Atogepant is a potent, selective, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics of a once-daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double-blind, placebo-controlled phase 1 trial in healthy participants. Overall safety, hepatic safety, and plasma pharmacokinetic parameters were evaluated. Thirty-four participants aged 23-55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except 1 serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were 2 discontinuations due to AEs, both with atogepant, 1 considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5× upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant was rapidly absorbed (median time to maximum plasma concentration, approximately 2 hours) with an apparent terminal half-life of approximately 11 hours, and no evidence of accumulation after once-daily dosing. Overall, atogepant at a high oral dose was safe and well tolerated in healthy participants with no clinically meaningful elevations in ALT.This article is protected by copyright. All rights reserved.