Two leading authorities in migraine management announced favorable results in separate trials targeting calcitonin gene-related peptide with mAb treatments for migraine pain.
By Vicki Moore, PhD with Lawrence Robbins, MD
Managing migraines may improve given the positive outcomes of two Phase 3 trials of monoclonal antibody migraine-preventive treatments directed against the calcitonin gene-related peptide (CGRP) and receptor system.1,2 CGRP, an alternative RNA-processing product of the calcitonin gene, is a vasodilator that is present in high amounts during migraines and cluster headaches.3
“This is an important class of new medicines; CGRP is crucial in addressing neuroinflammation, and tamping down CGRP makes sense,” Larry Robbins, MD, a neurologist at the Robbins Headache Clinic in Riverwoods, Illinois told Practical Pain Management when asked about the significance of CGRP to migraines. CGRP was targeted for both episodic and chronic migraine management.
Trials Targeting the CGRP system
One trial examined the efficacy of the human monoclonal antibody (mAb) erenumab as a preventive against episodic migraines (migraines or headaches occurring <15 days per month).1 Lead author Peter J. Goadsby, MD, PhD, of the National Institute for Health Research–Wellcome Trust King’s Clinical Research Facility at King’s College Hospital in London, UK, and colleagues performed this multicenter, international study.
The second study assessed the efficacy of the humanized monoclonal antibody, fremanezumab, for the prevention of chronic migraines (headaches ≥15 days per month and migraines for ≥ days per month). Fremanezumab targets CGRP.2 This international study was performed by lead author Stephen D. Silberstein, MD, of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia, PA, and colleagues.
Erenumab for Episodic Migraines
In the trial measuring the efficacy of erenumab against episodic ) migraines, 955 participants were followed from 18 to 65 years (mean age 40.9 years). Protocols involved treatments of 70 mg of erenumab (N=317), 140 mg of erenumab (N=319), or placebo (N=319) on day one and then 5 more times at 4-week intervals. Initial migraine days per month among all participants averaged 8.3.1
By months four to six of the study, the average migraine days per month decreased by 3.2 days (SE 0.2) for the 70 mg erenumab cohort (N=312), by 3.7 days (SE 0.2) for the 140 mg erenumab cohort (N=318), and 1.8 days (SE 0.2) for the placebo group (N=316; P < .001 for each treatment versus placebo). The odds ratios for ≥50% reduction of migraine days per month were 2.13 (95%CI, 1.52-2.98) for the 70 mg erenumab cohort and 2.81 (95%CI, 2.01-3.94) for the 140 mg erenumab cohort. A ≥50% reduction in migraine days per month occurred in 43.3%, 50.0%, and 26.6% of participants from the 70 mg erenumab, 140 mg erenumab, and placebo cohorts, respectively1.
Safety profiles were similar between treatment groups and the placebo group, with discontinuations due to adverse events occurring for 2.2% of each of the erenumab treatment groups and 2.5% of the placebo cohort.1 Of patients with available antibody data, 5.6% showed anti-erenumab binding antibodies. The research team acknowledged that long-term safety remains a question to be examined.
Fremanezumab for Chronic Migraines
In the trial examining the effectiveness of fremanezumab for treatment of chronic migraines, 1130 participants 18 to 70 years were placed into three treatment groups:2
- quarterly fremanezumab (675 mg of fremanezumab initially, and then placebo at weeks 4 and 8; N=376)
- monthly fremanezumab (675 mg of fremanezumab initially, and then 225 mg of fremanezumab at each of weeks 4 and 8; N=379),
- placebo for each time point (N=375). Participants initially averaged 13.2, 12.8, and 13.3 headache days per month, respectively
The mean number of headache days per month decreased by 4.3 days (SE 0.3) in the quarterly fremanezumab cohort, 4.6 days (SE 0.3) in the monthly fremanezumab cohort, and 2.5 days (SE 0.3) in the placebo cohort (P < .001 for each treatment versus placebo). A ≥50% reduction in mean headache days per month was seen in 38% of the quarterly fremanezumab cohort, 41% of the monthly fremanezumab cohort, and 18% of the placebo cohort.2 Chronic migraines are defined as occurring greater than or equal to 8 days per month.
Lead author, Stephen Silberstein, MD, professor and director of the Headache Center at Thomas Jefferson University in Philadelphia, Pennsylvania, and his research team reported injection-site reactions as the most common adverse events, occurring slightly more often among the fremanezumab treatment groups than for placebo, but not with significantly greater severity between the groups. Discontinuations due to adverse events occurred in 1% of the quarterly fremanezumab cohort and 2% in each of the monthly fremanezumab and placebo groups.
Among the fremanezumab treatment groups, there was one death during the study due to chronic obstructive pulmonary disease, and one patient with a history of depression showed suicidal ideation. The authors noted the need for long-term safety analysis.1
Clinical Outlook on These CRGP Treatments
While results with CGRP migraine-preventives have been positive, Dr. Robbins said, “I think they underestimate the impact of these drugs.” Regarding the manner in which results for these treatments are reported, he said, “that is the mean reduction in days of migraine; much more importantly, as with the Botox studies, there are significant numbers of patients who show an improvement of 75% to 95%; it is these individuals who will continue on these drugs long-term.”2
“The CGRP class of preventives will be extremely helpful for a group of chronic and episodic migraine patients, but many will not respond very much,” said Dr. Robbins. He continued, “I am concerned about potential long-term effects,” and also pointed out that these drugs may make for expensive treatments.2
Amgen and Novartis supported the clinical trial of erenumab (ClinicalTrials.gov number NCT02456740). Teva Pharmaceuticals supported the clinical trial of fremanezumab (ClinicalTrials.gov number NCT02621931). Disclosures are available for both studies at NEJM.org.
- Goadsby PJ, Reuter U, Hallström Y, Broessner G, et al. A controlled trial of erenumab for episodic migraine. New Engl J Med.2017;377(22):2123-2132.
- Silberstein SD, Dodick DW, Bigal ME, Yeiung PP, et al. Fremanezumab for the preventive treatment of chronic migraine. New Engl J Med.2017;377(22):2113-2121.
- Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache2017;57:S2:47-55.