Three new trials of novel headache drugs


July saw the publication of three trials of novel drugs for the treatment of acute migraine and cluster headache.

The first was rimegepant, an oral calcitonin gene-related peptide (CGRP) receptor antagonist, which is currently in development for acute migraine. Other drugs in this class are telcagepant (withdrawn due to hepatotoxicity concerns), ubrogepant, olcegepant and atogepant. In the phase III trial, 1186 patients with migraine (2-8 moderate/severe migraines/month) were randomized to rimegepant 75 mg/day or placebo for a single migraine attack (Lipton et al. N Engl J Med 2019;381:142-149). The proportion of patients who were pain-free two hours after dosing was 19.6% with rimegepant versus 12.0% with placebo. In addition, 37.6% of rimegepant-treated patients reported they were free from their most bothersome symptom compared to 25.2% receiving placebo.

The 7.6% treatment difference reported in the trial would appear to be less than what is seen with subcutaneous or oral sumatriptan (Derry et al. Cochrane database Syst Rev: CD009108).

A network meta-analysis of rimegepant and other oral CGRP antagonists in acute migraine found that olcegepant was the most effective of this class of agents and ubrogepant was associated with a lower risk of adverse events (Xu et al. Front Pharmacol 2019;10:795).7

A second class of acute migraine drugs is ditans (5-HT1F receptor agonists), which includes LY334370 (no longer in development due to hepatotoxicity concerns) and lasmiditan (LY573144). The clinical development program for lasmiditan has two phase III trials with a fighting theme (SAMURAI, SPARTAN) and an equally combative long-term extension (GLADIATOR). SAMURAI randomized 1856 patients to oral lasmiditan 200 mg or placebo for their next migraine (Kuca et al. Neurology 2018;91:e2222-e2232). The proportion free of headache pain at two hours was 32.2% with lasmiditan versus 15.3% with placebo. SPARTAN was a larger study (N=3005) that used the same study design (Goadsby et al. Brain 2019; epublished May 27, 2019). The proportion pain-free at two hours was 38.8% with lasmiditan 200 mg versus 21.3% with placebo; a higher proportion of lasmiditan-treated patients were also free of their most bothersome symptom (48.7% vs. 33.5%). The most common adverse events were dizziness, somnolence and paraesthesia. A subgroup analysis of patients using migraine prophylaxis in the two trials (n=698) found that those taking a preventive medication were more likely to be pain-free after lasmiditan dosing (Loo et al. J Headache Pain 2019;20:84).

A number of monoclonal antibodies targeting CGRP are approved or in development for chronic migraine, including erenumab, fremanezumab, galcanezumab and eptinezumab. Phase III results are also now available for galcanezumab in episodic cluster headache (Goadsby et al. N Engl J Med 2019;381:132-141). Patients were randomized to galcanezumab 300 mg s.c. or placebo at baseline and at one month. During weeks 1-3, the mean reduction in the number of cluster headaches was 8.7 with galcanezumab (baseline 17.8) and 5.2 with placebo (baseline 17.3). The proportion with >50% reduction in headache frequency at week 3 was 71% with galcanezumab versus 53.0% with placebo.

The U.S. Food and Drug Administration approved the use of galcanezumab for episodic cluster headache in June 2019. The drug is self-administered by injection at the onset of a cluster headache, with monthly doses until the end of the cluster headache period.

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