Long‐Term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine: Phase 3, Randomized, 52‐Week Extension Trial

Abstract

Objective.-To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine. Background.-Ubrogepant is an oral, calcitonin gene-related receptor antagonist in development for the acute treatment of migraine. The efficacy of ubrogepant was demonstrated in 2 phase 3 trials in which a significant improvement was observed in migraine headache pain, migraine-associated symptoms, and ability to function.Methods.-This was a phase 3, multicenter, randomized, open-label, 52-week extension trial. Adults with migraine with or without aura entered the trial after completing one of 2 phase 3 lead-in trials and were re-randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. Randomization to ubrogepant dose was blinded. Those randomized to usual care continued to treat migraine attacks with their own medication. The usual care arm was included in this trial to capture background rates of hepatic laboratory parameters and contextualize hepatic safety assessments. Safety and tolerability were the primary outcome measures. The safety population for the ubrogepant arms included all randomized participants who received at least 1 dose of treatment. All cases of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations of ≥3 times the upper limit of normal were adjudicated by an independent panel of liver experts who were blinded to dose.Results.-The safety population included 1230 participants (404 in the ubrogepant 50-mg group, 409 in the ubrogepant 100-mg group, and 417 in the usual care group). Participants were on average 42 years of age, 90% (1106/1230) female and 85% (1043/1230) white, with an average BMI of 30 kg/m 2 . Throughout the trial, 21,454 migraine attacks were treated with 31,968 doses of ubrogepant. Treatment-emergent adverse events (TEAEs) were reported by 268/404 (66%) participants receiving ubrogepant 50 mg and 297/409 (73%) receiving ubrogepant 100 mg. The most commonly reported TEAE was upper respiratory tract infection (<12%); findings were similar across dose groups. Treatment-related TEAEs were reported by 42/404 (10%) participants in the ubrogepant 50-mg group and 43/409 (11%) in the ubrogepant 100-mg group. Serious adverse events (SAEs) were reported by 9/404 (2%) participants in the ubrogepant 50-mg group and 12/409 (3%) participants in the ubrogepant 100-mg group. Twenty cases of ALT/AST levels of ≥3 times the upper limit of normal were reported and reviewed by an independent clinical adjudication committee of liver experts. There were no cases of Hy's Law.Conclusions.-Long-term intermittent use of ubrogepant 50 and 100 mg given as 1 or 2 doses per attack for the acute treatment of migraine was safe and well tolerated, as indicated by a low incidence of treatment-related TEAEs and SAEs and discontinuations due to adverse events in this 1-year trial.

Ubrogepant: First Approval

“…Of the 20 cases of AST/ ALT levels ≥ 3 × ULN reported across treatment groups, two cases in the ubrogepant 50 mg group were adjudicated by an independent panel of liver experts blinded to treatment to be possibly treatment-related and one case in the ubrogepant 100 mg group was judged to be probably related (confounding factors were noted in this case). There were no cases of Hy's Law [25].…”

“…No safety concerns were identified during longer-term acute treatment of migraine attacks with ubrogepant 50 mg or 100 mg, as required, in the 1-year extension study [25]. The safety population comprised 404, 409 and 417 patients in the ubrogepant 50 mg, ubrogepant 100 mg and usual care groups, respectively; over the 1-year study period, 21,454 migraine attacks were treated with 31,968 doses of ubrogepant.…”

Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies

“…The [52] and has the following structural formula ( Figure 2): The recommended single oral dose of ubrogepant is 50 mg or 100 mg depending on the intensity of pain, up to two doses per day, at least 2 h apart, and the maximum daily dose is 200 mg [52][53][54][55]. Clinical trials [54][55][56][57][58][59][60][61][62][63][64][65] confirmed its efficacy and good tolerance compared to placebo. Adverse reactions reported include mostly rare nausea, insomnia, and dry mouth, and potential hepatotoxicity should be considered [54][55][56][57][58][59][60][61][63][64][65].…”

“…Pharmacokinetics of ubrogepant is dose-proportional in the dose range from 1 mg to 400 mg; no accumulation was observed after multiple once daily dosing, and steady state is achieved within 2 days [57,68]. Age, sex, race, bodyweight, as well mild to moderate renal and hepatic impairment have been shown to have no effect on pharmacokinetics (AUC and C max ) of ubrogepant [57][58][59]64].…”

“…Ubrogepant is a substrate of BCRP and P-gp transporters; therefore, the use of inhibitors of BCRP and/or P-gp may increase exposure of this gepant which is explained in Section BCRP-and/or P-gp-Only Inhibitors below [53][54][55]57,58,63].…”