Zavegepant, an investigational nasal spray formulation of a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, met its co-primary endpoints in a phase III randomized placebo-controlled trial of acute migraine.
On both primary endpoints — 2-hour pain freedom (23.6% vs 14.9%, P<0.0001) and 2-hour freedom from most bothersome symptom (39.6% vs 31.1%, P=0.0012) — zavegepant was superior to placebo, reported Jelena Pavlovic, MD, PhD, of Albert Einstein College of Medicine and Montefiore Headache Center in New York City, in a presentation at the American Headache Society annual meeting.
“We saw superiority over placebo after a single dose as early as 15 minutes and sustained through 48 hours,” Pavlovic said. “Pain relief at 15 minutes, return to normal function at 30 minutes, and sustained pain relief through 48 hours are highlighted as secondary predefined points of interest.”
Zavegepant is a high-affinity, selective, structurally unique small-molecule CGRP receptor antagonist, Pavlovic noted. “It is the only molecule currently in the class that is delivered by nasal spray that is in late-stage development for the acute treatment of migraine,” she said.
A phase I study had shown that zavegepant 10 mg was rapidly absorbed with a Tmax of about 30 minutes, Pavlovic pointed out. “The phase II/III dose-ranging study demonstrated that 10 mg of zavegepant was the optimal dose for migraine,” she added.
The phase III trial studied adults with a history of two to eight moderate or severe monthly migraine attacks who had less than 15 monthly headache days. Preventive migraine drugs were permitted in the trial (excluding other CGRP antagonists), as long as the dose had been stable for 3 months or longer.
A total of 1,269 people (mean age 40.8, 82.9% female) were included in the study: 623 people randomized to zavegepant and 646 to placebo. At baseline, the mean number of moderate-to-severe attacks was 4.7 and untreated attacks lasted an average of 30.8 hours. Historically, the most bothersome symptoms among participants were photophobia (60.4%), nausea (24.7%), and phonophobia (15.0%). A total of 13.4% of participants used preventive migraine medication.
Participants self-administered one dose of zavegepant 10 mg nasal spray or placebo to treat one migraine attack of moderate or severe pain intensity and reported data into an eDiary starting at 15 minutes after dosing.
At 15 minutes post-dose, 15.9% of the zavegepant group reported pain relief, compared with 8.0% of placebo. At 30 minutes post-dose, those numbers increased to 30.5% for the zavegepant group and 20.3% for placebo (P<.0001 for all).
Other findings included return to normal function at 30 minutes (10.5% vs 6.1%, P=0.0059) and 2 hours (35.8% vs 25.6%, P=0.0001), and sustained pain relief 2 to 48 hours post-dose (36.1% vs 29.6%, P=0.013) for zavegepant and placebo, respectively.
The most common adverse events (AEs) in the zavegepant group were dysgeusia (20.5%), nasal discomfort (3.7%), and nausea (3.2%). Most AEs were mild or moderate; none were serious. One participant in the zavegepant group and two in the placebo group had transaminase elevations more than three times upper limit of normal.
Zavegepant is under FDA review with a decision date expected in the first quarter of 2023, drug developer Biohaven Pharmaceuticals announced in May. It is the only CGRP receptor antagonist in clinical development with both intranasal and oral formulations, the company said.
The study was supported by Biohaven Pharmaceuticals.
Pavlovic disclosed being a consultant for Allergan and serving on the Biohaven advisory board.