PHILADELPHIA — Atogepant, an investigational oral calcitonin gene-related peptide (CGRP) receptor antagonist for migraine prevention, led to fewer monthly migraine days in episodic monthly migraine patients, results of a phase IIb/III trial showed here.
Across a 12-week period, five tested doses of atogepant beat placebo in reducing the average number of monthly migraine days compared with baseline, reported Peter Goadsby, MD, of King’s College London, and colleagues at the American Academy of Neurology annual meeting.
Atogepant is a novel CGRP receptor antagonist with a high affinity at the CGRP receptor (Ki=15-26 pM) and about 100 times lower affinity at the human amylin 1 (AMY1) receptor. Unlike injectable anti-CGRP monoclonal antibodies approved for migraine prevention in the past year — erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality) — atogepant and other “gepant” agents are small-molecule drugs that can be taken orally.
An oral CGRP-receptor antagonist medicine would be easier for patients, Goadsby told MedPage Today: “It could facilitate, with time, the greater use of this mechanism in primary care,” he said. “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.”
The terminal half-life of atogepant is about 10 hours and the drug produces no apparent reactive metabolites, so “it doesn’t have a potential to have liver problems as some of its small-molecule predecessors had,” Goadsby added. Clinical trials of an earlier gepant, telcagepant, were terminated due to liver toxicity concerns.
In this multicenter, double-blind, placebo-controlled, parallel-group trial, researchers studied patients with a history of migraine, with or without aura, who had 4 to 14 migraine days in a 28-day baseline period. They randomized 834 patients 2:1:2:1:2:1 to placebo, atogepant 10 mg QD, 30 mg QD, 30 mg BID, 60 mg QD, or 60 mg BID, respectively, and treated them for 12 weeks. The primary efficacy endpoint was the change from baseline in mean monthly migraine days; safety and tolerability also were evaluated. Safety was assessed for an additional 4 weeks.
The average age of participants was about 40; most were white (76%) and female (86%). Most had never taken preventive treatment for migraine (72%), but nearly all (98%) had taken an acute treatment for migraine, most commonly nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans. Demographics and baseline data were similar across treatment groups. About half of the patients had a diagnosis of treatment without aura, and the average migraine duration was 19 years. The average baseline migraine days were 7.67.
Mean change in migraine days across the 12-week treatment period were (all P-values were vs placebo):
- Placebo: -2.85 days
- Atogepant 10 mg QD: -4.00 days (P=0.0236)
- 30 mg QD: -3.76 days (P=0.0390)
- 30 mg BID: -4.23 days (P=0.0034)
- 60 mg QD: -3.55 days (P=0.0390)
- 60 mg BID: -4.14 days (P=0.0031)
In total, 480 patients (58.2%) reported treatment-emergent adverse events; for 170 (20.6%), the adverse events were considered treatment-related. Seven people (0.8%) reported serious adverse events, none of which were considered treatment-related. Ten patients had treatment-emergent elevated ALT/AST (aspartate aminotransferase or alanine aminotransferase) numbers at least three times the upper limit of normal, balanced across treatment groups, which resolved, Goadsby said.
“All five atogepant groups showed statistically significant and clinically relevant reductions in mean migraine days across the 12-week treatment period,” the researchers concluded.
“I don’t think all would agree with the assertion that the reduction in mean migraine days in the active treatment groups is clinically relevant,” observed Elizabeth Loder, MD, MPH, of Brigham and Women’s Hospital in Boston, who was not involved with the study. “The mean reduction in monthly migraine days in the placebo group was 2.85 days, and reductions in the other groups ranged from 3.55 to 4.23 days, I would consider that a small effect that is of questionable clinical relevance,” she told MedPage Today.
“It’s worth remembering that results in this trial are probably a best-case scenario because the participants were mostly naive to preventive treatments,” Loder pointed out. “In clinical practice, a new and presumably expensive preventive migraine treatment will be used in many patients who have failed previous preventive treatments, who are probably harder to treat and more likely to be treatment-resistant than those in this trial.”
“Given these modest results, it will be important to know more about the serious adverse events and their distribution among the various groups,” she continued. “Liver problems are of particular concern because of problems with previous trials of gepants.”
Atogepant and other gepants might offer tolerability or other advances over existing preventive options and may be effective for some patients who have not benefited from other options, but “their efficacy seems quite low and those other benefits remain speculative,” she said. “Head-to-head clinical trials or network meta-analyses will be needed to better clarify the place of the gepants among other options for migraine prevention.”
Additional phase III studies of atogepant for episodic and chronic migraine are underway, Goadsby noted.
The study was supported by Allergan. Some co-authors are company employees.
Goadsby disclosed multiple relevant relationships with industry including Allergan.