Atogepant Proves Safe Without ALT Elevation in Healthy Participants

K. Chris Min, MD, PhD

K. Chris Min, MD, PhD

When administered once daily over the course of 28 days, the use of 170-mg oral atogepant (Allergan) was both safe and well-tolerated, with no evidence of clinically significant drug-related alanine aminotransferase (ALT) elevations in healthy adults.

The data, which were presented by K. Chris Min, MD, PhD, at the American Headache Society (AHS) virtual annual scientific meeting on June 13, 2020, showed that by Day 28, the geometric mean fold change in ALT from baseline levels was 0.79 (95% CI, 0.70—0.89) with atogepant compared to 0.99 (95% CI, 0.84–1.17) with placebo. Additionally, no ALT elevations ≥3 times the upper limit of normal were observed at any time post-dose.

“Two early versions of small-molecule CGRP receptor antagonists showed efficacy as migraine treatments, but clinical development was halted due to elevated ALT levels in clinical trials,” Min explained in his presentation. He noted that previously, the Allergan agent had shown efficacy in migraine prevention in doses ranging from 10 mg per day to 60 mg twice per day and was deemed safe and generally well-tolerated.

“The objective of this study was to evaluate the safety, tolerability, and pharmacokinetic profile of multiple oral 170-mg doses of atogepant in healthy adults,” Min added. All told, there was a 0.79-fold treatment difference between atogepant and placebo (95% CI, 0.67-0.94) with regard to ALT level change from baseline.

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This assessment was a single-center, randomized, double-blind, placebo-controlled study with healthy male and female participants aged 18 to 55 years, who were randomized 2:1 to an oral compressed tablet formulation of atogepant (n = 23) or placebo (n = 11). Of those 34 volunteers, 82.4% (n = 28) completed the study. Of the discontinuers, 5 were in the atogepant group; 2 each left due to protocol violation and adverse events (AEs), while 1 did so due to patient decision. A single participant dropped in the placebo group due to participant decision.

The median time to maximum concentration (C_max) was about 2 hours with atogepant (Day 1: geometric mean, 3170 nM [95% CI, 2250—3930]; Day 28: geometric mean, 3090 nM [95% CI, 2350–4070]), with a mean apparent terminal elimination half-life of approximately 10 hours (9.9 hours [95% CI, 41.1]).

All adverse events (AEs) were mild, except for a single serious AE, a subarachnoid hemorrhage, which was caused to a bicycle accident and unrelated to the study drug. That incidence, in addition to an AE of tachyphrenia—occurring in a female participant before her day 6 dose—were the only discontinuations related to AEs.

In the atogepant group, the most frequent AEs (in at least 13% of subjects) were fatigue (47.8%; n = 11), headache (30.4%; n = 7), decreased appetite (21.7%; n = 5), dizziness (21.7%; n = 5), nausea (13%; n = 3), back pain (13%; n = 3), vessel puncture-site pain (13%; n = 3), erythema (13%; n = 3), and pruritus (13%; n = 3). Comparatively, the placebo group experienced AEs at a rate of 13% or higher in the case of fatigue (36.4%; n = 4) and headache (27.3%; n = 3).

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REFERENCE

Min KC, Kraft WK, Bondiskey P, et al. Multiple, Once-daily, Oral Doses of 170 Mg Atogepant for 28 Days Are Safe and Well Tolerated with No Clinically Significant Effect on Alanine Aminotransferase in Healthy Adults. Headache. 2020;60(S1 suppl). 1-156. doi: 10.1111/head.13854