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Ubrogepant, an investigational oral calcitonin gene-related peptide (CGRP) receptor antagonist for acute migraine treatment, met both of its primary efficacy endpoints in the phase III for acute treatment of a single migraine attack.

Rates of pain freedom at 2 hours were significantly greater with ubrogepant 50 mg (21.8%) or 25 mg (20.7%) than with placebo (14.3%), reported Richard Lipton, MD, of the Montefiore Headache Center at the Albert Einstein College of Medicine in New York City, and colleagues.

In addition, rates of freedom from the most bothersome migraine-associated symptom -- photophobia, phonophobia, or nausea -- at 2 hours were significantly greater with the 50-mg (38.9%) dose, but not with the 25-mg (34.1%) dose, compared with placebo (27.4%), they reported in .

Ubrogepant is a small-molecule gepant agent that blocks the CGRP receptor, inhibiting a pathway known to play a role in the pathophysiology of migraine. "Ubrogepant will provide an acute treatment option for millions of people with migraine who do not respond to triptans or cannot take them," Lipton said. While triptans have been widely prescribed for acute migraine treatment for many years, some patients cannot use them because of cardiovascular contraindications.

"We once believed that migraine specific drugs had to constrict blood vessels to be effective, based on the vascular theory of migraine," Lipton told 乌鸦传媒. "Ergots and triptans constrict blood vessels. Gepants do not constrict blood vessels. The effectiveness of gepants is another nail in the coffin of the vascular theory of migraine."

Last year, the FDA approved three CGRP-targeted monoclonal antibodies for migraine prevention: erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality). Last month, the FDA approved the first ditan for acute migraine drugs, lasmiditan (Reyvow), a serotonin agonist that targets the 5-HT_1F receptor. Two gepant drugs, ubrogepant and its rival rimegepant, are novel oral agents for the acute treatment of migraine; both are under FDA review for approval.

"Gepants are remarkably similar," noted Stewart Tepper, MD, of the Geisel School of Medicine at Dartmouth College in Hanover, New Hampshire, who was not involved with the study. "It's really astonishing that if you look at the four randomized controlled trials of the two gepants at the primary endpoint of 2-hour pain freedom, give or take plus one, all four trials show about a 20% pain-free 2-hour response," he said.

What's encouraging about gepants is that "they have really high tolerability and a really low adverse event profile," Tepper added. "Gepants have relatively lower pain-free numbers at 2 hours than lasmiditan or triptans, but better tolerability," he told 乌鸦传媒. "Their assessment probably needs to be by looking at the adverse event profile compared to the efficacy profile: the number needed to harm versus the number needed to treat."

ACHIEVE II ran in 99 primary care and research clinics in the U.S. from August 2016 to February 2018. Researchers randomized 1,686 adults with migraine with or without aura experiencing two to eight migraine attacks a month 1:1:1 to ubrogepant 50 mg, 25 mg, or placebo.

Participants took one tablet of study medication as soon as possible, within 4 hours of the onset of a qualifying migraine attack. Qualified participants had a moderate or severe migraine attack, at least one symptom of photophobia, phonophobia, or nausea, had not taken any prohibited medications (including triptans, ergot derivatives, opioids, NSAIDs, or any analgesic), and were experiencing a new migraine headache that was not resolving. An optional second dose or rescue medication was allowed from 2 to 48 hours after the initial dose.

In total, 1,465 participants constituted the safety population and 1,355 people were in the primary analysis. The most common reason for discontinuing the trial was the lack of a qualifying event. In the safety population, 90% were women and had an average age of about 41; 97% had taken acute treatments for migraine. In the primary analysis population, 24% were using preventive migraine medication. Photophobia was the most frequently reported bothersome symptom (57%), followed by phonophobia (26%), and nausea (17%).

Treatment-emergent adverse events were reported within 48 hours of taking the initial or optional second dose by 12.9% of people in the 50-mg group, 9.2% in the 25-mg group, and 10.2% in the placebo group. Within 30 days after any dose, treatment-emergent adverse events were reported by 27.3% in the 50-mg group, 22.0% in the 25-mg group, and 22.4% in the placebo group, most commonly nausea at both time periods.

No serious adverse events occurred within 48 hours after the initial or optional second dose. Within 30 days of any dose, one participant in the 25-mg group reported seven serious adverse events related to a bicycle accident; none were considered treatment related. No deaths or discontinuations due to an adverse event were reported.

After the baseline measure, four participants had high liver enzyme values; three of the four cases were deemed unlikely to be related to ubrogepant and one was judged to be possibly related to treatment.

The ACHIEVE II trial had several limitations, Lipton and colleagues noted. Participants treated their migraine when headache pain was moderate or severe, in line with trial design recommended for regulatory approval but not in line with the to treat at the first sign of headache. This study, therefore, may not reflect treatment outcomes for patients who are treated while their headache pain intensity is mild.

Adverse events and tolerability reported in ACHIEVE II are based on outcomes after a single migraine attack and do not reflect tolerability after repeated use, the researchers added. Ubrogepant's consistency in relieving recurrent migraine attacks also cannot be determined in a single-attack trial.

An FDA decision about ubrogepant is expected in December, . If the agency approves the drug, ubrogepant could be the first oral CGRP for acute treatment of migraine and the first FDA-approved gepant.

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