Conclusions• Rimegepant showed an absence of undesirable CV safety signals in nonclinical in

vitro, ex vivo and in vivo assays at multiples of 10 to 20 times (Cmax) and 20 times (AUC) the oral 75 mg human exposure, with: – Only weak inhibition in the hERG assay and no effects on rabbit Purkinje fiber

action potentials at 30 µM– No active vasoconstrictive properties in ex vivo human coronary or cerebral

arteries at concentrations up to 3 to 10 µM– No altered CV parameters in telemetry or 9-month monkey study

• Data from 3 Phase 3 clinical trials with oral 75 mg rimegepant showed zero cases of CV-related treatment emergent AEs

• These results indicate that oral 75 mg rimegepant has the potential to become an important new treatment for people with migraine who have CV risk factors and/or CV contraindications to triptans

Experiment 2 – Ex Vivo Assay for Potential of Active Vasoconstriction by Rimegepant

• Sumatriptan showed progressive, concentration-dependent constriction of ex vivo human coronary artery (EC50 = 279±50 nM; Emax = 59%) and human cerebral artery (EC50 = 227±31 nM; Emax = 46%) with Emax compared to 10 µM 5-HT (Figures 2 and 3)

• In contrast, rimegepant produced no concentration-dependent constriction even when tested up to concentrations of 3-to-10 µM (Figures 2 and 3)

• Importantly, the absence of contraction by rimegepant could not be attributed to defective vessels since the addition of 10 µM 5-HT showed each vessel to be viable and capable of constriction

Results

Conclusions• Rimegepant exhibited no active vasoconstrictive properties in ex vivo human coronary or cerebral

arteries when tested at up to 3-to-10 µM• In contrast, sumatriptan showed progressive, concentration-dependent constriction of human coronary

and cerebral arteries• This reflects a key limitation of the triptan class (generally nonselective 5-HT1B/1D receptor agonists),

which are contraindicated in patients with coronary artery disease and uncontrolled hypertension

Figure 2. Coronary Artery Raw Data (n=3) From Ex Vivo Artery Ring Assay

• The potential for vasoconstrictive compound action on ex vivo artery tension was measured by cumulative addition of rimegepant, sumatriptan, or zolmitriptan into individual tissue baths with 1 mounted artery (n=4 to 5 per compound) (Figure 1)

• Compounds were added to tissue baths in half log units at intervals of around 8 minutes (for calculation of EC50’s) at up to 3 µM (intracranial) or 10 µM (coronary)

• As a positive control, 10 µM serotonin (5-HT) was added to each tissue bath at the end to provide a measure of maximal contractility (Emax) (Figure 2)

Methods

Figure 3. Sumatriptan Contracts Ex Vivo Human Coronary and Intracranial Arteries —The CGRP Receptor Antagonist Rimegepant Does Not

Experiment 4 – Phase 3 Summary of CV AEs with Oral 75 mg Rimegepant in 3 Trials

Table 1. Treatment Emergent Adverse Events in 3 Phase 3 Trials of Rimegepant 75 mg

• Clinical data for CV-related treatment emergent AEs (TEAEs) from 3 Phase 3 clinical trials administering 1762 rimegepant 75 mg oral doses and 1769 placebo doses, which showed zero CV TEAEs for rimegepant (Table 1)

Results

Conclusions• Clinical experience from 3 Phase 3 trials indicates an absence of CV safety issues (no cases of CV-

related TEAEs)• The absence of CV safety findings for rimegepant is consistent with previous results in Phase 2b8 and

appears to reflect the distinct mechanism of action for CGRP receptor antagonists

• Rimegepant’s CV safety profile was evaluated in 3 Phase 3 double-blind, randomized, placebo-controlled clinical trials in which subjects received rimegepant 75 mg oral tablets (Study 301, NCT03235479; Study 302, NCT03237845)5,6 or orally disintegrating tablets (Study 303, NCT03461757)7

Methods

Experiment 3 – In Vivo Assays in Monkeys for CV Safety Profile of Rimegepant

• Cynomolgus monkeys receiving 60 mg/kg rimegepant showed exposures (16.5 µM, at 8 hours) greater than 10 times above the 75 mg clinical dose Cmax (1.4 µM) with no effects on hemodynamic/electrocardiographic parameters

• For 9-month daily dosing, there were no changes in CV parameters up to 50 mg/kg/day at an AUC0-24hof 75,473 ng•h/mL, approximately 20 times the human 75 mg AUC (3,729 ng•h/mL)

Results

Conclusions• Rimegepant exhibited no perturbations of cardiovascular parameters in telemetered monkeys at 60

mg/kg or in monkeys with 9-months of oral dosing at 50 mg/kg where multiples were 10x (Cmax) and 20x (AUC), respectively, versus the 75 mg clinical dose

• Rimegepant’s CV safety profile was evaluated in vivo in telemetered monkeys at 60 mg/kg for effects on physical activity, body temperature, hemodynamic and electrocardiographic parameters

• Rimegepant was also evaluated in a 9-month oral toxicity study in monkeys at 50 mg/kg/day

Methods

• Approximately 3.5 million people with migraine must use triptans with caution or have experienced a cardiovascular (CV) event, condition, or procedure that contraindicates their use1,2

• Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist,3 has demonstrated efficacy in 3 Phase 3 trials for the acute treatment of migraine

• The overall objective of this study was to characterize the CV safety profile of rimegepant in nonclinical assays and compare results to clinical exposures and experience regarding CV adverse events (AEs)

• The first objective was to characterize the CV profile in vitro (Experiment 1)• The second objective was to assess the potential for active vasoconstriction in human arteries

(Experiment 2)• The third objective was to assess in vivo CV safety in monkeys (Experiment 3)• The fourth objective was to summarize the CV profile from clinical experience in Phase 3 (Experiment 4)

Objectives

• Rimegepant’s CV safety profile was evaluated in vitro using the gold standard human ether-a-go-go related gene (hERG) assay and rabbit Purkinje fiber assay

• In vitro, rimegepant showed an absence of undesirable CV safety signals at multiples 20 times above the human oral peak exposure (Cmax) at the 75 mg clinical dose

Conclusions

Introduction

• In vitro, rimegepant up to 30 µM was a weak inhibitor (≤36% inhibition) in the hERG assay and had no effects on rabbit Purkinje fiber action potentials

• The high drug concentration in these assays is more than 20 times greater than the human peak exposure (Cmax) at the clinical oral dose of 75 mg rimegepant (1.46 μM, Phase 1)4

Results

Methods

Experiment 1 – In Vitro Assessment of CV Safety Profile of Rimegepant

Figure 1. Ex Vivo Artery Ring Assay

Computer

4-5 mm

Human arteries were cleaned of connective tissue, cut into cylindrical segments of 4-5 mm in length, and mounted intissue baths between 2 stainless steel hooks: 1 fixed and the other connected to a force displacement transducer.Vessel tension was continuously recorded using a data acquisition system (Powerlab, ADInstruments, MountainView, CA). The tissue baths containing Krebs buffer were controlled for temperature (37°C), pH (7.4) andcontinuously bubbled with carbogen.

Cardiovascular Safety of Rimegepant 75 mg in 3 Randomized Clinical Trials and Systematic Evaluations from In Vitro, Ex Vivo, and In Vivo Nonclinical AssaysCharles M. Conway, PhD1; Robert Croop, MD1; Gene M. Dubowchik, PhD1; Vladimir Coric, MD1; Richard B. Lipton, MD2

1 Biohaven Pharmaceuticals, Inc., New Haven, CT; 2 Albert Einstein College of Medicine, Bronx, NY

Poster No. IHC-PO-365

To objectively assess the potential for vasoconstrictive properties, the effect of rimegepant was measured side-by-side withsumatriptan and zolmitriptan in the same experiment in viable, autopsy sourced ex vivo human coronary arteries and cerebralarteries. Figure shows raw data traces from 3 vessels placed into individual tissue baths with cumulative addition of eithersumatriptan, zolmitriptan or rimegepant followed by 10 µM 5-HT as a positive control at the end of each assay.

References: 1. Buse et al. 2017. Headache. 2017;57:31-44; 2. Lipton et al. Headache. 2017;57:1507-21; 3. Luo et al. 2012. J Med Chem. 2012;55:10644−51; 4. Tong et al. J Headache Pain. 2013;14 (Suppl 1):P118; 5. Lipton RB et al. Headache. 2018;58:1336–37 (Poster #PS123LB); 6; Lipton RB et al. N Engl J Med. 2019;381:142-49; 7. Croop R et al. Lancet. 2019. doi: 10.1016/S0140-6736(19)31606-X; 8. Marcus et al. Cephalalgia. 2014;34:114-25. Disclosures: This study was sponsored by Biohaven Pharmaceuticals. CC, GD, RC, and VC are employees and stockholders in Biohaven Pharmaceuticals; RL is a consultant and holds stock options in Biohaven Pharmaceuticals.

Treatment-Emergent Adverse Events

Study 301 Study 302 Study 303

RimegepantN=543

(%)

PlaceboN=541

(%)

Rimegepant N=537

(%)

PlaceboN=535

(%)

Rimegepant N=682

(%)

PlaceboN=693

(%)

Palpitations 0 0.2 0 0 0 0.1

Tachycardia 0 0 0 0.6 0 0.1

Sinus bradycardia 0 0 0 0 0 0

Bradycardia 0 0 0 0 0 0

Left ventricular hypertrophy 0 0 0 0 0 0

Combined CV-Related 0 0.2 0 0.6 0 0.2

Results cont.

19th International Headache Congress | September 5-8, 2019 | Dublin, IrelandTo download a copy of this

poster, scan QR code.

Mustafa, S. J., Ansari, H. R.and Abebe, W. (2009), P1(Adenosine) PurinoceptorAssays. Current Protocolsin Pharmacology, 45: 4.7.1-4.7.13.doi:10.1002/0471141755.ph0407s45. Copyright ©2009 John Wiley & Sons,Inc. Used with permission

Rimegepant is an investigational new drug, not approved or authorized for marketingin the U.S. or any country for any indication or treatment of any disease or condition.This material is being made available through Biohaven’s Medical Affairs Department.