What to expect from next-gen CGRP inhibitors for migraine, cluster headache

Fremanezumab

Fremanezumab is a fully humanized monoclonal antibody selectively targeting CGRP. Like galcanezumab and eptinezumab, it is now supported by phase 3 data from short-term, double-blind, placebo-controlled trials backed up by reassuring results from long-term, open-label studies.

Peter J. Goadsby, MD, PhD, presented interim 6-month results of an ongoing, randomized, multicenter, 12-month, double-blind safety and efficacy study of subcutaneous fremanezumab at either 225 mg once monthly or 675 mg quarterly in 1,110 patients with chronic migraine and 780 with episodic migraine. Most participants were rolled over after participating in the previously reported pivotal phase 3, 12-week, placebo-controlled, double-blind HALO CM trial in chronic migraine (N Engl J Med. 2017 Nov 30;377[22]:2113-22) or the same-design HALO EM episodic migraine trial (JAMA. 2018 May 15;319[19]:1999-2008).

During the 28 days prior to the start of the long-term, double-blind study, the chronic migraine patients averaged 16.4 migraine days, while the episodic migraine patients averaged 9.2. After 6 months on their assigned dosing regimen, the episodic migraine patients in the 225 mg monthly group had a mean 4.9 fewer monthly migraine days than at baseline, and the 675 mg quarterly group averaged 5.0 fewer days. The chronic migraine patients on 225 mg monthly had a mean 7.9-day reduction, while the 675 mg quarterly group averaged a 6.5-day reduction in monthly migraine days.

The key point in this interim analysis is that these clinically meaningful reductions in monthly number of migraine days at 6 months were of the same magnitude as at month 1, demonstrating solid maintenance of efficacy over time, noted Dr. Goadsby, professor of neurology at the University of California, San Francisco, and AHS president-elect.

Jessica Ailani, MD, presented evidence that fremanezumab is not only an effective migraine preventive therapy, it also shows potential as a medication for reversion from chronic migraine to episodic migraine.

That would be an important advance. Various lines of recent evidence suggest these two conditions are anatomically, clinically, and functionally distinct and may actually be separate conditions. Patients with chronic migraine – that is, at least 15 headache days per month, at least 8 of them migraines – typically have more comorbidities, are more prone to acute medication overuse, and are generally more difficult to treat, noted Dr. Ailani, a neurologist at Georgetown University in Washington and director of the MedStar Georgetown Headache Center.

She presented a post hoc analysis of the 1,130 chronic migraine patients who participated in the 12-week, placebo-controlled HALO CM trial. Thirty-two percent of them who were randomized to 675 mg of fremanezumab quarterly reverted from chronic to episodic migraine, meaning they had fewer than 15 headache days per month during all 3 months of the treatment period. So did 35% of patients who received 225 mg monthly. Both results were significantly better than the 23% placebo reversion rate, which is consistent with the effect of placebo in other studies.

The mean number of monthly headache days of at least moderate severity fell by 4.3 days from baseline in the fremanezumab quarterly group and by 4.6 with monthly therapy, significantly outperforming the 2.5-day reduction with placebo. And the patients who did well did very well indeed: those who reverted from chronic to episodic migraine went from a mean of 18-19 headache days per month at baseline to about 7 days during any month in the treatment period, she reported.

Two patients on 675 mg of fremanezumab quarterly developed antidrug antibodies.

Turning to fremanezumab’s impact on acute headache medication overuse, Stephen D. Silberstein, MD, presented another post hoc analysis of the HALO CM trial, this time focusing on the 587 participants who met the formal criteria for medication overuse headache (MOH) at baseline. That’s 52% of the total study population, underscoring just how prevalent MOH is among chronic migraine patients.

Patients with MOH at baseline experienced a mean reduction of 4.7 headache days of at least moderate severity per month on fremanezumab at 675 mg quarterly and a 5.2-day reduction with monthly fremanezumab, both significantly better than the 2.5-day reduction with placebo. A total of 35% of the fremanezumab quarterly group achieved a 50% or greater reduction in the monthly average number of at least moderately severe headaches, as did 39% of patients on monthly fremanezumab and 14% on placebo.

Moreover, during the 12-week study period, 55% of patients with MOH at baseline who were on fremanezumab quarterly reported no medication overuse, as did 61% of those on 225 mg of fremanezumab once monthly and 46% of controls, according to Dr. Silberstein, professor of neurology and director of the headache center at Thomas Jefferson University in Philadelphia.

Separately, Paul K. Winner, DO, made a powerful point: the standard clinical trial endpoint of change in frequency of monthly headache days fails to capture the full impact of migraine and its effective prevention. He illustrated this by presenting a secondary analysis of a randomized, double-blind, placebo-controlled, 12-week trial of fremanezumab, which included 1,121 chronic migraine patients. His analysis focused on changes in participants’ scores on the six-item Headache Impact Test, or HIT-6, a test that’s well established as a sensitive indicator of headache-related disability.

For the 1,034 participants who completed testing, the average baseline HIT-6 score was 64 points on a test that can range from 36-78, with higher scores indicating greater adverse impact. At repeat testing 4 weeks after the last dose, the quarterly dosing group showed a statistically significant and clinically meaningful 6.4-point reduction from baseline, and the monthly fremanezumab group had a 6.8-point reduction. Both of those outcomes were significantly better than the placebo group’s 4.5-point decrease, reported Dr. Winner, director of Palm Beach Neurology in West Palm Beach, Fla.

Those HIT-6 changes in fremanezumab-treated patients moved them from the severe disability category to moderate disability, he noted.

“We also evaluated other disability components in this study. The MSQ – the Migraine Specific Quality-of-Life Questionnaire – also showed significant improvement by patient assessment, and on a patient global assessment measure, over 50% of patients who got fremanezumab noted improvement in that 12-week study, getting back to work, functioning normally, etc.,” the neurologist added.