乌鸦传媒

LOS ANGELES -- Ubrogepant, an oral calcitonin gene-related peptide (CGRP) receptor antagonist, met both of its primary efficacy endpoints in the phase III ACHIEVE 1 trial for acute treatment of a single migraine attack, researchers reported here at the American Academy of Neurology annual meeting.

Ubrogepant at 100 mg resulted in pain freedom within 2 hours for 21.2% of patients, and at 50 mg for 19.2% of patients, compared with 11.8% for placebo.

Similarly, the percentage of patients who achieved an absence of their most bothersome migraine symptom -- mostly photophobia, phonophobia, and nausea -- was greater for patients treated with ubrogepant (100 mg: 37.7%; 50 mg: 38.6%) than placebo (27.8%).

Ubrogepant and its rival rimegepant (Zydis), another oral CGRP inhibitor with phase III trial data reported this week, are small-molecule drugs known collectively as gepants. Unlike the anti-CGRP monoclonal antibodies being developed for migraine prevention, gepants can partially pass the blood-brain barrier to possibly stop a migraine in progress. Clinical trials of an earlier gepant, were terminated due to liver toxicity concerns.

A spokesperson for ubrogepant's developer, Allergan, told 乌鸦传媒 the compound had been engineered to achieve higher potency than in earlier gepant agents and "decrease the formation of reactive metabolites, one potential cause of liver injury."

For , Joel Trugman, MD, director of clinical development for Allergan, and colleagues recruited 1,672 adult patients with a history of migraine with or without aura and randomized them to receive ubrogepant 50 mg or 100 mg, or placebo.

The average age of participants was about 41; a total of 87.5% were women, and 82.4% were white. At baseline, 63% of the participants had migraine with moderate pain and 37% had migraine with severe pain.

In addition to meeting the primary endpoints, the 100-mg dose of ubrogepant demonstrated statistically significant differences over placebo in sustained freedom from pain for up to 24 hours and the absence of photophobia at 2 hours.

In a poster accompanying their presentation, the researchers noted that "the liver safety data from this study do not suggest any signal of hepatotoxicity for ubrogepant." But five patients treated with the drug in the study had elevated aspartate aminotransferase or alanine aminotransferase numbers that were at least three times the upper limit of normal. A panel of blinded liver specialists examined the data and concluded that only one of the cases was "possibly related" to the study and that the others were unlikely to be related.

"If ubrogepant and rimegepant prove to be safe -- and there's this liver issue that's still in the background -- they are very well tolerated and they don't cause vasoconstriction," Stewart Tepper, MD, of the Geisel School of Medicine at Dartmouth in Hanover, N.H., who participated in the study as a site investigator, but was not a co-author, told 乌鸦传媒. "They're not like triptans -- so you could give them to people with coronary artery disease or cerebrovascular disease who have migraine."

"The excitement is that there are two new classes of acute migraine medications that don't cause vasoconstriction -- one is the gepants; the other is lasmiditan, a serotonin 1F receptor agonist," Tepper added.

In a press conference hosted by AAN's scientific committee, Trugman was asked about potential risks to women of reproductive age, especially those who might become pregnant. Though pregnant women were excluded from the ACHIEVE 1 trial, Trugman explained that drugs like ubrogepant are "small-molecule, orally available drugs that differ very much from the monoclonal antibodies that are being developed for prevention."

They're rapidly absorbed and "basically, they're gone from the system in 24 hours," Trugman said. "In that sense, they're safer than having a long-term monoclonal."

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