Atogepant (Qulipta) has become the first oral calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) specifically developed for migraine prevention to win US Food and Drug Administration approval.
The atogepant decision “reflects a broader shift in the treatment and management paradigm for the migraine community,” noted Dr Peter Goadsby, of the University of California Los Angeles and King's College London, who received the 2021 Brain Prize for his groundbreaking work in CGRP and migraine.
“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients," he said.
An oral CGRP-receptor antagonist is easier for patients, Goadsby noted when he presented data from atogepant's pivotal phase IIb/III trial at the 2019 American Academy of Neurology annual meeting. "Primary care doctors will more easily use a medicine that's relatively simple to use and well-tolerated, and that means more migraine patients can get treated."
"Millions of people living with migraine often lose days of productivity each month because attacks can be debilitating. Qulipta can help by reducing monthly migraine days with a once-daily, oral dose that works quickly and continuously," said Dr Michael Severino, vice chairman and president, AbbVie.
"We are proud that AbbVie is now the only pharmaceutical company to offer three products across the full spectrum of migraine treatment, which include preventive therapies for chronic and episodic migraine and an acute treatment for migraine attacks."
The approval is supported by data from a robust clinical programme evaluating the efficacy, safety and tolerability of Qulipta in nearly 2,000 patients who experienced four to 14 migraine days per month, including the pivotal Phase 3 ADVANCE study, which was published in The New England Journal of Medicine, the pivotal Phase 2b/3 study, and the Phase 3 long-term safety study.
Migraine is a complex disease with recurrent attacks that are often incapacitating and characterised by severe, throbbing headache pain as well as compounding associated symptoms like extreme sensitivity to light, sound or nausea. It is highly prevalent, affecting more than 1 billion people worldwide, including 39 million people in the US alone, and is the highest cause of disability worldwide for people under 50.
"This approval reflects a broader shift in the treatment and management paradigm for the migraine community. Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients," said Goadsby, who co-authored the ADVANCE study.
“This is a milestone in preventive migraine treatment that I hope will help many patients for years to come,” he said.
Highlights from the clinical programme supporting the approval and additional data analysis include:
In the pivotal Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group ADVANCE trial, the primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period.
All Qulipta dose groups met the primary endpoint and demonstrated statistically significant reductions in mean monthly migraine days compared to placebo. Patients treated with 60mg of Qulipta across 12 weeks experienced a 4.2-day reduction from baseline of 7.8.1
A key secondary endpoint in the ADVANCE trial measured the proportion of patients that achieved a ≥50% reduction in monthly migraine days across the 12-week treatment period. The trial demonstrated that 56%/59%/61% of patients in the 10mg/30mg/60mg Qulipta arms, respectively, achieved a 50-100% reduction, compared to 29% of patients in the placebo arm (all dose groups vs. placebo, p<.001).
All doses were well tolerated in the ADVANCE trial and pivotal Phase 2b/3 clinical trial evaluating the efficacy, safety and tolerability of orally administered Qulipta. Adverse reactions in both studies (incidence at least 2% and greater than placebo) included nausea (5%-9% across all doses versus 3% for placebo), constipation (6% across all doses versus 1% for placebo), fatigue/somnolence (4%-6% across all doses versus 3% for placebo) and decreased appetite (1%-2% across all doses versus <1% for placebo). The adverse reactions that most commonly led to discontinuation were constipation (0.5%), nausea (0.5%) and fatigue/somnolence (0.5%).1
The pivotal Phase 2b/3 trial demonstrated that all active treatment arms met the primary efficacy endpoint of change from baseline in mean monthly migraine days with significantly greater reductions in mean monthly migraine days across the 12-week treatment period for all three Qulipta treatment groups compared with placebo. All three Qulipta treatment groups also met the secondary efficacy endpoint of change from baseline in mean monthly headache days.
Study details
Atogepant for the Preventive Treatment of Migraine
Jessica Ailani, Richard Lipton, Peter Goadsby, Hua Guo, Rosa Miceli, Lawrence Severt, Michelle Finnegan, Joel M. Trugman, for the ADVANCE Study Group
Published in New England Journal of Medicine 19 August 2021
Abstract
Background
Atogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist that is being investigated for the preventive treatment of migraine.
Methods
In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine–Diary (AIM-D).
Results
A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were −3.7 days with 10-mg atogepant, −3.9 days with 30-mg atogepant, −4.2 days with 60-mg atogepant, and −2.5 days with placebo. The mean differences from placebo in the change from baseline were −1.2 days with 10-mg atogepant (95% confidence interval [CI], −1.8 to −0.6), −1.4 days with 30-mg atogepant (95% CI, −1.9 to −0.8), and −1.7 days with 60-mg atogepant (95% CI, −2.3 to −1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group.
Conclusions
Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention.
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