Ubrogepant Safe, Effective for Migraine in Second Phase 3 Trial

Deborah Brauser

April 30, 2018

On the heels of favorable results from the phase 3 ACHIEVE-I trial, which were presented last week at the American Academy of Neurology (AAN) 2018 Annual Meeting, topline results from the phase 3 ACHIEVE-2 trial also show that the novel oral calcitonin gene-related peptide (CGRP) receptor antagonist ubrogepant (Allergan) is safe and effective for treating acute migraine, the company announced.

In the earlier ACHIEVE-I, which included more than 1300 patients, significantly more participants receiving 50 or 100 mg of the study drug achieved pain freedom and absence of their most bothersome symptom (MBS) 2 hours after treatment than those who received matching placebo.

In ACHIEVE-2, which also included around 1300 patients in the modified intent-to-treat (mITT) analysis, significantly more of those randomly assigned to the drug at 25- or 50-mg doses achieved pain freedom at the 2-hour point vs those receiving placebo (the co-primary endpoint), while more of those receiving the 50-mg dose also achieved absence of MBS, Allergan reported in a press release and investor's call.

Investigators also found that the 50-mg group had significantly more members who achieved pain relief, absence of photophobia, and absence of phonophobia at 2 hours and sustained pain relief and sustained pain freedom from 2 to 24 hours after treatment compared with the placebo group.

The most commonly reported adverse events were nausea and dizziness, each of which occurred in less than 2.5% of the participants. Assessment of hepatic safety revealed four cases of aminotransferase elevations greater than three times and less than five times the upper limit of normal — but none were found by the liver safety adjudication board to be treatment related.

"Given the prevalence of migraine and significant disability that many patients face, ubrogepant may provide a new option for those having tolerability issues with current migraine-specific treatments," co-investigator Stephen Silberstein, MD, director of the Headache Center at Thomas Jefferson University, Philadelphia, Pennsylvania, said in the release.

Co-investigator David Dodick, MD, professor of neurology and director of the headache program at the Mayo Clinic, Scottsdale, Arizona, added during the investor's call that the novel drug "absolutely" has a place in the acute treatment of migraine.

"It doesn't constrict blood vessels, so it may be used in patients who have absolute or relative cardiovascular contraindications to the use of triptans. And importantly, patients are going to be able to use these treatments early in the course of an attack, when pain is mild, because they're not fearful of side effects," said Dodick.

The company announced that it anticipates filing a new drug application to the US Food and Drug Administration in 2019.

Co-Primary Endpoints

ACHIEVE-2 enrolled 1686 adult patients aged 18 to 75 years with a history of migraine. In the study's mITT population, 435 patients were randomly assigned to receive ubrogepant 25 mg, 464 to the drug at 50 mg, and 456 to placebo. All treatments were to be used in response to a single migraine attack judged to be moderate to severe in intensity.

As mentioned, significantly more members of the 25- and 50-mg groups achieved pain freedom 2 hours after initial treatment dose, the co-primary endpoint 1, than did placebo group members (P = .03 and .01, respectively).

While more patients in each ubrogepant group also achieved absence of MBS, co-primary endpoint 2, the difference was significant only for those receiving the higher dose of the study drug (P = .07 and .01, respectively). More details for these two primary efficacy endpoints are shown in the table below.

Table. Primary Endpoints for 25 and 50 mg of Ubrogepant vs Placebo

Outcome Ubrogepant 25 mg (%) Ubrogepant 50 mg (%) Placebo (%)
Pain freedom 20.7a 21.8a 14.3
Absence of MBS 34.1 38.9a 27.4
aAchieved statistical significance vs placebo.

 

Other outcomes that were met by a significantly greater percentage in the 50-mg group included the following:

  • Pain relief at 2 hours (P = .01);

  • Absence of photophobia at 2 hours (P = .02);

  • Absence of phonophobia at 2 hours (P = .04);

  • Sustained pain relief from 2 to 24 hours (P = .01); and

  • Sustained pain freedom from 2 to 24 hours (P = .01).

"The consistency in response between both ACHIEVE I and ACHIEVE 2 provides further evidence that ubrogepant…offers a promising opportunity for the acute treatment of migraine," David Nicholson, chief research and development officer at Allergan, said in the release.

The study was funded by Allergan.

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