Intranasal zavegepant shows promise for acute migraine treatment

The novel CGRP receptor antagonist zavegepant administered intranasally effectively reduces pain and the most bothersome symptom (MBS) in patients with migraine, shows a study presented at the AAN 2021 Annual Meeting.

Zavegepant is a third-generation, structurally unique, small molecule CGRP receptor antagonist which is highly selective and binds the receptor with high affinity.

In the dose-ranging, phase II/III trial, 1,581 patients with migraine (median age 40 years, 85.5 percent female, 14 percent were on preventive therapy) were randomized 1:1:1:1 to intranasal zavegepant 5 mg, 10 mg, 20 mg, or placebo for treatment of a single migraine attack of moderate to severe pain intensity. [AAN 2021, abstract S5.003]

Two hours after dosing, more patients treated with intranasal zavegepant were free from pain compared with those on placebo (23.1 and 22.5 percent vs 15.5 percent for zavegepant 20 mg and 10 mg vs placebo, respectively; p=0.0055). The difference between the lowest zavegepant dose of 5 mg (19.6 percent) was not significant compared with placebo.

“The intranasal formulation demonstrated some separation on pain relief as early as 15 minutes … [although the] differences were not significant [at this early time point],” said presenting author Professor Richard Lipton from the Albert Einstein College of Medicine in New York, New York, US.

The coprimary endpoint of freedom from the MBS — including photophobia, phonophobia, or nausea — occurred in more patients in the zavegepant group vs the placebo group (42.5 percent and 41.9 percent vs 33.7 percent; p=0.0094). For the 5-mg zavegepant dose, again, the rate of freedom from MBS (39 percent) was not significantly different than that in the placebo group.   

According to Lipton, intranasal zavegepant showed a favourable safety profile, with most associated adverse events (AEs) being mild to moderate in severity. The most common AEs (occurring in >5 percent of patients) were dysgeusia (13.5–16.1 percent vs 3.5 percent in the zavegepant groups vs the placebo group) and nasal discomfort (1.3–5.2 percent vs 0.2 percent). No signal of liver toxicity was observed with the drug.

“Zavegepant [represents] the only intranasal CGRP receptor antagonist [that is] in late-stage development for the acute treatment of migraine,” Lipton pointed out.

Previously, a single ascending dose study has suggested that the intranasal formulation might produce systemic exposures with therapeutic effects.

The rationale for developing an intranasal formulation for acute treatment of migraine stems from the belief that nasal preparations may have a faster onset of action than oral preparations, according to experts. 

Findings from the current study were promising and warrant larger phase III trials to be conducted, said the researchers.