A Phase 1 Study to Evaluate Bioequivalence Between BHV-0223 40 mg Zydis® Sublingual Formulation and Riluzole 50 mg Oral Tablet in Healthy Volunteers

Irfan A. Qureshi1, Vladimir Coric1, Kimberly Gentile1, Richard Larouche2, Mario Tanguay2, Matt Anderson,3 Robert M. Berman1

1Biohaven Pharmaceuticals, Inc., New Haven, CT, USA2Syneos Health, Québec City, Canada3Certara, Princeton, NJ

Dr. Berman is an employee and shareholder of Biohaven Pharmaceuticals

This material is being made available through Biohaven’s Medical Affairs Department.

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease • The disease is characterized by progressive muscle weakness• Median survival is 2 to 5 years following diagnosis

Riluzole prolongs survival and time to tracheostomy in patients with ALS• The registration trial demonstrated a life extension of 2 to 3 months• Postapproval observational studies suggest improved survival of 12 to 17 months• Yet approximately half of diagnosed patients are not prescribed medication

The optimal use of riluzole in clinical practice is limited by…• Difficulty swallowing (dysphagia) for many patients• A food effect limiting bioavailability that requires fasting• Dose-related hepatotoxicity

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Novel Sublingual Formulation

• Manufactured via a proprietary lyophilization process: Zydis® technology developed by Catalent Pharma Solutions

• Multiple prototypes and 3 years of formulation development

• Tablet rapidly dissolves in seconds when placed under tongue

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BHV-0223: Novel Riluzole 40 mg Rapidly Dissolving Zydis Formulation

No clinicallymeaningfulfood effect

PK, pharmacokinetics.

Designed to provide following attributes

Study Objective: Bioequivalence Study in Healthy Volunteers

Objectives

• Primary– To compare the rate and extent of absorption of BHV-0223 40 mg with riluzole 50 mg tablet in

healthy volunteers under fasting conditions– To evaluate the effect of food on the PK of BHV-0223 40 mg

• Secondary – To assess the safety and tolerability of BHV-0223– Assess the rate of absorption of BHV-0223 compared with crushed riluzole 50 mg tablet

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Study Design

BHV-022340 mg

Riluzole50 mg

Riluzole50 mg

BHV-022340 mg

BHV-022340 mg ³ 10 Hour Fast³ 10 Hour Fast

³ 4 Day Wash Out

³ 4 Day Wash Out

³ 4 Day Wash Out

Fed

Part 1BIOEQUIVALENCE

Part 2FOOD EFFECT

N = 138 N = 72

Supervised fast followed by ~800-1000 calorie (~50% from fat) meal

Sequence A

Sequence B

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BHV-0223 Sublingual Riluzole 40 mg is Bioequivalent to Riluzole 50 mg Tablet

Parameter Ratio (N/R) 90% CI

AUC0-t 89.9% 87.3%-92.5%

AUC0-inf 89.8% 87.3%-92.4%

Cmax 112.7% 105.5%-120.4%

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BHV-0223 40 mg Zydis sublingual - fasted

Riluzole 50 mg tablet swallowed with water - fasted

AUC, area under the concentration-time curve; 0-t, time zero to last nonzero concentration; 0-inf, time zero to infinity; CI, confidence interval; Cmax, maximum serum concentration; N/R, BHV-0223/Riluzole.

FDA-defined bioequivalence criteria fulfilled (i.e., 90% CI within 80 to 125% of reference drug)

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BHV-0223 Associated With Less PK Variability

1st quartile 2nd quartile 3rd quartile 4th quartile

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zole

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BHV-0223Riluzole

Exposure Quartile

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BHV-0223 is Not Subject to a Clinically Meaningful Food Effect based on AUC

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Fasted state

Fed state

Parameter Ratio (Fed/Fast) 90% CI

AUC0-t 91.2% 88.1%-94.3%

AUC0-inf 92.0% 89.0%-95.1%

Cmax 38.9% 36.3%-41.6%

Safety Profile

• No serious adverse events• Most common AEs (reported in more than 2 subjects)

– Headache• mostly mild; transient

– Oral hypoesthesia• all mild and transient with median duration of 34 min

– Dysphagia• all mild and transient with median duration of 30 min• Separate Phase 1 Video Fluoroscopic Swallowing Evaluation Study in Healthy Volunteers revealed no aspiration

and no clinically meaningful effect on swallowing function – including 1 subject reporting dysphagia

• Local tolerability and oral cavity assessments (visual inspection)– No clinically important effects

• No significant lab abnormalities or vital sign changes

10AE, adverse event.

• Convenient formulation that does not require swallowing or administration of liquids

• No unexpected safety concerns were observed• Oral hypoesthesia was mild and transient

• BHV-0223 bypasses first-pass liver metabolism and reduces the dosage size that needs to be administered, thereby potentially reducing risk for hepatic enzyme elevations

• No clinically meaningful food effect on total drug exposure as measured by AUC

• BHV-0223 40 mg sublingual formulation of riluzole is bioequivalent to riluzole 50 mg oral tablet

BHV-0223: Summary

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