Combination preventive therapy with onabotulinumtoxinA and atogepant for chronic migraine: A 24-week, prospective, real-world evaluation (SYNERGY study)

Background Chronic migraine (CM) is highly disabling, and many patients fail to respond to monotherapy with approved preventive treatments. OnabotulinumtoxinA (BoNTA) and atogepant act on distinct but complementary targets within the trigeminovascular system and may exert additive or synergistic effects when used together. Real-world data on their combination remain scarce. Methods We prospectively analyzed adult patients with CM who had received at least three prior BoNTA cycles and initiated atogepant 60 mg/day for a minimum of 24 weeks as add on to BoNTA. Co-primary outcomes were changes in monthly migraine days (MMDs) and ≥50% response rate at 24 weeks. Secondary outcomes included disability, medication use, tolerability and subgroup comparisons by prior monoclonal antibodies exposure. Results Among 101 patients, 82 completed 24 weeks of co-treatment. Mean MMDs decreased by 6.5 days ( p < 0.001) and 45.1% of patients achieved a ≥50% reduction. Acute medication days decreased by 6.0 ( p < 0.001) and Headache Impact Test-6 scores improved significantly (mean change: −4.0; p < 0.001). Patient’s Global Impression of Change scores indicated moderate-to-great improvement. Anti-calcitonin gene-related peptide naïve patients experienced larger reductions in MMDs (−7.75 vs. −5.87) and disability scores compared to non-naïve patients. Multivariable analysis identified only baseline acute medication use as predictor of response. Adverse events were mild and consistent with known safety profiles for both drugs separately; no novel safety concerns emerged. Conclusions The addition of atogepant to BoNTA might be effective and well tolerated in real-world setting, including CM patients previously exposed to multiple preventives. Prospective controlled trials and health-economic evaluations are warranted to validate these observations and inform future clinical guidelines.