Intranasal Zavegepant is Effective and Well Tolerated for the Acute Treatment of Migraine: A Phase 2/3 Dose-Ranging Clinical trial
Robert Croop1, Jennifer Madonia1, Charles Conway1, Alexandra Thiry1, Micaela Forshaw1, Abigail Murphy1, Christopher Jensen1, Gene Dubowchik1, Vlad Coric1, Richard Lipton2
1Biohaven Pharmaceuticals, 2Albert Einstein College of Medicine
Objective:

Evaluate the efficacy, safety, and tolerability of intranasal zavegepant in the acute treatment of migraine.

Background:

Zavegepant, a third-generation, high-affinity, selective and structurally unique, small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is the only intranasal CGRP receptor antagonist in late-stage development for the acute treatment of migraine. Findings from a previous single ascending dose study indicated that intranasal zavegepant produced potentially therapeutic systemic exposures.

Design/Methods:

In this randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults with migraine (NCT03872453), subjects treated a single attack of moderate to severe pain intensity with intranasal zavegepant 5, 10, 20 mg, or placebo. The coprimary efficacy endpoints were freedom from pain and the most bothersome symptom (MBS; i.e., photophobia, phonophobia, or nausea) at 2 hours postdose. Endpoints were tested at an alpha level of 0.0167.

Results:

Of the 1673 subjects randomized, 1588 were treated with study medication and 1581 were included in the modified intention-to-treat population [zavegepant 5 mg (n=387), 10 mg (n=391), 20 mg (n=402), placebo (n=401)]. Overall, median age was 40 years, 85.5% were female, and approximately 14% were taking preventive migraine medication. Zavegepant 10 mg and 20 mg demonstrated statistical superiority to placebo on the co-primary endpoints of pain freedom [placebo: 15.5%; 5 mg: 19.6% (p=0.1214); 10 mg: 22.5% (p=0.0113); 20 mg: 23.1% (p=0.0055)] and MBS freedom [placebo: 33.7%; 5 mg: 39.0% (p=0.1162); 10 mg: 41.9% (p=0.0155); 20 mg: 42.5% (p=0.0094)]. The most common (>5%) adverse events were dysgeusia (13.5%-16.1% with zavegepant vs 3.5% with placebo) and nasal discomfort (1.3%-5.2% with zavegepant vs 0.2% with placebo); The majority of adverse events were mild or moderate. There was no signal of hepatoxicity.

Conclusions:

Intranasal zavegepant 10 mg and 20 mg were effective for the acute treatment of migraine, with a favorable safety profile.