Ubrogepant — a small-molecule, orally delivered, and specific calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine — features a favorable tolerability profile in healthy adults, study results published in Cephalalgia suggest.

Calcitonin gene-related peptide receptor antagonism was previously shown to be effective in the acute treatment of migraine attacks. However, the first-generation small molecule

receptor antagonists in this class were discontinued due to data suggesting the potential for drug-induced liver injury. Adverse events were later attributed to molecule-specific metabolites rather than a class effect. The investigators aimed to evaluate the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing in healthy participants.

The study was a small phase 1 double-blind trial consisting of healthy adults between the age of 18 and 50 years. Participants were randomly assigned to receive either placebo (n=260) or ubrogepant (n=256). Treatment with ubrogepant was administered at 100 mg on 2 consecutive days, followed by 2 consecutive days of placebo. This alternating treatment pattern was continued for 8 weeks. The primary outcomes of this study were safety and tolerability as assessed by treatment-emergent adverse events (TEAEs), with a specific focus on hepatic safety.

A similar percentage of patients in the placebo and ubrogepant groups experienced TEAEs (45% and 44%, respectively). Headache was the most common event, reported in 10% of patients randomly assigned to receive placebo vs 11% of patients randomly assigned to receive ubrogepant. A total of 5 patients in the placebo group and 2 patients in the ubrogepant group had ALT and/or AST levels ≥3 times the upper limit of normal. These events were not likely to be related to therapy in 4 cases, the investigators reported. None of the hepatic TEAEs led to discontinuation of therapy.

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The inclusion of healthy patients with a relatively normal body weight may have reduced the generalizability of the findings across patients with migraine and/or patients with obesity.

“When administered at the studied frequency,” the researchers wrote, “ubrogepant was safe and well tolerated over an 8-week period, with no clinically relevant signal of hepatotoxicity.”

Disclosure: This clinical trial was supported by Allergan. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Goadsby PJ, Tepper SJ, Watkins PB, et al. Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: randomized, placebo-controlled trial in healthy adults [published online September 19, 2019]. Cephalalgia. doi:10.1177/0333102419869918