Safety and Tolerability of Fremanezumab for the Prevention of Migraine: A Pooled Analysis of Phases 2b and 3 Clinical Trials

Abstract

Objective Presentation of pooled analysis of safety data for fremanezumab in patients with chronic (CM) or episodic migraine (EM) from 4 placebo‐controlled phase 2b and phase 3 studies. Background There is a need for an effective, safe, and well‐tolerated preventive therapy that specifically targets the pathophysiology of migraine to reduce the frequency and severity of migraine attacks in patients with CM or EM who experience 4 or more migraine days per month. Fremanezumab is a fully humanized monoclonal antibody that targets calcitonin gene‐related peptide, a neuropeptide involved in the pathophysiology of migraine. Design/Methods The 4 placebo‐controlled phases 2b and 3 studies included in this analysis were 16‐week, multicenter, randomized, double‐blind, placebo‐controlled, and parallel‐group studies consisting of a screening visit, a 28‐day pretreatment baseline period, and a 12‐week treatment period with a final evaluation 4 weeks after the final dose of the study drug. Safety endpoints included adverse events (AEs) and immunogenicity. Results A total of 2566 patients were randomized across all studies (fremanezumab, n = 1704; placebo, n = 862), and 2563 patients were treated. Common reasons for study discontinuation were withdrawal by patient (n = 78), patient lost to follow‐up (n = 60), and AE (n = 50). The mean (standard deviation) duration of exposure was 83.8 (13.6) days for the patients who received fremanezumab, with a total exposure of 390.4 patient years and maximum exposure of 181 days. AEs were mostly mild to moderate in severity and were reported among 48‐69% of patients in all treatment groups, and most were injection site reactions (pain, induration, and erythema). Two deaths occurred (chronic obstructive pulmonary disease and intentional overdose of diphenhydramine), both of which were deemed unrelated to study drug by the investigators and sponsor. Cardiovascular adverse events, abnormal liver function tests, and hypersensitivity were uncommon and occurred at similar rates between the placebo and fremanezumab groups. Conclusions Fremanezumab is a generally safe and well‐tolerated preventive therapy for migraine in adults.

An Evidence-Based Review of Fremanezumab for the Treatment of Migraine

“…Serious AEs such as cardiovascular effects, hepatotoxicity, or hypersensitivity were rare and occurred at rates similar to those in placebo groups [80,85]. Consistent with these findings, a year-long study of fremanezumab in adults with episodic and chronic migraine demonstrated that the efficacy and safety of the drug were maintained over 12 months of treatment [85,106], but additional longitudinal studies are needed to confirm this. Fremanezumab is currently approved for use in adults, but it is important to note that there is insufficient data on safety in pregnant women, although studies in mating/ pregnant rats and rabbits found no adverse effects on fertility or embryo-fetal and postnatal development [76].…”

“…Fremanezumab needs to be stored in a refrigerator protected from light and should be discarded if it has been at room temperature for 24 h or longer [76]. Randomized placebo-controlled trials in adults with episodic and chronic migraine validated the effectiveness of fremanezumab as preventive therapy for migraine [76,77,[80][81][82][83][84][85]. The most common adverse reactions reported in clinical trials were injection site reactions which include pain, induration, and erythema at the site of injection [76].…”

“…No studies were conducted to determine the effect of renal impairment, severe hepatic impairment, or carcinogenesis on fremanezumab pharmacokinetics [76]. In a pooled safety analysis of four placebo-controlled phase 2b/3 studies (total n = 2563), the most common AEs were injection site reactions, most of which were mild to moderate [80,85]. Serious AEs such as cardiovascular effects, hepatotoxicity, or hypersensitivity were rare and occurred at rates similar to those in placebo groups [80,85].…”

“…In a pooled safety analysis of four placebo-controlled phase 2b/3 studies (total n = 2563), the most common AEs were injection site reactions, most of which were mild to moderate [80,85]. Serious AEs such as cardiovascular effects, hepatotoxicity, or hypersensitivity were rare and occurred at rates similar to those in placebo groups [80,85]. Consistent with these findings, a year-long study of fremanezumab in adults with episodic and chronic migraine demonstrated that the efficacy and safety of the drug were maintained over 12 months of treatment [85,106], but additional longitudinal studies are needed to confirm this.…”

“…In the most recent post hoc analysis, Silberstein et al [85] conducted a pooled analysis of safety and tolerability data from four phase 2b and 3 trials on fremanezumab in the preventive treatment of migraine [81][82][83][84][85]. In total, 2566 patients were randomized, and 2563 received either fremanezumab (n = 1704) or placebo (n = 86).…”