Ubrogepant for the Acute Treatment of Migraine: Pooled Efficacy, Safety, and Tolerability From the ACHIEVE I and ACHIEVE II Phase 3 Randomized Trials

DOI: https://doi.org/10.1007/s40120-021-00234-7

Abstract-Summary The efficacy and safety of ubrogepant were demonstrated in two pivotal phase 3, single-attack, randomized, placebo- controlled trials (ACHIEVE I and ACHIEVE II). We conducted a post hoc analysis of pooled data from the ACHIEVE trials to evaluate the efficacy, safety, and tolerability of ubrogepant 50 mg (the only dose evaluated in both trials) versus placebo across a large population of participants with migraine.

The coprimary efficacy outcomes were pain freedom and absence of the most bothersome migraine-associated symptom (including photophobia, phonophobia, and nausea) at 2 h post dose.

A total of 2240 eligible participants were randomized to placebo (n = 1122) or

ubrogepant 50 mg (n = 1118) in the ACHIEVE trials.

Pain freedom at 2 h was reported in 13.0% of participants in the pooled placebo group and 20.5% in the pooled ubrogepant 50 mg group (odds ratio [OR] 1.72; 95% confidence interval [CI] 1.34, 2.22; P < 0.001).

Absence of the most bothersome migraine-associated symptom at 2 h was reported by 27.6% in the pooled placebo group and by 38.7% in the pooled ubroge- pant 50 mg group (OR 1.68; 95% CI 1.37, 2.05; P < 0.001).

Adverse events (AEs) within 48 h after the initial or optional second dose were reported by 11.5 and 11.2% of participants in the pooled placebo and pooled ubro- gepant 50 mg groups, respectively.

Extended: People with clinically significant CV and GI conditions associated with precautions in the use of triptans or NSAIDs were not included in the ACHIEVE trials, and future studies evaluating the tolerability and safety in these patient popu- lations are necessary.

Digital Features This article is published with digital features, including a summary slide, to facili- tate understanding of the article.

To view digital features for this article go to https://doi.org/10.6084/

m9.figshare.13664162.

666

4 Treatment

Introduction Medications used for the acute treatment of migraine have included analgesics, non- steroidal anti-inflammatory drugs (NSAIDs), opioids, barbiturates, ergot deriva- tives, and triptans [108, 109].

In this acute treatment landscape, approximately 30–50% of those with migraine

reported dissatisfaction with available acute medications [110, 111].

New acute treatment options for migraine that do not increase the risk of medica- tion overuse headache and improve tolerability and efficacy profiles are needed to provide improved management of migraine.

Safety and tolerability are important factors when considering potential acute

treatments for migraine.

Both of the pivotal trials (ACHIEVE I and ACHIEVE II) included ubrogepant 50 mg and placebo treatment groups, allowing for the post hoc analysis of pooled data from the individual trials reported here to evaluate the efficacy and safety across a large population of participants with migraine.

Methods In both ACHIEVE I and II, participants rated headache pain severity as none, mild, moderate, or severe and recorded the presence or absence of migraine-associated symptoms (photophobia, phonophobia, and nausea) before dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 h after the initial dose; at the time of the optional second dose (if taken); and 2 h after the second dose.

In both trials, the co-primary efficacy outcomes were participant-assessed pain freedom (i.e., reduction from moderate or severe headache pain at baseline to no pain) and absence of the most bothersome migraine-associated symptom at 2 h after the initial dose.

The pooled primary efficacy analysis was conducted using the pooled modified intent-to-treat (mITT) population, which included randomized participants who received at least one dose of study medication, recorded baseline migraine headache severity, and reported at least one post-dose migraine headache severity rating or migraine-associated symptom outcome at or before 2 h after the initial dose.

Results More ubrogepant-treated participants reported sustained pain freedom from 2 to 24 h post initial dose (13.6%, n/N = 119/875) than those in the placebo group (8.4%, 76/903; OR 1.71; 95% CI 1.26, 2.32; P < 0.001).

In the pooled ubrogepant 50 mg mITT population, 39.8% (n/N = 353/887) of participants opted to take a second dose of study medication 2–48 h after the initial dose, compared with 44.8% (409/912) of participants in the placebo group.

Within 48 h of the initial or the optional second dose, treatment-emergent AEs (TEAEs) were reported by 11.5% (113/984) of participants in the pooled placebo group and by 11.2% (107/954) in the pooled ubrogepant 50 mg group.

Treatment-related TEAEs occurred in the same percentage of participants (7.2%) in the pooled placebo group and the pooled ubrogepant 50 mg group during the 48-h post-dose time frame.

4.1 Acute Treatment

667

Discussion The results of this pooled analysis of two pivotal clinical trials further support the role of ubrogepant, a novel CGRP receptor antagonist, as an effective and well toler- ated acute treatment of migraine attacks in adults.

The favorable efficacy and tolerability/safety profiles of ubrogepant in clinical trials suggest that it may be a useful treatment option for patients with contraindica- tions to other treatments.

The similarity in trial designs allowed for the data from nearly 1000 participants treated with ubrogepant 50 mg (the only dose evaluated in both trials) to be com- bined, improving the power to estimate treatment effects and to detect potential safety signals.

People with clinically significant CV and GI conditions associated with precau- tions in the use of triptans or NSAIDs were not included in the ACHIEVE trials, and future studies evaluating the tolerability and safety in these patient populations are necessary.

Conclusions Pooled analysis of the 50  mg ubrogepant and placebo groups from the pivotal ACHIEVE I and ACHIEVE II trials demonstrated significant improvements in pain relief, pain freedom, photophobia, and phonophobia with ubrogepant compared with placebo.

Ubrogepant 50 mg was well tolerated, with no new safety concerns identified

from the larger, pooled ACHIEVE I and II trial data.

Acknowledgement A machine generated summary based on the work of Hutchinson, Susan; Dodick, David W.; Treppendahl, Christina; Bennett, Nathan L.; Yu, Sung Yun; Guo, Hua; Trugman, Joel M. 2021 in Neurology and Therapy.

Mapping Migraine-Specific Quality of Life to Health State Utilities in Patients Receiving Rimegepant