advancing innovative therapies for neurological diseases...multiple formulations with the potential...

NYSE: BHVN© 2018 Biohaven Pharmaceuticals. All rights reserved.

January 7, 2019

Advancing Innovative Therapies for Neurological Diseases

Biohaven Investor Presentation

Disclaimer

This presentation contains forward-looking statements within the meaning of “safe harbor” provisions of The Private Securities Litigation Reform Act of 1995, including: statements about our plans to develop and commercialize our product candidates, our planned clinical trials for our rimegepant, BHV-3500, troriluzole, BHV-0223, BHV-5000 and BHV-3241 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 potential utility of our product candidates, alone and as compared to other existing or potential 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 and from the Company's current expectations. 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. The forward-looking statements in this presentation represent our views as of the date of this presentation. Subsequent events and developments may 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 obligation to do 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 Registration Statement related to this offering and the Company’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the ”SEC”) on November 14, 2018 and the Company’s other periodic reports filed with the SEC. References to www.biohavenpharma.com in this presentation are not intended to, nor shall they be deemed to, incorporate information on such website into this presentation by reference.

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.

JANUARY 2019 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 2


Positioned For Near-Term Milestones and Long-Term SuccessThree Novel Small-Molecule Platforms

Exclusive license agreements & Intellectual Property

Deep experience across all platforms

Cost-efficient R&D< 60 full-time employees

GLUTAMATE PLATFORM• Conduct Phase 2/3 trials troriluzole trials in

AD, ataxia, and initiate trials in GAD and OCD• Nurtec: NDA for ALS filed by FDA 4Q2018

CGRP PLATFORM• 3 positive Phase 3 acute treatment trials• Submit Rimegepant NDA in 2019

MPO PLATFORM• BHV-3241 Phase 2 in Multiple System

Atrophy (MSA) Completed by AZ • Commence Phase 3 in 2019

RIMEGEPANT (BHV3000-303) | Acute Treatment of Migraine Rapid Dissolving

Biohaven’s Advanced Pipeline


Preclinical Phase 1 Phase 2 Phase 3 Approval

RIMEGEPANT (BHV3000-301 and -302) | Acute Treatment of Migraine Tablet

Data inRIMEGEPANT (BHV3000-201) | Open Label Long-Term Safety Study Tablet

RIMEGEPANT (BHV3000-305) | Preventive Treatment of Migraine Tablet

NURTEC™ (BHV0223) | Amyotrophic Lateral Sclerosis (ALS)* Rapid Dissolving

TRORILUZOLE (BHV4157-203) | Alzheimer’s Disease (AD) † Capsule

TRORILUZOLE (BHV4157-202) | Obsessive-Compulsive Disorder (OCD) Capsule

TRORILUZOLE (BHV4157-206) | Spinocerebellar Ataxia (SCA) Capsule

BHV-5000 | Neuropsychiatric Indications Capsule

CGRP PLATFORM FOR MIGRAINE

GLUTAMATE PLATFORM FOR NEUROPSYCHIATRIC INDICATIONS

Delivery

BHV-3500 | Acute Treatment and Preventive Treatment of Migraine Nasal Spray

TRORILUZOLE (BHV4157-207) | Generalized Anxiety Disorder (GAD) Capsule Anticipate Phase 2/3 start 1Q19

Anticipate Phase 2/3 start 1Q19

Expect Phase 3 topline in 2019

MYELOPEROXIDASE INHIBITION PLATFORM FOR NEUROINFLAMMATION BHV-3241 | Multiple System Atrophy (MSA) Tablet

* 505(b)(2) † External collaboration with Alzheimer’s Disease Cooperative Study (ADCS) group

Anticipate Phase 3 start Mid 2019

Anticipate 2019 NDA

Submission for Acute Treatment

Anticipate Phase 2/3 start in 2019

FDA filed NDA for ALS 4Q2018

Completed Phase 1 trial 4Q18; Additional toxicology studies to be completed

6-month Futility Analysis 4Q19

Continue enrollment in Phase 2/3

Aspire to Achieve

• 3 Marketed drugs by 2021• Grow while maintaining

lean, efficient and high performing culture

meeting patient needs growing value


Goal:

CGRP PLATFORMTherapies for Migraine

Historical Segmentation of Migraine Therapy: Time to Revisit and Rethink

ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES

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

~36M People with Migraine

in the U.S.1

1. American Migraine Foundation2. ICHD-3b International Classification of Headache Disorders3. Lipton RB, Bigal ME, Diamond M, et al. Neurology. 2007;68(5):343-349.

~14M (39%3)~36M (100%)

ACUTE TREATMENT• 100% of patients need acute therapy• Diagnosis: Migraine with/without aura2

• Take as needed to abort attack• CGRP agents targeting indication:

• Small molecules: Biohaven, Allergan

Biohaven is disrupting the historical two segment migraine paradigm by advancing novel treatments with potential dual-therapy action (acute and preventive treatment)

Stylized pie-chart: NOT brain anatomy

JANUARY 2019 7

Multiple Formulations With the Potential to Meet Patient Needsfrom Acute to Preventive Treatment of Migraine


NOJECTION™ CGRP Drug Delivery Platform

1. Exclusive World-Wide License with Catalent for use of Zydis® Fast Dissolve Technology in our migraine product candidates2. Aptar Pharma Unit-Dose System (UDS) single shot nasal technology

Oral Rapid Dissolving1 Intranasal2

BHV-3500Rimegepant

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist: Mechanism of Action in Migraine1

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? 350:1073-1075, Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society."

Rimegepant Phase 1 and Phase 2b: 75 mg Dose Identified for Phase 3


Phase 1: Well tolerated at high doses (up to 1,500 mg)• 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 daysPhase 2b: Well tolerated at all doses (10 mg – 600 mg)• Most Adverse Events (AEs) of mild or moderate severity2

• 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 signsPreclinical: Large safety multiples at 75 mg (AUC)• 23x below rat NOEL3

• 56x below monkey NOAEL4

1. Marcus R, et al. (2014). Cephalalgia 34(2): 114-1252. Patients who took at least one tablet of study drug (Marcus et al., 2014) 3. NOEL = no observable effect level.4. NOAEL = no observable adverse effect level

Summary of Clinical Safety Data

Testing of very high doses in Phase 1 and 2b provides evidence of acceptable tolerability for 75 mg dose

0

25

50

75

100

Placebo 10 25 75 150 300 600

203 61 86 85 111 82100 71Patients (n)Rimegepant (mg)

**

Sustained Pain Freedom and Sustained Pain Relief 2-–24 Hours Post-Dosing1

**

**

**

**

**

****

**

**

*

Sumatriptan,100 mg

Patie

nts

(%)

2-24 hr Pain Freedom 2-24 hr Pain Relief* p < 0.05 ** p < 0.01

RIMEGEPANT (BHV-3000) PHASE 3 – STUDIES 301, 302 (75 MG TABLET) & 303 (75 MG ZYDIS ODT)

Successful Achievement of Both Co-primary Endpoints in Three Pivotal Phase 3 Trials with Rimegepant


• Primary endpoints achieved in three pivotal Phase 3 trials• Pain freedom at two hours• Freedom from most bothersome symptom (MBS) at two hours

• Achieved multiple secondary endpoints• Majority of patients achieved pain relief within two hours (speed of onset)• Sustained pain freedom and pain relief vs. placebo from 2 out to 48 hours• High proportion (~75%) of patients achieving normal function at 8 hours1

• ~80-85% of patients did not require rescue meds up to 24 hours1

• Placebo-like safety and tolerability• Safety profile similar to placebo including liver function tests• Adverse events profile similar to placebo

• Consistent results across endpoints and efficacy trials

1. Kaplan-Meier curve is an exploratory analysis

RIMEGEPANT (BHV-3000) PHASE 3 TOPLINE – STUDY 303, RIMEGEPANT 75 MG ZYDIS ODT

Increasing Benefit Over Time on Pain Freedom After Single Dose of Rimegepant 75 mg Zydis ODT Formulation

JANUARY 2019 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES

Single Dose of Rimegepant, No Rescue Meds

0

20

40

60

80

100

2 hr 3 hr 4 hr 6 hr 8 hr

% o

f Pat

ient

s Pa

in F

ree

Pain Freedom 2-8 HoursPost-Single Dosing with Rimegepant 75 mg Zydis ODT

Time

Rimegepant 75 mg (n=669)Placebo (n=682)

21%

56%

28% 39%

49%

Estimates computed using the mITT population and CMH methods. Subjects using rescue medications at or before the assessment, and subjects not providing data, are classified as failures. 3 to 8 hr are exploratory analyses.

12

RIMEGEPANT (BHV-3000) PHASE 3 – STUDY 303, RIMEGEPANT 75 MG ZYDIS ODT

Pain Relief: Early Separation and Continued Improvement for Rimegepant75 mg Zydis ODT

Kaplan-Meier Curve of Time to Pain Relief

up to 2 Hours Post Single Dose1

Single Dose of Rimegepant,

No Rescue Meds


Prob

abilit

y of

Pai

n R

elie

f

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 30 60 90 120

Time (minutes)15

Rimegepant (n=669)Placebo (n=682)

Log Rank p-value < 0.0001

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. Kaplan-Meier curve is an exploratory analysis.

13

Single Dose of Rimegepant, No Rescue Meds

RIMEGEPANT (BHV-3000) PHASE 3 – STUDY 303

Lasting Pain Relief Through 48 Hours After Single Dose of Rimegepant75 mg Zydis ODT

Sustained Pain Relief

Rimegepant n=669

Placebo n=682 p-value

2 to 24 hrs 47.8% 27.7% <0.0001

3 to 24 hrs 56.4% 33.1% <0.0001

4 to 24 hrs 61.7% 36.8% <0.0001

2 to 48 hrs 42.2% 25.2% <0.0001

3 to 48 hrs 49.9% 29.8% <0.0001

4 to 48 hrs 54.7% 33.0% <0.0001

Sustained Pain Relief1 from 2, 3, & 4 to 24 or 48 hours

24 hr

48 hr


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. Analyses of 3-24, 4-24, 3-48, and 4-48 hours are exploratory.

RIMEGEPANT (BHV-3000) PHASE 3 – 301, 302 (75 MG TABLET) & 303 (75 MG ZYDIS ODT)

Pooled Adverse Event (AE) Safety Data: Rimegepant was Well Tolerated and Similar to Placebo Across Studies

AEs from Studies 301, 302 and 303 with an incidence ≥ 1%

Adverse Event RimegepantN=1771

PlaceboN=1785

≥ 1 On-Study AE 1 252 (14.2%) 209 (13.2%)

Nausea 26 (1.5%) 15 (0.8%)

UTI 21 (1.2%) 12 (0.7%)

SAEs 2 3 (0.2%) 3 (0.2%)

1. No other individual AEs ≥ 1% in rimegepant treated subjects than those listed in table. Includes all AEs without attribution to drug relatedness. 2. No drug-related Serious Adverse Events (SAEs). Two of the subjects with SAE in rimegepant group and one in placebo group had not been dosed before onset of SAE.


RIMEGEPANT (BHV-3000) PHASE 3 – 301, 302 (75 MG TABLET) & 303 (75 MG ZYDIS ODT)

Pooled Liver Function Test (LFT) Profile: Rimegepant Liver Safety was Similar to Placebo Across Studies

ALT or AST RimegepantN=1771

Placebo N=1785

> ULN 2 48 (2.7%) 52 (2.9%)

> 3x ULN 2 (0.1%) 2 (0.1%)

> 5x ULN 1 (0.06%) 3 0

> 10x ULN 0 0

> 20x ULN 0 0

Pooled LFT Results from Studies 301, 302, and 3031

1. AST/ALT categories are not mutually exclusive; No bilirubin elevations > 2x ULN across Studies 301, 302 and 3032. Upper limit of normal; ALT: alanine aminotransferase; AST: aspartate aminotransferase. 3. AST elevation, Not Drug-Related as deemed by the investigator: subject newly initiated weight-lifting with laboratory results consistent with muscle injury.


RIMEGEPANT (BHV-3000) PHASE 3 – STUDY 303, RIMEGEPANT 75 MG ZYDIS ODT

Summary Study 303: Rimegepant Zydis® ODT – Profile of Rapid and Lasting Effect in the Acute Treatment of Migraine


• Rapid onset of pain relief with single dose• Numerical separation from placebo as early as 15 minutes and statistically significant by 60 minutes• Significantly greater percentage of patients returned to normal functioning by 60 minutes (p = 0.0025)

• Achieved statistical significance on regulatory co-primary endpoints of pain freedom (p < 0.0001) and freedom from most bothersome symptom (p = 0.0009) at 2 hours

• Superiority over placebo in 21 consecutive, prespecified, hierarchically-tested efficacy outcome measures, including:

• Clinical effect observed from 2 through 48 hours on freedom from pain (p < 0.0001), pain relief (p < 0.0001), freedom from most bothersome symptom (p = 0.0018), and freedom from functional disability (p < 0.0001)

• Safety profile similar to placebo, including liver function tests

• On-target for new drug application submission in the first half of 2019

17

RIMEGEPANT (BHV-3000) LONG TERM SAFETY STUDY – STUDY 201, INTERIM ANALYSIS 11/21/2018


• Over 91,000 doses of rimegepant 75 mg administered across 1,780 patients with migraine• Interim hepatic data were reviewed by an external independent panel of liver experts, who:

• provided a consensus opinion based upon Drug-Induced Liver Injury Network (DILIN) causality assessment• did not assess any liver cases as “probably related” to study drug; and no Hy’s Law cases identified• concluded there was no liver safety signal detected through the data analysis cut-off date, including a subset

of patients with near-daily dosing (≥15 doses/month)• In aggregate, the panel noted that, compared to placebo arms of other migraine treatments,

there was a very low incidence of overall elevations of liver laboratory abnormalities (1.0% incidence of serum ALT or AST > 3x ULN)

• Preliminary efficacy data suggest that rimegepant may be associated with a reduction in migraine days per month (30 days) compared to the observational lead-in period, suggesting a potential preventive effect that warrants further study

• Patients with ≥15 migraine days/month (N=172) during the standard of care observation period demonstrated a mean reduction of 4 migraine days/month by 12 weeks of intermittent dosing with rimegepant.

• Approximately 40% of patients who had ≥15 migraine days/month during the observation period showed at least a 30% or more reduction in their monthly number of migraine days by 12 weeks of treatment with rimegepant.

Summary Study 201 Interim Analysis: Rimegepant 75 mg (BHV3000-201) | Open Label Long-Term Safety Study

Rimegepant Potential to Be the Favored Choice for Acute Treatment of Migraine*


RIMEGEPANT UBROGEPANT LASMIDITAN CGRP ANTIBODIES

Mechanism of Action CGRP receptor antagonist CGRP receptor antagonist 5-HT1F receptor agonist

Antibody against CGRP receptor (Amgen) or CGRP peptide (Alder,

Lilly, Teva)

Stage of Development Phase 3 Phase 3 Phase 3 Aimovig approved; Others

Phase 3: BLA filed & earlier

Effectiveness in Acute Treatment of Migraine

Met both registrational endpoints (2 hr pain free & MBS) in three pivotal Phase 3 Trials

Treatment effect: pain relief, photophobia and phonophobia at 2 hours post-dose;

Durable treatment effect: 2 to 24 and 2 to 48 hour sustained pain freedom

Zydis ODT with early and lasting effect

Met both registrational endpoints (2 hr pain free & MBS) at 50 mg in two pivotal Phase 3 trials (multi-dose submission?)

Inconsistent effect on MBS across studies and doses

Lack of durable treatment effect: did not show 2 to 48 hour sustained pain freedom in Phase 3

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

No sig difference from Placebo on LFTs > ULN No single AE > 2% Tolerability profile similar to placebo Long-term safety study: over 91,000 doses

administered to date in over 1,700 patients up to daily dosing — ongoing (started Aug 2017)

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

in patient study and healthy subject study≥ 15 doses/mo for 2 mo at 100 mg — no drug-relatedliver signal

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 ofMechanism

Novel MOA targeting patients not satisfied with triptan efficacy or who are triptan intolerant or unresponsive

No reason to expect headache recurrence phenomena

Novel alternative for patients 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 exercise-induced angina (Amgen)

PREVENTION ONLY* These are cross-trial comparisons and no comparative head-to-head studies between rimegepant and competitors have been conducted.

Rimegepant Value Proposition


Oral Availability

Single dose & durable effect

Low cost of goods

Well tolerated

Effective on pain & MBSHigh potency

BHV-3500 HIGHLIGHTS


• First intranasal formulation of a small molecule CGRP receptor antagonist• Initial development for the acute treatment of migraine

• 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

• Favorable safety profile in preclinical studies even at very high doses• Pursuing development for the acute and preventive treatment of migraine

• IND submitted 3Q2018 for intranasal• Phase 1 study cohorts enrolling and administered BHV-3500

BHV-3500: Third Generation CGRP Receptor Antagonist

Aptar Pharma Unit-Dose System (UDS) single shot nasal technology

CGRP Platform Development Milestones & Next Steps


2019 Expect Phase 3 topline data for rimegepant in preventive treatment of migraine

2019 Anticipate Phase 2/3 start for intranasal BHV-3500 trial in acute treatment of migraine

2019 Anticipate NDA submission for rimegepant in acute treatment of migraine

2020 Anticipate rimegepant acute treatment of migraine LAUNCH!

GLUTAMATE PLATFORMTherapies for Neurologic and Neuropsychiatric Indications

NORMAL FUNCTIONHealthy State

The Role of Glutamate: Present in 90% of Brain Synapses


EXCITOTOXICITYDiseased State

AMYOTROPHIC LATERAL SCLEROSIS

SPINOCEREBELLAR ATAXIA

DEMENTIA

NEURODEGENERATION

NEUROTOXICITY SEIZURES

DEPRESSION ANXIETY

STRESSCANCER PAIN

STROKE MELANOMA

ABNORMAL CELL GROWTH

RETT SYNDROME

NEURO-TRANSMISSION

MEMORY

CELL SURVIVAL

SYNAPTO-PLASTICITY

LEARNING

NEUROTROPHIC

STRESS RESILIENCE

ACTION POTENTIAL

COGNITION

MOOD

NEURONAL CONNECTIONS

Biohaven is focused on normalizing glutamate to treat disease

Glutamate Mechanisms of Action in CNS


Glutamate Transporter Modulation

• Troriluzole• BHV-0223

Glutamate NMDA Receptor Antagonism

• BHV-5000

Third-party clinical trials provide basis for exploration of riluzole-related candidates, troriluzole and BHV-0223, in multiple neurologic and neuropsychiatric disorders

1

2

1

2

UNMED MEDICAL NEED IN ALS


Riluzole (Rilutek®) is approved for the treatment of patients with amyotrophic lateral sclerosis (ALS) and proven to extend survival

• Originally marketed by Sanofi, 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 understoodNeuroprotective, survival benefit in ALSWell 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)

Riluzole (Rilutek®): Use and Limitations

1. LFT = liver function test2. Poor oral bioavailability results in a high liver burden relative to efficacy as ~40% is either not absorbed or is metabolized in the liver

Troriluzole: Rational Drug Discovery to Optimize Therapy


• Improved absorption• Enhanced bioavailability• Reduced drug burden• Reduced first pass metabolism• Favorable safety profile• Once-daily dosing

Peptide Transporter 1 Enhances Absorption of Troriluzole

PepT1

PepT1 = Peptide Transporter 1

ACTIVE ABSORPTION IN INTESTINAL TRACT BY PEPT1


Social Anxiety Disorder

Generalized Anxiety Disorder

Bipolar Depression

Troriluzole: Targeted Lead-Indication Development Strategy

JANUARY 2019 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 29* = Third-party study / collaboration ongoing or planned (ADCS Collaboration for AD; ET Study Group Collaboration for ET)

Lead indications across an array of

potential neurologic and neuropsychiatric

indications

Obsessive-Compulsive & Related Disorders

Neurodegenerative Disorders

Mild-to-Moderate Alzheimer’s Disease*

Prodromal Alzheimer’s Disease

ALS (High Dose)

Affective Disorders

Cerebellar Disorders

Spinocerebellar Ataxia (SCA)

Friedreich’s Ataxia

Sporadic Ataxia

Other Ataxias

Essential Tremor*

Obsessive-Compulsive Disorder

Trichotillomania

Hoarding Disorder

Pathological Features of Alzheimer’s Disease

• Brain atrophy• Neuronal cell death• Amyloid and tau pathology

• Synapse loss (most highly correlated with clinical symptoms)

• Glial cell dysfunction

Congdon Nat Rev Neurol. 2018;14(7):399-415


Glial Cell and Synaptic Dysfunction Occurs Early in Alzheimer’s Disease


GLIAL CELLS • Protect and support neurons• Make up 80% of the human brain

GLIAL CELL DYSFUNCTION• Indicated by increased glial fibrillary acidic

protein expressing (GFAP+) cells• Present in human brain early in AD• Key consequence is reduced glial glutamate

transporter (GLT-1) expression• Associated with synaptic impairment

Glutamate Transporter (GLT-1) is Reduced in Human AD Brains


Human autopsy observations from AD and controls (n=13)GLT-1 immunoreactivity in temporal neocortex area in AD is significantly weaker than that in control

A. Hosi et al. Neuropathology and Applied Neurobiology (2018)

HEALTHY HUMAN BRAIN ALZHEIMER'S DISEASE

Increases GLT-1 Glutamate Transporter4


Riluzole Rescues Symptoms, Function and Pathology in AD Animal Models

1 Pereira Proc Natl Acad Sci 2014; 2 Hunsberger J Neurochem 2015; 3 Hunsberger, Metab Brain Dis 2016; 4 Pereira Molecular Psychiatry 2017; 5 Okamoto Transl Psychiatry 2018

Reduces Amyloid and Tau Pathology

Reduces amyloid plaque5

Reduces p-tau2

Control TauP301L Riluzole + TauP301L

CP-

13/A

ctin

(R

elat

ive

Rat

io)

Rescues Cognitive Symptoms(Learning and Memory)

Wat

er M

aze

Erro

rs

ControlTauP301LRiluzole + TauP301L

Morris water maze 2,3

Time (min)

Expl

orat

ion

Tim

e (s

ec)

Aged-control

Young-control

Aged-treated

Y-maze

Riluzole-treated aged animals perform like young-controls1

Riluzole-treated tau-overexpressing animals perform like controls

Vehicle control

RLZ treated

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 14–24

• 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

Troriluzole Phase 2/3 Clinical Trial Design in AD

Troriluzole280 mg QD

Placebo QD

Screening Phase42 days

Randomized Phase

48 weeks

R

Cerebellar Ataxias


• Characterized by:• Poor balance with falls • Dysarthria / dysphagia • Incoordination of limbs • Cognitive impairment• Postural or kinetic tremor • Oculomotor dysfunction

• Spinocerebellar ataxia (SCA; >40 subtypes)• Affects 1–5.6 per 100,000 (estimated 3,200–18,000 in US)• Neurodegeneration of cerebellum and input/output tracts• Relentlessly progressive, often fatal (aspiration)• Increasing disability over time (requiring wheelchair, assistance with

activities of daily living)• The 6 most common genotypes caused by triplet repeat expansion

mutations, sharing many phenotypic features • Genetic anticipation in some: subsequent generations affected at earlier

ages and with greater severity

• Other ataxias have similar core features • Can be recessive, dominant, immune, mitochondrial, post-stroke, e.g.,

Friedreich’s ataxia, ataxia telangiectasia, multiple system atrophy —cerebellar type

Atrophy of Cerebellum and Linked Structures

Spinocerebellar Ataxia type 2Cerebellar and brainstem volume loss

No FDA-approved medications for SCA

Study 201, Extension Phase


• Improvement in open-label troriluzole-treated group differentiates from decline shown in longitudinal data

• SCA1 and SCA2 represent groups with more reliable decline and trends of benefit

• Improvement in the SCA1 and SCA2 groups at Week 32 was numerically greater (0.45 improvement) vs. groups without SCA1 or SCA2 (0.29 improvement)

• SCA1 and SCA2 associated with anecdotal reports of patient benefits

Supports study with longer-term treatment duration and Enrichment with SCA1 & 2

Longitudinal Change on Total Modified SARA Scale

Natural History Cohort

Troriluzole-Treated

Mea

n C

hang

e (S

E)

Based on preliminary data after al subjects completed week 32 visit

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

Yale POC Study: Anti-Anxiety Effects of Nurtec (BHV-0223)

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=0.0259


RILUZOLE PRECLINICAL

Yale Human POC Study Is Consistent with Preclinical Models Showing Riluzole’s Anti-Anxiety Effects and Enhancement of Recognition Memory

Sugiyama et al 2017 (Brain Behavioral Research)


Anti-Anxiety Effects

%Ti

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Saline Riluzole

Enhances Recognition Memory

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Saline Riluzole

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

• Significant unmet need

• GAD has a 12-month prevalence in the United States of 3%

• 3,500,000 (est. treatment resistant in U.S.)

TRORILUZOLE1 PHASE 2/3 TRIAL DESIGN• Multicenter (US only), randomized, double-blind, placebo-controlled trial in outpatients

with GAD

• Troriluzole 100 mg vs Placebo BID*, N=260

• Primary Outcome: Change on HAM-A from baseline to Week 8

Expanding Biohaven’s Glutamate Modulating Platform into Generalized Anxiety Disorder (GAD)

NBC New, 28-JUL-18


* BID: twice daily 1. Yale IP protects riluzole in GAD, SAD & Panic Disorder

Open-label Trial of Riluzole in Generalized Anxiety Disorder

Meaningful benefits on anxiety severity (HAM-A) and disability (SDS)


HAM-A, Hamilton Anxiety Rating Scale; SDS, Sheehan Disability Scale

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Objective Biomarkers Correlate with Improvement


• Improvement in anxiety strongly correlated with increased hippocampal NAA (marker for neuronal function)1,2

• Increases precede therapeutic benefit

• Increases in hippocampus volume observed in remitters3 that correlate with improvement

1 Mathew et al, 2008; 2 Abdullah et al, 2012; 3 Abdullah et al 2013; MRS, Magnetic Resonance Spectroscopy; NAA, n-acetylaspartate; PSWQ, Penn State Worry Questionnaire

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Normalized Neuronal Function in Treatment Responders Increases in Hippocampus Volume Correlate with Improvement

in Anxiety Measures

Accumulating Evidence for Glutamatergic Dysfunction in OCD


GENES ANIMAL MODELS

NEURAL NETWORKS

PATIENTS IN THE CLINIC

Genetic association studies:

Glutamate transporter gene (SLC1A1 on chromosome 9p24) associated w/OCD1

GWAS studies are focusing attention on DLGAP1, a post-synaptic scaffolding molecule at glutamate synapse

↑Glutamatergic activity worsens OCD behaviors

SAPAP3 knockout mice (-/-) exhibit OCD-like behaviors2

SAPAP3 is an ortholog of DLGAP3, in the same family as a gene implicated by OCD GWAS studies

Multiple neuroimaging studies:

Increased activity in cortico-striatal-thalamic (CST) pathway3

MRS studies:Glutamate dysfunction in OCD suggested by some studies4,5

Spinal fluid studies: Increased glutamate in OCD patients6

Preliminary efficacy evidence:

Glutamate modulating agents show promise in OCD and anxiety disorder patients

1 Arnold et al 2006; 2 Aida et a; 2015; 3 Baxter et al 1987, 1988, 1992; Nordhal et al 1989; Swedo et al 1989; Sawle et al 1991; Rubin et al 1992, 1995; Adams et al 1993; Perani et al 1995; Adams et al 1993; Perani et al 1995; McGuire et al 1994; Breiter et al 1996; Rausch et al 1996; 4 Rosenberg et al 2000; 5 Bolton et al 2001; 6 Chakrabarty et al 2005

Neurochemical Evidence for Glutamate Dysregulation in OCD


Rosenberg et al. 2000

Consistent with pathologic hyperactivity in cortico-striatal circuit Suggests clinical testing of agents that enhance glutamate uptake

Healthy ControlSubjects

n = 11

Treatment NaïveOCD Patients

n = 11

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Randomized Controlled Trial with Riluzole Augmentation


• Outpatients with moderate to severe OCD severity (Y-BOCS score ≥ 21) and free of medication treatment for at least six weeks

• Randomized to receive fluvoxamine (up to 200 mg/day) plus either placebo or riluzole (50 mg twice daily)

• Robust benefit on primary outcome measure (change in Y-BOCS scores)

*, p<0.05; Cohen’s d 0.59

*

Placebo (n=25)

Riluzole (n=25)Y-BO

CS

Tota

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reYBOCS, Yale-Brown Obsessive Compulsive Scale

Emamzadehfard et al. 2016

Study BHV4157-202: Randomized Controlled Trial of Troriluzole

• Primary Outcome, Y-BOCS: a precedented outcome measure accepted by FDA

• Complete enrollment 2019


SOC + Troriluzole200 mg QD

SOC + Placebo QD

Screening Phase42 days

Randomization Phase

12 weeks

R

Extension Phase

48 weeks

SOC + Troriluzole200 mg QD

Subjects (n=226) with Moderate to severe OCD and inadequate response to standard of care

SOC, standard of care

Nurtec is an investigational drug not currently approved for the treatment of 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

NURTEC is Optimized to Address Riluzole Delivery Limitations for ALS

Only Riluzole Oral Dissolving Tablet meets needs with difficulty swallowing

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NURTEC (BHV-0223)

NURTEC Phase 1 Single Dose PK Results


Observations• 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• Lower exposures in

some patients• Attributed to poor

bioavailability and first-pass metabolism of oral dosing

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Rilutek (50 mg tablet)

BHV-0223 (35 mg SL)

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Single Dose

Time Post-Dose (h)


NURTEC (BHV-0223)


EASE OF ADMINISTRATION • An early symptom of ALS is difficulty swallowing; makes use of riluzole

tablets challenging

• BHV-0223 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

• BHV-0223 was designed to be absorbed sublingually; since absorption of BHV-0223 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

NURTEC Offers Potential Advantages Over Conventional Riluzole Tablets for ALS Patients

MORE PREDICTABLE PHARMACOKINETIC PERFORMANCE • Some patients with ALS crush their solid riluzole tablets and

take with food to ease administration(1)

• With BHV-0223, 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

• BHV-0223 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

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

BHV-5000: A Novel Low-Trapping NMDA Antagonist

BHV-5000 MOA


Lanicemine vs. Ketamine

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

BHV-5000: Novel Low-trapping NMDA Channel Blocker

82% trapping 52-59% trapping

LanicemineKetamine

A clinically meaningful advantage over ketamine-like agents

LANICEMINE


• Lanicemine (active metabolite of BHV-5000) studied in 2 single-dose RCTs and 2 multiple-dose RCTs in depressed patients

• POC demonstrated in both single-dose studies

BHV-5000: Demonstration of Target Engagement

Improvement of ~5 Points on MADRS:Superior to Adjunctive Atypicals (~3 Points)Sustained CGI-I Response After Treatment Period

RCT: randomized controlled trial

• 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

% P

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3-week treatment -------- 5-week follow-up ---------

Phase IIb (Study 9):

Very-much-improved or

much-improved

measured by CGI-I

CGI-I: Clinical Global Impression – Global Improvement scale

--- 3-week treatment --- -------- 5-week follow-up ---------

weeks

weeks

Phase IIb (Study 9): Change in MADRS score as adjunct in MDD

MAD

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ange

MADRS: Montgomery–Åsberg Depression Rating Scale

Sanacora ACNP 2012; Sanacora et al., 2013

Glutamate Platform Development Milestones & Next Steps


3Q2019 PDUFA for Nurtec NDA for treatment of ALS via 505(b)(2)

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

1Q2019 Begin Phase 2/3 trial of troriluzole in spinocerebellar ataxia

1Q2019 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

MPO PLATFORMTherapies for Neuroinflammation

BHV-3241 FOR NEUROINFLAMMATION


• 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: 3.5–5 years• Mean survival from symptom onset: 6–10 years

• No approved disease modifying treatments• Managed symptomatically

Multiple System Atrophy (MSA)



• 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)• Generally safe and well tolerated• Demonstrated target engagement (blood MPO activity)• Reduced neuroinflammation on Positron Emission

Tomography study (TSPO) in Parkinson’s disease

BHV-3241 Compound Background

Baseline AZD3241, 4w AZD3241, 8w

Jucaite et al., 2015.



• 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-3241 300 mg BID vs BHV-3241 600

mg BID• Outcome measures: UMSARS*, PET, safety (labs, AE’s,

ECGs, vitals)

• Generally 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• 600 mg dose shows numerical improvement on MSA

Quality of life scale

Phase 2 Study in MSA Completed by AstraZeneca

* UMSARS, Unified MSA Rating Scale: primary efficacy measure for the study

Mean Change on UMSARS Total Score

Number of Subjects by Categorical UMSARS Changes

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Driving Investor Value NYSE: BHVN

Biohaven’s Deep Therapeutic, Clinical and Commercial Experience

Robert Berman, M.D.Chief Medical Officer

Jim EngelhartChief Financial Officer

John TiltonChief Commercial Officer

Cliff BechtoldChief Operating Officer

Charlie Conway, Ph.D.Chief Scientific Officer

Robert Croop, M.D.Chief Development Officer —

Neurology

Elyse Stock, M.D.Chief Portfolio Strategy

and Development

Donnie McGrath, M.D. MPHChief of Corporate Strategy and

Business Development


Vlad Coric, M.D.Chief Executive Officer, Director

PRIOR PROFESSIONAL ROLES

SELECTED DEVELOPMENT EXPERIENCE

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


Financial Summary

IPO on NYSE at $17/share in May 2017

COMPANY OWNERSHIP• Top-tier institutional investors and company founders among long-term shareholders

• ~ $645MM raised since inception

• Cash on hand as of December 31, 2018 ~ $260M

JANUARY 2019 ADVANCING INNOVATIVE THERAPIES FOR NEUROLOGICAL DISEASES 601. Data based on latest available information per Thomson and SEC Filings; institutional investor ownership as of 4Q2017

4Q18: Tablet interim results from 12-month long-term safety study; ODT Phase 3 topline results* 1H19: Anticipate NDA submission for acute treatment of migraine; Expect Phase 3 topline in prevention

RimegepantAcute & Preventive

Treatment of Migraine

4Q18: Phase 1 trial with oral solid-dose formulation completed BHV-5000Neuropsychiatric

Indications 2

4Q18: IND submitted and Phase 1 underway (patient dosing ongoing)1H19: Anticipate Phase 2/3 start with intranasal BHV-3500 for acute treatment of migraine

BHV-3500Acute & Preventive

Treatment ofof Migraine

2019: Four Phase 2/3 trials: AD (ongoing), OCD (ongoing), GAD (expected 1Q19) & SCA (expected 1Q19)1Q19: Topline results of SCA long term extension phase to assess drug signal at one year

TroriluzoleAlzheimer’s disease

(AD), Anxiety & Ataxia (SCA)

4Q18: NDA for ALS filed by FDA 4Q2018 for treatment of ALS — 505(b)(2) regulatory pathway 3Q19: PDUFA for Nurtec NDA for treatment of ALS via 505(b)(2)

NurtecAmyotrophic Lateral

Sclerosis (ALS)

1. Alzheimer's Disease Cooperative Study2. Pain, Treatment Resistant Depression, RETT Syndrome

2018 Development Milestones and Next Steps


BHV-3241Multiple System Atrophy (MSA)

Mid 2019: Commence Phase 3 trial in Multiple System Atrophy

AD: Alzheimer’s Disease, OCD: Obsessive-Compulsive Disorder, GAD: Generalized Anxiety Disorder, SCA: Spinocerebellar Ataxia* bioequivalence of Zydis® ODT to oral tablet established 1Q18

advancing innovative therapies for neurological diseases...multiple formulations with the potential...

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