Subcutaneous fremanezumab, an investigational fully humanized monoclonal antibody, significantly reduced the number of migraine days per month compared with placebo in a randomized controlled trial of adults with episodic migraine, published in JAMA.
Fremanezumab selectively binds to both isoforms of the calcitonin gene-related peptide (CGRP) ligand, rather than the CGRP receptor, and is currently under review by the US Food and Drug Administration as a quarterly or monthly injection for the prevention of migraine in adults. The Prescription Drug User Fee Act action date for fremanezumab has been set for September 16, 2018.
As reported by David W. Dodick, MD, from Mayo Clinic Arizona, Phoenix, and colleagues, the efficacy, safety, and immunogenicity of two fremanezumab dosing regimens—monthly and a single higher dose—were explored compared with placebo in a parallel-group, multicenter, phase 3 trial that included 875 patients 18 to 70 years of age who had migraine 6 to 14 days/month. Patients were treated for 12 weeks.
Those treated monthly received 225 mg of fremanezumab at baseline (one 225-mg/1.5-mL injection and two placebo 1.5-mL injections) and at weeks 4 and 8 (one 225-mg/1.5-mL injection). The single higher dosing schedule consisted of 675 mg of fremanezumab at baseline (three 225-mg/ 1.5-mL injections) and placebo (one 1.5-mL injection) at weeks 4 and 8.
The primary endpoint of the study was the mean change from baseline (pretreatment period) in the mean number of monthly migraine days compared with the 12-week treatment period. Researchers defined a migraine day as a day with either ≥ 2 consecutive hours of a migraine with or without aura; probable migraine; or a day, when acute migraine-specific medication (triptans or ergots) was used to treat a headache, regardless of duration.
At baseline, patients treated with monthly dosing had a mean of 8.9 monthly migraine days. Those in the single higher dose group had 9.2 days and those in the placebo group 9.1 days. All had severe disability based on the MIDAS score, with mean baseline scores of 38.0, 41.7, and 37.2 points, respectively. A total of 791 patients (262 treated with fremanezumab monthly, 264 with fremanezumab single higher dose, and 265 with placebo) completed the study.
Compared with baseline, patients randomized to monthly dosing of fremanezumab experienced a mean of 3.7 fewer migraines per month during the 12-week treatment period, compared with 3.4 fewer in the single higher dose group, and 2.2 fewer in the placebo group.
The differences in the decrease in mean migraine days between placebo and fremanezumab monthly dosing (P < 0.001) and placebo and the fremanezumab single higher dose (P < 0.001) were statistically significant.
Nearly half of the patients in both groups treated with fremanezumab had at least a 50% reduction in mean number of monthly migraine days during the 12-week treatment period, compared with 27.9% in the placebo group.
The mean numbers of monthly days with any acute headache medication use during the 12-week treatment period declined by 1.4 days (P < 0.001) in the monthly dosing group, and by 2.9 days (P < 0.001) in the single higher dose fremanezumab groups compared with placebo.
Four weeks after administration of the third and last dose of the study drug, mean MIDAS scores were 7.0 points lower for the fremanezumab monthly dosing group (P < 0.001) and 5.4 points lower for the single-higher-dose group (P=0.002) compared with placebo, at 17.5 points lower.
At least one adverse event was reported by 66% in either fremanezumab group and by 58% of the placebo arm. The incidence of severe adverse events, serious adverse events, and adverse events leading to discontinuation was ≤ 2% across the treatment groups.
The most common adverse events in patients treated with fremanezumab were injection site reactions including pain, induration, and erythema. The proportion of patients with injection site pain, induration, and erythema was higher with fremanezumab than with placebo. In each treatment group, the proportion of patients who discontinued because of adverse events was about 2%.
In an accompanying editorial, authors Elizabeth W. Loder, MD, MPH, Division of Headache, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and Matthew S. Robbins, MD, Jack D. Weiler Hospital, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, pointed to the low burden of nuisance side effects as an advantage to fremanezumab over the three other CGRP monoclonal antibodies, but mentioned that three deaths have been reported in clinical trials of fremanezumab and the other CGRP monoclonals.
“It is thus sobering to consider that there have been three deaths in clinical trial participants who received CGRP monoclonal antibodies,” they noted. These deaths and several related adverse events are noteworthy because clinical trials usually aim to enroll participants with migraine who are otherwise healthy. The deaths may not have been treatment related.”
Drs. Loder and Robbins speculated that the results of the study by Dr. Dodick et al. may not apply to patients with severe, treatment-resistant migraine because patients with failure of as few as two preventive medications were excluded from the study.
Nevertheless, their results demonstrated significant benefits from fremanezumab in these patients.
“The clinical trial by Dodick et al. reported in this issue of JAMA adds important evidence about this new class of specific preventive therapies with benefits in both episodice and chronic migraine. The challenge will be to move from treatment based on general phenotypes to therapies that are based on a more sophisticated understanding of individual patients,” they concluded.