Efficacy of Ubrogepant Based on Prior Exposure and Response to Triptans

A Post Hoc Analysis

Andrew M. Blumenfeld MD; Peter J. Goadsby MD, PhD, DSc; David W. Dodick MD; Susan Hutchinson MD; Chengcheng Liu PhD; Michelle Finnegan MPH; Joel M. Trugman MD; Armin Szegedi MD, PhD

Disclosures

Headache. 2021;61(3):422-429. 

In This Article

Abstract and Introduction

Abstract

Objective: To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans.

Background: Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small-molecule, oral calcitonin gene–related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults.

Methods: This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double-blind, phase 3, single-attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants' historical experience with triptans: triptan responder, triptan-insufficient responder, and triptan naïve. Co-primary efficacy endpoints were pain freedom and absence of most bothersome migraine-associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated.

Results: In the pooled analysis population (n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan-insufficient responders, and triptan-naïve, respectively. Response rates on co-primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment-by-subgroup interaction p values based on odds ratios for pain freedom (p = 0.290) and absence of MBS (p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups.

Conclusions: Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan-insufficient responders, and triptan-naïve based on their historical experience with triptans.

Introduction

Migraine is a highly prevalent disease that has a negative impact on numerous aspects of an individual's life.[1,2] Options for acute treatment of migraine include triptans (serotonin 5-HT1B/1D receptor agonists), ditans (serotonin 5-HT1F receptor agonists), nonsteroidal anti-inflammatory drugs, dihydroergotamine, and combination analgesics; many of these fail to meet treatment goals.[3–5] As such, it is estimated that over 95% of people with migraine taking an orally administered acute prescription medication for headache have at least one unmet acute treatment need.[5]

Although the availability of triptans has improved the acute treatment of many people with migraine, use of triptans can be limited by insufficient efficacy and poor tolerability in some individuals.[6] In a study of current and past triptan users, the most common reasons for discontinuation cited by the 25% who discontinued use were lack of a therapeutic effect and side effects.[6] Based on their vasoconstrictive actions mediated by the 5-HT1B receptor, the use of triptans is contraindicated for individuals with cardiovascular disease, specifically individuals with coronary artery disease or a history of stroke, peripheral vascular disease, or chronically uncontrolled hypertension, and caution of triptan use may be warranted in individuals with other cardiovascular risk factors.[7–9] In addition, frequent use of triptans or analgesics has the potential to cause medication overuse headache.[10,11] Thus, to enable more individuals to achieve migraine freedom and reduce migraine-related disability, acute treatment options with different safety and tolerability profiles are needed, specifically for individuals not adequately managed by triptans.

Calcitonin gene–related peptide (CGRP) is an endogenous proinflammatory and pronociceptive neuropeptide that has been shown to have an important role in the pathogenesis of migraine.[12] Small-molecule CGRP receptor antagonists (gepants) have demonstrated efficacy for the acute treatment of migraine in phase 3 clinical trials.[13–16] Ubrogepant is a small-molecule, oral CGRP receptor antagonist approved by the US Food and Drug Administration for the acute treatment of migraine with or without aura in adults. In two identically designed pivotal clinical trials (ACHIEVE I and II), treatment with ubrogepant was associated with significantly greater rates of pain freedom and absence of most bothersome migraine-associated symptom (MBS) at 2 h compared with placebo.[13,14]

The goal of this post hoc analysis of pooled data from the ACHIEVE trials was to determine the impact, if any, of an individual's previous response to triptans on the efficacy and tolerability of ubrogepant versus placebo. Because of the different pharmacology of ubrogepant and triptans,[17,18] we hypothesized that the treatment response to ubrogepant would not be predicted by the participants' historical response to triptans. This work was presented in abstract form at the 61st Annual Scientific Meeting of the American Headache Society (July 11–14, 2019; Philadelphia, Pennsylvania, USA).[19]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....