By Matthew S. Robbins, MD, FAAN, FAHS

Neurology Residency Program Director, Assistant Professor of Neurology (Interim), Weill Cornell Medical College, NewYork-Presbyterian Hospital

Dr. Robbins reports no financial relationships relevant to this field of study.

SYNOPSIS: Two randomized clinical trials showed that calcitonin gene-related peptide targeting therapies are effective and safe for primary headache disorders.

SOURCES: Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med 2019;381:132-141.

Lipton RB, Croop R, Stock EG, et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med 2019;381:142-149.

Goadsby et al conducted a multicenter, randomized, controlled trial (RCT) of galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), for the prevention of episodic cluster headache (CH). Patients 18 to 65 years of age had to present with pre-existing CH with bouts lasting for at least six weeks. They were treated with either galcanezumab 300 mg subcutaneously or placebo. Patients could not use contemporaneous prophylaxis but could use common acute attack therapies, such as triptans and oxygen. After a screening interval and a prospective baseline period lasting 10-15 days, the eight-week treatment regimen began, featuring galcanezumab administration at treatment onset and at month one.

Trial enrollment was curtailed because of too few subjects in an active CH period. Ultimately, 57 subjects were treated with placebo and 49 subjects with galcanezumab, without major baseline differences between the two groups. For the primary endpoint, subjects who were treated with galcanezumab exhibited an 8.7 ± 1.4 reduction in weekly cluster headache attack frequency across weeks 1 through 3 vs. 5.2 ± 1.3 in the placebo group (95% confidence interval, 0.2-6.7; P = 0.04). The 50% attack frequency reduction rate at week 3 was 71% for galcanezumab vs. 53% for placebo (P = 0.046). Efficacy rates in the second month converged across the groups. No serious adverse events were reported, with injection site reactions reported most commonly. Drug discontinuations were rare.

In another study, Lipton et al conducted a large, multicenter RCT of a single dose of rimegepant, an oral CGRP receptor antagonist, for the acute treatment of migraine. The study included more than 1,000 subjects 18 years of age and older with two to eight migraine attacks monthly, excluding patients who would satisfy criteria for chronic migraine. There were no differences in baseline characteristics between the subjects receiving rimegepant 75 mg (n = 537) and placebo (n = 535).

For the first primary endpoint, patients receiving rimegepant reported higher rates of two-hour pain freedom than those receiving placebo (19.6% vs. 12.0%; P < 0.001). For the second primary endpoint, patients receiving rimegepant showed higher rates of two-hour most bothersome symptom freedom (mostly photophobia) than those receiving placebo (37.6% vs. 25.2%; P < 0.001).

Serious adverse events were rare and included one patient with back pain in the rimegepant group, one patient with chest pain in the placebo group, and one patient with a urinary tract infection (UTI) in the placebo group. Overall, adverse events were uncommon (nausea and UTI were the most frequently reported adverse events).


These two landmark articles document safe and effective treatments for primary headache disorders. Both treatments target CGRP, either via monoclonal antibody to the ligand itself (galcanezumab) or small molecule receptor antagonist (rimegepant). It is clear that CGRP is pivotally involved in headache pathophysiology in both the peripheral and central nervous systems. Presumably, the site of action of galcanezumab is peripheral, based on limited ability to cross the blood brain barrier, although rimegepant may act both peripherally and centrally. This study led galcanezumab to become the first-ever FDA-approved preventive treatment for CH, although in a separate study it did not demonstrate efficacy for chronic CH. Further, fremanezumab, another monoclonal antibody to the CGRP ligand, did not demonstrate efficacy in trials for episodic and chronic CH. This distinguishes CH from migraine, where CGRP-based therapies have shown consistent efficacy across drugs and migraine spectrum severity (episodic and chronic).

Previous guidelines show a major gap in preventive treatment for CH, which has a 1/1,000 lifetime prevalence. Whether galcanezumab can supplant verapamil, the most commonly used CH treatment believed to be the most effective, is unclear; certainly, cost and access will be major factors. Its potentially short treatment latency may place it at an advantage, reducing the need for simultaneous short-term preventive treatment such as oral steroids or greater occipital nerve injection.

Rimegepant, and potentially other gepants, will prove to be an additional treatment option for patients to treat acute migraine attacks, although efficacy rates seem to be similar to triptans and other acute treatments. Still, tolerability, apparent lack of contraindications (particularly cardiovascular), and lack of evidence for an association with medication overuse may place gepants at a distinct advantage over triptans. Gepants also may be more tolerable than lasmiditan, another triptan alternative (a 5HT1F receptor agonist that likely will receive FDA approval soon).

Long-term safety, tactics for repeat dosing, cost, and access will be major factors influencing rimegepant’s clinical practice niche, as may be safety with simultaneous CGRP targeting monoclonal antibodies.