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Novel agent prevents chronic migraine in trial
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Fremanezumab, given quarterly or monthly as subcutaneous injections, significantly reduced the average number of headache days per month in patients with chronic migraine compared with placebo, according to phase 3 trial results published in The New England Journal of Medicine.
“[Migraine] has a global prevalence of 15 to 18% and is a leading cause of disability worldwide ... Expert opinion has been that patients with chronic migraine should receive preventive treatment; however, these treatments may be underused, not adhered to, associated with side effects, or ineffective,” Stephen D. Silberstein, MD, from the Jefferson Headache Center at Thomas Jefferson University, and colleagues wrote.
Silberstein and colleagues conducted a double-blind, placebo-controlled phase 3 trial to investigate and compare the safety and efficacy of two subcutaneous dose regimens of fremanezumab with placebo for the preventive of chronic migraine. Chronic migraine was defined as having a headache of any duration or severity for 15 days or more per month and migraine for 8 days or more per month.
The researchers enrolled 1,130 patients with chronic migraine and randomly assigned 376 to receive fremanezumab quarterly, 379 to receive fremanezumab monthly and 375 to receive matching placebo. Patients in the quarterly group received a single dose of 675 mg of fremanezumab at baseline, then placebo at 4 and 8 weeks, whereas those in the monthly group received 675 mg of fremanezumab at baseline and 225 mg at 4 and 8 weeks. Fremanezumab and placebo were injected subcutaneously.
The researchers evaluated the mean change in the average number of baseline headache days per month over the 12 weeks following the initial dose of treatment. Headache days were defined as days when pain from headache persisted for 4 or more successive hours and had at least a moderate level of severity or days when acute migraine-specific medications were necessary to treat any severity or duration of headache.
Data showed that the mean number of headache days per month was 13.2 for the fremanezumab quarterly group, 12.8 for the fremanezumab monthly group and 13.3 for the placebo group. For the fremanezumab quarterly group, the least-squares mean (±SE) change in headache days was –4.3±0.3, whereas it was –4.6±0.3 for the fremanezumab monthly group and –2.5±0.3 for the placebo group.
A total of 38% of the fremanezumab-quarterly group, 41% of the fremanezumab-monthly group and 18% of the placebo group had at least a 50% decrease in average headache days per month. The researchers observed hepatic function abnormalities in five patients in the fremanezumab quarterly group, five in the fremanezumab monthly group and three in the placebo group.
“Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common,” Silberstein and colleagues concluded. “The long-term durability and safety of fremanezumab require further study.” – by Alaina Tedesco
Disclosure: Silberstein reports being a consultant for Alder BioPharmaceuticals, Allergan, Amgen, Automatic Technologies, Avanir Pharmaceuticals, Curelator, Depomed, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura, Insys Therapeutics, Supernus Pharmaceuticals, Teva Pharmaceuticals, Theranica BioElectronics and Trigemina. Please see study for all other authors’ relevant financial disclosures.
Perspective
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Teshamae Monteith, MD
Both migraine and chronic migraine remain underdiagnosed and undertreated. The first step to implementing the study findings is increasing awareness about the disease, diagnosis and migraine related disability. Clinicians should note that the compliance for oral preventive medications for migraine is strikingly low and that monthly dosing may substantially increase compliance.
If fremanezumab successfully becomes FDA-approved, clinicians should consider its use for the treatment of chronic migraine. There are three other monoclonal antibodies that target the calcitonin gene-related peptide pathway and confirm the excellent safety and tolerability profiles during the clinical trial periods.
Patients that have had intolerable side effects or contraindications to standard treatments or poor treatment responsiveness may best benefit. The next steps are to conduct long-term safety studies to monitor for adverse events related to immune therapies, for potential cardiovascular side effects and for exposure during pregnancy.
Perspective
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Roderick C. Spears, MD
This well-designed phase 3 randomized control study demonstrated a significant benefit of fremanezumab over placebo regarding the average number of headache days per month, the number of migraine days per month, and headache related disability. All of the above are goals that providers caring for patients with chronic migraine are hoping to achieve. The safety data presented in the study show mild to moderate adverse events in severity in 95 to 96% of patients, with injection site reactions being most common in both the fremanezumab groups and placebo group.
Clinicians should be excited about these data, but should start with groups that have been studied, such as chronic migraine patients. This study excluded patients using opioid or barbiturate medications frequently and those undergoing procedures such as nerve blocks and onabotulinumtoxinA injections within 4 months of the onset of the clinical trial, so there are no data reporting how they will respond to fremanezumab.
As for next steps, we are currently awaiting the FDA’s decision on fremanezumab. Thus far, the clinical trials have been conducted on relatively healthy patients. Future studies are needed in patients with more refractory migraine and in those with migraine and coexistent diseases.
The final important point is that elevated liver enzymes occurred in very few patients and resolved without intervention, but this should be monitored in patients chosen for this therapy.
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