Huong Tra Dang 1, Khanh Linh Duong 1, Sojeong Kim 1, Hwi-yeol Yun 1,2,3, Jung-woo Chae 1,2,3, Soyoung Lee 1,2,3
1 Chungnam National University (Daejeon, Republic of Korea), 2 Department of Bio-AI convergence, Chungnam National University (, Republic of Korea), 3 Senior Health Convergence Research Center, Chungnam National University (, Republic of Korea)
Objectives
Migraine is a common, recurrent primary headache disorder of moderate-to-severe intensity that may be accompanied by symptoms in various organ systems, impairment of daily functioning, reduced quality of life, and disability [1]. Calcitonin gene-related peptide (CGRP) – targeting agents, including anti-CGRP monoclonal antibodies (mAbs) and CGRP receptor antagonists (gepants), have recently been recommended as first-line options for migraine prevention [2–4] . Current evidence shows the effectiveness of CGRP-targeted agents, with safety profiles comparable to those of other migraine preventive medications[2]. Given the complexity of efficacy responses and ongoing development of the agents, understanding dose-response relationships and predicting drug effects in different populations may help optimize future research and individualize medication use[2–5]. Therefore, the objectives of this model-based meta-analysis are to assess the dose-response relationship and the roles of other factors on the efficacy of CGRP-targeting agents as preventive treatment of migraine in adult patients.
Method
A systematic review of randomized controlled trials (RCTs) evaluating CGRP antagonists for migraine prevention in adults was conducted in accordance with PRISMA[6]. Aggregate study and arm-level efficacy data were extracted for six CGRP-targeting agents (gepants and monoclonal antibodies), along with relevant study and population characteristics. Network meta-analysis (NMA) was performed across efficacy endpoints to characterise comparative effects across agents and dose regimens. Then, a landmark model-based meta-analysis (MBMA) was conducted for all agents for the outcomes: 50% responder rate (MMD50), and monthly migrain days change from baseline (MMD), using Emax dose-response structure with meta-regression. The current study extends this framework by developing an Atogepant-specific dose-response MBMA using a log-linear dose-response model via a nonlinear mixed-effect (NLME) approach. Clinical covariates were integrated into the model using stepwise covariate modeling (SCM) to establish the final multivariable structure. These factors were evaluated for their impact on both baseline response and dose-response parameters, with model selection based on a significant reduction in the Akaike Information Criterion (AIC).
Result
A total of 42 RCTs (24.781 participants) were included in the research. In the NMA, atogepant, rimegepant, and most monoclonal antibody regimens were generally superior to placebo for efficacy outcomes, particularly MMD50 and MMD, whereas telcagepant showed limited preventive benefit. Between-study heterogeneity was moderate to high (approximately >40% to 70%; MMD50 I2 = 67.8%). For the MBMA of all six agents, an Emax model provides the best fit for the MMD50 outcome (32 studies, 97 observations). The MMD50 model retained mean age and the proportion of episodic migraine as significant covariates, with an estimated placebo response of 29% and an atogepant ED50 of 11.72mg. In the Atogepant-specific log-linear NLME extension, the baseline model showed an AIC of 21.48, an estimated placebo response of 28.9%, and a baseline dose-response parameter of 0.247. SCM identified BMI as the primary significant covariate influencing baseline response (p=0.006). The simulations provided clinical insight, predicting that at the 60mg dose, patients with a high BMI (30.9 kg/m ²) achieve a 58.4% MMD50 responder rate, compared to 52.3% for those with low BMI (26.3 kg/m ²). This integrated framework demonstrates that patient BMI significantly shifts the dose-response trajectory.
Conclusion
This model-based meta-analysis suggests that CGRP-targeting agents are effective preventive therapies for migraine, with atogepant, rimegepant, and most monoclonal antibody regimens consistently superior to placebo across key efficacy outcomes. An Emax framework adequately characterized the dose-response relationship across six CGRP agents, while the Atogepant-specific log-linear NLME model provided a feasible extension supporting the shift toward BMI-informed dose selection to optimize outcomes in migraine prevention.
H. Dang, K. Duong, S. Kim, contributed equally to this work; corresponding authors: H.-y. Yun, J.-w. Chae, and S. Lee
References:
[1] Migraine Headache – StatPearls – NCBI Bookshelf, https://www.ncbi.nlm.nih.gov/books/NBK560787/ (accessed 25 February 2026).
[2] Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update. Headache 2024; 64: 333–341.
[3] Barnes S, Aldous L, Jenkins B. Calcitonin gene-related peptide–targeted therapies for migraine. Aust Prescr 2025; 48: 40–46.
[4] Sacco S, Amin FM, Ashina M, et al. European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update. Journal of Headache and Pain; 23. Epub ahead of print 1 December 2022. DOI: 10.1186/s10194-022-01431-x.
[5] Regnier SA, Lee XY. Meta-regression to explain the placebo effects in clinical trials of anti-CGRP monoclonal antibodies for migraine prevention. J Med Econ 2023; 26: 1072–1080.
[6] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ; 372. Epub ahead of print 29 March 2021. DOI: 10.1136/bmj.n71.
Reference: PAGE 34 (2026) Abstr 11975 [www.page-meeting.org/?abstract=11975]
Poster: Drug/Disease Modelling - Other Topics