A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single‐Dose, Phase 1 Crossover Trial

Abstract

Atogepant is a selective, oral calcitonin gene-related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double-blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open-label active control. The primary end point was a change from baseline in Fridericia-corrected QT intervals ( QTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline ( QTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2-, 3-, and 4-hour time points. Following single-dose atogepant 300 mg, mean atogepant QTcF and upper 90% confidence interval limits were lower than the 10-millisecond threshold at all time points. Atogepant mean peak plasma concentration was 3197 ng/mL, area under the concentrationtime curve from time 0 to time t was 16 640 ng • h/mL, area under the concentration-time curve from time 0 to 24 hours was 16 607 ng • h/mL, and median time to peak plasma concentration was 2.1 hours. The incidence of adverse events was low; no serious adverse events or elevations of liver enzymes were reported. Overall, a single supratherapeutic dose of atogepant was safe and did not impact cardiac repolarization in healthy participants.

Role of Atogepant in the Treatment of Episodic Migraines: Clinical Perspectives and Considerations

“… 42 Over 28 days of treatment (170 mg supratherapeutic dose), no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal (ULN). 44 A Phase I clinical study reported atogepant can be tolerated in single doses as high as 300 mg. 45 No cardiovascular AEs, such as prolonged QT/QTc, were observed. It remains uncertain whether chronic CGRP antagonism leads to receptor upregulation or tolerance.…”

Gepants — a long way to cure: a narrative review

“…To further test atogepant safety, supratherapeutic doses were administered in two clinical trials to investigate cardiac repolarization [ 59 ] and alanine aminotransferase elevations [ 60 ] in healthy adults.…”

“…Moxifloxacin 400 mg was the open-label active control. The trial did not report serious adverse events or elevated liver enzymes, nor the impact on cardiac repolarization in healthy participants [ 59 ].…”

Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale

“…Atogepant (Qulipta ® , AbbVie, Chicago, IL, USA) is a potent, selective, competitive, second-generation oral CGRP receptor antagonist with a T max of ~ 2 h and a half-life of ~ 11 h [ 114 ]. A phase I study found atogepant was tolerated in single doses up to 300 mg [ 115 ].…”