In patients with chronic migraine, monthly or quarterly doses of fremanezumab—an investigational humanized IgG2a monoclonal antibody with a selective affinity for calcitonin gene-related peptide—may be effective as preventive therapy. Fremanezumab may also significantly reduce the frequency of headaches, according to results of a study published in The New England Journal of Medicine.
In this 16-week, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial, researchers studied the efficacy of fremanezumab as a preventive treatment for migraine by comparing two dosing regimens with placebo. The study was comprised of a screening visit, a 28-day preintervention period, a 12-week intervention period, and a week 12 final evaluation.
Researchers randomized 1,130 patients with chronic migraine 1:1:1 to fremanezumab given subcutaneously quarterly (n=376; single dose, 675 mg at baseline or placebo at weeks 4 and 8), monthly (n=379; 675 mg at baseline and 225 mg at weeks 4 and 8), or placebo (n=375). The primary endpoint was mean change in the average number of headache days per month during the 12 weeks after the first dose. A headache day was defined as headache pain lasting 4 or more consecutive hours with at least moderate peak severity or days when triptans or ergots were used to treat headache of any severity or duration.
Mean number of headache days per month at baseline was 13.2 in those dosed with fremanezumab quarterly, 12.8 in those dosed monthly, and 13.3 days in those receiving placebo. During the 12-week intervention period, these days were reduced to an average of 8.5, 8.0, and 10.4 days, respectively.
Least-squares mean reductions in days were significantly greater in both groups treated with fremanezumab compared with placebo (4.3, 4.6, and 2.5 days, respectively; P < 0.001 for both).
Further, significantly more patients treated with fremanezumab had at least a 50% reduction in their average number of headache days per month, with 38% and 41% of patients treated with fremanezumab quarterly or monthly, respectively, exhibiting a ≥ 50% reduction, compared with only 18% of placebo recipients (P < 0.001 for both comparisons with placebo).
Patients in both groups treated with fremanezumab had greater reductions in the average number of days per month when acute headache medications were used compared with placebo (3.7, 4.2, and 1.9 days, respectively; P < 0.001 for both).
The degree of headache-related disability was also significantly decreased between baseline and 4 weeks after last dosing in patients treated with both regimens of fremanezumab compared with placebo. Results showed a 6.4-point reduction in Headache Impact Test-6 score in patients dosed with fremanezumab quarterly, 6.8-point reduction with fremanezumab monthly, and 4.5-point reduction with placebo (P < 0.001 for both).
Adverse events were mainly mild to moderate, and were comparable between the three groups (70%, 71%, and 64%, respectively; P=0.06). Injection-site reactions were seen in 47% (P=0.08), 47% (P=0.03), and 40%, respectively, with no significant differences between the three groups. Abnormalities of hepatic function were observed in 1% of each fremanezumab group, and in less than 1% of those in the placebo group (P=0.73 for each fremanezumab group compared with placebo; P=0.56 for combined fremanezumab groups compared with placebo).
Serious adverse events occurred in < 1% of those dosed quarterly, 1% of those dosed monthly, and in 2% of placebo patients. One death occurred, but was determined to be due to chronic obstructive pulmonary disease, and not the study medication. All serious adverse events had resolved or were resolving by the end of the trial.
“Although the current trial included patients with a long history of disease and those who had previously not had a response to or were currently taking preventive medications, it did not include patients with more refractory disease—those who had not had a response to at least two clusters of preventive medications or who had continuous headache,” noted the authors, led by Dr. Stephen Silberstein, MD, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA.
“This phase 3 trial of fremanezumab in chronic migraine showed a significant benefit of fremanezumab over placebo with respect to the average number of headache days per month (difference vs placebo, approximately -2 days per month), the number of migraine days, and headache-related disability. Treatment effects were seen within 4 weeks after the initial dose,” concluded these authors.
On December 18, 2017, the US Food and Drug Administration (FDA) accepted Teva Pharmaceutical Industries Ltd., Biologics License Application for fremanezumab for the preventive treatment of migraine. At this time, the FDA also granted fast track designation for fremanezumab as treatment for the prevention of cluster headache.
This study was supported by Teva Pharmaceuticals.