Zavegepant could become the first intranasal drug that targets CGRP in migraine sufferers to gain FDA approval.
Treatment with zavegepant nasal spray (Biohaven) produced positive findings in a phase 2/3 trial (BHV3500-201; NCT03872453) for the calcitonin gene-related peptide (CGRP) receptor antagonist for the acute treatment of migraine.
The results of the study, published in Headache, showed that zavegepant 10 mg and 20 mg were more effective than placebo for the primary end points of pain freedom at 2 hours after dose administration (placebo: 15.5% [98.3% CI, 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; P = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; P = 0.0055]) and freedom from the most bothersome symptom (MBS) at 2 hours after administration (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; P = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; P = 0.0094]).
The FDA set the Prescription Drug User Fee Act date for zavegepant in Q1 2023. If approved, zavegepant would become the first intranasal drug that targets CGRP in migraine sufferers to gain FDA approval.
"These results suggest that zavegepant may have a therapeutic role in the acute treatment of migraine as an effective alternative to oral and parenteral agents,” the study authors wrote. "Patients most likely to benefit from the use of zavegepant will be adults seeking a rapid onset of action (e.g., people regularly awakened by attacks) and those whose attacks typically involve marked gastrointestinal distress. The nasal spray formulation may be a particularly advantageous nonoral, needle-free approach to avoid exacerbations of nausea or vomiting, facilitate drug administration, and eliminate the effects of gastroparesis on drug absorption."
The study authors evaluated 1673 patients 18 to 79 years of age, administered either zavegepant 5 mg, 10 mg, 20 mg, or placebo. Pain freedom was evaluated using ratings of pain intensity on a 4-point scale.
The study randomized 1588 individuals to the safety cohort and 1581 to the efficacy cohort. Most of the patients were female (85.5%) and White (78.3%), with a mean body mass index of 27.4 kg/m2. At the start of the study, 13.6% of participants used preventive migraine medications.
Whereas the 10 and 20 mg doses of zavegepant showed statistical significance for the coprimary end points, the results for the 5 mg dose were not deemed significant. For the trial’s secondary efficacy end points, 53.6% patients in the placebo cohort had pain relief at 2 hours postdose compared with 60.6% and 61.2% for the zavegepant 10- and 20-mg cohorts, respectively. Zavegepant was found to be superior to placebo on multiple secondary end points, which included return to normal function at 30 min postdose with zavegepant 20 mg and sustained pain freedom from 2 to 48 hours postdose with zavegepant 5, 10, and 20 mg.
The most common treatment-emergent adverse events (AEs) in the zavegepant cohort were dysgeusia (zavegepant: 13.5% to 16.1%; placebo: 3.5%), nausea (zavegepant: 2.6% to 4.1%; placebo: 0.5%) and nasal discomfort (zavegepant: 1.3% to 5.2%; placebo, 0.2%). There were 5 participants who experienced serious AEs, but these were not found to be related to the active treatment, according to the study authors.
Croop R, Madonia J, Stock DA, et al. Zavegepant nasal spray for the acute treatment of migraine: a phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial. Headache. Published online October 14, 2022. doi:10.1111/head.14389.