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Clinical Trial
. 2021 Apr;41(5):546-560.
doi: 10.1177/0333102420970523. Epub 2020 Nov 26.

Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications

Peter J Goadsby  1 , Andrew M Blumenfeld  2 , Richard B Lipton  3 , David W Dodick  4 , Kavita Kalidas  5 , Aubrey M Adams  6 , Abhijeet Jakate  7 , Chengcheng Liu  7 , Armin Szegedi  7 , Joel M Trugman  7
Affiliations
Clinical Trial

Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications

Peter J Goadsby et al. Cephalalgia. 2021 Apr.

Abstract

Background: The full utility of an acute treatment requires examination of the entire time course of effect during a migraine attack. Here the time course of effect of ubrogepant is evaluated.

Methods: ACHIEVE-I and -II were double-blind, single-attack, Phase 3 trials. Adults with migraine were randomised 1:1:1 to placebo or ubrogepant (50mg or 100mg, ACHIEVE-I; 25 mg or 50 mg, ACHIEVE-II). Pain freedom, absence of most bothersome symptom, and pain relief were assessed at various timepoints. Samples were collected for pharmacokinetic analysis. Data were pooled for this post-hoc analysis.

Results: Participants' (n = 912 placebo, n = 887 ubrogepant 50 mg, pooled analysis population) mean age was 41 years, with a majority female and white. Pain relief separated from placebo by 1 h (43% versus 37% [OR, 95% CI: 1.30, 1.0-1.59]), absence of most bothersome symptom by 1.5 h (28% versus 22% [1.42, 1.14-1.77]), and pain freedom by 2 h (20% vs. 13% [1.72, 1.33-2.22]). Efficacy was sustained from 2-24 h (pain relief: 1.71, 1.1-2.6; pain freedom: 1.71, 1.3-2.3) and remained separated at 48 h (pain relief: 1.7, 1.1-2.6; pain freedom: 1.31, 1.0-1.7). Pharmacokinetic analysis demonstrated maximum plasma concentrations were achieved at 1 h, with pharmacologically active concentrations reached within 11 min and remaining above the EC90 for nearly 12 h.

Conclusions: Evaluation of the time course of effect of ubrogepant showed pain relief as the most sensitive and earliest measure of clinical effect, followed by absence of most bothersome symptom, and pain freedom. Efficacy was demonstrated out to 48 h, providing evidence of the long-lasting effect of ubrogepant. This evaluation supports the role of examining the entire time course of effect to understand fully the utility of an acute treatment for migraine.Trial registration: ACHIEVE I (ClinicalTrials.gov, NCT02828020) and ACHIEVE II (ClinicalTrials.gov, NCT02867709).

Keywords: Migraine; acute; calcitonin gene-related peptide.

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Conflict of interest statement

Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PJG received grants and personal fees from Amgen and Eli Lilly and Company, grant from Celgene, and personal fees from Aeon Biopharma, Alder Biopharmaceuticals, Allergan (now AbbVie), Biohaven Pharmaceuticals Inc., Clexio, ElectroCore LLC, eNeura, Epalex, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Santara Therapuetics, Teva Pharmaceuticals, Trigemina Inc., WL Gore, MedicoLegal work, Up-to-Date, Oxford University Press, Massachusetts Medical Society, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.

AMB received fees from Allergan (now AbbVie), Aeon, Amgen, Alder, Biohaven, Eli Lilly and Company, ElectroCore, Novartis, Revance, Theranica, and Teva Pharmaceuticals.

RBL reports the following conflicts from within the past 48 months: Serves on the editorial boards of Neurology and Cephalalgia and as senior advisor to Headache. He has received research support from the NIH. He also receives support from the Migraine Research Foundation and the National Headache Foundation. He has reviewed for the NIA and NINDS; serves as consultant, advisory board member, or has received grant support or honoraria from Alder, Allergan (now AbbVie), Amgen, Autonomic Technologies, Avanir, Boston Scientific, Dr. Reddy’s, Electrocore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta. He receives royalties from Wolff’s Headache, 8th Edition, Oxford University Press, 2009, and Informa. He holds stock options in eNeura Therapeutics and Biohaven.

DWD reports consulting: Amgen, Association of Translational Medicine, University Health Network, Daniel Edelman Inc., Autonomic Technologies, Axsome, Aural Analytics, Allergan (now AbbVie), Alder BioPharmaceuticals, Biohaven, Charleston Laboratories, Dr Reddy's Laboratories/Promius, Electrocore LLC, Eli Lilly, eNeura, Neurolief, Novartis, Ipsen, Impel, Satsuma, Supernus, Sun Pharma (India), Theranica, Teva, Vedanta, WL Gore, Nocira, PSL Group Services, University of British Columbia, XoC, Zosano, ZP Opco, Foresite Capital, Oppenheimer; Upjohn (Division of Pfizer), Pieris, Revance, Equinox, Salvia, Amzak Health. CME fees or royalty payments: HealthLogix, Medicom Worldwide, MedLogix Communications, Mednet, Miller Medical, PeerView, WebMD Health/Medscape, Chameleon, Academy for Continued Healthcare Learning, Universal Meeting Management, Haymarket, Global Scientific Communications, Global Life Sciences, Global Access Meetings, UpToDate (Elsevier), Oxford University Press, Cambridge University Press, Wolters Kluwer Health; Stock options: Precon Health, Aural Analytics, Healint, Theranica, Second Opinion/Mobile Health, Epien, GBS/Nocira, Matterhorn/Ontologics, King-Devick Technologies; Consulting without fee: Aural Analytics, Healint, Second Opinion/Mobile Health, Epien; Precon Health, Board of Directors: Epien, Matterhorn/Ontologics, King-Devick Technologies. Patent: 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis without fee; research funding: American Migraine Foundation, US Department of Defense, PCORI, Henry Jackson Foundation; Professional society fees or reimbursement for travel: American Academy of Neurology, American Brain Foundation, American Headache Society, American Migraine Foundation, International Headache Society, Canadian Headache Society.

KK received personal fees from Amgen, Eli Lilly and Company, Allergan (now AbbVie), Novartis, and Theranica.

AMA is a full-time employee and stockholder of AbbVie.

AJ was a full-time employee and stockholder of AbbVie at the time of the trial conduct and drafting of the manuscript.

CL is a full-time employee and stockholder of AbbVie.

AS was a full-time employee and stockholder of AbbVie at the time of the trial conduct and drafting of the manuscript.

JMT is a full-time employee and stockholder of AbbVie.

Figures

Figure 1.
Figure 1.
Participant disposition.
Figure 2.
Figure 2.
Pain relief by timepoint – pooled mITT population from ACHIEVE I and ACHIEVE II. *Indicates p < 0.05 versus placebo. N1 = number of patients with non-missing post-dose pain severity assessment at or prior to the timepoint in the modified intent-to-treat population. For the analysis that included data after use of rescue medication or optional second dose of trial treatment, missing data were handled using last observation carried forward. Response rates presented following multiple imputation represent a mean across 100 imputations. Odds ratio (95% CI) and p-value are based on logistic regression with treatment group, historical triptan response, use of medication for migraine prevention, and baseline headache severity as explanatory variables; these data are provided in Table 2 and Table 3. Percentages calculated as 100 × (n/N1).
Figure 3.
Figure 3.
Absence of MBS by timepoint – pooled mITT population from ACHIEVE I and ACHIEVE II. *Indicates p < 0.05 versus placebo. N1 = number of patients with non-missing post dose pain severity assessment at or prior to the timepoint in the modified intent-to-treat population. For the analysis that included data after use of rescue medication or optional second dose of trial treatment, missing data were handled using last observation carried forward. Response rates presented following multiple imputation represent a mean across 100 imputations. Odds ratio (95% CI) and p-value are based on logistic regression with treatment group, historical triptan response, use of medication for migraine prevention, and baseline headache severity as explanatory variables; these data are provided in Table 2 and Table 3. Percentages calculated as 100 × (n/N1).
Figure 4.
Figure 4.
Pain freedom by timepoint – pooled mITT population from ACHIEVE I and ACHIEVE II. *Indicates p < 0.05 versus placebo. N1 = number of patients with non-missing post dose pain severity assessment at or prior to the timepoint in the modified intent-to-treat population. For the analysis that included data after use of rescue medication or optional second dose of trial treatment, missing data were handled using last observation carried forward. Response rates presented following multiple imputation represent a mean across 100 imputations. Odds ratio (95% CI) and p-value are based on logistic regression with treatment group, historical triptan response, use of medication for migraine prevention, and baseline headache severity as explanatory variables; these data are provided in Table 2 and Table 3. Percentages calculated as 100 × (n/N1).
Figure 5.
Figure 5.
Mean ubrogepant 50 mg plasma concentration-time curve (n = 498; pooled data from ACHIEVE I and ACHIEVE II). Represents data collected from participants who took an additional single dose of trial treatment at the clinic for pharmacokinetic analysis at visit 3. Trendline indicates EC90 value derived from a human capsaicin-induced dermal vasodilation model.
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