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Fremanezumab, a calcitonin gene-related peptide (CGRP) inhibitor, met its primary endpoint in an , researchers reported.

From a baseline of about 9 headache days per month, monthly subcutaneous doses of fremanezumab led to 4.9 fewer mean monthly migraine days and a single higher dose led to 5.3 fewer mean monthly migraine days, according to David Dodick, MD, of the Mayo Clinic in Phoenix, and colleagues. These reductions were greater than the drop from 9.1 to 6.5 days in the placebo group, the team reported in .

Episodic migraine -- headaches that occur on fewer than 15 days per month -- is the most common form of migraine. Fremanezumab is a fully humanized monoclonal antibody that binds to both isoforms of the CGRP ligand (not the receptor) and is administered by subcutaneous injection.

This study supplements previous research that showed fremanezumab's efficacy in preventing chronic and episodic migraine and adds to recent findings that support migraine prevention with three other monoclonal antibodies -- erenumab (Aimovig), eptinezumab, and galcanezumab.

This randomized, double-blind, placebo-controlled trial, which was conducted at 123 sites in nine countries from March 2016 to April 2017, included a screening visit, a 28-day pretreatment period, a 12-week treatment period, and a final evaluation at week 12.

Participants were 18 to 70 years old and had 6 to 14 headache days per month, including at least 4 migraine days during a 28-day pretreatment period. The researchers excluded patients if they used onabotulinum toxin A (Botox) during the 4 months before screening or if two classes of migraine-preventive medications had failed.

The team allowed a subset of patients to use one concomitant preventive migraine medication if the dosing was stable for at least 2 months before the pretreatment period began and did not change during the study.

In total, 875 patients were randomized to receive subcutaneous monthly dosing of fremanezumab (n=290; 225 mg at baseline, week 4, and week 8), a single higher dose of fremanezumab to support a quarterly dose regimen (n=291; 675 mg at baseline; placebo at weeks 4 and 8), or placebo (n=294; at baseline, week 4, and week 8). Participants were an average age of 42, and 85% were women. About 21% of patients had treatment with one concomitant preventive medication during the trial.

Of the 875 patients, 90.4% completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 to 4.9 days in the fremanezumab monthly-dosing group, from 9.2 to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 to 6.5 days in the placebo group.

This resulted in significantly fewer monthly migraine days with monthly dosing of fremanezumab (–1.5 days) and with a single higher dose at baseline (–1.3 days) than placebo over 12 weeks (P<0.001 for both).

Treatment-related adverse events were higher in the fremanezumab treatment groups (48% in the monthly group and 47% in the single-higher-dose group) than in the placebo group (37%) and primarily were related to injection site reactions.

"An important apparent benefit of fremanezumab and the other three CGRP monoclonal antibodies in development is their low burden of common nuisance adverse events," observed Elizabeth Loder, MD, MPH, of Brigham and Women's Hospital in Boston and Matthew Robbins, MD, of Montefiore Headache Center in Bronx, N.Y., in an

They noted that these agents are convenient and offer the benefit of monthly or quarterly dosing, but long-term safety remains unknown. Migraine often starts in early life and if CGRP monoclonal antibodies are approved by the FDA, patients will use them much longer than the span of any clinical trials.

"It is thus sobering to consider that there have been three deaths in clinical trial participants who received CGRP monoclonal antibodies," Loder and Robbins wrote, citing a suicide 109 days after treatment in the current trial, a death due to chronic obstructive pulmonary disease 69 days after treatment in , and a death reported in an interim analysis of an that the researchers called an "arteriosclerosis event."

These deaths stand out because clinical trials aim to enroll participants with migraine who are otherwise healthy, Loder and Robbins added. While the deaths may not have been treatment related, "cardiovascular ischemia and myocardial infarction are safety problems that have been considered likely to occur with suppression of CGRP, which also may play a role in airway homeostasis. Psychiatric adverse effects must also be monitored with treatments that directly or indirectly affect brain processes, which is why the FDA requires suicide and depression inventories in trials of all such drugs."

The researchers listed several limitations to the study: It was powered to detect a 1.6-day difference in mean monthly migraine days between fremanezumab and placebo, but the observed effect sizes were 1.5 and 1.3 days. However, no minimally clinically important difference has been established for this outcome, the authors noted. The trial also did not include treatment-refractory patients and was limited to 3 months of follow-up, but a 12-month extension is ongoing.