More Positive Phase 3 Results ‘Raise the Bar’ for Migraine Drug
Atogepant, a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist approved last year for migraine, is superior to placebo not only in terms of a 50% or greater responder rate but also for a 75% or greater and 100% responder rate, a new study shows.
Results from a secondary analysis of the phase 3 ADVANCE trial “raise the bar” for communicating to patients “a clinically meaningful benefit,” lead author Richard B. Lipton, MD, professor and vice-chair, Department of Neurology, Albert Einstein College of Medicine, and director at the Montefiore Headache Center, Bronx, New York, told Medscape Medical News.
“Patients and doctors want to get a broad picture of what to expect from therapy, and having these additional endpoints just rounds out the efficacy picture for them,” said Lipton.”
He added the new information underscores that atogepant is an important addition to the migraine treatment toolbox because “you don’t need dose escalation, because the benefits kick in quickly, and because adverse events are relatively uncommon.”
The findings were published online June 8 in JAMA Network Open.
ADVANCE was a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 clinical trial of various daily doses of atogepant (10, 30, and 60 mg) or placebo taken orally by participants with migraine for 12 weeks.
As reported by Medscape Medical News, main results from the ADVANCE trial were published last year in The New England Journal of Medicine.
They showed mean monthly migraine days (MMDs) decreased by an average of about 4 for doses of the active treatment vs 2.5 days for placebo, a difference that was statistically significant (P < .001).
The new analysis focused on the 50% or greater secondary alpha-controlled endpoint, which corrects for multiple comparisons. It also included the prespecified secondary endpoints of 25% or greater, 75% or greater, and 100% reduction in 12-week mean MMDs.
The analysis included 902 participants (mean age, 41.6 years; 88.8% women; 83.4% White, 13.7% African American or Black). Baseline mean MMDs was 7.6.
Atogepant treatment resulted in a 50% or greater reduction in mean MMDs in 55.6% of patients in the 10-mg group, 58.7% in the 30-mg group, and 60.8% in the 60-mg group vs 29% in the placebo group (P < .001).
The odds ratios for achieving a 50% or greater reduction in MMDs for atogepant vs placebo were 3.1 (95% CI, 2.1-4.6) for the 10-mg group, 3.5 (95% CI, 2.4-5.3) for the 30-mg group, and 3.8 (95% CI, 2.6-5.7) for the 60-mg group.
Percentages of participants reporting a 25% or greater reduction in mean MMDs were higher for all treatment groups compared with the placebo group (P < .002), as was the case for those reporting a 75% or greater reduction in mean MMDs (P < .001).
For those reporting a 100% reduction in mean MMDs, the percentages were also higher for all treatment doses than for placebo (P = .004 for 10 mg, P = .02 for 30 mg, and P = .003 for 60 mg).
“Atogepant and placebo separated on virtually everything that was measured, except for some things with the 10-mg dose,” said Lipson. “I think this is an astonishingly effective drug.”
Traditional oral therapies for migraine, including beta-blockers and antiseizure medications, require starting low and gradually increasing the dose. However, this study showed all atogepant doses were effective in the first 4 weeks for all responder groups, Lipton noted.
“You don’t have to titrate the dose upward, and the benefits kick in very quickly,” he said.
Higher doses appeared to produce the greatest responder rates. Lipton, a headache specialist, said he “almost always” starts at 60 mg but might cut this to 30 mg if constipation is an issue.
In addition, treated patients reported feeling better or much better. More participants in the 10-mg (72.1%), 30-mg (73.2%), and 60-mg groups (76.1%) met Patient Global Impression of Change responder criteria than in the placebo group (46.1%).
Patients also reported being satisfied or extremely satisfied with the treatment. A greater proportion of patients in each atogepant group met treatment satisfaction responder criteria than patients in the placebo group (77.7%-82.6% for atogepant vs 54.8% for placebo; P < .001).
Atogepant was well tolerated, with no new safety concerns. The percentage of participants reporting treatment-emergent adverse effects (TEAE) was similar among all atogepant groups (52.9% for the 10-mg, 52.2% for the 30-mg, and 53.7% for the 60-mg groups vs 56.8% for the placebo group.) The most reported TEAEs for atogepant were constipation and nausea.
No Adverse Event Penalty?
Commenting for Medscape Medical News, Elizabeth Loder, MD, vice-chair, Academic Affairs, Department of Neurology, Brigham and Women’s Hospital, and professor of neurology at Harvard Medical School, Boston, Massachusetts, said that the trial was well conducted and adds to the evidence for efficacy and safety of oral CGRP inhibitors.
However, she noted that only one of the secondary analyses presented in the paper (the 50% or greater responder rate) was a prespecified, alpha-controlled outcome.
“The authors appropriately point out this limitation and say that the other results need further study,” said Loder, who was not involved with the research.”
The drug is “clearly more effective than placebo,” although, perhaps, a bit less so than other preventive treatments, such as CGRP injectable antibody treatments, she said. “But without a head-to-head trial, such comparisons are tricky.”
As would be expected with treatments that work on CGRP, the benefits with atogepant are apparent early in treatment, Loder noted.
She called the dose-response relationship “interesting,” but pointed out the difference between doses “doesn’t appear to be of substantial magnitude.”
Still, she added that as this drug class is well tolerated, “there’s probably no adverse event penalty for using the higher doses if they’re slightly more effective than lower doses.”
The study was sponsored by Allergan, before its acquisition by AbbVie. Lipton reported having received personal fees for study design, data analysis, and attending advisory board service from Allergan/AbbVie during the conduct of the study and grants and nonfinancial support from Allergan/AbbVie, grants and personal fees from Amgen, personal fees from Eli Lilly, grants, personal fees, and stocks/stock options from Biohaven, grants and personal fees from GlaxoSmithKline, personal fees from Impel, grants from BioDelivery Sciences International, grants and personal fees from Teva, stock options and grants from Manistee, and stock options from Ctrl M Health outside the submitted work. Loder has reported no relevant financial relationships.
JAMA Netw Open. Published online June 8, 2022. Full article
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