Ubrogepant—an investigational calcitonin gene-related peptide receptor antagonist (CGRP-RA)—was effective at treating migraine attacks, according to a new study published in Cephalagia, lending further support to the use of this novel class of drug in acutely treating migraine.
“CGRP plays an important role in the pathophysiology of migraine,” wrote senior author David Michelson, MD, Department of Neurology, Stanford University Medical Center, Palo Alto, CA, and fellow authors. “Various small-molecule CGRP receptor antagonists (RAs) have been studied in clinical trials and shown positive efficacy and tolerability. CGRP RAs may be of use for those in whom triptans are not effective or well tolerated.”
Although triptans are first-line therapy for migraines, many people fail to respond to them. This lack of response results in migraineurs cycling through different medications, and is linked to heightened disability and conversion from episodic to chronic migraines. Moreover, triptans constrict arteries and pose risk to migraine patients with comorbid cardiovascular disease (CVD), a group that comprises 19% of those with migraine between 40 and 59 years of age. Importantly, migraineurs and physicians alike are concerned with adverse cardiac events secondary to triptans, and CGRP-RAs may make for a viable treatment option in migraine patients with cardiovascular disease. Nevertheless, some research suggests that an off-target effect of CGRP-RAs might be hepatotoxicity, indicated by increased liver enzymes among a minority of subjects who took CGRP-RAs on consecutive days.
In this current phase 2b, multicenter, double-blind, placebo-controlled study, researchers looked at the clinical efficacy, safety, and tolerability of ubrogepant in the treatment of a single migraine attack plus or minus aura. They randomized adults with a ≥ 1-year history of migraine in a stratified manner based on self-reported triptan response into four experimental and one control group:
- 138 subjects to ubrogepant 1 mg;
- 139 subjects to ubrogepant 10 mg;
- 139 subjects to ubrogepant 25 mg;
- 139 subjects to ubrogepant 50 mg;
- 140 subjects to ubrogepant 100 mg;
- 139 subjects to placebo.
The team instructed participants to take a single dose after experiencing a qualifying migraine attack. Two hours after taking the dose, patients were permitted to take non-study rescue medications for headaches that did not respond.
Self-reported primary endpoints included pain freedom at 2 hours post-dose and headache response at 2 hours post-dose.
Dr. Voss and colleagues used statistical analysis methods and multiplicity strategy to test the following three primary efficacy hypotheses:
- A positive response trend spanning ubrogepant doses, as determined by the ratio of participants with 2-hour pain freedom;
- At least one ubrogepant dose outperforming placebo in the treatment of acute migraine, as determined by the ratio of participants with 2-hour pain freedom;
- At least one ubrogepant dose outperforming placebo in the treatment of acute migraine, as determined by the ratio of participants with 2-hour headache response.
The investigators discovered a positive response trend spanning ubrogepant doses. Specifically, ubrogepant 100 mg statistically outperformed other doses with respect to 2-hour pain freedom but not 2-hour headache response.
Importantly, placebo response in this study was high (44.6%), which could be because with five active treatments, patients could have anticipated improvement thus resulting in bias. The researchers suggest that the “sensitivity of headache response to placebo effects supports the use of the more stringent pain freedom endpoint for determining treatment effects.”
Although statistical significance for 2-hour freedom from pain was attained only for the 100-mg dose of ubrogepant, the investigators observed other treatment effects for the 25-, 50-, and 100-mg doses, suggesting that various doses may be effective. This possibility would need to be further explored in future clinical trials.
Ubrogepant was well-tolerated by subjects, and the researchers observed neither resultant cardiovascular events nor increase in liver enzymes. Of note, the team excluded patients with frank CVD from the study.
“In conclusion,” the researchers wrote, “results from this trial provide evidence for the efficacy of ubrogepant on the 2-hour pain freedom endpoint and further evidence that CGRP-RAs are viable options for the acute treatment of migraine.”
This study was supported by Merck & Co. Inc.