References: 1. Luo et al. J Med Chem. 2012;55(23):10644-51; 2. Tong G et al. J Headache Pain. 2013;14 (Suppl 1):P118.; 3. Marcus et al. Cephalalgia. 2014; 34(2):114-25; 4. Hougaard A et al. Expert Opin Drug Metab Toxicol. 2015;11(9):1409-18. Disclosures This study was sponsored by Biohaven Pharmaceuticals. CMC, GMD, RC, and VC are employed by and own stock/stock options in Biohaven Pharmaceuticals.

Experiment 3 – Phase 2b Identifies 75 mg as Efficacious Dose to Advance to Phase 3

Figure 3. Rimegepant Plasma Concentrations in Phase 1 SAD and MAD

• Rimegepant dosed at 75 mg was observed to have statistically significant, durable improvement as compared to placebo.[3] At this dose level, statistically significant results were observed on all four key migraine symptoms—pain, nausea, photophobia and phonophobia. Higher doses of rimegepant, while also showing improvement compared to placebo, did not appear to convey any meaningful additional benefit above the 75 mg dose. The observed improvement profile is consistent with the published literature showing a lack of a progressive dose-response curve for anti-migraine drugs used in the acute treatment of migraine[4]

• Rimegepant also was observed to have evidence of durable improvement as demonstrated by statistically significant effects on 2-to-24 hour and 2-to-48 hour pain freedom and 2-to-24 hour pain relief, as compared to placebo (not shown, see details in [3]); this durable improvement is significant because other common migraine medications, such as triptans, have been associated with headache recurrence

Results

Conclusions• Rimegepant 75 mg was observed to have a comprehensive and durable

treatment effect that was statistically different from placebo on freedom from pain, nausea, phonophobia and photophobia at 2 hours post-dose.

• A single dose of rimegepant exhibited evidence of lasting improvement with statistically significant effects on 2-to-24 and 2-to-48 hour pain freedom and 2-to-24 hour pain relief.

• The Phase 2b study was a double-blind, randomized, placebo-controlled,dose-ranging clinical trial for the acute treatment of migraine

• 812 patients suffering from migraine attacks received either placebo, sumatriptan 100 mg or rimegepant dosed at 10, 25, 75, 150, 300, or 600 mg

• Patients in the trial were provided with an electronic diary, which they used to record and rank their assessments of pain, nausea, photophobia, and phonophobia at specified time points after they had taken the study medication following the occurrence of a migraine attack with moderate to severe pain intensity

Methods

• The human Vss and CLTp predicted by allometric scaling was 0.5 L/kg and 3.0 mL/min/kg, respectively (Figure 1)

• The absorption rate constant and bioavailability was 0.5 h-1 and 48%, respectively• Rimegepant (hCGRP Ki = 0.027 nM, 6.9% fraction unbound) antagonized the

CGRP-induced increases in marmoset facial blood flow showing 75% to 80% inhibition at total plasma levels of <800 nM and free levels <50 nM (Figure 2).[1]

• The human dose was estimated by a 1-compartment model with first-order absorption

• Using the projected human efficacy and PK parameters, the human doses required for achieving predicted efficacious exposures were estimated to be 1-2 mg/kg, which in a 70-kg human would translate to a 70 to 140 mg unit dose

• Identifying a safe and efficacious human dose is among the most difficult initial challenges in clinical drug development

• We describe the predicted (from discovery) and actual (from Phase 1 and 2) safe and efficacious dose of oral rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist that is FDA-approved for the acute treatment of migraine

• Identify the predicted clinically efficacious dose range from nonclinical assays (Experiment 1)

• Assess the safety, tolerability and pharmacokinetics (PK) of rimegepant in healthy subjects, including identification of a maximum tolerated dose (MTD) in Phase 1 (Experiment 2)

• Identify the lowest fully effective dose for the acute treatment of migraine in Phase 2b (Experiment 3) to advance into Phase 3

Objectives

• The human clinically efficacious dose range was predicted by considering efficacy and exposure in the marmoset facial blood flow assay, plus interspecies allometric scaling to predicted human steady-state volume of distribution (Vss) and total plasma clearance (CLTp), together with absorption rate constant and bioavailability derived from the IV and PO plasma concentration-time profiles in monkey

• Allometric scaling from discovery assays predicted the therapeutic dose range for acute treatment of migraine to be a single oral dose of 70 to 140 mg rimegepant

Conclusions

Introduction

Results

Methods

Experiment 1 – Nonclinical Prediction of Clinically Efficacious Dose is 70 to 140 mg

Figure 1. Allometric Scaling Predicted Volume of Distribution and Clearance

Experiment 2 – Phase 1 Defines Safety, Tolerability and PK of 25 mg to 1500 mg

• Single doses of rimegepant were well tolerated up to 1500 mg, and likewise, multiple doses of rimegepant up to 600 mg for 14 days were well tolerated without significant adverse events (Figure 3)[2]

• A maximum tolerated dose (MTD) was not reached despite achieving exposures that were greater than 50 times higher (Cmax 20,499 ng/mL and AUC 198,750 ng•h/mL) than those observed near the low predicted therapeutic dose of 75 mg (Cmax 784 ng/mL and AUC 3,729 ng•h/mL)

Results

Conclusions• Rimegepant was safe and well tolerated over the doses tested in this healthy

population, including at exposures greater than 50 times the lowest predicted efficacious dose

• As an MTD was not reached, doses below and above the target therapeutic doses (70 to 140 mg) were selected (25, 75, 150, 300, and 600 mg) for advancement into Phase 2/3 dose ranging clinical trial for the acute treatment of migraine (NCT01430442)

Figure 2. Rimegepant Efficacy and Exposure in the Marmoset Laser Doppler Facial Blood Flow Assay

• A Phase 1 study was designed to evaluate the safety, tolerability, and PK of single- and multiple-dose rimegepant with the aim of identifying an MTD and selecting doses for Phase 2/3

• In total, 8 healthy subjects received a single dose of rimegepant (25, 75, 150, 300, 600, 900, or 1500 mg) or placebo, and 8 healthy subjects received daily doses of rimegepant (75, 150, 300, 450, or 600 mg) or placebo

Methods

Rimegepant exhibited durable efficacy in the marmoset facial blood flow assay against a strong CGRP stimulus (designed to mimic repeated waves of CGRP release during severe migraine). Each marmoset received 4 injections of hαCGRP (10 µg/kg, IV) delivered at -0.5 hr (baseline), and 0.25, 1, and 1.75 hr relative to rimegepant (0 hr) at 7 mg/kg SC. The baseline control response to CGRP is shown on left (blue bar), and three post-dose responses on right (red bars). Total plasm levels are shown in blue and free plasma levels in green. Facial blood flow data are mean peak flux ± SEM expressed as % increase over basal flow. *P < 0.05 vs. CGRP baseline (-0.5 hr), significant ANOVA followed by Dunnett’s test for treatment versus control.

Conclusions• Discovery assay predictions of 70 to 140 mg as the safe and

efficacious dose range were confirmed in Phase 1 and Phase 2b– Allometric scaling and the marmoset facial blood flow assay

predicted 70 to 140 mg as the safe and efficacious dose range– Phase 1 SAD and MAD studies defined the safety of 25 to 1500

mg which was well tolerated (an MTD was not found)– Phase 2b identified 75 mg as fully efficacious in the 2 hour

endpoints of pain, nausea, photophobia and phonophobia. A single dose produced a lasting effect through 48 hours post-dose.

• Rimegepant is a high affinity antagonist at the human receptor with Kiof 0.027 nM and 6.9% unbound by human plasma proteins

– The protein-adjusted Ki of rimegepant is 0.39 nM– 75 mg showed a Cmax in Phase 1 of 784 ng/mL (~100 nM free)– Free plasma levels >100x above the protein-adjusted Ki appear

to be needed for efficacy in the acute treatment of migraine

Figure 4. Rimegepant 2-hour Pain Freedom in Phase 2b

Figure 5. 2-hour Freedom from Nausea, Phonophobia and Photophobia

Phase 1 and 2 Safety, Tolerability and Pharmacokinetics of Single and Multiple Dose Rimegepant as Compared to the Predicted Clinically Efficacious Dose RangeCharles M. Conway, PhD; Gene M. Dubowchik, PhD; Robert Croop, MD; Vladimir Coric, MDBiohaven Pharmaceuticals, Inc., New Haven, CT

Poster No. P13.004

American Academy of Neurology 2020 Annual Meeting | Virtual Poster To download a copy of this poster, scan QR code.

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through Biohaven Medical Affairs.