Advancing Innovative Therapies for Neurological Diseases

Transcription

1 Advancing Innovative Therapies for Neurological Diseases Biohaven Investor Presentation November 01, 2018 NYSE: BHVN 2018 Biohaven Pharmaceuticals. All rights reserved.

2 Disclaimer This presentation contains forward-looking statements, including: statements about our plans to develop and commercialize our product candidates, our planned clinical trials for our rimegepant, BHV3500, troriluzole, BHV0223, BHV5000 and BHV3241 development programs, the timing of the availability of data from our clinical trials, the timing of our planned regulatory filings, the timing of and our ability to obtain and maintain regulatory approvals for our product candidates and the clinical utility of our product candidates, alone and as compared to other treatment options. These statements involve substantial known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. You should, therefore, not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this presentation. For further information regarding these risks, uncertainties and other factors you should read the Risk Factors section of the Company s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the SEC ) on August 14, 2018 and the Company s other periodic reports filed with the SEC. This presentation also contains market data and other statistical information that are based on independent industry publications, reports by market research firms or published independent sources. Some market data and statistical information are also based on the Company's good faith estimates, which are derived from management's knowledge of its industry and such independent sources referred to above. While the Company is not aware of any misstatements regarding the market and industry data presented herein, such data involve risks and uncertainties and are subject to change based on various factors. NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 2

3 BIOHAVEN CORPORATE OVERVIEW Positioned For Near-Term Milestones and Long-Term Success Three Novel Small-Molecule Platforms CGRP PLATFORM GLUTAMATE PLATFORM MPO PLATFORM Migraine and Pain Two positive Phase 3 trials Alzheimer s and Anxiety Four Phase 2/3 trials Neuroinflammation Phase 2 study in MSA Deep experience across all platforms Strong intellectual property protection; exclusive license agreements Cost-efficient R&D < 60 full-time employees NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 3

4 Biohaven s Advanced Pipeline CGRP PLATFORM FOR MIGRAINE RIMEGEPANT (BHV and -302) Acute Treatment of Migraine RIMEGEPANT (BHV ) Open Label Long-Term Safety Study Delivery Tablet Tablet Preclinical Phase 1 Phase 2 Phase 3 Approval Data in RIMEGEPANT (BHV ) Acute Treatment of Migraine RIMEGEPANT (BHV ) Prevention of Migraine Rapid Dissolving Tablet Anticipated start 4Q2018 BHV-3500 Acute Treatment and Prevention of Migraine Nasal Spray GLUTAMATE PLATFORM FOR NEUROPSYCHIATRIC INDICATIONS NURTEC (BHV0223) Amyotrophic Lateral Sclerosis (ALS)* Rapid Dissolving Anticipated start 4Q2018 TRORILUZOLE (BHV ) Alzheimer s Disease (AD) TRORILUZOLE (BHV ) Obsessive-Compulsive Disorder (OCD) Capsule Capsule TRORILUZOLE (BHV ) Generalized Anxiety Disorder (GAD) Capsule Anticipated start 1Q2019 TRORILUZOLE (BHV ) Spinocerebellar Ataxia (SCA) BHV-5000 Neuropsychiatric Indications Capsule Capsule Anticipated start 4Q2018 MYELOPEROXIDASE INHIBITION PLATFORM FOR NEUROINFLAMMATION BHV-3241 Multiple System Atrophy (MSA) Tablet Anticipated start Mid 2019 * 505(b)(2) External collaboration with Alzheimer s Disease NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES Cooperative Study (ADCS) group 4

5 CGRP PLATFORM Therapies for Migraine

6 CGRP Platform for Migraine Delivery Preclinical Phase 1 Phase 2 Phase 3 Approval RIMEGEPANT (BHV ) Acute Treatment of Migraine Submit NDA in 2019 Tablet RIMEGEPANT (BHV ) Acute Treatment of Migraine Submit NDA in 2019 Tablet RIMEGEPANT (BHV ) Open Label Long-Term Safety Study Initial results expected 4Q2018 Tablet Data in RIMEGEPANT (BHV ) Acute Treatment of Migraine Topline results expected 4Q2018 RIMEGEPANT (BHV ) Prevention of Migraine Rapid Dissolving Zydis ODT Fast Dissolve Technology Tablet Start Phase 3 in 4Q2018 BHV3500 Acute Treatment and Prevention of Migraine File IND and commence Phase 1 in 2018 Nasal Spray Aptar UDS Single shot technology NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 6

7 Historical Segmentation of Migraine Therapy: Time to Revisit and Rethink Biohaven is disrupting the historical two segment migraine paradigm by advancing novel treatments with potential dual-therapy action (acute and preventive treatment) ~36M (100%) ~14M (39% 3 ) ACUTE TREATMENT 100% of patients need acute therapy Diagnosis: Migraine with/without aura 2 Take as needed to abort attack CGRP agents targeting indication: Small molecules: Biohaven, Allergan ~36M People with Migraine in the U.S. 1 PREVENTIVE TREATMENT Indicated based on headache frequency & headache related impairment, including: Chronic Migraine (CM) patients (~3.6M) Patients appropriate for prevention without CM diagnosis (~10.4M) These patients also need acute treatment CGRP agents targeting indication: Antibodies: Alder, Amgen, Lilly, Teva Small molecules: Biohaven, Allergan Stylized pie-chart: NOT brain anatomy 1. American Migraine Foundation 2. ICHD-3b International Classification of Headache Disorders 3. Lipton RB, Bigal ME, Diamond M, et al. Neurology. 2007;68(5): NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 7

8 Multiple Formulations, Meeting Patient Needs from Acute Treatment to Prevention of Migraine NOJECTION CGRP Drug Delivery Platform Oral Rapid Dissolving* Intranasal** * Exclusive World-Wide License with Catalent for use of Zydis Fast Dissolve Technology in our migraine product candidates ** Aptar Pharma Unit-Dose System (UDS) single shot nasal technology NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 8

9 Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist: Mechanism of Action in Migraine 1 Inhibition of Pain Transmission Decreasing Artery Dilation Blocking Neurogenic Inflammation 1 From N Engl J Med, Durham PL, CGRP-Receptor Antagonists A Fresh Approach to Migraine Therapy? 350: , Copyright 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society." NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 9

10 Rimegepant: Well Tolerated in Phase 1 and Phase 2b Summary of Clinical Safety Data Phase 1: Well tolerated at high doses Ultra-high exposures up to 1,500 mg well tolerated high doses achieved daily exposures >50-fold therapeutic dose 600 mg administered for up to 14 days Phase 2b: Well tolerated at all doses Most AEs of mild or moderate severity 75 mg dose with comparable AEs to placebo AEs of chest discomfort only reported in sumatriptan group No clinically important findings on ECG, physical exam, lab assessments or vital signs Preclinical: Large safety multiples at 75 mg (AUC) 23x below rat NOEL (3) 56x below monkey NOAEL (4) (1) Marcus R, et al. (2014). Cephalalgia 34(2): (2) Adverse events occurring in 2% of patients in any treatment group; ordered by frequency in the rimegepant 600 mg group. n: number (%) of patients who took at least one tablet of study drug (3) NOEL = no observable effect level (4) NOAEL = no observable adverse effect level Patients, n (%) Phase 2b Safety Data Number (%) of Patients Reporting a Commonly Occurring Adverse Event within 48 Hours Post-Dose (1)(2) 10 mg n=72 25 mg n=62 Rimegepant Sumatriptan Placebo 75 mg n= mg n= mg n= mg n= mg n=100 n=209 Nausea 1 (1) - 3 (3) 3 (3) 5 (4) 7 (8) 2 (2) 5 (2) Dizziness 2 (3) 1 (2) 1 (1) 2 (2) - 3 (4) 1 (1) 2 (1) Vomiting - 2 (3) 2 (2) (2) 1 (1) 5 (2) Diarrhea 4 (6) (1) Paresthesia (2) 2 (1) Dysgeusia 2 (3) Chest Discomfort (2) - Myalgia 2 (3) Testing of very high doses in Phase 1 and 2b provides evidence of acceptable tolerability for 75 mg dose NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 10

11 Rimegepant: Comprehensive and Durable Treatment Effect Observed in Phase 2b Overview of Phase 2b Trial (1) Pain Freedom Two Hours Post-Dosing Double-blind, randomized, placebo-controlled, doseranging clinical trial completed by BMS 812 patients suffering from migraine attacks received either placebo, sumatriptan 100 mg or rimegepant dosed at 10, 25, 75, 150, 300 or 600 mg Rimegepant dosed at 75 mg was observed to have comprehensive and durable treatment effect Patients (%) Patients (n) ** ** ** Placebo Sumatriptan, mg Rimegepant (mg) ** Sustained Pain Freedom and Pain Relief 2-24 Hours Post-Dosing Nausea, Phonophobia and Photophobia Freedom Two Hours Post-Dosing Patients (%) ** ** * ** ** ** ** ** ** ** ** Patients (%) ** ** ** ** * ** ** ** ** ** ** ** ** (1) Marcus R, et al. (2014). Cephalalgia 34(2): Patients (n) Placebo Sumatriptan, mg Rimegepant (mg) Pain Freedom Pain Relief 0 Placebo Sumatriptan, mg Rimegepant (mg) Patients (n) Nausea Freedom Phonophobia Freedom Photophobia Freedom * p < 0.05 ** p < 0.01 NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 11

12 Rimegepant Demonstrates Comprehensive and Durable Efficacy across Two Pivotal Phase 3 Trials with a Single Dose RIMEGEPANT (BHV-3000) PHASE 3 HIGHLIGHTS Primary endpoints achieved in two pivotal Phase 3 trials Pain freedom at two hours Freedom from most bothersome symptom (MBS) at two hours Clinically important drug benefit across multiple outcome measures Majority of patients achieved pain relief within two hours (speed of onset) Sustained efficacy out to 48 hours on multiple measures (durable benefit) High proportion of patients achieving normal function Low use of rescue meds Placebo-like safety and tolerability Safety profile similar to placebo including liver function tests Adverse events profile similar to placebo and favorable compared to historical triptan experience Consistent results across endpoints and efficacy trials NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 12

13 Increasing Benefit Over Time on Pain Freedom After Single Dose RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Pain Freedom 2-8 Hours Post-Single Dosing with Rimegepant 75 mg % of Patients Pain Free Rimegepant 75 mg (n=537) Placebo (n=535) 33% 20% 43% 54% 66% 0 2 hr 3 hr 4 hr 6 hr 8 hr Time Single Dose of Rimegepant, No Rescue Meds Data are Kaplan-Meier estimates of Pain Freedom; subjects were censored (not included) who took rescue medication or were lost to follow-up during the specified interval NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 13

14 Durable Pain Freedom Benefit through 48 Hours After Single Dose RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Sustained Pain Freedom 1 from 2, 3, & 4 to 24 or 48 hours Sustained Pain Freedom Rimegepant n=537 Placebo n=535 p-value 2 to 24 hrs 12.3% 7.1% hr 3 to 24 hrs 19.9% 10.8% < to 24 hrs 26.8% 14.4% < to 48 hrs 9.9% 5.6% hr 3 to 48 hrs 16.2% 9.7% to 48 hrs 21.4% 12.2% < Single Dose of Rimegepant, No Rescue Meds 1. Sustained Pain Freedom is defined as having no headache pain during the specified interval, with no use of rescue medication NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 14

15 Pain Relief 1 : Early Separation and Continued Improvement Without Additional Dosing or Rescue Medications RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Kaplan-Meier Curve of Time to Pain Relief up to 8 Hours Post Single Dose Single Dose of Rimegepant, No Rescue Meds Probability of Pain Relief Rimegepant (n=537) Placebo (n=535) 63% 79% 91% Time (minutes) 1. Pain Relief is defined as patients who have either mild-pain or no-pain during the specified interval. Data are Kaplan-Meier estimates of Pain Relief; subjects were censored (not included) who took rescue medication or were lost to follow-up during the specified interval. NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 15

16 Durable Pain Relief Through 48 Hours After Single Dose RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Sustained Pain Relief 1 from 2, 3, & 4 to 24 or 48 hours Sustained Pain Relief Rimegepant n=537 Placebo n=535 p-value 2 to 24 hrs 42.6% 26.5% < hr 3 to 24 hrs 49.5% 29.9% < to 24 hrs 52.9% 36.1% < to 48 hrs 36.3% 22.6% < hr 3 to 48 hrs 42.3% 25.0% < to 48 hrs 45.1% 29.9% < Single Dose of Rimegepant, No Rescue Meds 1. Sustained Pain Relief is defined as patients who have either mild-pain or no-pain pain during the specified interval, with no use of rescue medication NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 16

17 Increasing Proportion of Patients Are Free from Most Bothersome Symptom (MBS) 1 Following Single Dose of Rimegepant, No Rescue Meds RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Kaplan-Meier Curve of Time to MBS Freedom up to 8 Hours Post Single Dose Single Dose of Rimegepant, No Rescue Meds Probability of MBS Freedom Rimegepant (n=537) Placebo (n=535) Time (minutes) 1. Freedom from Most Bothersome Symptom defined by each patient as either photophobia, phonophobia or nausea for this attack. Data are Kaplan-Meier estimates of MBS Freedom; subjects were censored (not included) who took rescue medication or were lost to follow-up during the specified interval NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 17

18 Freedom from Functional Disability: Greater Proportion of Patients Achieving Normal Function on Rimegepant RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Kaplan-Meier Curve of Time to Functional Disability Freedom up to 8 Hours Post Single Dose Single Dose of Rimegepant, No Rescue Meds Probability of Functional Disability Freedom Rimegepant (n=537) Placebo (n=535) Time (minutes) Four Point Scale: Normal Function Mild Impairment Severe Impairment Required Bedrest Data are Kaplan-Meier estimates of Functional Disability Freedom; subjects were censored (not included) who took rescue medication or were lost to follow-up during the specified interval NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 18

19 Rescue Medicine Use: Rimegepant Treated Patients Had Lower Use of Rescue Medicine and Delayed Time to Use RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Kaplan-Meier Curve of Time to Rescue Medicine Use up to 24 Hours Post Single Dose Single Dose of Rimegepant, No Rescue Meds Probability of Rescue Medicine Use Rimegepant (n=537) Placebo (n=535) Time (hours) Data are Kaplan-Meier estimates of Rescue Medicine Use; subjects were censored (not included) at the time of taking rescue medication, and those lost to follow-up were censored at the end of the specified interval NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 19

20 More Than 3x of Subjects Who Responded to Treatment Preferred Rimegepant Over Their Previous Treatment RIMEGEPANT (BHV-3000) PHASE 3 STUDY 302 Preference of Medication at 24 Hours in Subjects Who Responded to Treatment No Preference, 21% 62% Preferred Rimegepant over Prior Standard of Care Preferred Previous Treatment, 17% n=232 who responded to treatment and provided a response (Study 302); Placebo Responders (n=176) 47% preferred study medication, 28% previous treatment, 24% no preference. NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 20

21 Rimegepant was Well Tolerated in Phase 3: No Single Adverse Event Occurring > 2% RIMEGEPANT (BHV-3000) PHASE 3 STUDY 301 & 302 Pooled Adverse Event (AE) Safety Data from Study 301 and Study 302 PERCENT (NUMBER) OF PATIENTS REPORTING AN ADVERSE EVENT WITHIN 48 HOURS POST-DOSE 1% INCIDENCE Adverse Event Placebo n=1092 Rimegepant n= On-Study AE* 12.5% (136) 14.9% (162) Nausea 1.1% (12) 1.4% (15) UTI 0.7% (8) 1.0% (11) SAEs** 0.3% (3) 0.3% (3) * No other individual AEs 1% than listed in table. Includes all AEs without attribution to drug relatedness. ** No drug-related Serious Adverse Events (SAEs). 2 of the subjects with SAE in rimegepant group and 1 in placebo group had not been dosed before onset of SAE. NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 21

22 Rimegepant Ph 3 Pooled Liver Function Test (LFT) Profile: Rimegepant was Similar to Placebo in Both Studies RIMEGEPANT (BHV-3000) PHASE 3 STUDY 301 & 302 COMPLETE DATASET OF LFT RESULTS FROM STUDY 301 AND STUDY ALT or AST Placebo n=1092 Rimegepant n=1089 > ULN 2 32 (2.9%) 24 (2.2%) > 3x ULN 1 (0.1%) 1 (0.1%) > 5x ULN 0 0 > 10x ULN 0 0 > 20x ULN No bilirubin elevations >2x ULN across both Studies 301 and ULN: upper limit of normal; ALT: alanine aminotransferase; AST: aspartate aminotransferase NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 22

23 Rimegepant Met Both Primary Endpoints and Achieved Benefits Over Placebo in 11 of 13 Primary and Secondary Endpoints in 2 Pivotal Trials RIMEGEPANT (BHV-3000) PHASE 3 STUDY 301 & 302 Study 301 (n=1084) Study 302 (n=1072) PRIMARY ENDPOINTS BHV PBO P-VALUE PRIMARY ENDPOINTS BHV PBO P-VALUE 2hrs 19.2% 14.2% hrs 19.6% 12.0% hrs 36.6% 27.7% hrs 37.6% 25.2% < SECONDARY ENDPOINTS BHV PBO P-VALUE SECONDARY ENDPOINTS BHV PBO P-VALUE 2 hours 34.9% 24.8% hours 37.4% 22.3% < hours 38.6% 30.9% hours 36.7% 26.8% Pain 2 hours 56.0% 45.7% Pain 2 hours 58.1% 42.8% < hours 46.9% 41.6% hours 48.1% 43.3% Prob of Rescue Meds in 24 hours 20.4% 31.8% < Prob of Rescue Meds in 24 hours 21.0% 37.0% < SP Freedom 2 to 24 hours 14.0% 8.1% SP Freedom 2 to 24 hours 12.3% 7.1% SP Relief 2 to 24 hours 38.9% 27.9% SP Relief 2 to 24 hours 42.6% 26.5% < SP Freedom 2 to 48 hours 11.6% 7.2% SP Freedom 2 to 48 hours 9.9% 6.0% SP Relief 2 to 48 hours 33.7% 23.9% SP Relief 2 to 48 hours 36.3% 22.6% < Pain Relapse 2 to 24 (*n=181) 40.1% 50.0% Pain Relapse 2 to 24 (*n=169) 49.6% 50.0% Functional Disability at 2 hours 33.3% 21.8% < Functional Disability at 2 hours 32.6% 23.4% * Represents only approximately 16% of sample size NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 23

24 Rimegepant Potential to Be the Favored Choice for Acute Treatment of Migraine RIMEGEPANT UBROGEPANT LASMIDITAN CGRP ANTIBODIES Mechanism of Action Stage of Development CGRP receptor antagonist CGRP receptor antagonist 5-HT1F receptor agonist Phase 3 Phase 3 Phase 3 Antibody against CGRP receptor (Amgen) or CGRP peptide (Alder, Lilly, Teva) Aimovig approved; Others Phase 3: BLA filed & earlier Effectiveness in Acute Treatment of Migraine Met both registrational endpoints (2 hr pain free & MBS) in two pivotal Phase 3 Trials Comprehensive treatment effect: pain relief, photophobia and phonophobia at 2 hours postdose; Durable treatment effect: 2 to 24 and 2 to 48 hour sustained pain freedom No sig difference from Placebo on LFTs > ULN No single AE > 2% Tolerability profile similar to placebo without difference from placebo on triptan AEs of interest Long-term safety study: up to daily dosing ongoing (started Aug 2017) Met both registrational endpoints (2 hr pain free & MBS) at 50 mg in two pivotal Phase 3 trials (multidose submission?) Inconsistent effect on MBS across studies and doses Durable treatment effect: did not show 2 to 48 hour sustained pain freedom Imbalance 6 cases of LFTs > 3x ULN, 5 on ubrogepant vs 1 on placebo; 2 cases of LFTs > 5x ULN on ubrogepant (1 case > 10x ULN attributed to pancreatitis) nausea, somnolence dry mouth >2.5% No single AE > 5%; treatment AEs appear to increase with dose Long-term safety study: up to 8 doses per month pending 4Q2018; Planned 2 nd LTS study 15 doses per mo for 2 mo at 100 mg Novel alternative for patients who are triptan intolerant or unresponsive No reason to expect headache recurrence phenomena Met both registrational endpoints (2 hr Pain Free & MBS) in two pivotal Phase 3 Trials Phase 2 Durable treatment effect: headache recurrence at 24 hour not different from placebo No data showing 2 to 24 hour or 2 to 48 hour sustained pain freedom or sustained pain relief Preventive use only Durable treatment effect: vast majority of patients show residual ongoing migraine attacks Safety / Tolerability Higher rates of treatment-emergent AEs compared to placebo (dizziness, paresthesia, somnolence, nausea, fatigue, lethargy and vertigo) Phase 2 Higher rates of severe AEs and treatment-emergent AEs compared to placebo (dizziness, fatigue, vertigo, paresthesias, somnolence and sensation of heaviness) Ongoing study of effect on driving Well tolerated Cumbersome route of administration (IV, SC) Benefits / Unknowns of Mechanism Novel MOA targeting patients not satisfied with triptan efficacy or who are triptan intolerant or unresponsive No reason to expect headache recurrence phenomena Mechanism represents an advance on triptans Uncertainty regarding triptans e.g., rebound Uncertain appeal in triptan non-responders Relatively long duration of action (1 dose per month or 1 dose per 3 months) Lack of CV effect on exerciseinduced angina (Amgen) PREVENTION ONLY NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 24

25 Rimegepant Value Proposition Oral Availability Ultra-high potency Effective on pain & MBS Single dose & durable effect Well tolerated Low cost of goods NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 25

26 BHV-3500: Third Generation CGRP Receptor Antagonist BHV-3500 HIGHLIGHTS Superior chemical attributes; potent antagonist at the human CGRP receptor highly soluble high free fraction Multiple potential routes of delivery nasal, inhalation, subcutaneous and oral potential for rapid onset Optimized safety profile in preclinical studies even at very high doses Low cost of goods, higher value to patients and payors Pursuing development for the acute treatment and prevention of migraine Phase 1 started October 2018 Topline phase 2/3 data anticipated 4Q2019 Aptar Pharma Unit-Dose System (UDS) single shot nasal technology NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 26

27 CGRP Platform Development Milestones & Next Steps 4Q2018 Preliminary data from long-term safety study with rimegepant to support NDA submission 4Q2018 Top-line results from Phase 3 rimegepant Zydis ODT trial for acute treatment of migraine* 4Q2018 Initiate Phase 3 rimegepant trial for prevention of migraine 4Q2019 Topline phase 2/3 data anticipated for intranasal BHV-3500 trial in acute treatment of migraine 2019 Submit New Drug Application (NDA) for rimegepant to the FDA 2020 Anticipated rimegepant LAUNCH! * ODT trial results are not required for NDA filing (bioequivalence criteria met for ODT and tablet) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 27

28 GLUTAMATE PLATFORM Therapies for Neurologic and Neuropsychiatric Indications

29 Glutamate Platform for Neuropsychiatric Indications Delivery Preclinical Phase 1 Phase 2 Phase 3 Approval NURTEC (BHV0223) Amyotrophic Lateral Sclerosis (ALS) Submit NDA 505(b)(2) expected 2H2018 TRORILUZOLE (BHV ) Alzheimer s Disease (AD) 6-month Futility Analysis 4Q2019 TRORILUZOLE (BHV ) Obsessive-Compulsive Disorder (OCD) Enrollment Active TRORILUZOLE (BHV ) Generalized Anxiety Disorder (GAD) FPFV expected 1Q2019 TRORILUZOLE (BHV ) Spinocerebellar Ataxia (SCA) FPFV expected 4Q2018 TRORILUZOLE (BHV ) SCA Long-Term 96-Week Ext Topline Results at 48-Weeks Expected 4Q2018 BHV5000 Neuropsychiatric Indications Complete Phase 1 in 2018 Rapid Dissolving Capsule Capsule Capsule Capsule Capsule Capsule NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 29

30 The Role of Glutamate: Present in 90% of Brain Synapses EXCITOTOXICITY Diseased State NORMAL FUNCTION Healthy State AMYOTROPHIC LATERAL SCLEROSIS ANXIETY DEPRESSION ABNORMAL CELL GROWTH STROKE MELANOMA NEURODEGENERATION SPINOCEREBELLAR ATAXIA DEMENTIA STRESS CANCER RETT SYNDROME PAIN NEUROTOXICITY SEIZURES GLUTAMATE REGULATION SYNAPTOPLASTICITY MEMORY NEURONAL CONNECTIONS MOOD STRESS RESILIENCE CELL SURVIVAL NEUROTRANSMISSION NEUROTROPHIC ACTION POTENTIAL COGNITION LEARNING Biohaven is focused on normalizing glutamate to treat disease NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 30

31 Glutamate Mechanisms of Action in CNS 1 Glutamate Transporter Modulation Troriluzole BHV Glutamate NMDA Receptor Antagonism BHV Third-party clinical trials provide basis for exploration of riluzole-related candidates, troriluzole and BHV0223, in multiple neurologic and neuropsychiatric disorders NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 31

32 Riluzole: Use and Limitations Riluzole is approved for the treatment of patients with amyotrophic lateral sclerosis (ALS) and proven to extend survival Originally marketed by Sanofi, Rilutek (riluzole) received FDA approval in 1995 In 2013, the FDA approved the first generic versions of riluzole Doses above 100 mg for efficacy not approved due to dose-dependent liver effects BENEFITS Mechanism of action well understood Neuroprotective, survival benefit in ALS Well tolerated, safe in clinical settings at approved dose LIMITATIONS Twice daily dosing, low bioavailability Fasting required for 6 hours/day, can t be taken with meals Dose dependent LFT liability (1) Marked PK variability High drug burden relative to efficacy (2) Only one approved indication (ALS) 1. LFT = liver function test 2. Poor oral bioavailability results in a high liver burden relative to efficacy as ~40% is either not absorbed or is metabolized in the liver NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 32

33 Troriluzole: Rational Drug Discovery to Optimize Therapy Improved absorption Enhanced bioavailability Reduced drug burden Reduced first pass metabolism Favorable safety profile Once-daily dosing NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 33

34 Peptide Transporter 1 Enhances Absorption of Troriluzole ACTIVE ABSORPTION IN INTESTINAL TRACT BY PEPT1 PepT1 PepT1 = Peptide Transporter 1 NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 34

35 Troriluzole: Targeted Lead-Indication Development Strategy TRORILUZOLE Neurodegenerative Disorders Neuropsychiatric Disorders Cerebellar Disorders Lead indications across an array of potential neurologic and neuropsychiatric indications Mild-to-Moderate Alzheimer s Disease* Prodromal Alzheimer s Disease Obsessive-Compulsive Disorder Social Anxiety Disorder Spinocerebellar Ataxia (SCA) Pending further evaluation of Phase 2/3 SCA data Friedreich s Ataxia ALS (High Dose) GAD Sporadic Ataxia Bipolar Depression Other Ataxia Essential Tremor* * = Third-party study / collaboration ongoing or planned (ADCS Collaboration for AD; ET Study Group Collaboration for ET) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 35

36 Rationale for Troriluzole in Alzheimer s Disease (AD) TRORILUZOLE Validated glutamate mechanism for treating neurodegenerative disease Multimodal activity goes beyond simply targeting tau or amyloid Therapeutic and pharmacologic effects of troriluzole in AD models rescues cognitive symptoms and reverses hippocampal gene expression changes found in human AD tissue Potential to improve AD symptoms and reduce disease progression Relevant to all stages of AD Hallmarks of Human Alzheimer s Disease Cognitive and behavioral symptoms Loss of hippocampal synapses (highly correlated with AD severity) Impairments in glutamate synapse structure and function Amyloid and tau pathology NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 36

37 Glia Dysfunction in Aging and Alzheimer s Disease 1 GLIAL CELL FAILURE IS AN EARLY MARKER OF PATHOPHYSIOLGY Glial cells protect and support neurons Glial cell failure is associated with neuronal cell death in AD animal models Glial fibrillary acidic protein expression (GFAP+) can be used to mark glial cell failure GFAP+ is reported to increase in animal models of AD and aging (and occurs earlier than amyloid deposits and brain atrophy) Key feature of glial cell failure is impaired glutamate transporter (GLT-1) function 1 Ugbode et al 2016 Biochemical Journal (2017) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 37

38 Glutamate Transporter (GLT-1) Implicated in Pathophysiology of AD HUMAN PATHOPHYSIOLOGY IN AD Healthy Brain Alzheimer s Brain A. Hosi et al. Neuropathology and Applied Neurobiology (2018) GLT-1: glutamate transporter-1 is the dominant astrocytic glutamate transporter in the cerebral cortex Glutamine synthetase (GS): converts glutamate to glutamine in astrocytes * Human autopsy observations from AD and controls (n=13) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 38

39 Glutamate Transporter (GLT-1) Implicated in Pathophysiology of AD GLT-1 immunoreactivity (IR) in each temporal neocortex area in the AD group is significantly weaker than that in the control group INFERIOR TEMPORAL MIDDLE TEMPORAL SUPERIOR TEMPORAL GLT-1 IR GLT-1 IR GLT-1 IR Control AD Control AD Control AD **P < 0.01 vs. control A. Hosi et al. Neuropathology and Applied Neurobiology (2018) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 39

40 Riluzole Rescues Symptoms, Function and Pathology in AD Animal Models Rescues Cognitive Symptoms (Learning and Memory) Attenuates Impairments in Hippocampal Glutamate Synapses Reduces Amyloid and Tau Pathology Exploration Time (sec) Young-control Aged-treated Aged-control Y-maze Riluzoletreated aged animals perform like youngcontrols Increases Glutamate Transporter I (GLT-1) Reduces amyloid plaque Time (min) Water Maze Errors Morris water maze Control TauP301L Riluzole + TauP301L Riluzoletreated tauoverexpressing animals perform like controls Young-control Normal Spine Density Aged-control Reduced Spine Density Aged-treated Restored Spine Density Increases neuronal spine density CP-13/Actin (Relative Ratio) Reduces p-tau Control TauP301L Riluzole + TauP301L Pereira Proc Natl Acad Sci 2014; Hunsberger J Neurochem 2015; Hunsberger, Metab Brain Dis 2016; Pereira Molecular Psychiatry 2017; Okamoto Transl Psychiatry 2018 NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 40

41 Troriluzole Phase 2/3 Clinical Trial Design in AD TRORILUZOLE (BHV-4157) PHASE 2/3 Key entry criteria Diagnosis of mild to moderate Alzheimer s disease with Mini-Mental State Exam (MMSE) score of Co-primary efficacy endpoints Alzheimer's Disease Assessment Scale (ADAS)-Cog11 Clinical Dementia Rating-Sum of Boxes (CDR-SB) Secondary efficacy endpoints Brain volumes: MRI imaging Activities of daily living: ADCS-ADL Neuropsychiatric: NPI Neuropsychological: NTB Cognitive: MMSE/MoCA Sample size: 292 subjects Randomization: 1:1 Collaborator: Alzheimer s Disease Cooperative Study Screening Phase 6 weeks Randomized Double-Blind, Placebo-Controlled Phase 48 weeks Troriluzole 280 mg qd R Placebo Interim Futility Analysis when first 100 subjects reach week 24 NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 41

42 Troriluzole in SCA: Signal-to-Noise Challenges at 8 Weeks TRORILUZOLE (BHV-4157) PHASE 2/3 Two double-blind (1,2), placebo-controlled academic trials with riluzole show therapeutic effects (p<0.05) Biohaven Phase 2/3 SCA trial with troriluzole failed to separate from placebo at 8 week time point; extension phase ongoing Romano et al (2) Study on the use of riluzole in patients with hereditary cerebellar ataxias over a 12-month period Multi-center, double-blind, placebo-controlled trial with 60 subjects diagnosed with either SCA or Friedreich s ataxia (enrolled 2:1) Subjects randomized to receive 12 months of treatment with either placebo or 100 mg riluzole (50 mg riluzole tablets, BID) Primary endpoint was the proportion of patients with a minimum 1-point improvement on the SARA (3) after 12 months Demonstrated statistically significant efficacy in patients with hereditary cerebellar ataxia (both SCA and Friedreich s ataxia) % of Patients with Change in SARA Scores Improved SARA Score 1 pt 60% 2.00 Biohaven Multicenter Phase 2/3 (Oct 2017) This was the first multi-center randomized clinical trial in North America for SCA. High variability observed in primary rating scale (SARA) and unexpected high placebo response rates at 8 weeks. At 8 wks, troriluzole with improvement of points [95% CI: -1.4 to -0.2] on the SARA vs points [95% CI: -1.6 to -0.4] in placebo, p-value = Troriluzole demonstrated a favorable safety and tolerability profile, with no drug-related SAEs and low discontinuation rates due to adverse events. Long-term, open-label, extension phase is ongoing. This extension phase will allow for potential signal detection at later time points. Topline data from the extension phase is expected in 4Q2018. % of Patients with Improved SARA Score 1 pt 60% 2.00 Change in SARA Scores % of Patients 40% 20% 0% 3 Months 12 months Change in SARA Score ** ** 3 Months 12 months % of Patients 40% 20% 0% 8 weeks Change in SARA Score weeks Riluzole (n=28) Placebo (n=27) ** p < 0.01 Trigriluzole (n=63) Placebo (n=68) p = Week Extension Phase Ongoing to Assess Efficacy (Topline 4Q2018) 1. Ristori et al., Neurology 2010; 74: Romano et al., Lancet Neurol 2015; 14: Scale for the Assessment and Rating of Ataxia NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 42

43 Scale Learnings Inform SCA Analyses and Trial Considerations TRORILUZOLE (BHV-4157) PHASE 2/3 Based upon available literature, a 1 point change in total SARA was believed to be clinically relevant In this trial, 2 point change was unexpectedly observed between screening and baseline in over 1/3 patients Limits ability to detect 1pt efficacy signal at 8 weeks Observations from 8-week randomization phase High scale variability between screening and baseline without drug on-board, limits signal detection at 8 weeks Placebo response for progressive neurodegenerative disease unexpectedly high Site rater experience appears critical to reducing variance and placebo response Cannot rule out short term efficacy signal Troriluzole well tolerated with favorable safety profile Full dataset analysis and ongoing extension to be presented at medical conferences Favorable trends identified in subpopulations defined to reduce variability Additional analyses of dataset, interactions with FDA ongoing Number of Subjects 36% of patients with 2pt change in SARA between screening and baseline - 2pt + 2pt Δ SARA [Screening SARA Baseline SARA] Points NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 43

44 Biohaven s Long-Term Data Supports Efficacy to Natural History Cohort TRORILUZOLE (BHV-4157) PHASE 2/3 DATA Natural History Cohort Total Modified SARA (Mean Change ± SE) Troriluzole-Treated SE: Standard Error NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 44

45 Yale POC Study: Anti-Anxiety Effects of Nurtec (BHV-0223) NURTEC (BHV-0223) DESIGN Double blind, placebo controlled crossover trial with two Impromptu Speech Task sessions Subjects diagnosed with Social Anxiety Disorder N=22 randomized (21 completed) BHV-0223 vs PBO, dosed 1 hour prior to public speaking stress task; separated by two to ten days to allow for medication washout Primary outcome: trial powered at 80%, to detect an effect size of 0.58, at an alpha of p=0.10; prespecified analysis showed p=0.056 and likelihood-based analysis showed p= NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 45

46 Yale Human POC Study Is Consistent with Preclinical Models Showing Riluzole s Anti-Anxiety Effects and Enhancement of Recognition Memory RILUZOLE PRECLINICAL Anti-Anxiety Effects Enhances Recognition Memory %Time Spent in Open Arm Discrimination Index Saline Riluzole Saline Riluzole Sugiyama et al 2017 (Brain Behavioral Research) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 46

47 Anti-Anxiety Effects of Riluzole Appear Similar to Benzodiazepines in Preclinical Models RILUZOLE PRECLINICAL Treatment with riluzole increases amount of time spent in open arms and number of entries (Diazepam used as active anxiolytic control) %Time Spent in Open Arm %Open Arm Entry Sugiyama et al 2012 (Psychopharmacology) Riluzole (mg/kg, p.o.) Diazepam (mg/kg, p.o.) Riluzole (mg/kg, p.o.) Diazepam (mg/kg, p.o.) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 47

48 Expanding Biohaven s glutamate modulating platform into Generalized Anxiety Disorder (GAD) TRORILUZOLE (BHV-4157) PHASE 2/3 TRIAL DESIGN GENERALIZED ANXIETY DISORDER Chronic or excessive worry, restlessness, fatigue, difficulty concentrating, insomnia Impairs ability to function socially or at work Irritable bowel-like gastrointestinal issues GAD has a 12-month prevalence in the United States of 3% 3,500,000 (est. treatment resistant in U.S.) RILUZOLE PHASE 2/3 TRIAL DESIGN Multicenter (US only), randomized, double-blind, placebo-controlled trial in outpatients with GAD Troriluzole 140 mg QHS* & 60 mg QAM* vs Placebo BID*, N=260 Primary Outcome: Change on HAM-A from baseline to Week 8 Significant unmet need Yale IP protects riluzole in GAD, SAD & Panic Disorder NBC New, 28-JUL-18 * QHS: every bedtime, QAM: every morning, BID: twice daily NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 48

49 NURTEC is Optimized to Address Riluzole Delivery Limitations for ALS NURTEC (BHV-0223) Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that causes muscle weakness, difficulties with breathing and swallowing and death Generic riluzole has been proven to extends survival in ALS Yet, swallowing is a challenge for patients with ALS About 1/3 of patients have dysphagia at diagnosis; over 80% during advanced disease Many crush riluzole tablet and mix with food, yet label cautions results in lower drug levels Fasting required 3 hours per dose (fast 2 hours before and one hour after meals) Nurtec is a proprietary, novel formulation of riluzole optimized for sublingual administration Nurtec rapidly dissolves when placed under tongue Active ingredient efficiently absorbed by sublingual mucosa No need to swallow tablet with liquid Only Riluzole Oral Dissolving Tablet meets needs with difficulty swallowing Caution: New Drug - Limited by United States law to investigational use NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 49

50 NURTEC Phase 1 Single Dose PK Results NURTEC (BHV-0223) Observations Mean Plasma Concentrations with Individual PK Profiles Superimposed Single Dose Mean Plasma Riluzole Concentration (pg/ml) BHV-0223 (35 mg SL) Mean Individual Results Rilutek (50 mg tablet) Mean Individual Results Sublingual (SL) 35 mg dose of BHV0223 vs. 50 mg dose of oral Rilutek (riluzole) BHV-0223 associated with less PK variability Oral Rilutek associated with large PK variability A Lower exposures in some patients Attributed to poor bioavailability and first-pass metabolism of oral dosing Actual Time (h) A Time Post-Dose (h) NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 50

51 NURTEC Offers Potential Advantages Over Conventional Riluzole Tablets for ALS Patients NURTEC (BHV-0223) EASE OF ADMINISTRATION An early symptom of ALS is difficulty swallowing; makes use of riluzole tablets challenging BHV0223 uses fast-dissolving technology that does not require swallowing or administration of liquids NO FOOD EFFECT Prescribing instructions for riluzole tablets state that it should be taken at least an hour before, or two hours after, a meal to avoid food-related decreases in bioavailability Patients who do not strictly adhere to these fasting requirements or administer crushed riluzole in food, may not be obtaining desired therapeutic levels of riluzole BHV0223 was designed to be absorbed sublingually; since absorption of BHV0223 occurs in the vasculature under the tongue, fasting requirements are not anticipated This will be particularly beneficial to patients who require a continuous feeding tube for nutrition MORE PREDICTABLE PHARMACOKINETIC PERFORMANCE Some patients with ALS crush their solid riluzole tablets and take with food to ease administration (1) With BHV0223, patients will not have to crush or alter the form of administration In Phase 1 trial, observed less pharmacokinetic variability with BHV0223 compared to 50 mg riluzole REDUCED DRUG LOAD AND LIVER EXPOSURE Riluzole associated with dose-dependent liver issues resulting from high dose loads / extensive liver metabolism BHV0223 is sublingually absorbed, bypassing first-pass liver metabolism and reducing the dosage size that needs to be administered, thereby reducing potential risk for hepatic enzyme elevations 1. Leads to uncertain pharmacokinetic performance as well as oral numbness NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 51

52 BHV-5000: A Novel Low-Trapping NMDA Antagonist BHV-5000 Potential first-in-class, next-generation NMDA receptor antagonist Exclusive license from AstraZeneca Low-trapping agent Orally bioavailable prodrug of the IV drug lanicemine NMDA modulation has the potential for applicability across a number of CNS disorders BHV-5000 demonstrate markedly mitigated risk of dissociative effects in the clinic Attributed to its distinct ability to uncouple from the NMDA receptor more freely than other agents Well tolerated in a Phase 1 single and multiple ascending dose trial BHV-5000 doses up to 95 mg studied to date in Phase 1 Active metabolite, lanicemine, has been administered to ~770 subjects in single or multiple doses in 18 clinical trials; generally well tolerated NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 52

53 BHV-5000: Novel Low-trapping NMDA Channel Blocker BHV-5000 MOA Lanicemine vs. Ketamine Ketamine Lanicemine NMDA receptor / ion channel complex exists in an open or closed state Blockers bind to the open state but may be trapped if they do so deep within the channel High trapping agents narrow the therapeutic window; low trapping agents expand it 82% trapping 52-59% trapping A clinically meaningful advantage over ketamine-like agents NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 53

54 BHV-5000: Demonstration of Target Engagement LANICEMINE Lanicemine (active metabolite of BHV-5000) studied in 2 single-dose RCTs and 2 multipledose RCTs in depressed patients POC demonstrated in both single-dose studies Sustained CGI-I Response After Treatment Period Efficacy demonstrated in one multiple dose study in Treatment Resistant Depression (Study 9) on primary endpoint (Week 3 MADRS) and multiple secondary endpoints, with effects sustained beyond dosing period Improvement of ~5 Points on MADRS: Superior to Adjunctive Atypicals (~3 Points) Phase IIb (Study 9): Change in MADRS score as adjunct in MDD % Patients with CGI-I score 2 3-week treatment week follow-up weeks Phase IIb (Study 9): Very-muchimproved or muchimproved measured by CGI-I MADRS score change week treatment week follow-up weeks Sanacora ACNP 2012; Sanacora et al., 2013 RCT: randomized controlled trial CGI-I: Clinical Global Impression Global Improvement scale MADRS: Montgomery Åsberg Depression Rating Scale NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 54

55 Glutamate Platform Development Milestones & Next Steps 2H2018 Submit NDA via 505(b)(2) pathway for Nurtec in ALS 4Q2018 Continue enrollment in a Phase 2/3 trial of troriluzole in AD 4Q2018 Continue enrollment in a Phase 2/3 trial of troriluzole in OCD 4Q2018 Begin Phase 2/3 trial of troriluzole in spinocerebellar ataxia 4Q2018 Complete Phase 1 trial for BHV Q2019 Begin Phase 2/3 trial of troriluzole in GAD ALS: amyotrophic lateral sclerosis, AD: Alzheimer s Disease, OCD: Obsessive- Compulsive Disorder, GAD: Generalized Anxiety Disorder, SCA: Spinocerebellar Ataxia NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 55

56 MPO PLATFORM Therapies for Neuroinflammation

57 Multiple System Atrophy (MSA) BHV-3241 Rare, rapidly progressive and fatal neurodegenerative disease Clinical symptoms: Parkinsonism: characteristic tremor (not responsive to L-DOPA), rigidity, dysarthria, falls Cerebellar ataxia Autonomic failure: orthostatic hypotension, urinary dysfunction, erectile dysfunction REM sleep behavior disorder Prevalence: 2 5 per 100,000 Pathology: glial cytoplasmic inclusions containing alpha-synuclein Prognosis: more rapidly progressive than Parkinson s disease Time to loss of ambulation: years Mean survival from symptom onset: 6 10 years No approved disease modifying treatments Managed symptomatically NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 57

58 BHV-3241 Compound Background BHV-3241 Potent myeloperoxidase inhibitor (MPO-I) developed by AstraZeneca (formerly AZ3241) Effective neuroprotection in MSA animal models Reduces intracellular aggregates of alpha-synuclein Suppresses microglial activation, rescues neurodegeneration Promotes functional (motor) improvements (motor score, flex field, pole test, and stride length test) Clinical experience Studied in approximately 250 subjects (healthy volunteers, Parkinson s disease, multiple system atrophy) Safe and well tolerated Demonstrated target engagement (blood MPO activity) Reduced neuroinflammation on Positron Emission Tomography study (TSPO) in Parkinson s disease Baseline AZD3241, 4w AZD3241, 8w NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 58

59 Phase 2 Study in MSA Completed by AstraZeneca BHV-3241 Phase 2 study: randomized double-blind controlled trial N=61 subjects (MSA-C, 34; MSA-P, 24) Randomized to 12 weeks treatment Placebo BID vs BHV mg BID vs BHV mg BID Outcome measures: UMSARS*, PET, safety (labs, AE s, ECGs, vitals) Safe and well tolerated Emerging efficacy signals warrant further study in MSA Dose proportional benefit on mean UMSARS decline Dose proportional rates of clinically meaningful improvement 600 mg dose with statistical trends (p<0.10) for superiority over placebo on multiple UMSARS items (cutting food/handling utensil, dressing, arising from chair) 600 mg dose shows numerical improvement on MSA Quality of life scale Mean Change on UMSARS Total Score Number of Subjects by Categorical UMSARS Changes * UMSARS, Unified MSA Rating Scale NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 59 UMSARS Total Change from Baseline

60 Driving Investor Value NYSE: BHVN

61 Biohaven s Deep Therapeutic, Clinical and Commercial Experience PRIOR PROFESSIONAL ROLES Vlad Coric, M.D. Chief Executive Officer, Director Cliff Bechtold Chief Operating Officer Jim Engelhart Chief Financial Officer John Tilton Chief Commercial Officer Robert Berman, M.D. Chief Medical Officer Charlie Conway, Ph.D. Chief Scientific Officer SELECTED DEVELOPMENT EXPERIENCE Robert Croop, M.D. Chief Development Officer Neurology Elyse Stock, M.D. Chief Portfolio Strategy and Development Donnie McGrath, M.D. MPH Chief of Corporate Strategy and Business Development NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 61

62 Licenses and Intellectual Property Founded on intellectual property from Yale University focused on glutamate modulation Licensed lanicemine prodrugs from AstraZeneca Expanded glutamate patent portfolio with licenses from Rutgers, MGH and ALSBiopharma Licensed CGRP antagonist program from Bristol-Myers Squibb Collaboration with Catalent on ZYDIS ODT technology across glutamate and CGRP antagonist programs Kleo Pharmaceuticals investment to develop small molecule immuno-oncology platform NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 62

63 Financial Summary IPO on NYSE at $17/share in May 2017 COMPANY OWNERSHIP Top-tier institutional investors and company founders among long-term shareholders $500MM raised since inception raised $150M with Royalty Pharma CGRP platform transaction Cash on hand as of June 30, 2018 = $217.5M Top 15 Institutional Investors (38%), Insiders (33%), Other (29%) 1 1. Data based on latest available information per Thomson and SEC Filings; institutional investor ownership as of 4Q2017 NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 63

64 2018 Development Milestones and Next Steps Rimegepant Acute Treatment of Migraine BHV-3500 Acute Treatment and Prevention of Migraine Troriluzole Alzheimer s disease (AD), Spinocerebellar Ataxia (SCA) 4Q18: Tablet Initial results from 12-month long-term safety study 4Q18: ODT Phase 3 topline results (bioequivalence of Zydis ODT to oral tablet established 1Q18) 4Q18: Initiate Phase 1 clinical trial with intranasal BHV-3500 for acute treatment of migraine 4Q19: Topline phase 2/3 data anticipated for intranasal BHV-3500 trial in acute treatment of migraine 2019: 4 Phase 2/3 trials in AD (started 3Q18), OCD (active), GAD (expected 1Q19) & SCA (expected 4Q18) 4Q18: Topline results of SCA long term extension phase to assess drug signal at one year Nurtec Amyotrophic Lateral Sclerosis (ALS) 2H18: Submit NDA for treatment of ALS 505(b)(2) regulatory pathway BHV-5000 Neuropsychiatric Indications : Complete Phase 1 trial with oral solid-dose formulation BHV-3241 Multiple System Atrophy (MSA) Mid 2019: Commence Phase 2/3 trial in Multiple System Atrophy 1. Alzheimer's Disease Cooperative Study 2. Pain, Treatment Resistant Depression, RETT Syndrome AD: Alzheimer s Disease, OCD: Obsessive-Compulsive Disorder, GAD: Generalized Anxiety Disorder, SCA: Spinocerebellar Ataxia NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 64

65 Biohaven Well Positioned for Growth BIOHAVEN CORPORATE OVERVIEW GLUTAMATE PLATFORM Alzheimer s and Anxiety Initiated Phase 2/3 trials in ALS, Alzheimer s, ataxia, anxiety, depression and OCD Nurtec: submit NDA for ALS in 2018 CGRP PLATFORM Migraine and pain Two positive Phase 3 trials Program for acute to prevention Rimegepant: submit NDA in 2019 MPO PLATFORM Neuroinflammation Phase 2 Study in Multiple System Atrophy (MSA) Completed by AZ 1 BHV-3241: Complete Phase 3 in 2019 Advancing Late- Stage Clinical Programs from Three Novel Neurology Small- Molecule Platforms Well positioned to deliver potential best-in-class therapies to patients and grow company value 1. ASTRAZENECA NOVEMBER 2018 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 65