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Biohaven Pharmaceutical Holding Company Ltd. Financial Statements For the Years Ended December 31, 2017, 2016 and 2015

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or emerging growth company. See the definitions of "large accelerated filer," "accelerated filer," "smaller reporting company," and "emerging growth company" in Rule 12b-2 of the Exchange Act. (Check one):

Large accelerated filer oý

Accelerated filer o

Non-accelerated filer ý (Do not check if a smaller reporting company)o

Smaller reporting company o Emerging growth company ý o

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.   ý

o

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes o    No ý

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The aggregate market value of the registrant's common shares held by non-affiliates of the registrant as of the last business day of the registrant's most recently completed second fiscal quarter, June 30, 2017,2018, based on the last reported sale price of the registrant's common stock on the New York Stock Exchange on June 30, 201729, 2018 of $25.00,$39.52, was $492.3 million.$1.585 billion. The calculation does not reflect a determination that certain persons are affiliates of the registrant for any other purpose. As of March 2, 2018,February 26, 2019, there were 36,520,44244,262,658 common shares, no par value per share, outstanding.

Documents Incorporated by Reference

Portions of the registrant's definitive Proxy Statement to be filed pursuant to Regulation 14A under the Securities Exchange Act of 1934 for its 20182019 Annual Meeting of Shareholders are incorporated by reference into Part III of this Annual Report on Form 10-K.

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Cautionary Note Regarding Forward-Looking Statements

This Annual Report on Form 10-K, or this report, contains forward-looking statements that involve risks and uncertainties. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. All statements other than statements of historical facts contained in this report are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as "may", "will", "should", "expects", "intends", "plans", "anticipates", "believes", "estimates", "predicts", "potential", "continue" or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to, statements about:

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the accuracy of our estimates regarding expenses, future revenues and capital requirements;

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our ability to obtain and maintain regulatory approval of our product candidates for any indications, and the labeling under any approval we may obtain;

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intense competition in the market and the ability of our competitors, many of whom have greater resources than we do, to offer different, better or lower cost therapeutic alternatives than our product candidates;

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anticipated regulatory developments in the United States and foreign countries;

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our plans to develop and commercialize our product candidates;

•our ongoing and planned clinical trials for our rimegepant, troriluzole (previously referred to as trigriluzole or BHV-4157), BHV-0223, BHV-3500, BHV-5000 and verdiperstat (previously referred to as BHV-3241) development programs;

•the timing of the availability of data from our clinical trials;

•the timing of our planned regulatory filings, including expected preclinicalour planned NDA submissions for rimegepant;

•the timing of and clinical results and timing;

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our ability to obtain and maintain intellectual property protection for our proprietary assets;

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the size and growth of the potential marketsregulatory approvals for our product candidates, and our ability to serve those markets;

candidates;

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the rate and degree of market acceptanceclinical utility of our product candidatescandidates;

•our commercialization, marketing and manufacturing capabilities and strategy;

•our intellectual property position; and

•our estimates regarding future revenues, expenses and needs for any indication;

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our ability to obtain additional financing; and

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the loss of key scientific or management personnel.

financing.

Any forward-looking statements in this report reflect our current views with respect to future events and with respect to our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by these forward-looking statements. Factors that may cause actual results to differ materially from current expectations include, among other things, those described under Part I, Item 1A. Risk Factors and elsewhere in this report. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Except as required by law, we assume no obligation to update or revise these forward-lookingforward- looking statements for any reason, even if new information becomes available in the future.

This report contains estimates, projections and other information concerning our industry, the general business environment, and the markets for certain diseases, including estimates regarding the potential size of those markets and the estimated incidence and prevalence of certain medical conditions. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties and actual events, circumstances or numbers, including actual disease prevalence rates and market size, may differ materially from the information reflected in this report. Unless otherwise expressly stated, we obtained this industry, business information, market data, prevalence information and other data from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data, and similar sources, in some cases applying our own assumptions and analysis that may, in the future, not prove to have been accurate.

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				Page
Part I.
Item 1.						Business					1	Page
Part I. Item 1A.									Risk Factors					62
Item 1.			Business			1
Item 1A.			Risk Factors			50
Item 1B.						Unresolved Staff Comments					12597
Item 2.			Properties			97 Properties					125
Item 3.						Legal Proceedings					12597
Item 4.						Mine Safety Disclosures					12597
Part II. II.
Item 5.						Market for Registrant's Common Equity, Related Shareholder Matters and Issuer Purchases of Equity Securities					12698
Item 6.						Selected Consolidated Financial Data					12899
Item 7.						Management's Discussion and Analysis of Financial Condition and Results of Operations					130101
Item 7A.						Quantitative and Qualitative Disclosures About Market Risk					151117
Item 8.						Financial Statements and Supplementary Data					151117
Item 9.						Changes in and Disagreements with Accountants on Accounting and Financial Disclosure					152117
Item 9A.						Controls and Procedures					152117
Item 9B						Other Information					153119
Part III. III.
Item 10.						Directors, Executive Officers and Corporate Governance					155120
Item 11.						Executive Compensation					155120
Item 12.						Security Ownership of Certain Beneficial Owners and Management and Related Shareholder Matters					155120
Item 13.						Certain Relationships and Related Transactions, and Director Independence					155120
Item 14.						Principal Accounting Fees and Services					155120
Part IV. IV.
Item 15.						Exhibits and Financial Statement Schedules					155121
Item 16.						Form 10-K Summary					158124
			Signatures			125 Signatures					159

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PART I

Item 1.    Business

Overview

We are a clinical-stage biopharmaceutical company with a portfolio of innovative, late-stage product candidates targeting neurologicalcentral nervous system diseases, including neurological and rare disorders. OurMost of our product candidates are small molecules and based on twothree distinct mechanistic platforms—calcitonin gene-related peptide ("CGRP"), receptor antagonists, glutamate modulators, and glutamate modulators—myeloperoxidase inhibitor—which we believe have the potential to significantly alter existing treatment approaches across a diverse set of neurologic indications with high unmet need in both large markets and orphan indications. The most advanced product candidate from our CGRP receptor antagonist platform is rimegepant, an orally available, potent and selective small molecule human CGRP receptor antagonist that we are developing for the acute treatment of migraine. We expect to receive the topline results of our two Phase 3 clinical trials in the first quarter of 2018.

        Our glutamate platform includes three clinical-stage product candidates being developed for the treatment of various neurological indications: trigriluzole for the treatment of obsessive-compulsive disorder ("OCD"), spinocerebellar ataxia ("SCA") and Alzheimer's disease; BHV-0223 for the treatment of amyotrophic lateral sclerosis("ALS"); and BHV-5000 for the treatment of neurological and psychiatric illnesses such as Rett syndrome, neuropathic pain and treatment-resistant depression. One of our advanced product candidates from our glutamate platform is BHV-0223, which we are developing for the treatment of ALS, a neurodegenerative disease that affects nerve cells in the brain and spinal cord. We have received orphan drug designation from the U.S. Food and Drug Administration ("FDA") for BHV-0223 in ALS, and we have observed results suggesting bioequivalence to Rilutek in a recently completed Phase 1 clinical trial. We plan to file a new drug application ("NDA") with the FDA for BHV-0223 in the second half of 2018. With respect to our next most advanced product candidate in our glutamate platform, trigriluzole, we expect to receive the results from an open-label 48-week extension study in SCA in the fourth quarter 2018. We expect to complete enrollment in our Phase 2 clinical trial of trigriluzole for the treatment of OCD by the end of 2018. With respect to BHV-5000, we initiated a Phase 1 study in December 2017 which we expect to be completed in the second half of 2018.

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Product Candidates

   The following table summarizes our leadmost advanced development programs. We hold the worldwide rights to all of our product candidates.

Our CGRP Receptor Antagonist Platform

Migraine Overview and Market Opportunity

Migraine is a chronic and debilitating disorder characterized by recurrent attacks lasting four to 72 hours with multiple symptoms, including typically one-sided, pulsating headaches of moderate to severe pain intensity that are associated with nausea or vomiting, and/or sensitivity to sound (phonophobia) and sensitivity to light (photophobia). Migraines are often preceded by transient neurological warning symptoms, known as auras, which typically involve visual disturbances such as flashing lights, but may also involve numbness or tingling in parts of the body. Migraine is both widespread and disabling. The Migraine Research Foundation ranks migraine as the world's third most prevalent illness, and the Global Burden of Disease Study 2015 rates migraine as the seventh highest specific cause of disability worldwide. According to the Migraine Research Foundation, in the United States, approximately 36 million individuals suffer from migraine attacks. While most sufferers experience migraine attacks once or twice per month, more than 4 million people have chronic migraine, defined as experiencing at least 15 headache days per month, of which at least eight are migraine, for more than three months. Others have episodic migraine, which is characterized by experiencing less than 15 migraine days per month. People with episodicfrequent episodes of migraine may progress to chronic migraine over time. Migraine attacks can last four hours or up to three days. More than 90% of individuals suffering from migraine attacks are unable to work or function normally during a migraine attack, with many experiencing comorbid conditions such as depression, anxiety and insomnia.

Triptans are the current first-line prescription therapy for the acute treatment of migraine, with over 13.9 million annual prescriptions in the United States. Despite the market for triptans being highly genericized, branded options continue to be popular. For example, even at a price of approximately $400-600/month, Maxalt

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is a commonly prescribed triptan. There has been minimal improvement in the standard treatment for migraine since the early 1990s. Reformulations of generic triptans or incremental improvements with new agents that target the same pathway are predicted to generate additional sales in the near

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term, but major sales growth for the migraine market are expected from novel therapeutics over the next several years. We believe that rimegepant will be a potential best-in-class small molecule CGRP receptor antagonist for the acute treatment of migraine and could achieve meaningful penetration of the market of migraine sufferers whose symptoms are not adequately addressed with current treatments.

It is important to recognize that all migraine patients require acute treatment, including patients who take preventive medicine (as they typically do not eliminate all migraine attacks).

The prevention of migraine in the United States is a multi-billion dollar potential market. According to a report published byNeuropsychiatric Disease and Treatment, 38% to 50% of diagnosed migraine sufferers may be candidates for migraine prevention therapy. Currently, preventive medications approved for migraine include beta blockers, such as propranolol, topiramate, sodium valproate, and botulinum toxin ("Botox") (chronic migraine only) and generate nearly 10 million prescriptions annually.

 Three CGRP monoclonal antibodies (mABs) were approved in 2018 for the preventive treatment of migraine in adults. There was rapid early uptake of this class, but utilization will be defined over the next 24 months.

In patients with high frequency and chronic migraine, beta blockers, topiramate and sodium valproate are commonly used.used to reduce the frequency of migraine. These medications are often not well tolerated by patients because of adverse events ("AEs") such as cognitive impairment, nausea, fatigue and sleep disturbance. In clinical trials with topiramate, the reduction in number of migraine days per month has been observed to be relatively small; for example, migraine days reduced by 2.5 days from six to seven days at baseline, or reduced by 3.5 days from 15 to 16 days at baseline. Migraine is twice as prevalent in women as compared to men. In the affected female patient population, predominantly women of child-bearing age, the association of these agents with poor pregnancy outcomes and fetal abnormalities can limit their use. Botox is only approved for the prevention of migraine in patients diagnosed with chronic migraine. Approximately 47% of Botox-treated patients experience a 50% reduction in either migraine days per month or migraine frequency per month within six months, which leaves more than half of patients inadequately treated. In addition, the Botox dosing regimen consists of approximately 31 subcutaneous injections at various sites on the head and neck, with recommended repetition every 12 weeks if the patient has a therapeutic response.

The CGRP mAbs have a similar profile across the agents approved to date. The three new FDA-approved drugs, Aimovig (erenumab-aooe), Ajovy (fremanezumab-vfrm), and Emgality (galcanezumab-gnlm), are all administered subcutaneously. The side effects from the new CGRP monoclonal antibody drugs are generally mild, including pain and redness at the site of injection and nasal congestion. Studies show that the monoclonal antibodies reduce the number of headache days by 50% or more in approximately half of the patients who take them. In only a small percentage of patients do these drugs eliminate migraine attacks, with the vast majority of patients also needing additional effective acute treatment. 

CGRP's Role in Migraine

The CGRP receptor is located within pain-signaling pathways, intracranial arteries and mast cells and its activation is thought to play a causal role in migraine pathophysiology. For example, research and clinical studies have shown:shown serum levels of CGRP are elevated during migraine attacks, infusion of intravenous CGRP produces persistent pain in migraine sufferers and non-migraine sufferers, and treatment with anti-migraine drugs normalizes CGRP activity. Additionally, multiple clinical studies show that small molecule CGRP receptor antagonists, which inhibit the binding of endogenous CGRP to CGRP receptors, are effective in diminishingthe acute treatment of migraine attacks.

Treatment with a CGRP receptor antagonist is believed to relieve migraine through the following mechanisms:

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Blocking Neurogenic Inflammation:  Binding of CGRP receptor antagonists to CGRP receptors located on mast cells inhibitinhibits inflammation caused by trigeminal nerve release of CGRP onto mast cells within the tough outer covering of the brain, or the meninges.

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Decreasing Artery Dilation:  By blocking the CGRP receptors located in smooth muscle cells within vessel walls, CGRP receptor antagonists inhibit the pathologic dilation of intracranial arteries without the unwanted effect of active vasoconstriction.

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Inhibiting Pain Transmission:  Binding of CGRP receptor antagonists to CGRP receptors suppress the transmission of pain by inhibiting the central relay of exaggerated pain signals from the trigeminal nerve to the caudal trigeminal nucleus.

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The graphic below depicts the mechanism of action by which CGRP receptor antagonism is thought to alleviate migraine.

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From N Engl J Med, Paul L. Durham "CGRP-Receptor Antagonists—PL, CGRP-Receptor Antagonists — A Fresh Approach to Migraine Therapy," March 11, 2004.Therapy? 350:1073-1075, Copyright © 2018 Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society.

Our Lead Product Candidate: Rimegepant, an Oral CGRP Receptor Antagonist for the Acute and Preventive Treatment of Migraine

We are developing rimegepant as an orally available, selective and potent small molecule CGRP receptor antagonist for the acute and preventive treatment of migraine. The first indication being pursued is the acute treatment of migraine. We believe

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that rimegepant has the potential to be the best-in-class CGRP receptor antagonist for the acute treatment of migraine with the ability to address important unmet needs, such as early onset of pain relief, durable efficacy across all four traditional migraineof pain relief and relief from most bothersome symptoms and reduced incidencerapid return to normal function (decreased disability). Importantly, these benefits are noted without the cardiovascular contraindications of headache recurrence, without contraindications triptan therapy and/or warnings in patients with cardiovascular disease or cardiovascular risk factors such as hypertension.

        Rimegepant dosed at 75 mg was observed to have statistically significant, durable improvement as compared to placebo in a Phase 2b, double-blind, randomized, placebo-controlled, dose-ranging clinical trial completed by Bristol-Myers Squibb Company ("BMS"). In this trial, 812 patients suffering from migraine attacks received either placebo, sumatriptan 100 mg (a currently approved triptan medication for migraine) or rimegepant dosed at 10, 25, 75, 150, 300 or 600 mg. The Phase 2b data showed statistically significantthe bothersome side effects of rimegepant starting at the 75 mg dose compared to placebo, meaning

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that at this dose level, statistically significant results were observed on all four key migraine symptoms—pain, nausea, photophobia and phonophobia. Higher doses of rimegepant, while also showing improvement compared to placebo, did not appear to convey any meaningful additional benefit above the 75 mg dose. The observed improvement profile is consistent with the published literature showing a lack of a progressive dose-response curve for anti-migraine drugs used in the acute treatment of migraine. To our knowledge and based on publicly available information, rimegepant is the onlyimpact utilization. Additionally, oral small molecule CGRP receptor antagonist currently in development that has achieved statistically significant improvement on all four of the traditional endpoints within a single study, which suggests a broad efficacy profile important both to patientsantagonists with high receptor affinity and physicians. Rimegepant also was observed to have evidence of durable improvement as demonstrated by statistically significant effects on two-to-24 hour and two-to-48 hour pain freedom and two-to-24 hour pain relief, as compared to placebo. In these measurements, benefits were present at two hours after dosing and persisted through 24 hours after dosing and, with respect to pain freedom, through 48 hours after dosing. This durable improvement is significant because other common migraine medications,long half-lives, such as triptans, have been associatedrimegepant, may possess dual-therapy action with headache recurrence.

        The Phase 2b trial successfully completed its aim of identifying a Phase 3 dose. Based on these observations, we are advancing the 75 mg dose of rimegepant in our Phase 3 clinical trials. ability to provide both acute relief and preventive effects.

In July 2017, we initiated two Phase 3 clinical trials of rimegepant, and we completed enrollment in these trials in November 2017. We expect to receive toplineTopline results from both of these Phase 3 trials were reported in the first quarterMarch, 2018. Additionally,The co-primary endpoints (pain freedom at 2 hours and reduction of most bothersome symptoms) were both met as well as key secondary endpoints (return to function, pain relief). These results are described in November 2017, we received agreement from the FDAgreater detail below under “—Our Clinical Program for Rimegepant in Acute Treatment of an initial pediatric study plan. In February 2018, we submitted a request for scientific advice for rimegepant to the Committee for Medicinal Products for Human Use ("CHMP") a committee of the European Medicines Agency ("EMA")Migraine— Phase 3 Clinical Trials: Studies 301 and we anticipate receiving feedback in the first half of 2018.

302.”

Those suffering from migraine often have accompanying nausea and have an aversion to consuming food or liquids during an attack. We are also developing an oral solid dosage formulation of rimegepant that disperses almost instantly in the mouth, without the need for water. The Zydis oral dissolving tablet ("ODT") formulation being utilized uniquely addresses this issue. Biohaven hasWe have exclusive worldwide rights to the Zydis ODT fast-dissolving formulation for the development of rimegepant pursuant to a January 2018 license agreement with Catalent U.K. Swindon Zydis Limited, a subsidiary of Catalent, Inc. ("Catalent"). The agreement also provides exclusivity with respect to other small molecule CGRP receptor antagonists with the Zydis ODT technology. In February 2018, a bioequivalence study was conducted to compare this new ODT formulation to the tablet in current clinical development and provided evidence of equivalence. A third Phase 3 efficacy study withclinical trial evaluatiing the Zydis ODT formulation of rimegepant commenced in February 2018. This study, utilizing2018 and the new ODT formulation, is designed to replicateresults from this trial were reported in December 2018.

Consistent with the other two ongoingprior Phase 3 studies, the ODT formulation met the co-primary endpoints of pain freedom and freedom from the most bothersome symptoms.  Importantly the Zydis ODT formulation had a faster onset of action with rapid onset of pain relief beginning to show an effect as early as 15 minutes and becoming statistically significant by 60 minutes.  Furthermore, this study met 21 consecutive pre-specified, hierarchically tested outcome measures including durability of effect out to 48 hours post-dose without the use of rescue medication. Importantly, consistent with the other trials, placebo-level tolerability was also noted. These results are described in greater detail below under “—Our Clinical Program for Rimegepant in Acute Treatment of Migraine— Phase 3 Clinical Trials: Study 303.”

In December 2018 data became available from our ongoing rimegepant long-term safety study. The positive results from the interim analysis of this trial included over 91,000 doses of rimegepant 75 mg across 1,780 patients with migraine. The safety and tolerability profile of rimegepant with up to one year of dosing in patients with migraine was consistent with the safe and well tolerated profile previous seen in clinical trials with rimegepant. No liver safety signal was detected, including a subset of patients with near-daily dosing (≥15 doses/month). Additionally, preliminary efficacy observations suggest that intermittent dosing of rimegepant 75 mg may reduce the number of headache days per month and a separate, double-blind placebo controlled preventive treatment study with rimegepant is being conducted. Overall, safety and tolerability data from this interim analysis and ongoing data from this study are expected be sufficient to support new drug application ("NDA") submissions for the new formulation. The study is expected to completeZydis ODT and tablet formulations planned for second quarter of 2019.

Based on emerging data from repeat dosing of rimegepant in the fourth quarterlong-term safety trial, a Phase 3 trial to evaluate rimegepant as a preventative treatment of migraine was initiated in November 2018.

In November 2017, we received agreement from the FDA on an initial pediatric study plan. In 2018, we submitted requests for scientific advice for rimegepant to the Committee for Medicinal Products for Human Use ("CHMP") a committee of the European Medicines Agency ("EMA") and feedback suggests there are several options for pursuing indications for rimegepant in Europe which are currently under consideration.

Additionally, in January 2019, we announced with our wholly-owned subsidiary, BioShin, that the National Medical Products Administration (formerly, the China FDA) has accepted the investigation new drug ("IND") application for rimegepant for the treatment of migraine. We had previously announced the formation of BioShin in November of 2018; the subsidiary was established to develop and potentially commercialize our late-stage migraine and neurological disorder product development portfolio in China and other Asia-Pacific markets.

Acute Treatment of Migraine and Limitation of Current Treatments

Clinicians use a number of pharmacologic agents for the acute treatment of migraine. A study published by the American Headache Society in 2015 concluded that the medications deemed effective for the acute treatment of migraine fell into the following classes: triptans, ergotamine derivatives, non-steroidal anti-inflammatory drugs ("NSAIDs"), opioids and combination medications. The current standard of care for the acute treatment of migraine is prescription of triptans, which are serotonin 5-HT1B/1D receptor agonists. Triptans have been developed and approved for the acute treatment of migraine over the

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past two decades. The initial introduction of triptans represented a shift toward drugs more selectively targeting the suspected pathophysiology of migraine. While triptans account for almost 80% of anti-migraine therapies prescribed at office visits by healthcare providers, issues such as an incomplete effect or headache recurrence remain important clinical limitations. In fact, only about 30%for any given attack, almost 50% of patients from clinical trials aretake a second dose in search of pain free at two hours after taking triptans.relief. In addition, triptans are

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contraindicated in patients with cardiovascular disease, cerebrovascular disease, or significant risk factors for either because of potential systemic and cerebrovascular vasoconstriction from the 5-HT_1B-mediated effects. The package insert for triptans includes warnings and precautions for migraine patients with risk factors for cardiovascular disease and states that high risk patients, including those with increased age, diabetes, hypertension, smoking, obesity or a strong family history of coronary artery disease, should be evaluated prior to receiving the first dose of a triptan. Triptans are contraindicated in patients with a history of ischemic heart disease, coronary artery vasospasm, history of stroke, peripheral vascular disease or uncontrolled hypertension. Even in patients who have a negative cardiovascular evaluation, product labeling for triptans recommends that consideration be given to administration of the first dose in a medically-supervised setting and performing an electrocardiogram immediately following administration. Additionally, periodic cardiovascular evaluation should be considered for long-term users of triptans who have cardiovascular risk factors. According to a January 2017 study published in the journalHeadache, an estimated 2.6 million migraine sufferers in the United States have a cardiovascular event, condition or procedure that limits the potential of triptans as a treatment option. Thus, we believe there remains a significant unmet medical need for a novel migraine-specific medication that does not increase the risk of cardiovascular liability.

The Potential Benefits of Rimegepant Compared to Other Treatments

Traditionally, for approval of drugs for the acute treatment of migraine, the FDA required the drug to meet four co-primary endpoints at two hours after dosage in clinical trials: pain freedom or pain relief, and freedom from nausea, phonophobia and photophobia. In October 2014, the FDA issued new less stringent draft guidance (and formal guidance in February 2018) indicating that pivotal migraine trials could use a preferred approach of co-primary 2-hour endpoints of freedom from pain and freedom from most bothersome symptom (among nausea, photophobia or phonophobia) to support approval. We believe rimegepant may be superior to other acute treatments for migraine currently approved and in development because, based on our Phase 2b clinical trial data, rimegepant was observed to result in statistically significant improvement in all four endpoints of pain, nausea, photophobia and phonophobia at the 75 mg dose, compared to placebo, with a favorable safety profile.

The table below compares what we believe are key features of rimegepant contrasted to two other product candidates targetingand standard of care treatments for the acute treatment of migraine thatmigraine.*

*These are currently in developmentcross-trial comparisons and that we anticipate could receive marketing approval as early as 2019-2020,no comparative head-to-head studies between rimegepant and to CGRP antibodies, which represent another class of

competitors have been conducted. 

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migraine-targeting product candidates in development and which target migraine prevention rather than acute treatment of migraine.

Based on the results from the Phase 2b trial and earlier-stage development,rimegepant clinical trials to date, we believe rimegepant offers the following clinical and product benefits for the acute treatment of migraine:

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Oral Availability.  To  Rimegepant is the only oral CGRP currently formulated in a Zydis ODT that can be administered sublingually for the potential for rapid onset of action. In our knowledge, rimegepant is one of only two small molecule CGRP receptor antagonists that is currently in late-stagePhase 3 clinical development and that offers patients convenient oral administration.

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Comprehensive Treatment Effect.  In the Phase 2b trial, the 75 mg doserimegepant Zydis ODT formulation demonstrated pain relief beginning as early as 15 minutes (becoming statistically significant by 60 minutes), with patients returning to normal functioning by 60 minutes. We have an exclusive worldwide agreement with Catalent for the use of rimegepant showed statistically significant improvement as comparedin the Zydis ODT fast-dissolving formulation (which also provides exclusivity with respect to placebo across all four key migraine symptoms (pain, nausea, photophobia and phonophobia), while the other small molecule CGRP receptor antagonists currentlywith the Zydis ODT technology). We believe oral availability in development have failedan easy to show statistically significant improvement on nausea,use formulation will provide advantages over injectable migraine treatments.

•Comprehensive Treatment Effect. Rimegepant has demonstrated consistent comprehensive treatment effect across 3 large Phase 3 trials and also failed to show significant improvement on pain relief.

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Durable Improvement.  In thea Phase 2b trial the improvementwith significant pain freedom, pain relief and relief from most bothersome symptoms. These effects were all noted with a single dose of the 75 mg tablet or ODT. The majority of patients treated with a single dose of rimegepant 75 mg did not require the use of additional rescue medications after treating their migraine.  

•Durable Improvement.  In the Phase 3 trials, rimegepant demonstrated durable impact on pain freedom was statistically significant at two-to-24 hours and two-to-48 hours after dosing, and on pain relief was statistically significant at two and 24through 48 hours after dosing, in each as compared to placebo, showingplacebo. We believe that this durability of treatment effect.

effect is related to the half-life of rimegepant and is an important differentiator from other products that have a shorter half-life and require additional doses of medications or rescue medications.

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Favorable Safety Profile.  In the3 Phase 2b trial,three studies of over 3500 patients,  rimegepant was generally well tolerateddemonstrated a safety profile similar to placebo. There were no AEs greater than 1.6%. Consistent with low rates of AEs, no discontinuations for AEs, no treatment-related serious adverse events ("SAEs") and no deaths. AEs in the 75 mg treatment group were comparable to the placebo group, and most AEs across all treatment groups were mild to moderate in intensity and dose-dependent. Rimegepant does not cross the blood brain barrier, so there is low potential for centrally mediated AEs. In addition, the  preclinical anddata, there was no clinical evidence suggestssuggesting that CGRP receptor antagonists, such as rimegepant have an absence ofhas vasoconstrictor activity and lackor other undesirable cardiovascular side effects, such as changes in the blood pressure or heart rate, that are commonly associated with triptans.

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Potency.  Rimegepant is highly potent with subnanomolar affinity for the human CGRP receptor, which allows for a relatively low dose to provide maximal treatment effect.



effect with a single 75 mg dose.

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        Patients were given an electronic diary to record improvements and returned to the study site within seven days of study treatment for review of the data. Patients who experienced relief of headache pain to a mild intensity or pain-free intensity level at two hours post-dosing were considered to be responders. The patients who did not experience such relief at the end of two hours were permitted to use an approved rescue medication. Use of rescue medication within 48 hours was also recorded. Whatever the case, the patient was required to continue to complete his or her electronic diary for up to 48 hours after dosing. Secondary efficacy variables included total migraine freedom: a composite endpoint consisting of freedom from headache pain coupled with no symptoms of photophobia, phonophobia or nausea, at two hours post-dosing, and sustained pain freedom from two-to-24 hours. Exploratory measures included pain relief at two hours post-dosing, sustained pain relief from two-to-24 hours post-dosing, freedom from photophobia, phonophobia or nausea at two hours post-dosing, and sustained pain freedom from two-to-48 hours post-dosing. Safety variables included AEs, SAEs, clinical laboratory evaluations, vital sign measurements, physical examinations, and electrocardiograms ("ECGs"). The following graphic illustrates the study design of the Phase 2b clinical trial:

        With regard to the primary study outcome, the percentage of patients who were pain free at two hours after dosing is depicted in the figure below. The rimegepant 75 mg, 150 mg, and 300 mg dose groups each were significantly superior to placebo (p£ 0.01). Among the rimegepant dose groups, the percentage of subjects who were pain free at two hours after dosing was 31.4% (27/86) in the 75 mg group; 32.9% (28/85) in the 150 mg group; and 29.7% (33/111) in the 300 mg group, compared to

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15.2% of patients in the placebo group. Statistical separation from placebo was not seen with the 600 mg group (24.4%, 20/82) as compared to the lower doses.

Pain Freedom 2 hours Post-Dosing (+/–95% Confidence)

        The table below shows the percentage of patients in the placebo, sumatriptan, and each rimegepant dose groups who experienced pain freedom and pain relief in the trial, and the corresponding p-values. P-value is a conventional statistical method for measuring the statistical significance of clinical results. A p-value of 0.05 represents statistical significance, meaning that there is only a 5% likelihood that the observed results occurred by chance. The table shows that rimegepant 75 mg showed statistically significant improvements compared to placebo on sustained pain freedom from two-to-24 hours and two-to-48 hours post-dose, on pain relief two hours post-dose and on sustained pain relief from two-to-24 hours post-dose (all with a 0.1% likelihood that the observed results were merely due to chance).

        The figure below shows the percentage of patients who reported sustained pain freedom and sustained pain relief at two-to-24 hours after dosing among the placebo dose group, the sumatriptan

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dose group, and each dose group of rimegepant. Rimegepant was statistically superior to placebo on pain freedom and pain relief at two-to-24 hours across all dose groups 75 mg and above.

Sustained Pain Freedom and Pain Relief 2-24 Hours Post-Dosing (+/–95% Confidence)

        The figure below shows the Phase 2 trial results for the three other traditional co-primary endpoints previously required by the FDA—freedom from nausea, phonophobia and photophobia, showing the proportion of patients with alleviation of these symptoms at two hours after dosing in the placebo dose group, the sumatriptan dose group, and in each of the rimegepant dose groups. Rimegepant 75 mg was statistically superior to placebo on nausea, photophobia and phonophobia freedom at two hours after dosing.

Nausea, Phonophobia and Photophobia Freedom 2 Hours Post-Dosing (+/–95% Confidence)

        With regard to safety and tolerability in the Phase 2 clinical trial, the overall incidence of AEs was comparable across the placebo and rimegepant treatment groups. The most commonly seen AE in the rimegepant dosing groups was nausea, which appeared to exhibit a dose dependent trend at the higher

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doses: 1.4% in the 10 mg dose group; 0% in the 25 mg dose group; 3% in each of the 75 mg and 150 mg dose groups; 4% in the 300 mg dose group; and 8% in the 600 mg dose group. Importantly, although the patient numbers were small, the reported events of chest discomfort, chest pain, muscle tightness, and jaw pain were only observed in the sumatriptan-treated patients, with no rimegepant treated patients reporting chest pain-related symptoms. Most of the AEs reported were mild to moderate in intensity. Two SAEs were reported (post-lumbar puncture headache and pneumonia), but neither was deemed by the trial investigators to be treatment-related. No deaths were reported, and no patients discontinued because of AEs. There were no clinically important ECG findings, vital sign abnormalities, or physical examination findings after administration of rimegepant.

        The table below shows the number and percentage of patients reporting a commonly occurring AE within 48 hours post-dosing. Rimegepant was generally well tolerated with no events of chest discomfort and low rate of AEs across dose groups.

        Treatment-emergent AEs that occurred within two hours post-dosing were reported most often in the sumatriptan group (10.0%), followed by the 600 mg (8.3%), 300 mg (8.0%), 150 mg (7.0%), 10 mg (6.9%), 25 mg (4.8%), and the 75 mg (4.7%) dose groups, and the placebo group (2.9%). In the rimegepant dose groups, the most common AEs reported within two hours post-dosing were primarily low rates of dizziness and somnolence, and gastrointestinal disorders, primarily nausea and vomiting.

        The liver has been a target of interest in certain small molecule CGRP receptor antagonists, as indications of liver toxicity have been associated with frequent use. In the Phase 2b trial, one patient in the rimegepant 75 mg dose group and one patient in the placebo group had a report of an asymptomatic and mild increase in certain hepatic enzymes, which are types of liver enzyme measured in a liver function test to detect damage and inflammation to the liver. The subject in the rimegepant 75 mg dose group had peak alanine transaminase ("ALT") and aspartate transaminase ("AST") elevations that were less than 1.22 times the upper limit of normal ("ULN") and reported as an AE, while the placebo subject had a total bilirubin level that was greater than 2xULN. No subjects in the Phase 2b trial had AST or ALT elevation that exceeded 3xULN, a level that is considered to be a potentially meaningful indicator of a drug's potential to cause severe drug-induced liver injury ("DILI"), based on FDA guidance.

        In conclusion, in the Phase 2b clinical trial, rimegepant was observed to be superior to placebo in the acute treatment of migraine and the trial identified the lowest dose that is fully effective in patients. More specifically, the selection of 75 mg rimegepant as the dose for advancement in Phase 3 trials was based on observed improvement as compared to placebo on the key primary outcome measure, pain freedom at two hours (31.4% vs 15.2% placebo; p = 0.0018) and key secondary and exploratory outcome measures: total migraine freedom at two hours (27.9% vs 11.8%; p = 0.0008),

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sustained pain freedom two-to-24 hours (27.9% vs 7.4%, p < 0.0001), freedom from photophobia at two hours (41.9% vs 24.0%, p = 0.0023), freedom from phonophobia at two hours (52.3% vs 27.9%, p < 0.0001), freedom from nausea at two hours (67.4% vs 51.0%, p = 0.0074), pain relief at two hours (72.1% vs 51.2%, p = 0.0007), and sustained pain relief from two-to-24 hours (69.8% vs 42.4%, p < 0.0001). Notably, rimegepant is the only small molecule and orally available CGRP receptor antagonist that has shown statistically significant improvement on the key migraine symptoms of pain, nausea, photophobia and phonophobia in a single trial.

Phase 3 Clinical Trial Development Plan

Trials: Studies 301 and 302

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In designing the Phase 3 trials, care was taken to minimize any changes in study populations compared to the already completed Phase 2 trial with rimegepant with no major changes in inclusion and exclusion criteria between the completed and planned trials. The main differences in trial design between the previous Phase 2 trials andMarch 2018, we announced positive topline data from our ongoingfirst two Phase 3 clinical trials include:

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Change inof rimegepant. In each trial, treatment with a single 75 mg dose of rimegepant met the primary outcome measure and statistical analysis planco-primary efficacy endpoints of the trial, which were superior to conform to recent FDA guidance.    The Phase 2b trial identified pain freedomplacebo, at two hours as the primary outcome measure and included various secondary and exploratory outcomepost-dose, on measures to assess the associated symptoms of nausea, photophobia and phonophobia. The Phase 3 trials utilize pain freedom and freedom from the patient’s most bothersome symptom, or MBS, selected as either nausea, photophobia or phonophobia.

The figures below show, for each trial, Kaplan-Meier curves depicting the effect of rimegepant on pain freedom as compared to placebo over the course of eight hours after dosing. A Kaplan-Meier curve is a method of statistical analysis used to show estimates of data over time even though data was only collected at intervals throughout that time period.

Kaplan-Meier Curve Showing Pain Freedom 0-8 Hours Post-Dosing









Rimegepant showed a numerical improvement in pain freedom as compared to placebo as early as 45-60 minutes post-dosing, with continued improvement over the course of eight hours post-dosing. The magnitude of the treatment effect over placebo at two hours post-dosing or later, as shown in the figures above, ranged from 5% to 19% in Study 301 and 7% to 22% in Study 302. This continued improvement in pain freedom was observed in patients who received a single dose of rimegepant and did not use rescue medications. Rescue medications are additional medications that patients in clinical trials may take concurrently with the study drug or placebo after the 2 hour endpoint has been registered when the patient experiences inadequate relief. Each of the figures above excludes patients who took rescue medication or who were lost to follow-up during the specified interval.

Pain freedom at two hours post-dosing, one of the co-primary endpoints of these trials, was 19.2% and 19.6% for rimegepant-treated patients in Study 301 and 302, respectively, as compared to 14.2% and 12.0% for patients receiving placebo, with corresponding p-values of <0.03 and <0.001, respectively. P-value is a conventional statistical method for measuring the

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statistical significance of clinical results. A p-value of 0.05 or less represents statistical significance, meaning that there is a less than 1-in-20 likelihood that the observed results occurred by chance. The table below summarizes these results.

Rimegepant also achieved statistically significant results on a second co-primary endpoint, freedom from MBS, selected from photophobia, phonophobia or nausea, at two hours post-dosing. As shown in the table below, freedom from MBS for patients treated with rimegepant were 36.6% and 37.6% in Study 301 and Study 302, respectively, as compared to 27.7% and 25.2% for patients receiving placebo, with corresponding p-values of <0.002 and <0.0001, respectively.




Co-Primary Regulatory Endpoints in Study 301 and 302

Study 302

2 Hour Endpoint						Rimegepant (N=537)						Placebo  (N=535)												p-value
Pain Freedom						19.6		%				12.0		%										< 0.001
Freedom from MBS(1)						37.6		%				25.2		%										< 0.0001




Study 301

2 Hour Endpoint						Rimegepant (N=543)						Placebo  (N=541)												p-value
Pain Freedom						19.2		%				14.2		%										< 0.03
Freedom from MBS(1)						36.6		%				27.7		%										< 0.002

(1) MBS: Most Bothersome Symptom of Photophobia, Phonophobia or Nausea.




We also evaluated rimegepant’ s effect on pain relief, which is the transition from experiencing moderate-to-severe pain to either no pain or mild pain, as a secondary endpoint in both trials. Although pain relief does not always indicate that a patient has no pain, unlike pain freedom, it is a clinically important endpoint because it often is associated with reduced disability due to migraine attacks. In each of the Phase 3 trials, onset of pain relief in patients treated with rimegepant was observed early after dosing, with separation between rimegepant and placebo evident between 30 and 45 minutes post-dosing. In both trials, by two hours post-dosing, over 55% of patients receiving only a single dose of rimegepant achieved pain relief (p-values of 0.0006 in Study 301 and <0.0001 in Study 302). The figures below show, for each trial, Kaplan-Meier curves depicting the effect of rimegepant on pain relief as co-primary endpoints. compared to placebo over the course of eight hours after dosing.

Kaplan-Meier Curve Showing of Time to Pain Relief Up to 8 Hours Post Single Dose






Each of the figures above excludes patients who took rescue medication or who were lost to follow-up during the specified interval. 

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In addition to conformachieving both co-primary endpoints in each of the trials, rimegepant also was observed to recent FDA developments,be generally well-tolerated in the trials, with a safety profile similar to placebo. In particular, pooled liver function test, or LFT, results showed that rimegepant was no more likely than placebo to increase ALT or AST levels above the upper limit of normal, or ULN. An LFT is a blood test that gives an indication of whether the liver is functioning properly. Across both trials, one patient treated with placebo and confirmedone patient treated with rimegepant showed LFTs above 3x ULN.

In both trials, no single adverse event, or AE, occurred with an incidence higher than 2% and the overall AE rates in our recent regulatory interactions, we intendthe rimegepant groups were similar to analyzethose in the data collectedplacebo groups. The most common AEs seen in our patients treated with rimegepant were similar to placebo in a pooled analysis of both trials. There were no serious adverse events, or SAEs, determined by the study investigators to be drug related.

Phase 3 trials onClinical Trials: Study 303

Our third Phase 3 trial was a non-completer-equals-failure (NC=F) basis, rather than on a last-observation-carried-forward (LOCF) basis used inrandomized, controlled Phase 3 clinical trial (“Study 303”) evaluating the Phase 2b trial;



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Number of treatment arms.    The Phase 2b trial included six different dose groupsefficacy and safety of rimegepant sumatriptan75 mg Zydis ODT conducted with the rimegepant 75 mg Zydis ODT and placebo arms. Thewas initiated after bioequivalence between the tablet and ODT were established. This Phase 3 trials only include 75 mgZydis ODT sStudy 303 was conducted to further characterize the ODT formulation and was designed in keeping with the previous Phase 3 studies.

In December 2018, we announced positive topline data from Study 303. In Study 303, rimegepant versusZydis ODT statistically differentiated from placebo since 75 mg rimegepant was identifiedon the two co-primary endpoints as well as the lowest dose in the Phase 2b trial at which improvements were observed in the four key migraine symptoms; and



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Increase in sample size.    The two Phase 3 trials enrolled approximately 3,000 patients with the aim of treating around 550 patients per arm with placebo or 75 mg rimegepant, respectively, in each trial; whereas in the Phase 2b trial 203 patients received placebo and just under 100 patients per arm received rimegepant. This increase in sample size is expected to support statistical comparisons on bothfirst 21 consecutive primary and secondary endpoints.

        This change in the hierarchy of outcome measures sample size and number of treatment arms reflect somewhat standard changesthat were pre-specified in clinical trial design to increase technical and regulatory chances of success inhierarchical testing. Consistent with the registrational program. We also developed a commercial-grade, tablet formulation of rimegepant that we are using in ourtwo previous Phase 3 clinical trials, Study 303 met its co-primary endpoints of pain freedom and freedom from most bothersome symptom (MBS) at 2 hours using a single dose (Table 1). Importantly, patients treated with the rimegepant Zydis ODT formulation began to numerically separate from placebo on pain relief as early as 15 minutes, and this difference was statistically significant at 60 minutes (p < 0.0001) (Figure 1). Additionally, a significantly greater percentage of patients treated with rimegepant Zydis ODT returned to normal functioning by 60 minutes as compared to placebo (p < 0.002). Lasting clinical benefit was observed through 48 hours after a single dose of rimegepant on freedom from pain (p < 0.001), pain relief (p < 0.001), freedom from the most bothersome symptom (p < 0.001), and freedom from functional disability (p < 0.003). Superiority over placebo was also demonstrated in multiple other secondary endpoints. The vast majority of rimegepant Zydis ODT treated patients (85%) did not use any rescue medications.

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        Those suffering from migraine often have accompanying nausea and have an aversion to consuming food or liquids during an attack. We are also developing an oral solid dosage formulation of rimegepant that disperses almost instantly in the mouth, without the need for water. The Zydis ODT formulation uniquely addresses this issue. Biohaven has exclusive worldwide rights to the Zydis ODT fast-dissolving formulation for the development of rimegepant through a January 2018 license agreement with Catalent. The agreement also provides exclusivity with respect to other small molecule CGRP receptor antagonists with the Zydis ODT technology. In February 2018, a bioequivalence study was conducted to compare this new ODT formulation to the tablet in current clinical development and provided evidence of equivalence. A third Phase 3 clinical trial with rimegepant commenced in February 2018. This study, utilizing the new ODT formulation, is designed to replicate the other two ongoing Phase 3 trials. The trial compares placebo to 75 mg of the ODT formulation and will randomize approximately 850 patients with migraine to evaluate approximately 425 patients per treatment arm. We expect to complete this Phase 3 clinical trial in the fourth quarter 2018.

preventive treatment of migraine was initiated in November of 2018 to examine the efficacy and safety of rimegepant 75 mg dosed on an intermittent schedule planned for 800 adult subjects who have suffered from migraine for at least one year and who have a frequency of 4 to 14 migraine attacks of moderate to severe pain intensity per month over the three months prior to enrollment. The primary outcome measure is the change from baseline at week 12 in the mean number of migraine days per month. Secondary outcome measures include the achievement of at least a 50% reduction from baseline in mean monthly migraine days across the double-blind treatment phase, and the mean number of rescue medication days per month, each as measured over the course of the double-blind, treatment phase. We expect to report topline results from this trial in 2019.

Clinical Trials with Rimegepant

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Since no data are available regarding the effects of rimegepant on human fetuses or newborns, women of childbearing potential must use adequate birth control and have a negative serum or urine pregnancy test to be eligible to receive rimegepant. Female subjects should avoid attempts at pregnancy in the month prior to exposure to rimegepant and eight weeks after exposure to rimegepant. All urine pregnancy testing results must be confirmed by serum pregnancy testing. Drug interaction studies with oral contraceptives demonstrated modest increase in exposure to estrogen and norelgestromin upon multiple doses of rimegepant 75 mg. Co-administration of rimegepant with oral contraceptives was safe and well tolerated. These results enabled enrollment of women of child bearing potential receiving oral contraceptives to be enrolled in the Phase 3 studies.

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Our Product Candidate BHV-3500, a CGRP Receptor Antagonist for Acute Treatment and PreventionPreventive Treatment of Migraine

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Clinical Development Plans

        We have commenced a toxicology development program to support the submission

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Lower Overall Drug Burden to the Liver—As a prodrug that mitigates first-pass liver metabolism and enhances bioavailability, therapeutic concentrations of the active metabolite riluzole can be achieved with a lower drug dose as compared to riluzole tablets. In addition, release of the active metabolite over time will result in a reduced bolus hepatic concentration as compared to that associated with riluzole tablets. Taken together, we believe these attributes of trigriluzoletroriluzole will reduce the potential for adverse liver effects.






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Optimized Dosing Regimen and Compliance—TrigriluzoleTroriluzole has been developed as a convenient once-daily dose, which could improve regimen compliance for patients. We believe these are important features to optimize long-term health outcomes in the treatment of patients with chronic diseases.






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Potential for Developing Multiple Formulations—TrigriluzoleTroriluzole is highly soluble and does not exhibit the profound oral numbness associated with riluzole tablets. As such, we believe trigriluzoletroriluzole has the potential to be developed in multiple formulations including intranasal, subcutaneous, intravenous, sublingual and other forms.

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        Within the first quarter of this year, Biohaven will haveAfter a pre-NDA meeting with the FDA and subsequently plans to submitin the first quarter of 2018, we submitted a NDA to the FDA to pursue the regulatory approval of BHV-0223 for ALS under Section 505(b)(2) of the U.S. Federal Food, Drug, and Cosmetic Act in the second half ofSeptember 2018.

The PDUFA date is in July 2019.

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Nonclinical Toxicology Experience with Lanicemine and BHV-5000

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CGRP Receptor Antagonist Platform

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Other Acute Treatments for Migraine

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With respect to the product candidates in our glutamate modulation platform,and MPO platforms, we currently intend to build a neurological specialty sales force to manage orphan drug commercialization for these product candidates on our own.

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BHV-0223

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third-party manufacturers, is subject to BMS's prior written consent, which cannot be unreasonably withheld or delayed. While we will be responsible for preparing, prosecuting and maintaining the licensed patents and applications and for defending them in post-grant proceedings, BMS must consent before a licensed patent or application is abandoned in a major jurisdiction. We will also be responsible for listing licensed patents in the Orange Book and for determining which patents will be extended based on any regulatory delays.

Our Development, Regulatory and Commercialization Obligations

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BMS has the right to terminate the agreement upon our insolvency or bankruptcy, our uncured material breach, including our failure to meet our development and commercialization obligations, our challenge to any BMS patent rights, or our failure to close a financing within specified parameters. We have the right to terminate the agreement if BMS materially breaches the agreement or if, after we provide notice, we choose not to move forward with development and commercialization in a specific country. In the event that BMS exercises its right to terminate the agreement following our insolvency, our breach of the agreement or our failure to develop or commercialize the licensed compounds, or if we terminate the agreement after providing notice, all rights and licenses granted to us will terminate, and all patent rights and know-how transferred pursuant to the agreement will revert to BMS. In addition, upon such termination, we agree to, at BMS's election, (i) assign all regulatory filings, approvals and regulatory documents necessary to further develop and commercialize the reverted products or (ii) withdraw or inactivate such filings and approvals.

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Under the agreement, we are responsible for conducting clinical trials and for preparing and filing regulatory submissions. We have the right to sublicense our rights under the agreement subject to Catalent's prior written consent. Catalent has the right to enforce the patents covering the Zydis technology and to defend any allegation that a formulation using Zydis technology, such as BHV-0223, infringes a third party's patent.

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The agreement also requires us to meet certain due diligence requirements based upon specified milestones. We can elect to extend the due diligence requirements by a maximum of one year upon payments to Rutgers of up to $500,000 in the aggregate.

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Preclinical and Human Clinical Trials in Support of an NDA

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In addition, other federal health reform measures have been proposed and adopted in the United States since the ACA was enacted. For example, as a result of the Budget Control Act of 2011, providers are subject to Medicare payment reductions of 2% per fiscal year through 2025 unless additional Congressional action is taken. Further, the American Taxpayer Relief Act of 2012 reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments from providers from three to five years. The Medicare Access and CHIP Reauthorization Act of 2015 also introduced a quality payment program under which certain individual Medicare providers will be subject to certain incentives or penalties based on new program quality standards. Payment adjustments for the Medicare quality payment program will begin in 2019. At this time, it is unclear how the introduction of the quality payment program will impact overall physician reimbursement under the Medicare program.

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Corporate Information

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We will need substantial additional funding to pursue our business objectives. If we are unable to raise capital when needed or on terms favorable to us, we could be forced to curtail our planned operations and the pursuit of our growth strategy.

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the revenue, if any, received from commercial sales of our product candidates for which we receive marketing approval;



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our ability to establish strategic collaborations for the development or commercialization of some of our product candidates; and



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the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending any intellectual property-related claims brought by third parties against us.