, new research shows. In a randomized dose-ranging, placebo-controlled, phase 2/3 trial, investigators found both the 10- and 20-mg doses of the drug were associated with pain freedom in more than 20% of patients and alleviated the most bothersome symptom, defined as photophobia, phonophobia, or nausea, in more than 40% of patients.
Most adverse events associated with zavegepant were mild or moderate. The drug is not associated with liver toxicity.
Dr. Richard B. Lipton
“The intranasal formulation demonstrated some separation on pain relief as early as 15 minutes, though in terms of the statistical hierarchy, those differences were not significant,” said study investigator Richard B. Lipton, MD, professor and vice chair of neurology at Albert Einstein College of Medicine, New York, who presented the findings at the American Academy of Neurology’s 2021 annual meeting.
“Sustained pain freedom was observed from 2 to 48 hours post-dose,” Dr. Lipton added. A phase 3 clinical trial has been initiated to compare the efficacy of the 10-mg dose with that of placebo for the acute treatment of migraine.
Three doses
Zavegepant is the only intranasal CGRP receptor antagonist undergoing late-stage development for the acute treatment of migraine. A previous single ascending dose study suggested the drug provided systemic exposure and had potentially therapeutic effects.
The study included participants age 18 years or older who had a diagnosis of migraine for at least 1 year, had two to eight migraine attacks of moderate or severe intensity and fewer than 15 monthly headache days over the previous 3 months.
The investigators randomly assigned participants in this phase 2/3 trial to placebo or a 5-mg, 10-mg, or 20-mg dose of intranasal zavegepant. Participants treated a single attack of moderate to severe pain with their assigned treatment.
The study’s two primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after dosing.
The investigators randomly assigned 1,673 participants to treatment. Of this group, 1,588 treated an attack with study medication. The researchers also included 1,581 participants in the modified intention-to-treat population. Of this group, 387 received the 5-mg dose, 391 received the 10-mg dose, 402 received the 20-mg dose, and 401 received placebo.
Pain freedom
The population’s median age was approximately 41 years, 86% of participants were female, and 14% were taking preventive migraine medication. Participants’ mean number of moderate or severe attacks per month was 4.9 overall. The most common most bothersome symptom was photophobia.
The researchers observed a difference in outcome between the active and placebo arms as early as 15 minutes post-dose, but this difference was not statistically significant. At 2 hours, the rate of pain freedom was 15.5% in the placebo group, 22.5% in the 10-mg group (P = .0113), and 23.1% in the 20-mg group (P = .0055). The result for the 5-mg group (19.6%) was not significantly different from that of the placebo group.
The rate of freedom from the most bothersome symptom was 33.7% in the placebo group, 41.9% in the 10-mg group (P = .0155), and 42.5% in the 20-mg group (P = .0094). For this endpoint as well, the result of the 5-mg group (39%) was not significantly different from that among controls.
The most common adverse events were dysgeusia (impaired sense of taste) and nasal discomfort. The rate of dysgeusia ranged from 13.5% to 16.1% in the zavegepant groups, compared with 3.5% among controls. The rate of nasal discomfort ranged from 1.3% to 5.2% in the zavegepant groups, compared with 0.2% among controls. The investigators concluded that intranasal zavegepant had a favorable safety profile.