Zavegepant, an investigational nasal spray formulation of a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, met its primary endpoints in a stage 3 randomized placebo-controlled trial in acute migraine.
On the two main evaluation criteria: absence of pain for 2 hours (23.6% versus 14.9%, PP= 0.0012) — zavegepant was superior to placebo, reported Jelena Pavlovic, MD, PhD, of the Albert Einstein College of Medicine and Montefiore Headache Center in New York, in a presentation at the annual meeting of the American Headache Society.
“We found superiority over placebo after a single dose as early as 15 minutes and maintained for 48 hours,” Pavlovic said. “Pain relief at 15 minutes, return to normal function at 30 minutes, and sustained pain relief for 48 hours are highlighted as pre-defined secondary points of interest.”
Zavegepant is a high-affinity, selective and structurally unique small-molecule CGRP receptor antagonist, Pavlovic noted. “It is the only molecule currently in class that is delivered via 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 Tmaximum about 30 minutes,” Pavlovic said. “The phase II/III Dosing study demonstrated that 10mg 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 headache days per month. Migraine preventative medications were allowed in the trial (excluding other CGRP antagonists), provided the dose had been stable for 3 months or more.
A total of 1,269 people (mean age 40.8 years, 82.9% women) were included in the study: 623 people randomized to zavegepant and 646 to the placebo. At baseline, the average number of moderate to severe seizures was 4.7, and untreated seizures 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 migraine preventative medication.
Participants self-administered a dose of zavegepant 10mg nasal spray or a placebo to treat a migraine attack of moderate or severe pain intensity and recorded the data in an electronic diary beginning 15 minutes after administration .
15 minutes after administration, 15.9% of the zavegepant group reported pain relief, compared to 8.0% of the placebo group. At 30 minutes after administration, these figures increased to 30.5% for the zavegepant group and 20.3% for the placebo group (P<.0001 for all>
Other outcomes included return to normal function at 30 minutes (10.5% vs. 6.1%, P=0.0059) and 2 hours (35.8% versus 25.6%, P=0.0001) and sustained pain relief 2-48 hours after dosing (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 elevations in transaminases greater than three times the upper limit of normal.
Zavegepant is under FDA review with an expected decision date in Q1 2023, drug developer Biohaven Pharmaceuticals announcement in May. It is the only CGRP receptor antagonist in clinical development with intranasal and oral formulations, the company said.
Disclosures
The study was supported by Biohaven Pharmaceuticals.
Pavlovic revealed that he is a consultant for Allergan and sits on Biohaven’s advisory board.
