Zavegepant Intranasal Migraine Agent Meets Coprimary Endpoints in Phase 3 Trial, Pfizer Announces

Pfizer announced on Thursday that the phase 3 clinical trial of its investigational intranasal migraine therapy zavegepant met its coprimary endpoints. The findings were simultaneously published in The Lancet Neurology.

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Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray for the acute treatment of migraine and is the only intranasal formulation of the anti-CGRP molecule studied in a phase 3 trial, according to a company statement. The study showed that a single 10 mg dose of zavegepant was more effective than placebo for both freedom from pain and from the most bothersome symptom (MBS) at 2 hours post-dose. Onset of relief from migraine pain began 15 minutes after administration and for many patients lasted for up to 48 hours.

“This was the first Phase 3 clinical trial of a non-oral CGRP receptor antagonist developed for the acute treatment of migraine in adults. With this evidence of sustained treatment benefits, good tolerability, and an alternative administration method, I believe zavegepant has the potential to fill an important gap in the available options for the acute treatment of migraine,” said lead author Richard B. Lipton, MD, of the department of neurology at the Albert Einstein College of Medicine.

The study, conducted at 90 US locations, included 1405 participants aged ≥18 years with a history of 2 to 8 moderate or severe migraine attacks per month with untreated attacks that lasted a mean of 30.8 hours. Participants were randomized to receive a single dose of either zavegepant 10 mg nasal spray (n=703) or placebo (n=702). Randomization was stratified by use or nonuse of preventive medication. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h after the treatment dose

During the study participants recorded migraine headache pain intensity based on a 4-point scale, identified current MBS associated with migraine (phonophobia, photophobia or nausea) and recorded their level of functional disability immediately before dosing the treated attack and at various intervals post-dose.

RESULTS

At 2 hours after the treatment dose, more participants in the zavegepant group than in the placebo group had freedom from pain (24% vs 15%, P<.001) and freedom from MBS (40% vs 31%, P=.001). Zavegepant also was more effective than placebo on 13 of the 17 secondary endpoints, including treatment benefits for pain relief beginning as early as 15 minutes and sustained pain relief from 2 through 48 hours post-dose.

Treatment with zavegepant was also associated with higher rates of return to normal functional ability at 30 minutes and at 2 hours post-treatment.

Zavegepant was well tolerated during the study with a safety profile consistent with earlier studies of the drug. The most common adverse events in either treatment group (≥2%) were dysgeusia (21% vs 5%) nasal discomfort (4% vs 1%), and nausea (3% vs 1%). The investigators reported no serious adverse events associated with the study drug and no signal of hepatotoxicity related to zavegepant.

"The intranasal formulation for zavegepant embodies breakthrough innovation in patient-centric drug development,” said James Rusnak, MD, PHD, Pfizer senior vice president, chief development officer, Internal Medicine and Hospital, Global Product Development. “If approved by the FDA, zavegepant has the potential to be a significant new treatment option for people with migraine, particularly those who desire fast-acting relief or would benefit from an alternative delivery method.”

The small molecule CGRP antagonist was previously assessed in a phase 2/3 trial. It is the only moleculue of its kind in clinical development with both oral and intranasal formulations, Pfizer says. The current study demonstrates zavegepant efficacy in the treatment of acute migraine. Additional trials are needed to establish the long-term safety and consistency of effect across attacks, according to the company.

The PDUFA date for final FDA review of the new drug application is set for the first quarter of this year.

Study: Lipton RB, Croop R, Stock DA, et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 2023;22:209-217. doi:10.1016/S1474-4422(22)00517-8