associated with the new clinical investigations before the expiration of three years from the date of approval. Such
exclusivity, however, would not prevent the approval of another application if the applicant submits a Section 505(b)(1) NDA and has conducted its own adequate, well-controlled clinical trials
demonstrating safety and efficacy, nor would it prevent approval of a generic product or Section 505(b)(2) product that did not incorporate the exclusivity-protected changes of the approved
drug product. Under the Hatch-Waxman
Amendments, newly-approved drugs and indications may also benefit from a statutory period of non-patent marketing exclusivity. The Hatch-Waxman Amendments provide five-year marketing exclusivity to
the first applicant to gain approval of an NDA for an NCE, meaning that the FDA has not previously approved any other drug containing the same active API, or active moiety, which is the molecule
responsible for the action of the drug substance. Although protection under the Hatch-Waxman Amendments will not prevent the submission or approval of another full Section 505(b)(1) NDA, such
an NDA applicant would be required to conduct its own preclinical and adequate, well-controlled clinical trials to demonstrate safety and effectiveness. While the FDA granted a three year marketing
exclusivity period for Oxtellar XR, it did not grant a similar marketing exclusivity period for Trokendi XR. If we are unable to obtain marketing exclusivity for our subsequent product candidates,
then our competitors may obtain approval of competing products more easily than if we had such marketing exclusivity, and our future revenues could be reduced, possibly materially.
Delays or failures in the completion of testing of our product candidates would increase our costs and delay or limit our ability to generate revenues.
Delays or failures in the completion of clinical trials for our product candidates could significantly raise our product development costs. We do not
know whether current or planned trials will be completed on schedule, if at all. The commencement and completion of clinical development can be delayed or halted for a number of reasons,
including:
-
-
difficulties obtaining regulatory approval to commence a clinical trial or complying with conditions imposed by a
regulatory authority regarding the scope or term of a clinical trial;
-
-
delays in reaching or failure to reach agreement on acceptable terms with prospective clinical research organizations, or
CROs, and trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;
-
-
insufficient or inadequate supply or quantity of a product candidate for use in trials;
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-
difficulties obtaining IRB or ethics committee approval to conduct a trial at a prospective site;
-
-
challenges recruiting and enrolling patients to participate in clinical trials for a variety of reasons, including
competition from other programs for the treatment of similar conditions;
-
-
severe or unexpected drug-related side effects experienced by patients in a clinical trial;
-
-
difficulty retaining patients who have initiated a clinical trial but may be prone to withdraw due to side effects from
the therapy, lack of efficacy or personal issues; and
-
-
clinical holds imposed by the FDA.
Clinical
trials may also be delayed as a result of ambiguous or negative interim results. In addition, clinical trials may be suspended or terminated by us, an IRB or ethics committee overseeing the
clinical trial at a trial site (with respect to that site), the FDA or other regulatory authorities due to a number of factors, including:
-
-
failure to conduct the clinical trial in accordance with regulatory requirements or the trial protocols;
-
-
observations during inspection of the clinical trial operations or trial sites by the FDA or other regulatory authorities
that ultimately result in the imposition of a clinical hold;
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-
-
unforeseen safety issues; or
-
-
lack of adequate funding to continue the trial.
In
addition, failure to conduct the clinical trial in accordance with regulatory requirements or the trial protocols may also result in the inability to use the data to support product approval. For
instance, the efficacy demonstrated by SPN-810 in its most recent Phase IIb study was not statistically significant for all efficacy measures for the study. Changes in regulatory requirements
and guidance may occur, and we may need to amend clinical trial protocols to reflect these changes. Amendments may require us to resubmit our clinical trial protocols to institutional review boards or
ethics committees for reexamination, which may impact the costs, timing or successful completion of a clinical trial. In addition, many of the factors that cause, or lead to, a delay in the
commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of our product candidates. If we experience delays in completion of, or if we terminate any
of our clinical trials, our ability to obtain regulatory approval for our product candidates may be materially harmed, and our commercial prospects and ability to generate product revenues will be
diminished.
We expect intense competition and, if our competitors develop or market alternatives for treatments of our target indications, our commercial opportunities will be reduced
or eliminated.
The pharmaceutical industry is characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary
therapeutics. We face competition from a number of sources, some of which may target the same indications as our products and product candidates, including large pharmaceutical companies, smaller
pharmaceutical companies, biotechnology companies, academic institutions, government agencies and private and public research institutions. The availability of competing products will limit the demand
and the price we are able to charge for any of our products or product candidates that are commercialized unless we are able to differentiate them. We anticipate that we will face intense competition
when our product candidates are approved by regulatory authorities and we begin the commercialization process for our products. For instance, there are over 15 branded products, as well as their
generic counterparts, on the U.S. market indicated to treat epilepsy. In addition, several NCEs have entered the epilepsy market including Potiga, Vimpat and Banzel. Another NCE, Aptiom was approved
in 2013 and is expected to enter the market in 2014. In addition, competition in the ADHD market in the United States has increased with the commercial launch of several products in recent years,
including the launch of generic versions of branded drugs such as Adderall XR. As a result, we may not be able to recover expenses incurred in connection with the development of our product candidates
or realize revenues from any commercialized product.
In
addition to already marketed competing products, we believe certain companies are developing other products which could compete with our product candidates should they be approved by regulatory
authorities. For example, according to Datamonitor, as of April 2010, there were 47 compounds in preclinical and clinical development for epilepsy across the United States, Japan, France, Germany,
Italy, Spain and the United Kingdom. Datamonitor reported that approximately 13 were in late-stage (Phase II or later) clinical trials as of June 2011. We are also aware that Upsher-Smith's
Qudexy XR (extended release topiramate) has received FDA approval. Such competing product could limit the potential success of Trokendi XR and our growth prospects could be materially
impaired by the success of this competing product. In addition, we are aware of companies who are marketing outside of the United States modified-release oxcarbazepine products, such as Apydan, which
is developed by Desitin Arzneimittel GmbH and requires twice-daily administration. We are also aware that Qsymia, an oral drug containing ER topiramate and another API, is available in extended
release for treatment of weight management. If companies with modified-release oxcarbazepine products outside of the United States obtain approval for their products within the United States, then
such competing products may limit the potential success of Oxtellar XR. In addition, several companies have various product candidates they are developing for ADHD. For example, Alcobra is developing
a non-stimulant product
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candidate
that is expected to enter Phase III clinical trials in 2014 and that could compete with our SPN-812 product candidate. Further, new developments, including the development of other
drug technologies, may render our product candidates obsolete or noncompetitive. As a result, our products and product candidates may become obsolete before we recover expenses incurred in connection
with their development or realize revenues from any commercialized product.
Further,
many competitors have substantially greater:
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capital resources;
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research and development resources and experience, including personnel and technology;
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drug development, clinical trial and regulatory resources and experience;
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sales and marketing resources and experience;
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manufacturing and distribution resources and experience;
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name recognition; and
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resources, experience and expertise in prosecution and enforcement of intellectual property rights.
As
a result of these factors, our competitors may obtain regulatory approval of their products more rapidly than we are able to or may obtain patent protection or other intellectual property rights
that limit or block us from developing or commercializing our product candidates. Our competitors may also develop drugs that are more effective, more useful, better tolerated, subject to fewer or
less severe side effects, more widely prescribed or accepted or less costly than ours and may also be more successful than us in manufacturing and marketing their products. If we are unable to compete
effectively with the products of our competitors or if such competitors are successful in developing products that compete with any of our product candidates that are approved, our business, results
of operations, financial condition and prospects may be materially adversely affected. Mergers and acquisitions in the pharmaceutical industry may result in even more resources being concentrated at
competitors. Competition may increase further as a result of advances made in the commercial applicability of technologies and greater availability of capital for investment.
Our products and our product candidates, if they receive regulatory approval, may be subject to restrictions or withdrawal from the market and we may be subject to penalties
if we fail to comply with regulatory requirements.
Even though U.S. regulatory approval has been obtained for two of our products, the FDA may still impose significant restrictions on a product's
indicated uses or marketing or impose ongoing requirements for potentially costly post-approval studies. Our product candidates would also be, and our approved product and our collaborators' approved
products are, subject to ongoing FDA requirements governing the labeling, packaging, storage, advertising, promotion, recordkeeping and submission of safety and other post-market information. In
addition, manufacturers of drug products and their facilities are subject to continual review and periodic inspections by the FDA and other regulatory authorities for compliance with cGMP regulations.
If we, our collaborators or a regulatory authority discovers previously unknown problems with a product, such as side effects of unanticipated severity or frequency, or problems with the facility
where the product is manufactured, a regulatory authority may impose restrictions on that product or the manufacturer, including requiring withdrawal of the product from the market or suspension of
manufacturing. If we or our collaborators, or our or our collaborators' approved products or product candidates, or the manufacturing facilities for our or
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our
collaborators' approved products or product candidates fail to comply with applicable regulatory requirements, a regulatory authority may:
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issue warning letters or untitled letters;
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impose civil or criminal penalties;
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suspend regulatory approval;
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suspend any ongoing bioequivalence and/or clinical trials;
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refuse to approve pending applications or supplements to applications filed by us;
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impose restrictions on operations, including costly new manufacturing requirements, or suspension of production; or
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seize or detain products or require us to initiate a product recall.
In
addition, our product labeling, advertising and promotion of our approved products, and our product candidates upon FDA approval, are subject to regulatory requirements and continuing regulatory
review. The FDA strictly regulates the promotional claims that may be made about prescription products. In particular, a product may not be promoted for uses that are not approved by the FDA as
reflected in the product's approved labeling. Physicians may nevertheless prescribe our products and, upon receiving FDA approval, our product candidates to their patients in a manner that is
inconsistent with the approved label. The FDA and other authorities 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 sanctions. The federal government has levied large civil and criminal fines against companies for alleged improper promotion and has
enjoined several companies from engaging in off-label promotion. If we are found to have promoted off-label uses, we may be enjoined from such off-label promotion and become subject to significant
liability, which would have an adverse effect on our reputation, business and revenues, if any.
If we fail to produce our products and product candidates in the volumes that we require on a timely basis, or fail to comply with stringent regulations applicable to
pharmaceutical drug manufacturers, we may face delays in the development and commercialization of our products and product candidates.
We do not currently own or operate manufacturing facilities for the production of any of our products or product candidates beyond Phase II
clinical trials, nor do we have plans to develop our own manufacturing operations for Phase III clinical materials or commercial products in the foreseeable future. We currently depend on
third-party contract manufacturers for the supply of the APIs for our products or product candidates, including drug substance for our preclinical research and clinical trials. For Oxtellar XR and
Trokendi XR, we currently rely on single suppliers for raw materials including API and single manufacturers to produce and package final dosage forms. Any future curtailment in the availability of raw
materials could result in production or other delays with consequent adverse effects on us. In addition, because regulatory authorities must generally approve raw material sources for pharmaceutical
products, changes in raw material suppliers may result in production delays or higher raw material costs.
The
manufacture of pharmaceutical products requires significant expertise and capital investment, including the development of advanced manufacturing techniques and process controls. Pharmaceutical
companies often encounter difficulties in manufacturing, particularly in scaling up production of their products. These problems include manufacturing difficulties relating to production costs and
yields, quality control, including stability of the product and quality assurance testing, shortages of qualified personnel, as well as compliance with federal, state and foreign regulations. If we
are unable to demonstrate stability in accordance with commercial requirements, or if our manufacturers were to encounter difficulties or otherwise fail to comply with their obligations to us, our
ability to obtain FDA
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approval
and market our products and product candidates would be jeopardized. In addition, any delay or interruption in the supply of clinical trial supplies could delay or prohibit the completion of
our bioequivalence and/or clinical trials, increase the costs associated with conducting our bioequivalence and/or clinical trials and, depending upon the period of delay, require us to commence new
trials at significant additional expense or to terminate a trial.
Manufacturers
of pharmaceutical products need to comply with cGMP requirements enforced by the FDA through their facilities inspection programs. These requirements include, among other things, quality
control, quality assurance and the maintenance of records and documentation. Manufacturers of our products and product candidates may be unable to comply with these cGMP requirements and with other
FDA and foreign regulatory requirements. A failure to comply with these requirements may
result in fines and civil penalties, suspension of production, suspension or delay in product approval, product seizure or recall, or withdrawal of product approval. If the safety of any of our
products or product candidates is compromised due to failure to adhere to applicable laws or for other reasons, we may not be able to obtain regulatory approval for such product candidate or
successfully commercialize such products or product candidates, and we may be held liable for any injuries sustained as a result. Any of these factors could cause a delay in clinical developments,
regulatory submissions, approvals or commercialization of our products or product candidates, entail higher costs or result in our being unable to effectively commercialize our product candidates.
Furthermore, if we fail to obtain the required commercial quantities on a timely basis from our suppliers and at commercially reasonable prices, we may be unable to meet demand for our approved
products or product candidates, and would lose potential revenues.
If the FDA or other applicable regulatory authorities approve generic products that compete with any of our products or product candidates, the sales of those products or
product candidates would be adversely affected.
Once an NDA, including a Section 505(b)(2) application, is approved, the product covered thereby becomes a "listed drug" which can, in turn,
be cited by potential competitors in support of approval of an ANDA. The FDCA, FDA regulations and other applicable regulations and policies provide incentives to manufacturers to create modified,
non-infringing versions of a drug to facilitate the approval of an ANDA or other application for generic substitutes. These manufacturers might only be required to conduct a relatively inexpensive
study to show that their product has the same active ingredient(s), dosage form, strength, route of administration, and conditions of use, or labeling, as our product candidate and that the generic
product is bioequivalent to ours, meaning it is absorbed in the body at the same rate and to the same extent as our product candidate. These generic equivalents, which must meet the same quality
standards as branded pharmaceuticals, would be significantly less costly than ours to bring to market and companies that produce generic equivalents are generally able to offer their products at lower
prices. Thus, after the introduction of a generic competitor, a significant percentage of the sales of any branded product is typically lost to the generic product. Accordingly, competition from
generic equivalents to our product candidates would materially adversely impact our revenues, profitability and cash flows and substantially limit our ability to obtain a return on the investments we
have made in our product candidates. For example, as disclosed in Part I Item 3 Legal Proceedings of this Annual Report on Form 10-K, we received a Paragraph IV Notice
Letter against our Oxtellar XR Orange Book patents from several generic drug makers. We have filed a lawsuit against these drug makers alleging infringement of our Oxtellar XR patents. In the event
that we are not successful in this lawsuit, our future sales of Oxtellar XR will be adversely affected by competition from these generic drug manufacturers.
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We intend to rely on third-party collaborators to market and commercialize our products and product candidates outside of the United States, who may fail to effectively
commercialize our products and product candidates.
Outside of the United States, we currently plan to utilize strategic partners or contract sales forces, where appropriate, to assist in the
commercialization of our products and product candidates, if approved. We currently possess limited resources and may not be successful in establishing collaborations or co-promotion arrangements on
acceptable terms, if at all. We also face competition in our search for collaborators and co-promotion partners. By entering into strategic collaborations or similar arrangements, we will rely on
third parties for financial resources and for development, commercialization, sales and marketing and regulatory expertise. Our collaborators may fail to develop or effectively commercialize our
products and product candidates because they cannot obtain the necessary regulatory approvals, they lack adequate financial or other resources or they decide to focus on other initiatives. Any failure
of our third-party collaborators to successfully market and commercialize our product candidates outside of the United States would diminish our revenues and harm our results of operations.
Limitations on our patent rights relating to our products and product candidates may limit our ability to prevent third parties from competing against us.
Our success will depend on our ability to obtain and maintain patent protection for our proprietary technologies and our product candidates, preserve
our trade secrets, prevent third parties from infringing upon our proprietary rights and operate without infringing upon the proprietary rights of others. To that end, we seek patent protection in the
United States and internationally for our product candidates. Our policy is to actively seek to protect our proprietary position by, among other things, filing patent applications in the United States
and abroad (including Europe, Canada and certain other countries when appropriate) relating to proprietary technologies that are important to the development of our business.
The
strength of patents in the pharmaceutical industry involves complex legal and scientific questions and can be uncertain. Patent applications in the United States and most other countries are
confidential for a period of time until they are published, and publication of discoveries in scientific or patent literature typically lags actual discoveries by several months or more. As a result,
we cannot be certain that we were the first to conceive inventions covered by our patents and pending patent applications or that we were the first to file patent applications for such inventions. In
addition, we cannot be certain that our patent applications will be granted, that any issued patents will adequately protect our intellectual property or that such patents will not be challenged,
narrowed, invalidated or circumvented.
We
also rely upon unpatented trade secrets, unpatented know-how and continuing technological innovation to develop and maintain our competitive position, which we seek to protect, in part, by
confidentiality agreements with our employees and our collaborators and consultants. We also have
agreements with our employees and selected consultants that obligate them to assign their inventions to us. It is possible that technology relevant to our business will be independently developed by a
person that is not a party to such an agreement. Furthermore, if the employees and consultants that are parties to these agreements breach or violate the terms of these agreements, we may not have
adequate remedies, and we could lose our trade secrets through such breaches or violations. Further, our trade secrets could otherwise become known or be independently discovered by our competitors.
Any failure to adequately prevent disclosure of our trade secrets and other proprietary information could have a material adverse impact on our business.
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In
addition, the laws of certain foreign countries do not protect proprietary rights to the same extent or in the same manner as the United States, and therefore, we may encounter problems in
protecting and defending our intellectual property in certain foreign jurisdictions.
If we are sued for infringing intellectual property rights of third parties, it will be costly and time consuming, and an unfavorable outcome in that litigation would have a
material adverse effect on our business.
Our commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market and sell their approved products
and our product candidates and use our proprietary technologies without infringing the proprietary rights of third parties. Numerous U.S. and foreign issued patents and pending patent applications,
which are owned by third parties, exist in the fields in which we and our collaborators are developing product candidates. As the pharmaceutical industry expands and more patents are issued, the risk
increases that our collaborators' approved products and our product candidates may give rise to claims of infringement of the patent rights of others. There may be issued patents of third parties of
which we are currently unaware, that may be infringed by our collaborators' approved products or Oxtellar XR or Trokendi XR, which could prevent us from being able to fully commercialize Oxtellar XR,
Trokendi XR or any of our product candidates, respectively. Because patent applications can take many years to issue, there may be currently pending applications which may later result in issued
patents that our collaborators' approved products or our product candidates may infringe.
We
may be exposed to, or threatened with, future litigation by third parties alleging that our collaborators' approved products or our products or product candidates infringe their intellectual
property rights. If one of our collaborators' approved products or our products or product candidates is found to infringe the intellectual property rights of a third party, we or our collaborators
could be enjoined by a court and required to pay damages and could be unable to commercialize the applicable approved products and product candidates unless we obtain a license to the patent. A
license may not be available to us on acceptable terms, if at all. In addition, during litigation, the patent holder could
obtain a preliminary injunction or other equitable relief which could prohibit us from making, using or selling our approved products, pending a trial on the merits, which may not occur for several
years.
There
is a substantial amount of litigation involving patent and other intellectual property rights in the pharmaceutical industry generally. If a third party claims that we or our collaborators
infringe its intellectual property rights, we may face a number of issues, including, but not limited to:
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infringement and other intellectual property claims which, regardless of merit, may be expensive and time-consuming to
litigate and may divert our management's attention from our core business;
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substantial damages for infringement, which we may have to pay if a court decides that the product at issue infringes on
or violates the third party's rights, and, if the court finds that the infringement was willful, we could be ordered to pay treble damages and the patent owner's attorneys' fees;
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a court prohibiting us from selling Oxtellar XR, Trokendi XR, or any product candidate approved in the future, if any,
unless the third party licenses its rights to us, which it is not required to do;
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if a license is available from a third party, we may have to pay substantial royalties, fees or grant cross-licenses to
our intellectual property rights; and
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redesigning Oxtellar XR, Trokendi XR, or any of our product candidates so they do not infringe, which may not be possible
or may require substantial monetary expenditures and time.
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We may become involved in lawsuits to protect or enforce our patents, which could be expensive, time consuming and unsuccessful.
Competitors may infringe our patents. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be
expensive and time consuming. For example, we are involved in the following matters related to Paragraph IV Certification Notice Letters that we have received in connection with our
collaborators' products. In connection with an ANDA, a Paragraph IV Certification Notice Letter notifies the FDA that one or more patents listed in the FDA's Approved Drug Product List (Orange
Book) is alleged to be invalid, unenforceable or will not be infringed by the ANDA product.
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Oxtellar XR Litigation.
The Company received a
Paragraph IV Notice Letter against our Oxtellar XR Orange Book patents from generic drug maker Watson Laboratories, Inc.Florida ("WLF") on June 26, 2013. On
August 7, 2013 the Company filed a lawsuit against Actavis, Inc., WLF, Actavis Pharma, Inc., Watson Laboratories, Inc., and Anda, Inc. (collectively "Watson")
alleging infringement of two patents that are listed in the FDA's Orange Book covering its antiepileptic drug Oxtellar XR. Supernus's United States Patent Nos. 7,722,898 and 7,910,131 ("the
patents-in-suite") generally cover once-a-day oxcarbazepine formulations and methods of treating seizures using those formulations. Both patents do not expire until April 13, 2027. The
Complaintfiled in the U.S. District Court for the District of New Jerseyalleges that Watson infringed Supernus's Oxtellar XR patents by submitting to the Food and Drug
Administration ("FDA") an Abbreviated New Drug Application ("ANDA") seeking to market a generic version of Oxtellar XR prior to the expiration of Supernus's patents. Filing its Complaint within
45 days of receiving Watson's Paragraph IV certification notice entitles Supernus to an automatic stay preventing the FDA from approving Watson's ANDA for 30 months. On
September 25, 2013, Watson answered, denying the substantive allegations of the Complaint. One defendant, Watson Laboratories, Inc.Florida, asserted Counterclaims, seeking
declaratory judgments of non-infringement and invalidity of the patents-in-suit. On October 30, 2013 the Company filed its Reply, denying the substantive allegations of the Counterclaims. The
case has been assigned to Renee M. Bumb, U.S.D.J. and Joel Schneider, U.S.M.J. The case is in its early stages and discovery is proceeding.
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Oracea Litigation and Inter Partes Review.
We are involved
in a patent infringement case filed in the District of Delaware in response to Paragraph IV Certification Notice Letters that we received in September 2011 and September 2012 regarding an ANDA
submitted to the FDA by Amneal Pharmaceuticals LLC, requesting approval to market and sell generic versions of Oracea (30 mg immediate release, 10 mg delayed release doxycycline), a product
that is manufactured and sold by Galderma Laboratories, L.P. Amneal alleged its notice letters that U.S. Patent Nos. 7,749,532, or the '532 patent, and 8,206,740, or the '740 patent,
which are both assigned to us, are invalid, unenforceable and/or will not be infringed by the manufacture, use or sale of the product described in its ANDA. In June 2013, Amneal also filed petitions
with the Patent Trial and Appeal Board for
inter partes review
of the '740 patent, as well as U.S. Patent Nos. 8,394,405, or the '405 patent, and
8,394,406, or the '406 patent. The Patent Trial and Appeal Board initiated
inter partes review
for each of the '740, '405 and '406 patents in December
2012, and we are currently involved in these proceedings. In addition, in October 2010, we received a complaint for declaratory judgment from Mylan Pharmaceuticals Inc., or Mylan, alleging
invalidity of the '532 patent. This case was tried in July 2011 in the District of Delaware. The district court held that Mylan infringed certain claims of the patent, and that the patent claims are
valid. Following an appeal by Mylan; Lupin Limited and Lupin Pharmaceuticals, Inc.; and Impax Laboratories, Inc. to the U.S. Court of Appeals for the Federal Circuit, the Federal Circuit
affirmed the district court's decision regarding the '532 patent. The '532, '740, '405 and '406 patents cover once-daily formulations of doxycycline, including their
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methods
use in treating rosacea and processes regarding their preparation. The '532 patent expires on December 19, 2027, the '740 patent expires on December 24, 2005, and the '405 and
'406 patents expire on April 7, 2024. The '532, '740, '405 and '406 patents are licensed to Galderma Laboratories, L.P. We intend to support Galderma Laboratories, L.P. in these
matters. We do not expect an adverse decision in the foregoing matters will have a material adverse effect on our current business.
In
any infringement proceeding including the foregoing, a court may decide that a patent of ours is not valid or is unenforceable, or may refuse to stop the other party from using the technology at
issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation or defense proceedings could put one or more of our patents at risk of being
invalidated or interpreted narrowly and could put our patent application at risk of not issuing.
Interference
proceedings brought by the USPTO may be necessary to determine the priority of inventions with respect to our patents and patent applications or those of our collaborators. An unfavorable
outcome could require us to cease using the technology or to attempt to license rights to it from the prevailing party. Our business could be harmed if a prevailing party does not offer us a license
on terms that are acceptable to us. Litigation or interference proceedings may fail and, even if
successful, may result in substantial costs and distraction of our management and other employees. We may not be able to prevent, alone or with our collaborators, misappropriation of our proprietary
rights, particularly in countries where the laws may not protect those rights as fully as in the United States.
Furthermore,
because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised
by disclosure during this type of litigation. In addition, there could be public announcements of the results of hearings, motions or other interim proceeding or developments. If securities analysts
or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock. There can be no assurance that our products or product candidates will
not be subject to the same risks.
We depend on collaborators to work with us to develop, manufacture and commercialize their and our products and product candidates.
We have a license agreement with United Therapeutics to use one of our proprietary technologies for an oral formulation of treprostinil
diethanolamine, or treprostinil, for the treatment of PAH, as well as for other indications. On December 20, 2013, United Therapeutics announced that the FDA had approved Orenitram
(treprostinil). We expect United Therapeutics to launch this product in 2014, which will trigger a milestone payment due to us of $2.0 million. We are entitled to receive milestones and
royalties for use of this formulation in other indications. If we materially breach any of our obligations under the license agreement, however, we could lose the potential to receive any future
royalty payments thereunder, which could be financially significant to us.
We
also have license agreements with Especificos Stendhal, S.A., DE C.V. and we may enter into additional collaborations in the future. Our future collaboration agreements may have the effect
of limiting the areas of research and development that we may pursue, either alone or in collaboration with third parties. Much of the potential revenues from these future collaborations may consist
of contingent payments, such as payments for achieving development milestones and royalties payable on sales of developed products. The milestone and royalty revenues that we may receive under these
collaborations will depend upon our collaborators' ability to successfully develop, introduce, market and sell new products. Future collaboration partners may fail to develop or effectively
commercialize products using our products, product candidates or technologies because they, among other things:
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may change the focus of their development and commercialization efforts or may have insufficient resources to effectively
develop our product candidates. Pharmaceutical and
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biotechnology
companies historically have re-evaluated their development and commercialization priorities following mergers and consolidations, which have been common in recent years in these
industries. The ability of some of our product candidates to reach their potential could be limited if our future collaborators decrease or fail to increase development or commercialization efforts
related to those product candidates;
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may decide not to devote the necessary resources due to internal constraints, such as limited personnel with the requisite
scientific expertise or limited cash resources, or the belief that other drug development programs may have a higher likelihood of obtaining marketing approval or may potentially generate a greater
return on investment;
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may develop and commercialize, either alone or with others, drugs that are similar to or competitive with the product
candidates that are the subject of their collaborations with us;
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may not have sufficient resources necessary to carry the product candidate through clinical development, marketing
approval and commercialization;
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may fail to comply with applicable regulatory requirements;
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may not be able to obtain the necessary marketing approvals; or
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may breach or terminate their arrangement with us.
If
collaboration partners fail to develop or effectively commercialize our products or product candidates for any of these reasons, we may not be able to replace the collaboration partner with another
partner to develop and commercialize the product or product candidate under the terms of the collaboration. Further, even if we are able to replace the collaboration partner, we may not be able to do
so on commercially favorable terms. As a result, the development and commercialization of the affected product or product candidate could be delayed, curtailed or terminated because we may not have
sufficient financial resources or capabilities to continue development and commercialization of the product candidate on our own, which could adversely affect our results of operations.
We rely and will continue to rely on outsourcing arrangements for certain of our activities, including clinical research of our product candidates and manufacturing of our
compounds and product candidates beyond Phase II clinical trials.
We rely on outsourcing arrangements for some of our activities, including manufacturing, preclinical and clinical research, data collection and
analysis, and electronic submission of regulatory filings. We may have limited control over these third parties and we cannot guarantee that they will perform their obligations in an effective and
timely manner. Our reliance on third parties, including third-party CROs and CMOs entails risks including, but not limited to:
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non-compliance by third parties with regulatory and quality control standards;
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sanctions imposed by regulatory authorities if compounds supplied or manufactured by a third party supplier or
manufacturer fail to comply with applicable regulatory standards;
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the possible breach of the agreements by the CROs or CMOs because of factors beyond our control or the insolvency of any
of these third parties or other financial difficulties, labor unrest, natural disasters or other factors adversely affecting their ability to conduct their business; and
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termination or non-renewal of an agreement by the third parties, at a time that is costly or inconvenient for us, because
of our breach of the manufacturing agreement or based on their own business priorities.
We
do not own or operate manufacturing facilities for the production of any of our products or product candidates beyond Phase II clinical trials, nor do we have plans to develop our own
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manufacturing
operations for Phase III clinical materials or commercial products in the foreseeable future. We currently depend on third-party CMOs for all of our required raw materials and
drug substance for our preclinical research and clinical trials. For Oxtellar XR and Trokendi XR, we currently rely on single suppliers for raw materials, including API, and rely on third-party
suppliers and manufacturers for the final commercial products. If any of these vendors is unable to perform its obligations to us, including due to violations of the FDA's requirements, our ability to
meet regulatory requirements or projected timelines and necessary quality standards for successful manufacture of the various required lots of material for our development and commercialization
efforts would be adversely affected. Further, if we were required to change vendors, it could result in delays in our regulatory approval efforts and significantly increase our costs. Accordingly, the
loss of any of our current or future third-party manufacturers or suppliers could have a material adverse effect on our business, results of operations, financial condition and prospects.
We
have entered into supply agreements for both Oxtellar XR and Trokendi XR with leading CMOs headquartered in North America for the manufacture of the final commercial products. However, there is a
risk that the counterparties to these agreements will not perform their respective obligations or will terminate these agreements. In addition, we do not have contractual relationships for the
manufacture of commercial supplies of all of our product candidates. The number of third-party manufacturers with the expertise, required regulatory approvals and facilities to manufacture drug
substance and final drug product on a commercial scale is limited. Therefore, we may not be able to enter into such arrangements with third-party manufacturers in a timely manner, on acceptable terms
or at all. Failure to secure such contractual arrangements would harm the commercial prospects for our product candidates, our costs could increase and our ability to generate revenues could be
delayed.
We have in-licensed or acquired a portion of our intellectual property necessary to develop certain of our psychiatry product candidates, and if we fail to comply with our
obligations under any of these arrangements, we could lose such intellectual property rights.
We are a party to and rely on several arrangements with third parties, such as those with Afecta and Rune, which give us rights to intellectual
property that is necessary for the development of certain of our product candidates including SPN-810 and SPN-809, respectively. In addition, we may enter into similar arrangements in the future. Our
current arrangements impose various development, royalty and other obligations on us. If we materially breach these obligations or if Afecta or Rune fail to adequately perform their respective
obligations, these exclusive arrangements could be terminated, which would result in our inability to develop, manufacture and sell products that are covered by such intellectual property.
Even if our product candidates receive regulatory approval in the United States, we or our collaborators may never receive approval to commercialize our product candidates
outside of the United States.
In order to market any products outside of the United States, we must establish and comply with numerous and varying regulatory requirements of other
jurisdictions regarding safety and efficacy. Approval procedures vary among jurisdictions and can involve product testing and administrative review periods different from, and greater than those in
the United States. The time required to obtain approval in other jurisdictions might differ from that required to obtain FDA approval. The regulatory approval process in other jurisdictions may
include all of the risks detailed above regarding FDA approval in the United States as well as other risks. For example, legislation analogous to Section 505(b)(2) of the FDCA in the United
States, which relates to the ability of an NDA applicant to use published data not developed by such applicant, may not exist in other countries. In territories where data is not freely available, we
may not have the ability to commercialize our products without negotiating rights from third parties to refer to their clinical data in our regulatory applications, which could require the expenditure
of significant additional funds.
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In addition, regulatory approval in one jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one jurisdiction
may have a negative effect on the regulatory processes in others. Failure to obtain regulatory approvals in other jurisdictions or any delay or setback in obtaining such approvals could have the same
adverse effects detailed above regarding FDA approval in the United States. As described above, such effects include the risks that any of our product candidates may not be approved for all
indications requested which could limit the uses of our product candidates and have an adverse effect on their commercial potential or require costly post-marketing studies.
Guidelines and recommendations published by various organizations can reduce the use of our products and product candidates.
Government agencies promulgate regulations and guidelines directly applicable to us and to our products and product candidates. In addition,
professional societies, practice management groups, private health and science foundations and organizations involved in various diseases from time to time may also publish guidelines or
recommendations to the health care and patient communities. Recommendations of government agencies or these other groups or organizations may relate to such matters as usage, dosage, route of
administration and use of concomitant therapies. Recommendations or guidelines suggesting the reduced use of our products or
product candidates or the use of competitive or alternative products that are followed by patients and health care providers could result in decreased use of our products or product candidates.
We are subject to uncertainty relating to payment or reimbursement policies which, if not favorable for our products or product candidates, could hinder or prevent our
commercial success.
Our ability or our collaborators' ability to successfully commercialize our products and product candidates, including Oxtellar XR and Trokendi XR,
will depend in part on the coverage and reimbursement levels set by governmental authorities, private health insurers, managed care organizations and other third-party payors. As a threshold for
coverage and reimbursement, third-party payors generally require that drug products have been approved for marketing by the FDA. Third-party payors also are increasingly challenging the effectiveness
of and prices charged for medical products and services. Government authorities and these third-party payors have attempted to control costs, in some instances, by limiting coverage and the amount of
reimbursement for particular medications or encouraging the use of lower-cost generic AEDs. We cannot be sure that reimbursement will be available for any of the products that we develop and, if
reimbursement is available, the level of reimbursement. Reduced or partial payment or reimbursement coverage could make our products or product candidates, including Oxtellar XR and Trokendi XR, less
attractive to patients and prescribing physicians. We also may be required to sell our products or product candidates at a discount, which would adversely affect our ability to realize an appropriate
return on our investment in our products or product candidates or compete on price.
We
expect that private insurers and managed care organizations will consider the efficacy, cost effectiveness and safety of our products or product candidates, including Oxtellar XR and Trokendi XR,
in determining whether to approve reimbursement for such products or product candidates and at what level. Because each third-party payor individually approves payment or reimbursement, obtaining
these approvals can be a time consuming and expensive process that could require us to provide scientific or clinical support for the use of each of our products or product candidates separately to
each third-party payor. In some cases, it could take several months or years before a particular private insurer or managed care organization reviews a particular product, and we may ultimately be
unsuccessful in obtaining coverage. Our competitors generally have larger organizations, as well as existing business relationships with third-party payors relating to their products. Our business
would be materially adversely affected if we do not receive approval for reimbursement of our products or
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product
candidates from private insurers on a timely or satisfactory basis. Our products and product candidates, may not be considered cost-effective, and coverage and reimbursement may not be
available or sufficient to allow us to sell our products or product candidates on a profitable basis. Our business would also be adversely affected if private insurers, managed care organizations, the
Medicare program
or other reimbursing bodies or payors limit the indications for which our products or product candidates will be reimbursed to a smaller set than we believe they are effective in treating.
In
some foreign countries, particularly Canada and the countries of Europe, the pricing of prescription pharmaceuticals is subject to strict governmental control. In these countries, pricing
negotiations with governmental authorities can take six to 12 months or longer after the receipt of regulatory approval and product launch. To obtain favorable reimbursement for the indications
sought or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our products or product candidates to other available therapies. If
reimbursement for our products or product candidates is unavailable in any country in which reimbursement is sought, limited in scope or amount, or if pricing is set at unsatisfactory levels, our
business could be materially harmed.
In
addition, many managed care organizations negotiate the price of products and develop formularies which establish pricing and reimbursement levels. Exclusion of a product from a formulary can lead
to its sharply reduced usage in the managed care organization's patient population. If our products or product candidates are not included within an adequate number of formularies or adequate payment
or reimbursement levels are not provided, or if those policies increasingly favor generic products, our market share and gross margins could be negatively affected, which would have a material adverse
effect on our overall business and financial condition.
We
expect to experience pricing pressures due to the potential healthcare reforms discussed elsewhere in this Annual Report on Form 10-K, as well as the trend toward programs aimed at reducing
health care costs and the increasing influence of health maintenance organizations and additional legislative proposals.
We face potential product liability exposure, and, if successful claims are brought against us, we may incur substantial liabilities.
The use of our product candidates in clinical trials and the sale of any of our products expose us to the risk of product liability claims. Product
liability claims might be brought against us by consumers, healthcare providers or others selling or otherwise coming into contact with our products and product candidates. If we cannot successfully
defend ourselves against product liability claims, we could incur substantial liabilities. In addition, product liability claims may result in:
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decreased demand for any product or product candidate that has received approval and is being commercialized;
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impairment of our business reputation and exposure to adverse publicity;
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withdrawal of bioequivalence and/or clinical trial participants;
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initiation of investigations by regulators;
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costs of related litigation;
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distraction of management's attention from our primary business;
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substantial monetary awards to patients or other claimants;
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loss of revenues; and
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the inability to commercialize any of our product candidates for which we obtain marketing approval.
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Our
product liability insurance coverage for our clinical trials is limited to $10 million per claim and $10 million in the aggregate, and covers bodily injury and property damage
arising from our clinical
trials, subject to industry-standard terms, conditions and exclusions. Our insurance coverage may not be sufficient to reimburse us for any expenses or losses we may suffer. Moreover, insurance
coverage is becoming increasingly expensive, and, in the future, we may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses. We have
expanded our insurance coverage to include the sale of commercial products prior to the commercialization of our products. On occasion, large judgments have been awarded in class action lawsuits based
on drugs that had unanticipated side effects. A successful product liability claim or series of claims brought against us could cause our stock price to decline and, if judgments exceed our insurance
coverage, could decrease our cash and adversely affect our business.
Our failure to successfully develop and market products or product candidates would impair our ability to grow.
As part of our growth strategy, we intend to develop and market additional product candidates. We are pursuing various therapeutic opportunities
through our pipeline. We may spend several years completing our development of any particular current or future internal product candidate, and failure can occur at any stage. The product candidates
to which we allocate our resources may not end up being successful. In addition, because our internal research capabilities are limited, we may be dependent upon pharmaceutical companies, academic
scientists and other researchers to sell or license products or technology to us. The success of this strategy depends partly upon our ability to identify, select, discover and acquire promising
pharmaceutical product candidates and products.
The
process of proposing, negotiating and implementing a license or acquisition of a product candidate or approved product is lengthy and complex. Other companies, including some with substantially
greater financial, marketing and sales resources, may compete with us for the license or acquisition of product candidates and approved products. We have limited resources to identify and execute the
acquisition or in-licensing of third-party products, businesses and technologies and integrate them into our current infrastructure. Moreover, we may devote resources to potential acquisitions or
in-licensing opportunities that are never completed, or we may fail to realize the anticipated benefits of such efforts. We may not be able to acquire the rights to additional product candidates on
terms that we find acceptable, or at all.
In
addition, future acquisitions may entail numerous operational and financial risks, including:
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exposure to unknown liabilities;
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disruption of our business and diversion of our management's time and attention to develop acquired products or
technologies;
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incurrence of substantial debt, dilutive issuances of securities or depletion of cash to pay for acquisitions;
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higher than expected acquisition and integration costs;
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difficulty in combining the operations and personnel of any acquired businesses with our operations and personnel;
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increased amortization expenses;
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impairment of relationships with key suppliers or customers of any acquired businesses due to changes in management and
ownership; and
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inability to motivate key employees of any acquired businesses.
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Further,
any product candidate that we acquire may require additional development efforts prior to commercial sale, including extensive clinical testing and approval by the FDA and applicable foreign
regulatory authorities. All product candidates are prone to risks of failure typical of pharmaceutical
product development, including the possibility that a product candidate will not be shown to be sufficiently safe and effective for approval by regulatory authorities.
Healthcare reform measures could hinder or prevent the commercial success of our products or product candidates.
The U.S. government and other governments have shown significant interest in pursuing healthcare reform. Government-adopted reform measures could
adversely impact the pricing of healthcare products and services in the United States or internationally and the amount of reimbursement available from governmental agencies or other third-party
payors. The continuing efforts of the U.S. and foreign governments, insurance companies, managed care organizations and other payors of health care services to contain or reduce healthcare costs may
adversely affect our ability to set prices for any approved product candidate which we believe are fair, and our ability to generate revenues and achieve and maintain profitability.
In
both the United States and some foreign jurisdictions, there have been a number of legislative and regulatory proposals and initiatives to change the health care system in ways that could affect
our ability to sell any approved product profitably. Some of these proposed and implemented reforms could result in reduced reimbursement rates for our products, which would adversely affect our
business strategy, operations and financial results. For example, in March 2010, President Obama signed into law a legislative overhaul of the U.S. healthcare system, known as the Patient Protection
and Affordable Care Act of 2010, as amended by the Healthcare and Education Affordability Reconciliation Act of 2010. These laws and their regulations, which we refer to collectively as the Health
Care Reform Law, may have far reaching consequences for biopharmaceutical companies like us. As a result of the Healthcare Reform Law, substantial changes could be made to the current system for
paying for healthcare in the United States, including changes made in order to extend benefits to those who currently lack insurance coverage or changing coverage parameters. Extending coverage to a
large population could substantially change the structure of the health insurance system and the methodology for reimbursing medical services and drugs. These structural changes could entail
modifications to the existing system of private payors and government programs, such as Medicare and Medicaid, creation of a government-sponsored healthcare insurance source, or some combination of
both, as well as other changes. Restructuring the coverage of medical care in the United States could impact the reimbursement for prescribed drugs, including our products and product candidates. If
reimbursement for our approved products is substantially less than we expect in the future, or rebate obligations associated with them are substantially increased, our business could be materially and
adversely impacted.
In
September 2007, the Food and Drug Administration Amendments Act of 2007 was enacted, giving the FDA enhanced post-marketing authority, including the authority to require post-marketing studies and
clinical trials, labeling changes based on new safety information, and compliance with risk evaluations and mitigation strategies approved by the FDA. In July 2012, the Food and Drug Administration
Safety and Innovation Act was enacted, expanding drug supply chain requirements and strengthening FDA's response to drug shortages, among other things. The FDA's exercise of this authority could
result in delays or increased costs during product development, clinical trials and
regulatory review, increased costs to assure compliance with post-approval regulatory requirements, and potential restrictions on the sale and/or distribution of any approved product candidates.
Future
federal and state proposals and health care reforms could limit the prices that can be charged for the product candidates that we develop and may further limit our commercial opportunity. Our
results of operations could be materially adversely affected by the Health Care Reform Law by
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reducing
the amounts that private insurers will pay and by other health care reforms that may be enacted or adopted in the future.
Implementation of the Health Care Reform Law could cause us to incur significant compliance expenses or could subject us to substantial penalties and fines if our business
is found to violate these requirements.
The Health Care Reform Law was signed into law in 2010. The Health Care Reform Law is multi-faceted and is being implemented in phases. The financial
impact of all of the provisions of the Health Care Reform Law on our business is unclear, and there can be no assurance that our business will not be materially harmed by future implementation of the
Health Care Reform Law. In addition, if we are found not to be in full compliance with the Health Care Reform Law, we could face enforcement action, fines and other penalties and we could receive
adverse publicity.
The
Health Care Reform Law also includes various provisions designed to strengthen significantly fraud and abuse enforcement, such as increased funding for enforcement efforts and the lowering of the
intent requirement of the federal anti-kickback statute and criminal health care fraud statute such that a person or entity no longer needs to have actual knowledge of this statute or specific intent
to violate it.
If
our past or present operations are found to be in violation of any such laws or any other governmental regulations that may apply to us, we may be subject to penalties, including civil and criminal
penalties, damages, fines, exclusion from federal health care programs and/or the curtailment or restructuring of our operations.
The
risk of our being found in violation of the Health Care Reform Law, its underlying regulations, or other laws impacted by its implementations is increased by the fact that many of them have not
been fully interpreted by the regulatory authorities or the courts, and their provisions are subject to a variety of interpretations. Any action against us for violation of these laws, even if we
successfully defend against them, could cause us to incur significant legal expenses and divert our management's attention from the operation of our business.
We will need to increase the size of our organization, and we may experience difficulties in managing growth.
We will need to manage our anticipated growth and increased operational activity. Our personnel, systems and facilities currently in place may not be
adequate to support this future growth. Our future financial performance and our ability to compete effectively will depend, in part, on our ability to effectively manage any future growth. Our need
to effectively execute our growth strategy requires that we:
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manage our regulatory approvals and clinical trials effectively;
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manage our internal development efforts effectively while complying with our contractual obligations to licensors,
licensees, contractors, collaborators and other third parties;
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develop internal sales and marketing capabilities;
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commercialize our product candidates;
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improve our operational, financial and management controls, reporting systems and procedures; and
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attract and motivate sufficient numbers of talented employees.
This
future growth could place a strain on our administrative and operational infrastructure and may require our management to divert a disproportionate amount of its attention away from our
day-to-day activities. We may not be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel, which may result in weaknesses in our
infrastructure, give rise to
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operational
mistakes, loss of business opportunities, loss of employees and reduced productivity among remaining employees. We may not be able to make improvements to our management information and
control systems in an efficient or timely manner and may discover deficiencies in existing systems and controls. If our management is unable to effectively manage our expected growth, our expenses may
increase more than expected, our ability to generate or increase our revenues could be reduced and we may not be able to implement our business strategy.
We may not be able to manage our business effectively if we are unable to attract, motivate and retain key members of our management team.
We may not be able to attract or motivate qualified management and scientific and clinical personnel in the future due to the intense competition for
qualified personnel among biotechnology, pharmaceutical and other businesses. Our industry has experienced a high rate of turnover of management personnel in recent years. If we are not able to
attract and motivate necessary personnel to accomplish our business objectives, we may experience constraints that will significantly impede the achievement of our objectives.
We
are highly dependent on the development, regulatory, commercial and financial expertise of our management, particularly Jack A. Khattar, our President and Chief Executive Officer. We do not have
any employment agreements with any member of our senior management team except Mr. Khattar. If we lose key members of our management team, we may not be able to find suitable replacements in a
timely fashion, if at all. We cannot be certain that future management transitions will not disrupt our operations and generate concern among employees and those with whom we do business.
In
addition to the competition for personnel, our corporate officers are located in the greater Washington D.C. metropolitan area, an area that is characterized by a high cost of living. As such, we
could have difficulty attracting experienced personnel to our Company and may be required to expend significant financial resources in our employee recruitment efforts.
We
also have scientific and clinical advisors who assist us in formulating our product development and clinical strategies. These advisors are not our employees and may have commitments to, or
consulting or advisory contracts with, other entities that may limit their availability to us, or may have arrangements with other companies to assist in the development of products that may compete
with ours.
If we fail to comply with healthcare regulations, we could face substantial penalties and our business, operations and financial condition could be adversely affected.
As a supplier of pharmaceuticals, certain federal and state healthcare laws and regulations pertaining to fraud and abuse and patients' rights are
and will be applicable to our business. We could be subject to healthcare fraud and abuse and patient privacy regulation by both the federal government and the states in which we conduct our business.
The regulations include:
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the federal healthcare program anti-kickback law, which prohibits, among other things, persons from soliciting, receiving
or providing remuneration, directly or indirectly, to induce either the referral of an individual, for an item or service or the purchasing or ordering of a good or service, for which payment may be
made under federal healthcare programs such as the Medicare and Medicaid programs;
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federal false claims laws which prohibit, among other things, individuals or entities from knowingly presenting, or
causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payors that are false or fraudulent, and which may apply to entities like us which provide coding and billing
advice to customers;
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the federal Health Insurance Portability and Accountability Act of 1996, 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;
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the federal transparency requirements under the Health Care Reform Law requires manufacturers of drugs, devices,
biologics, and medical supplies to report to the Department of Health and Human Services information related to physician payments and other transfers of value and physician ownership and investment
interests;
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the FDCA, which among other things, strictly regulates drug product marketing, prohibits manufacturers from marketing drug
products for off-label use and regulates the distribution of drug samples; and
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state law equivalents of each of the above federal laws, such as anti-kickback, Sunshine Act, and false claims laws which
may apply to items or services reimbursed by any third-party payor, including commercial insurers, and state laws governing the privacy and security of health information in certain circumstances,
many of which differ from each other in significant ways and often are not preempted by federal laws, thus complicating compliance efforts.
Efforts
to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations could be costly. If our operations are found to be in violation of any
of the laws described above or any governmental regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines and the curtailment or
restructuring of our operations. Any penalties, damages, fines, curtailment or restructuring of our operations could adversely affect our ability to operate our business and our financial results.
Although compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, the risks cannot be entirely eliminated. Any action against us for violation of these
laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management's attention from the operation of our business. Moreover, achieving and
sustaining compliance with applicable federal and state privacy, security and fraud laws may prove costly.
Our business involves the use of hazardous materials, and we must comply with environmental laws and regulations, which can be expensive and restrict how we do business.
Our activities and our third-party manufacturers' and suppliers' activities involve the controlled storage, use and disposal of hazardous materials
owned by us. We and our manufacturers and suppliers are subject to federal, state, city and local laws and regulations governing the use, manufacture, storage, handling and disposal of these hazardous
materials. Although we believe that the safety procedures we use for handling and disposing of these materials comply with the standards prescribed by these laws and regulations, we cannot eliminate
the risk of accidental contamination or injury from these materials. In the event of an accident, local, city, state or federal authorities may curtail the use of these materials and interrupt our
business operations, including our commercialization and research and development efforts. Although we believe that the safety procedures utilized by our third-party manufacturers for handling and
disposing of these materials generally comply with the standards prescribed by these laws and regulations, we cannot guarantee that this is the case or eliminate the risk of accidental contamination
or injury from these materials. In such an event, we may be held liable for any resulting damages and such liability could exceed our resources. We do not currently maintain biological or hazardous
materials insurance coverage.
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Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by
governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other
provisions during the patent process. There are situations in which noncompliance can result in abandonment or lapse of a patent or patent application, resulting in partial or complete loss of patent
rights in the relevant jurisdiction. In such an event, competitors might be able to enter the market earlier than would otherwise have been the case.
We may be subject to claims that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.
We employ individuals who were previously employed at other pharmaceutical companies, including our competitors or potential competitors and, as
such, we may be subject to claims that we or these employees have used or disclosed trade secrets or other proprietary information of their former employers. Litigation may be necessary to defend
against these claims. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.
Security breaches and other disruptions could compromise our information and expose us to liability, which would cause our business and reputation to suffer.
In the ordinary course of our business, we collect and store sensitive data, including intellectual property, our proprietary business information
and that of our customers, suppliers and business partners, and personally identifiable information of our employees and patients in our clinical trials, in our data centers and on our networks. The
secure processing, maintenance and transmission of this information is critical to our operations and business strategy. Despite our security measures, our information technology and infrastructure
may be vulnerable to attacks by hackers or breached due to employee error, malfeasance or other disruptions. Any such breach could compromise our networks and the information stored there could be
accessed, publicly disclosed, lost or stolen. Any such access, disclosure or other loss of information could result in legal claims or proceedings, liability under laws that protect the privacy of
personal information, and regulatory penalties, disrupt our operations, and damage our reputation, which could adversely affect our business, revenues and competitive position.
We will need to obtain FDA approval of any proposed product names, and any failure or delay associated with such approval may adversely impact our business.
Any name we intend to use for our product candidates will require approval from the FDA regardless of whether we have secured a formal trademark
registration from the USPTO. The FDA typically conducts a review of proposed product names, including an evaluation of potential for confusion with other product names. The FDA may object to any
product name we submit if it believes the name inappropriately implies medical claims. We have in the past been required to change a proposed product name. If the FDA objects to any of our proposed
product names, we may be required to adopt an alternative name for our product candidates. If we adopt an alternative name, we would lose the benefit of our existing trademark applications for such
product candidate, and may be required to expend significant additional resources in an effort to identify a suitable product name that would qualify under applicable trademark laws, not infringe the
existing rights of third parties and be acceptable to the FDA. We may be unable to build a successful brand
identity for a new trademark in a timely manner or at all, which would limit our ability to commercialize our product candidates.
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In certain circumstances we could be required to pay damages if we fail to perform our obligations under the license agreements related to Sanctura XR and Oracea.
In December 2011, we sold 100% of our equity ownership interests in Royalty Sub. In accordance with the terms of the sale, we retained certain duties
and obligations under two licensing agreements related to Sanctura XR and Oracea. If we fail to perform the continuing duties and obligations under these licensing agreements, we may be required to
indemnify the purchaser of Royalty Sub for damages arising due to such failure. For example, pursuant to these agreements, we have an obligation to use commercially reasonable efforts to preserve,
maintain, and maximize the commercial value of our licensed patents covering Sanctura XR and Oracea, which includes the obligation to pay patent office maintenance fees in order to keep these patents
in force. If we fail to pay such patent office maintenance fees, these patents may expire and Royalty Sub's royalty stream from such patents may terminate. In such a scenario, we may be called upon to
pay damages to the purchaser of Royalty Sub due to the loss of patent licensing revenue that Royalty Sub would have received from the sale of Sanctura XR and Oracea.
Provisions in our agreement with Shire impose restrictive covenants on us, which could limit our ability to operate effectively in the future.
In 2005, we purchased substantially all of the assets of Shire Laboratories Inc. Pursuant to this agreement, we agreed to refrain perpetually
from engaging in any research, formulation development, analytical testing, manufacture, technology assessment or oral bioavailability screening that relate to five specific drug compounds
(amphetamine, carbamazepine, guanfacine, lanthanum and mesalamine) and any derivative thereof. Although these various restrictions and covenants on us do not currently impact our product candidates or
business, they could in the future limit or delay our ability to take advantage of business opportunities that may relate to such compounds.
Risks Related to Our Finances and Capital Requirements
We have incurred significant operating losses since our inception.
In recent years, we have focused primarily on developing our current products and product candidates, with the goal of commercializing these products
and supporting regulatory approval for these product candidates. We have financed our operations primarily through the following transactions:
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private placements of convertible preferred stock;
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our collaboration and license arrangements;
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the monetization of certain future royalty streams under our existing licenses for Oracea, Sanctura XR and Intuniv;
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the sale of our subsidiary, Royalty Sub, which held the license rights to Oracea and Sanctura XR;
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borrowing via secured loans;
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the completion of our $52.3 million initial public offering in May 2012;
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the completion of our follow-on $49.9 million equity offering in November 2012; and
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the completion of $90 million private placement offering of 7.50% Convertible Senior Secured Notes Due 2019 (the
"Notes") in May 2013.
We
have incurred significant operating losses since our inception in 2005. We incurred net losses of approximately $33.5 million, $38.5 million, $46.3 million and
$92.3 million in the years ended December 31, 2008, 2010, 2012 and 2013, respectively. We realized net income of approximately
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$0.5 million
and $53.8 million in the years ended December 31, 2009 and 2011, respectively, due to one-time items. As of December 31, 2013, we had an accumulated deficit of
approximately $178.5 million. Substantially all of our operating losses resulted from costs incurred in connection with our development programs, expenses associated with launching our
products, and from selling, general and administrative costs associated with our operations. We expect our research and development costs to continue to be substantial and to increase with respect to
our product candidates as we advance those product candidates through preclinical studies, clinical trials, manufacturing scale-up and other pre-approval activities. We expect our selling, general and
administrative costs to continue to be substantial and to increase as we continue to expand our sales force and support the ongoing commercialization of our products. As a result, we expect to
continue to incur significant and increasing
operating expenses for the foreseeable future. Because of the numerous risks and uncertainties associated with developing pharmaceutical products, we may never become profitable.
Our
prior losses, combined with expected future losses, have had and will continue to have an adverse effect on our stockholders' equity and working capital. Furthermore, since the completion of our
initial public offering in May 2012, we have incurred additional costs associated with operating as a public company. As a result, we expect to continue to incur significant operating expenses for the
foreseeable future.
We may need additional funding and may be unable to raise capital when needed, which would force us to delay, reduce or eliminate our product development programs or
commercialization efforts.
Developing product candidates, conducting clinical trials, establishing manufacturing relationships and marketing drugs are expensive and uncertain
processes. Although we believe the proceeds of the November 2012 public offering and the May 2013 issuance of the Notes, together with our cash, cash equivalents and marketable securities and
anticipated future product revenues, will be sufficient to allow us to fund the continued commercialization of Oxtellar XR and Trokendi XR, we may need to obtain additional capital through equity
offerings, payments under new or existing licensing and research and development collaboration agreements, or any combination thereof, in order to become cash flow positive and to develop and
commercialize additional product candidates. If sufficient funds on acceptable terms are not available when needed, or at all, we could be required to significantly reduce operating expenses and
delay, reduce the scope of, or eliminate one or more of our development programs, which may have a material adverse effect on our business, results of operations and financial condition.
In
addition, unforeseen circumstances may arise, or our strategic imperatives could change, causing us to consume capital significantly faster than we currently anticipate, requiring us to seek to
raise additional funds sooner than expected. We have no committed external sources of funds.
The
amount and timing of our future funding requirements will depend on many factors, including, but not limited to:
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the rate of progress and cost of our trials and other product development programs for our product candidates;
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the costs and timing of in-licensing additional product candidates or acquiring other complementary companies;
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the timing of any regulatory approvals of our product candidates;
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our ability to successfully launch our products and to the rate of increase in the level of sales in the marketplace;
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the actions of our competitors and their success in selling competitive product offerings;
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the costs of establishing sales, marketing, manufacturing and distribution capabilities for our products; and
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the status, terms and timing of any collaborative, licensing, co-promotion or other arrangements.
Additional
financing may not be available when we need it or may not be available on terms that are favorable to us, or at all. In addition, we may seek additional capital due to favorable market
conditions or strategic considerations, even if we believe we have sufficient funds for our current or future operating plans. If adequate funds are not available to us on a timely basis, or at all,
we may be required to delay, reduce the scope of or eliminate one or more of our development programs or our commercialization efforts.
We may never achieve or maintain profitability.
Our ability to become profitable depends upon our ability to generate increasing levels of revenues from sales of our products and our product
candidates. 2013 was the first year in which we generated revenue from our first commercial products, Oxtellar XR and Trokendi XR. Prior to the commercial launch of these products, our historical
revenues have been generated through fees for development services and payment for the achievement of specified development, regulatory and sales milestones, as well as royalties, on product sales of
Oracea, Sanctura XR and Intuniv licensed products and the sale or license of certain of our assets.
Our
ability to generate product revenues is dependent on our ability to continue the successful commercialization Oxtellar XR and Trokendi XR.
After
our product candidates are approved for commercial sale, we anticipate incurring significant costs associated with commercialization. It is possible that we will never have sufficient product
sales revenues to achieve profitability.
Our operating results may fluctuate significantly.
We expect our operating results to be subject to quarterly and annual fluctuations. We expect that any revenues we generate will fluctuate from
quarter to quarter and year to year as a result of the timing, market acceptance of our products, and amount of development milestones and royalty revenues received under our collaboration license
agreements.
Our
net loss and other operating results will be affected by numerous factors, including:
-
-
our execution of any collaborative, licensing or similar arrangements, and the timing of payments we may make or receive
under these arrangements;
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-
the achievement and timing of milestone payments under our existing collaboration and license agreements; and
-
-
the level of market acceptance for any approved product candidates and underlying demand for that product and wholesalers'
buying patterns.
-
-
variations in the level of expenses related to our development programs;
-
-
the success of our bioequivalence and clinical trials through all phases of clinical development;
-
-
any delays in regulatory review and approval of product candidates in clinical development;
-
-
potential side effects of our future products that could delay or prevent commercialization, cause an approved drug to be
taken off the market, or result in litigation;
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-
any intellectual property infringement lawsuit in which we may become involved;
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our ability to establish an effective sales and marketing infrastructure;
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our dependency on third-party manufacturers to supply or manufacture our product candidates;
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-
competition from existing products or new products that may emerge;
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-
regulatory developments affecting our products and product candidates;
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-
changes in reimbursement environment and regulatory changes.
Due
to the various factors mentioned above, and others, the results of any prior quarterly period should not be relied upon as an indication of our future operating performance. If our quarterly
operating results fall below the expectations of investors or securities analysts, the price of our common stock could decline substantially. Furthermore, any quarterly fluctuations in our operating
results may, in turn, cause the price of our stock to fluctuate substantially.
Prior to May 1, 2012 we operated as a private company and therefore, have limited experience operating as a public company and complying with public company
obligations. Complying with these requirements has increased our costs and requires additional management resources, and we still may fail to meet all of these obligations.
We face increased legal, accounting, administrative and other costs and expenses as a public company. Compliance with the Sarbanes-Oxley Act of 2002,
the Dodd-Frank Act of 2010, as well as rules of the Securities and Exchange Commission and Nasdaq, for example, has resulted in significant initial cost to us as well as ongoing increases in our
legal, audit and financial compliance costs, particularly after we are no longer an "emerging growth company", which status we anticipate losing on December 31, 2017. The Securities Exchange
Act of 1934, as amended, or the Exchange Act, requires, among other things, that we file annual, quarterly and current reports with respect to our business and financial condition. Our board of
directors, management and other personnel need to devote a substantial amount of time to these compliance initiatives. Moreover, these rules and regulations make it more difficult and more expensive
for us to obtain director and officer liability insurance, and require us to incur substantial costs to maintain the same or similar coverage.
As
a public company, we are subject to Section 404(a) of the Sarbanes-Oxley Act relating to internal controls over financial reporting and we expect to incur significant expense and devote
substantial management effort toward ensuring compliance with Section 404(a). We currently do not have an internal audit group, and we will need to hire additional accounting and financial
staff with appropriate public company experience and technical accounting knowledge. Implementing any appropriate changes to our internal controls may require specific compliance training for our
directors, officers and employees, entail substantial costs to modify our existing accounting systems, and take a significant period of time to complete. Such changes may not, however, be effective in
maintaining the adequacy of our internal controls, and any failure to maintain that adequacy, or consequent inability to produce accurate consolidated financial statements or other reports on a timely
basis, could increase our operating costs and could materially impair our ability to operate our business. We cannot assure you that our internal controls over financial reporting will prove to be
effective.
If we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our financial results or prevent fraud. As a
result, stockholders could lose confidence in our financial and other public reporting, which would harm our business and the trading price of our common stock.
Effective internal controls over financial reporting are necessary for us to provide reliable financial reports and, together with adequate
disclosure controls and procedures, are designed to prevent fraud. Any failure to implement required new or improved controls, or difficulties encountered in their implementation could cause us to
fail to meet our reporting obligations. In addition, any testing by us conducted in connection with Section 404(a) of the Sarbanes-Oxley Act, or the subsequent testing by
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our
independent registered public accounting firm conducted in connection with Section 404(b) of the Sarbanes-Oxley Act after we no longer qualify as an "emerging growth company," may reveal
deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive changes to our consolidated financial statements
or identify other areas for further attention or improvement. Inferior internal controls could also cause investors to lose confidence in our reported financial information, which could have a
negative effect on the trading price of our common stock.
We
are required to disclose changes made in our internal control procedures on a quarterly basis and our management is required to assess the effectiveness of these controls annually. However, for as
long as we are an "emerging growth company" under the JOBS Act, our independent registered public accounting firm will not be required to attest to the effectiveness of our internal control over
financial reporting pursuant to Section 404(b). We could be an "emerging growth company" until December 31, 2017. An independent assessment of the effectiveness of our internal controls
could detect problems
that our management's assessment might not. Undetected material weaknesses in our internal controls could lead to financial statement restatements and require us to incur the expense of remediation.
Our ability to use net operating loss and tax credit carryforwards and certain built-in losses to reduce future tax payments is limited by provisions of the Internal Revenue
Code, and may be subject to further limitation as a result of our follow-on offering in November 2012 and the Convertible Note Offering that occurred in May 2013.
Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, contain rules that limit the ability of a company that
undergoes an ownership change, which is generally any change in ownership of more than 50% of its stock over a three-year period, to utilize its net operating loss and tax credit carryforwards and
certain built-in losses recognized in years after the ownership change. These rules generally operate by focusing on ownership changes involving stockholders owning directly or indirectly 5% or more
of the stock of a company and any change in ownership arising from a new issuance of stock by the company. Generally, if an ownership change occurs, the yearly taxable income limitation on the use of
net operating loss and tax credit carryforwards and certain built-in losses is equal to the product of the applicable long term tax exempt rate and the value of the company's stock immediately before
the ownership change. We may be unable to offset our taxable income with losses, or our tax liability with credits, before such losses and credits expire and therefore would incur larger federal
income tax liability.
In
addition, it is possible that the follow-on offering that occurred in November 2012 and the Convertible Note Offering that occurred in May 2013, either on a standalone basis or when combined with
future transactions, including issuances of new shares of our common stock, will cause us to undergo one or more additional ownership changes. With respect to our Convertible Note Offering, as of
March 14, 2014, $50.0 million in principal of Notes had been converted to common stock, resulting in the issuance of 11.0 million shares. In the event of ownership changes, we
generally would not be able to use our pre-change loss or credit carryovers or certain built-in losses prior to such ownership change to offset future taxable income in excess of the annual
limitations imposed by Sections 382 and 383 and those attributes already subject to limitations as a result of our prior ownership changes may be subject to more stringent limitations. As of
December 31, 2013, we had approximately $144.3 million of federal net operating loss carryforwards. We also had federal and state research and development tax credit carryforwards of
approximately $4.2 million available to offset future taxable income. These federal and state net operating loss and federal and state tax credit carryforwards will begin to expire at various
dates beginning in 2030, if not utilized. Our ability to utilize the aforementioned carryforwards and tax credits may be limited. As a result, we may not be able to take full advantage of these
carryforwards or tax credits for federal and state tax purposes.
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Risks Related to Our Indebtedness
Our significant level of indebtedness could adversely affect our business, financial condition and results of operations and prevent us from fulfilling our obligations under
the Notes.
We have a significant amount of indebtedness and substantial debt service requirements. As of December 31, 2013, we have issued and
outstanding convertible notes in the aggregate principal amount of $49.5 million. Subject to certain conditions and limitations in the Indenture governing the Notes, we may also incur
additional indebtedness, including secured debt, to meet future financing needs.
Our
substantial indebtedness could have important and significant effects on our business, financial condition and results of operations. For example, it
could:
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-
make it more difficult for us to satisfy our financial obligations, including with respect to the Notes;
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-
result in an event of default if we fail to comply with the covenants contained in the Indenture governing the Notes and
any agreement governing our existing or future indebtedness, if any, which event of default could result in all of our debt becoming immediately due and payable;
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increase our vulnerability to general adverse economic, industry and competitive conditions;
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-
reduce the availability of our cash flow to fund working capital, capital expenditures, acquisitions and other general
corporate purposes because we will be required to dedicate a substantial portion of our cash flow from operations to the payment of principal and interest on our indebtedness;
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-
subject us to increased sensitivity to interest rate increases on our existing and future indebtedness, if any, with
variable interest rates;
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-
limit our flexibility in planning for, or reacting to, and increasing our vulnerability to changes in our business, the
industry in which we operate and the general economy;
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-
prevent us from raising funds necessary to repurchase Notes tendered to us if there is a "fundamental change" or pay the
interest make-whole payment that may be due in cash in connection with certain conversions of the Notes under the Indenture governing the Notes;
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-
place us at a competitive disadvantage compared to our competitors that have less indebtedness or are less highly
leveraged and that, therefore, may be able to take advantage of opportunities that our debt levels or leverage prevent us from exploiting; and
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limit our ability to obtain additional financing.
Each
of these factors may have a material and adverse effect on our business, financial condition and results of operations and our ability to meet our payment obligations under the Notes and our
future indebtedness, if any.
Our
ability to make payments with respect to the Notes and to satisfy any other debt obligations will depend on our future operating performance and our ability to generate significant cash flow in
the future, which will be affected by prevailing economic conditions and financial, business, competitive, legislative and regulatory factors as well as other factors affecting our company and
industry, many of which are beyond our control.
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Servicing our indebtedness requires a significant amount of cash, and we may not have sufficient cash flow from our business to pay our substantial indebtedness.
As of December 31, 2013, we have issued and outstanding convertible notes in the aggregate principal amount of $49.5 million, bearing
an interest rate of 7.5% per annum. Servicing our indebtedness will require the dedication of a portion of our expected cash flow from operations, thereby reducing the amount of our cash flow
available for other purposes. In addition, our ability to make scheduled payments of the principal of, to pay interest on or to refinance our indebtedness, including the Notes, depends on our future
performance, which is subject to economic, financial, competitive, regulatory and other factors beyond our control. Historically, our business has generated losses and we expect to continue to incur
significant and increasing operating losses for the foreseeable future. Accordingly, the cash flow from operations in the future may be insufficient to service our debt and make necessary capital
expenditures. If we are unable to generate such cash flow, we may be required to adopt one or more alternatives, such as selling assets, restructuring debt or obtaining additional equity capital on
terms that may be onerous or highly dilutive. Our ability to refinance our indebtedness will depend on the capital markets and our financial condition at such time. If we raise additional debt, it
could increase our interest expense, leverage and operating financial costs. In addition, the terms of the Indenture governing the Notes and the agreements governing our future indebtedness may
restrict us from adopting any of these alternatives. We may not be able to engage in any of these activities or engage in these activities on desirable terms, which could result in a default on our
debt obligations. Our lack of cash resources or failure to generate sufficient cash flow or to affect any of these alternatives could significantly adversely affect our ability to pay amounts due
under the Notes.
The Indenture governing the Notes contains restrictions that will limit our operating flexibility, and we may incur additional debt in the future that may include similar or
additional restrictions.
The Indenture governing the Notes contains covenants that, among other things, restrict our and our existing and future subsidiaries' ability to take
specific actions, even if we believe them to be in our best interest. These covenants include restrictions on our ability to:
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incur additional indebtedness and issue certain types of preferred stock;
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-
make investments in our foreign subsidiaries; and
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enter into mergers, consolidations or sales or leases of all or substantially all of our assets.
These
covenants limit our operational flexibility and could prevent us from taking advantage of business opportunities as they arise, growing our business or competing effectively.
A
breach of any of these covenants or other provisions in our debt agreements could result in an event of default, which if not cured or waived, could result in such debt becoming immediately due and
payable. This, in turn, could cause our other debt to become due and payable as a result of cross-default or cross-acceleration provisions contained in the agreements governing such other debt. In the
event that some or all of our debt is accelerated and becomes immediately due and payable, we may not have the funds to repay, or the ability to refinance, such debt.
We may not be permitted, by the agreements governing our existing or future indebtedness, to pay any interest make-whole payment upon conversion in cash, requiring us to
issue shares for such amounts, which could result in significant dilution to our stockholders.
If a holder elects to convert some or all of their Notes on or after November 1, 2013, if, for at least 20 trading days (whether or not
consecutive) during the 30 consecutive trading day period ending within five trading days prior to a conversion date the last reported sale price of our common stock exceeds the applicable conversion
price on each such trading day, we will pay such holder an interest make-whole payment in cash or common stock for the Notes being converted. We have the option to
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issue
our common stock to any converting holder in lieu of making the interest make-whole payment in cash. If we elect to issue our common stock for such payment, then the stock will be valued at 95%
of the simple average of the daily volume-weighted average price, or VWAP, of our common stock for the
10 trading days ending on and including the trading day immediately preceding the conversion date. Agreements governing our existing or future indebtedness may prohibit us from making cash payments in
respect of the interest make-whole amount upon a conversion. Notwithstanding the foregoing, in no event will the shares we deliver in connection with a conversion, including those delivered in
connection with the interest make-whole amount and repayment of principal, exceed 221.7294 shares per $1,000 principal amount of Notes, subject to adjustment or , in aggregate, 19.96 million
shares. If, pursuant to our election to deliver common stock in connection with the payment of the interest make-whole amount, we would be required to deliver a number of shares of common stock in
excess of such threshold, we will deliver cash in lieu of any shares otherwise deliverable upon conversions in excess thereof (based on the simple average of the daily VWAP for the 10 trading days
ending on and including the trading day immediately preceding the conversion date).
We may not have the ability to raise the funds necessary to pay the interest on our Notes, the principal amount of the Notes when due at maturity, redemption or otherwise,
the amount of cash due upon conversion of the Notes, if relevant, or the fundamental change purchase price due when a holder submits its Notes for purchase upon the occurrence of a fundamental change,
and the agreements governing our existing and future indebtedness may contain limitations on our ability to pay certain of such cash obligations.
Our Notes bear interest annually at a rate of 7.50% per year which interest is payable semi-annually on May 1 and November 1 beginning
on November 1, 2013. In addition, in certain circumstances, we are obligated to pay additional interest on the Notes. At maturity or on the redemption date, if any, the entire outstanding
principal amount of the Notes will become due and payable by us with respect to Notes that have not been previously converted or purchased by us. Also, upon the occurrence of an event of default, we
may be required to repay the principal amount of Notes. Also, upon the occurrence of a fundamental change, holders may require us to purchase, for cash, all or a portion of their Notes at a
fundamental change purchase price. Further, if we obtain stockholder approval, we may elect to settle conversions of the Notes partially or entirely in cash.
Such
payments could be significant, and there can be no assurance that we will have sufficient financial resources, or will be able to arrange financing, so that we can make such payments when due.
The terms of the Indenture that govern the Notes may limit our ability to obtain such financing. In addition, the occurrence of a fundamental change may cause an event of default under agreements
governing our or our existing or future subsidiaries' indebtedness. Agreements governing any future debt may also restrict our ability to make certain of the required cash payments even if we have
sufficient funds to make them. Furthermore, our ability to satisfy such cash obligations may be limited by law or regulatory authority. In addition, if we fail to pay such cash obligations, we will be
in default under the Indenture. A default under the Indenture or the fundamental change itself could also lead to a default under agreements governing our indebtedness, which in turn may result in the
acceleration of other indebtedness we may then have. If the repayment of the other indebtedness were to be accelerated, we may not have sufficient funds to repay that indebtedness and to make such
payments.
The fundamental change provisions of the Notes may delay or prevent an otherwise beneficial takeover attempt of us.
The fundamental change purchase rights, which will allow holders to require us to purchase all or a portion of their Notes upon the occurrence of a
fundamental change, and the provisions requiring an increase to the conversion rate for conversions in connection with a make-whole fundamental change may in certain circumstances delay or prevent a
takeover of us and the removal of incumbent management that might otherwise be beneficial to investors.
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Risks Related to Securities Markets and Investment in Our Stock
Future sales of our common stock may depress our stock price.
Sales of our common stock, or the perception in the market that the holders of a large number of shares intend to sell shares, could reduce the
market price of our common stock which would impair our ability to raise future capital through the sale of additional equity securities. We have outstanding 39,983,437 shares of common stock as of
December 31, 2013, of which approximately 18,319,322 shares are restricted securities that may be sold only in accordance with the resale restrictions under Rule 144 of the Securities
Act of 1933, as amended. In addition, as of December 31, 2013, we had outstanding options to purchase 1,463,043 shares of common stock and warrants to purchase 42,083 shares of common stock
that, if exercised, will result in these additional shares becoming available for sale. A large portion of these shares and options are held by a small number of persons and investment funds.
Moreover, certain holders of shares of common stock will have rights, subject to some conditions, that require us to file registration statements covering the shares they currently hold, or to include
these shares in registration statements that we may file for ourselves or other stockholders.
We
have also registered all common stock subject to options outstanding or reserved for issuance under our 2005 Stock Plan, 2012 Equity Incentive Plan and 2012 Employee Stock Purchase Plan. An
aggregate of 1,380,543 and 131,903 shares of our common stock are reserved for future issuance under
the 2012 Equity Incentive Plan and the 2012 Employee Stock Purchase Plan, respectively. These shares may now be freely sold in the public market upon issuance. As of December 31, 2013, there
are 9,342,471 shares of our common stock reserved for issuance under our Convertible Note that matures in May, 2019. If a large number of these shares are sold in the public market, the sales could
reduce the trading price of our common stock.
We have never paid dividends on our capital stock, and because we do not anticipate paying any cash dividends in the foreseeable future, capital appreciation, if any, of our
common stock will be your sole source of gain on an investment in our common stock.
We have paid no cash dividends on any of our classes of capital stock to date, and we currently intend to retain our future earnings, if any, to fund
the development and growth of our business. We do not anticipate paying any cash dividends on our common stock in the foreseeable future. As a result, capital appreciation, if any, of our common stock
will be your sole source of gain for the foreseeable future. There is no guarantee that shares of our common stock will appreciate in value or even maintain the price at which our stockholders have
purchased their shares.
If securities or industry analysts do not publish research or reports or publish unfavorable research or reports about our business, our stock price and trading volume could
decline.
The trading market for our common stock will depend in part on the research and reports that securities or industry analysts publish about us, our
business, our market or our competitors. We currently have very limited research coverage by securities and industry analysts. If securities or industry analysts presently covering our business do not
continue such coverage or if additional securities or industry analysts do not commence coverage of our Company, the trading price for our stock could be negatively impacted. In the event we obtain
securities or industry analyst coverage, if one or more of the analysts who covers us downgrades our stock, our stock price would likely decline. If one or more of these analysts ceases to cover us or
fails to regularly publish reports on us, interest in our stock could decrease, which could cause our stock price or trading volume to decline.
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The concentration of our capital stock ownership with our directors and their affiliated entities and our executive officers will limit your ability to influence certain
corporate matters.
Our directors and their affiliated entities, and our executive officers beneficially own, in the aggregate, approximately 30.3% of our outstanding
common stock. As a result, these stockholders are collectively able to significantly influence or control all matters requiring approval of our stockholders, including the election of directors and
approval of significant corporate transactions such as mergers, consolidations or the sale of all or substantially all of our assets. The concentration of ownership may delay, prevent or deter a
change in control of our Company even when such a change may be in the best interests of some stockholders, impede a merger, consolidation, takeover or other business combination involving us, or
could deprive our stockholders of an opportunity to receive a premium for their common stock as part of a sale of our Company or our assets and might adversely affect the prevailing market price of
our common stock.
Anti-takeover provisions under our charter documents and Delaware law could delay or prevent a change of control which could negatively impact the market price of our common
stock.
Provisions in our certificate of incorporation and bylaws, as amended, may have the effect of delaying or preventing a change of control. These
provisions include the following:
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Our board of directors is divided into three classes serving staggered three-year terms, such that not all members of the
board will be elected at one time. This staggered board structure prevents stockholders from replacing the entire board at a single stockholders' meeting.
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Our board of directors has the right to elect directors to fill a vacancy created by the expansion of the board of
directors or the resignation, death or removal of a director, which prevents stockholders from being able to fill vacancies on our board of directors.
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Our board of directors may issue, without stockholder approval, shares of preferred stock. The ability to authorize
preferred stock makes it possible for our board of directors to issue preferred stock with voting or other rights or preferences that could impede the success of any attempt to acquire us.
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Stockholders must provide advance notice to nominate individuals for election to the board of directors or to propose
matters that can be acted upon at a stockholders' meeting. Furthermore, stockholders may only remove a member of our board of directors for cause. These provisions may discourage or deter a potential
acquiror from conducting a solicitation of proxies to elect such acquiror's own slate of directors or otherwise attempting to obtain control of our Company.
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Our stockholders may not act by written consent. As a result, a holder, or holders, controlling a majority of our capital
stock would not be able to take certain actions outside of a stockholders' meeting.
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Special meetings of stockholders may be called only by the chairman of our board of directors or a majority of our board
of directors. As a result, a holder, or holders, controlling a majority of our capital stock would not be able to call a special meeting.
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A supermajority (75%) of the voting power of outstanding shares of our capital stock is required to amend or repeal or to
adopt any provision inconsistent with certain provisions of our certificate of incorporation and to amend our by-laws, which make it more difficult to change the provisions described above.
In
addition, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which may prohibit certain business combinations with stockholders owning 15% or more of
our outstanding voting stock. These and other provisions in our certificate of incorporation, our bylaws and in the Delaware General Corporation Law could make it more difficult for stockholders or
potential
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acquirers
to obtain control of our board of directors or initiate actions that are opposed by the then-current board of directors.
We may not be able to maintain an active public market for our common stock.
There was no public market for our common stock prior to the closing of our initial public offering in May 2012. We cannot predict the extent to
which investor interest in our common stock will allow us to maintain an active trading market on The NASDAQ Global Market or otherwise or how liquid that market might become. If an active public
market is not sustained, it may be difficult for you to sell your shares of common stock at a price that is attractive to you, or at all. Further, an inactive market may also impair our ability to
raise capital by selling shares of our common stock and may impair our ability to enter into strategic partnerships or acquire companies or products, product candidates or technologies by using our
shares of common stock as consideration.
To the extent outstanding stock options or warrants are exercised, there will be dilution to new investors.
As of December 31, 2013, we had options to purchase 1,463,043 shares of common stock outstanding, with exercise prices ranging from $0.40 to
$12.92 per share and a weighted average exercise price of $7.27 per share. Upon the vesting of each of these options, the holder may exercise his or her options, which would result in dilution to
investors. You will also experience dilution if we issue additional shares of common stock under the warrants that we issued to our lenders. As of December 31, 2013, the lender warrants to
purchase 18,750 shares of common stock at an exercise price of $4.00 per share and 23,333 shares of common stock at an exercise price of $5.00 per share remain outstanding.
The price of our common stock may fluctuate substantially.
The market price for our common stock is likely to be volatile, in part because our common stock has been previously traded publicly for only a short
time. In addition, the market price of our common stock may fluctuate significantly in response to a number of factors, including:
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the commercial performance of Oxtellar XR, Trokendi XR, or any of our product candidates that receive marketing approval;
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filing of ANDAs by generic companies seeking approval to market generic versions of our products;
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plans for, progress in and results from clinical trials of our product candidates generally;
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FDA or international regulatory actions, including actions on regulatory applications for any of our product candidates;
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announcements of new products, services or technologies, commercial relationships, acquisitions or other events by us or
our competitors;
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market conditions in the pharmaceutical and biotechnology sectors;
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-
fluctuations in stock market prices and trading volumes of similar companies;
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-
fluctuations in stock market prices for the U.S. stock market;
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-
variations in our quarterly operating results;
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-
changes in accounting principles;
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-
litigation or public concern about the safety of our potential products;
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-
actual and anticipated fluctuations in our quarterly operating results;
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deviations in our operating results from the estimates of securities analysts;
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additions or departures of key personnel;
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sales of large blocks of our common stock, including sales by our executive officers, directors and significant
stockholders;
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any third-party coverage and reimbursement policies for our product candidates, and
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discussion of us or our stock price in the financial or scientific press or in online investor communities.
The
realization of any of the risks described in these "Risk Factors" could have a dramatic and material adverse impact on the market price of our common stock. In addition, class action litigation
has often been instituted against companies whose securities have experienced periods of volatility. Any
such litigation brought against us could result in substantial costs and a diversion of management attention, which could hurt our business, operating results and financial condition.
We may issue additional shares of our common stock or instruments convertible into shares of our common stock, including in connection with the conversion of our Notes, and
thereby materially and adversely affect the market price of our common stock and the trading price of our Notes.
We may conduct future offerings of our common stock, preferred stock or other securities convertible into our common stock to fund acquisitions,
finance operations or for other purposes. In addition, as of December 31, 2013, we had outstanding 39,983,437 shares of common stock, of which approximately 18,319,322 shares are restricted
securities that may be sold only in accordance with the resale restrictions under Rule 144 of the Securities Act. Also, as of December 31, 2013, we had outstanding options to purchase
1,463,043 shares of common stock and warrants to purchase 42,083 shares of common stock that, if exercised, would result in these additional shares becoming available for sale. A large portion of
these shares, options and warrants are held by a small number of persons and investment funds. Moreover, certain holders of shares of common stock have rights, subject to some conditions, that require
us to file registration statements covering the shares they currently hold, or to include these shares in registration statements that we may file for ourselves or other stockholders. We have also
registered all common stock subject to options outstanding or reserved for issuance under our 2005 Stock Plan, 2012 Equity Incentive Plan and 2012 Employee Stock Purchase Plan. An aggregate of
1,380,543 and 131,903 shares of our common stock are reserved for future issuance under the 2012 Equity Incentive Plan and the 2012 Employee Stock Purchase Plan, respectively. In addition, as of
December 31, 2013, 9,342,471 shares of our common stock are presently reserved for future issuance upon conversion of the Notes. These shares will be eligible for resale in the public market
upon issuance.
The number of shares of our common stock that may be issued upon conversion of the Notes may have an adverse effect on our stock price.
The holders of the $49.5 million of Notes have the right to convert the Notes into an aggregate of 9,342,471 shares of our common at any time.
In addition, in certain instances we may issue additional shares of our common stock to holders who convert their Notes in order to satisfy our obligation to pay an interest make-whole payment to
these note holders or who convert their Notes in connection with a transaction that constitutes a "make-whole fundamental change" under the Indenture governing the Notes. The possibility that we may
issue a substantial number of shares of common stock to the holders of Notes in connection with conversions and thus substantially increase the number of issued shares of our common stock outstanding
may have an adverse effect on our stock price for as long as the Notes remain outstanding.
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