Abstract and Introduction
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/m2. 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.
Introduction
Migraine is a highly prevalent and burdensome chronic disease with attacks characterized by 1-sided pulsatile pain associated with sensitivity to light and sound, and nausea in various combinations.[1] Based on the recent Global Burden of Disease study, migraine ranks second among the leading causes of years lived with disability,[2,3] impacting not only a person's daily living activities but having a negative effect on their families as well.[4–9] Effective and safe treatment options are needed to help reduce the burden of migraine.
Several acute treatment options are currently available, including analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, and triptans.[10–12] Even with the number of acute treatments available, approximately 50% of those with migraine are not satisfied with their acute treatment for migraine and most have significant unmet treatment needs.[13] In the Migraine in America Symptoms and Treatment study,[14] of the 15,133 adults with migraine, only 15% were using a triptan and 95.8% had at least 1 unmet treatment need.[15] Among migraine-specific acute medications, ergot derivatives and triptans, though effective, are associated with safety and tolerability issues as well as contraindications.[11,16] This supports the need for additional migraine-specific treatment options with desirable efficacy and safety profiles.
Calcitonin gene–related peptide (CGRP) plays an important role in migraine pathophysiology and as a result, small molecule CGRP receptor antagonists, known as gepants, are being studied for their efficacy in treating migraine.[17,18] Ubrogepant is an oral gepant in development for the acute treatment of migraine. The efficacy and safety of ubrogepant have been shown in proof-of-concept and large, placebo-controlled trials.[19–21] The phase 3 ACHIEVE I and II single-attack trials met their co-primary endpoints for the 50- and 100-mg doses, thereby establishing ubrogepant's efficacy. Rates of headache pain freedom 2 hours post-dose were significantly superior to placebo with ubrogepant 25, 50, and 100 mg (P ≤ .01).[20,21] In addition, the rates of absence of the most bothersome migraine-associated symptom (photophobia, phonophobia, or nausea) at 2 hours were significantly greater with ubrogepant 50 and 100 mg than placebo (P ≤ .01), but not with ubrogepant 25 mg.
The primary objective of this phase 3, multicenter, randomized, 52-week extension trial was to evaluate the long-term safety and tolerability of intermittent treatment with ubrogepant for the acute treatment of migraine over 1 year. Treatment groups included ubrogepant 50 mg, ubrogepant 100 mg, and a usual care arm. The usual care arm was included to contextualize any hepatic safety findings over the course of this trial. Many treatments were included in the usual care arm, often treatments the patients were already using; therefore, non-laboratory adverse events (AEs) were not captured in relation to treatment in this arm.
Headache. 2020;60(1):141-152. © 2020 Blackwell Publishing