• Because some drugs may affect ion channels in cardiac cells, delaying cardiac repolarization, and resulting in proarrhythmic behavior, it is important to test for prolongation of the QT interval in new drugs with systemic exposure

• Rimegepant is an orally administered small molecule calcitonin gene-related peptide receptor antagonist that has demonstrated efficacy and safety in the acute treatment of migraine in 3 separate Phase 3 clinical trials1-3

• The effects of rimegepant on the QT interval have not been previously assessed in a dedicated study

• The objective of this study was to evaluate the effect of therapeutic and supratherapeutic doses of rimegepant on the Fredericia corrected QT interval (QTcF) in healthy fasted adults

Objective

• This was a single-center, Phase 1, partially double-blind, randomized, placebo- and actively-controlled, 12-sequence, 4-period crossover study

Methods

• Subjects included adult nonsmokers aged ≥18 and ≤80 years, with body mass index (BMI) ≥18.5 and ≤30.0 kg/m2 weight ≥50.0 kg (males) and ≥45.0 kg (females); and a score of 0 on the Sheehan Suicidality Tracking Scale (S-STS)4

Subjects

• In each period, blood samples for pharmacokinetic (PK) analysis were collected at baseline and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 12, and 24 hours postdose

• PK parameters included area under the curve from time 0 to the last quantifiable concentration time point (AUC0-t), AUC from time 0 to infinity (AUC0-inf), and maximum observed plasma concentration (Cmax), residual area, Tmax, T½ el, and Kel

• Safety assessments: AEs, ECGs, vital signs, physical measurements, S-STS, and clinical laboratory parameters, including liver function tests

Assessments

• For the cardiodynamic ECG assessment, the primary analysis was based on concentration-QTc modeling of the relationship between rimegepant and placebo-corrected change-from-baseline QTcF (ΔΔQTcF) with the intent to exclude an effect >10 msec at clinically relevant rimegepant plasma concentrations; only timepoints with matching placebo values were included in the modeling

• The effect of rimegepant on ΔΔQTcF was evaluated at postdose timepoints using the intersection union test

• Assay sensitivity was evaluated using a model similar to the primary analysis

Statistical Analysis

Introduction

Conclusions• In healthy adults, single therapeutic (75 mg) and supratherapeutic (300 mg) doses of rimegepant:•Had no clinically meaningful effect on QTcF•Were safe and well tolerated, with safety profiles comparable to placebo

Table 2. Treatment-Emergent Adverse Events

Results

• Of the 50 subjects who enrolled, 38 were dosed and received at least 1 dose of the study medications, and 33 (86.8%) completed all treatment periods

• Subjects were randomized to rimegepant 75 mg (n=37), rimegepant 300 mg (n=38), moxifloxacin, and placebo (n=36 each)

• Subjects’ mean age was 43 years, 57% were male, and 91% were White

Subjects

Rimegepant Moxiflaxin 400 mg(N = 36)

Placebo(N = 36)

Overall(N = 38)75 mg

(N = 37)300 mg(N = 38)

TEAEs, n 7 10 10 10 37

Subjects with TEAEs, n (%) 6 (16.2) 6 (15.8) 6 (16.7) 6 (16.7) 17 (44.7)

Headache, n (%) 1 (2.7) 4 (10.5) 2 (5.6) 2 (5.6) 6 (15.8)

Dizziness, n (%) 0 0 2 (5.6) 1 (2.8) 3 (7.9)

Somnolence, n (%) 0 1 (2.6) 2 (5.6) 0 3 (7.9)

Results cont.

• Subjects were randomized to 1 of 12 sequences consisting of: – 4-tablet dose of rimegepant 75 mg (1 x 75 mg + 3 placebo)– Rimegepant 300 mg (4 x 75 mg)– Placebo (4 x)– 1 tablet of moxifloxacin hydrochloride 400 mg as a positive drug control to establish assay sensitivity

• Subjects were confined to the research facility from Day -1, at least 12 hours before treatment, until after the 24-hour postdose blood draw in each treatment period

Treatments

Figure 2. Model-Predicted ΔΔQTcF (Mean and 90% CI) and Observed ΔΔQTcF (Mean and 90% CI) Across Deciles of Rimegepant Plasma Concentrations

Safety• Seventeen (44.7%) subjects experienced at least 1 TEAE (Table 2)

Pharmacokinetics

• The Cmax and AUC0-t of rimegepant oral tablets administered as a single supratherapeutic dose of 300 mg (4 times the therapeutic dose) produced respective Cmax and AUC0-t values approximately 5.7 to 7.1 times higher than those of the 75 mg therapeutic dose (Table 1)

• The peak rimegepant concentration for rimegepant 300 mg was observed approximately 29 minutes later than the 75 mg dose (median Tmax of 2.597 hours vs 2.108 hours postdose)

Geometric mean Rimegepant 75 mg(N = 37)

Rimegepant 300 mg(N = 38)

Cmax, ng/mL 867.64 4942.58

AUC0-t, h*ng/mL 4920.74 35083.98

AUC0-inf, h*ng/mL 5096.56 37530.23

Tmax, ha 2.108 2.597

aMedian

Table 1. Pharmacokinetic Parameters in Rimegepant-Treated Subjects

• Mean ΔΔQTcF was also very small, ranging from −1.4 msec at 2 hours postdose to 2.0 msec at 3.5 hours after dosing with 75 mg rimegepant

• ΔΔQTcF was within ±1.6 msec after treatment with 300 mg rimegepant• Following dosing with moxifloxacin, there was a clear increase in mean ΔΔQTcF• Its peak value was 14.1 msec (90% CI: 12.10–16.20) at 3.5 hours postdose• There were no treatment-emergent T-wave or U-wave morphology changes • The goodness-of-fit plot in Figure 2 presents the observed mean ΔΔQTcF (90% CI) within each

rimegepant concentration decile and the model-predicted mean ΔΔQTcF with 90% CI and shows that the observed ΔΔQTcF values are close to the predicted ΔΔQTcF

Red circles with bars: mean ΔΔQTcF with 90% CI shown at the median plasma concentration within each decile for rimegepant. Solid black line with gray shaded area: model-predicted mean ΔΔQTcF with 90% CI. Horizontal red line with notches: range of rimegepant concentrations divided into deciles.

• The majority of TEAEs (33/37, 89.2%) were mild; 2 placebo-treated subjects reported 4 moderate TEAEs• Of the 26 TEAEs considered to be related to the study medication, 12 were considered to be possibly

related to rimegepant• The most frequently reported TEAE considered possibly related to treatment was headache (15.8%),

which affected 1 subject treated with rimegepant 75 mg and 4 subjects treated with rimegepant 300 mg; no other TEAE was reported by >1 subject

• There were no reports of alanine aminotransferase (ALT), alkaline phosphatase (ALP), or aspartate aminotransferase (AST) values >3x ULN, and no subjects had total bilirubin levels >2x ULN

• No clinically meaningful changes in vital signs or ECGs were identified

Error bars for ΔΔQTcF are 90% CI from statistical modeling

Figure 1. Mean Plasma Concentrations Over 24 Hours, 300 mg Rimegepant, and Placebo-Corrected Change-From-Baseline QTcF Across Time Points

• Baseline ECG values were within expectations for a healthy population• Across treatment periods, mean:

– Heart rate was 54.1–55.2 bpm– QTcF interval was 405.7–407.5 msec– PR interval was 139.8–142.7 msec– QRS interval was 105.0–105.5 msec

• A single rimegepant dose of 75 mg (therapeutic) or 300 mg (supratherapeutic) had no clinically relevant effect on ECG parameters, including the RR, PR, QRS, and QT/QTcF intervals

Cardiodynamic Evaluation

• Mean ΔQTcF values for rimegepant were negative at all postdose time points, except for a value of .2 msec at 5 hours postdose among subjects dosed with 300 mg

• The time course of mean rimegepant plasma concentration for the 300 mg supratherapeutic dose is superimposed on the mean ΔQTcF values for rimegepant in Figure 1

Rimegepant Has No Clinically Relevant Effects on ECG Parameters: A Thorough QT Study Versus Placebo and Moxifloxacin in Healthy SubjectsMichael Hanna, MD1; Vladimir Coric, MD1; Joseph Stringfellow, MS2; Andrea Ivans, MHS1; Robert Croop, MD1

1 Biohaven Pharmaceuticals, Inc., New Haven, CT; 2 DataCeutics, Inc., Pottstown, PA

Poster No. IHC-PO-131

References: 1. Lipton RB et al. Headache. 2018;58:1336–37 (Poster #PS123LB); 2. Lipton RB et al. N Engl J Med. 2019;381:142-49; 3. Croop R et al. Lancet. 2019. doi: 10.1016/S0140-6736(19)31606-X; 4. Coric V et al. Psychiatry (Edgmont). 2009;6:26–31. Disclosures This study was sponsored by Biohaven Pharmaceuticals. MH, VC, AI, and RC are employed by and own stock/stock options in Biohaven Pharmaceuticals. 19th International Headache Congress | September 5-8, 2019 | Dublin, Ireland

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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.