Safety, tolerability, and efficacy of atogepant added to onabotulinumtoxinA for the preventive treatment of chronic migraine: A phase 3, multicenter, 24-week, open-label study

BackgroundTreatment with onabotulinumtoxinA is effective in reducing migraine day frequency and duration in individuals with chronic migraine (CM), but given the severity of the disease, those with CM often need additional treatment to achieve optimal outcomes. Combining preventive treatments with distinctly different physiological targets may yield greater benefit than monotherapy. This study evaluated the safety, tolerability, and efficacy of adding atogepant to onabotulinumtoxinA for preventive treatment of CM.MethodsIn this 24-week, Phase 3, open-label, single arm, multicenter study (NCT05216263), 75 participants on a stable dose of onabotulinumtoxinA (155-200U) with baseline mean monthly migraine days (MMDs) of 8-23 (inclusive) received add-on atogepant 60 mg once daily. Primary safety endpoints included treatment-emergent adverse events (TEAEs), and exploratory efficacy endpoints included changes in MMDs, changes in mean monthly headache days (MHDs) and responder rates (RRs) (≥50%, ≥75%, and 100% MMDs) over Weeks 1-12, Weeks 13-24, and at each 4-week interval.ResultsThe mean age of study participants was 48 (13.68) years (mean (SD)); 89% were women, and 97% were white. Participants had an established CM diagnosis for 15 (13.27) years (mean (SD)) and had been treated with onabotulinumtoxinA for 4 (3.45) years (mean (SD)). In the safety population (n = 75), the incidence of TEAEs was 65.3%. TEAEs occurring in ≥5% of participants were constipation (n = 12, 16.0%), nausea (n = 10, 13.3%), and urinary tract infection (n = 6, 8.0%). An AE was considered the primary reason for drug discontinuation in 2 (2.7%) participants. Treatment-emergent serious AEs (TESAEs) occurred in 2 participants; neither were considered treatment-related by the investigators. In the modified intention-to-treat population (n = 72), the least squares (LS) mean change from baseline of 14.34 MMDs was -6.45 MMDs (95% CI: -7.7, -5.1) at Weeks 1-4, -6.89 MMDs (95% CI: -8.1, -5.6) across Weeks 1-12, and -7.20 MMDs (95% CI: -8.4, -5.9) across Weeks 13-24. The least square mean change from baseline of 17.00 MHDs was -6.57 MHDs (95% CI: -7.8, -5.3) at Weeks 1-4, -7.33 MHDs (95% CI: -8.6, -6.0) across Weeks 1-12 and -8.15 MHDs (95% CI: -9.4, -6.8) across Weeks 13-24. A ≥ 50% RR in MMD was achieved by 54.2% and 61.9% of participants across Weeks 1-12 and Weeks 13-24 of combined treatment, respectively. A ≥ 75% RR was achieved by 30.6% and 38.1% of participants.ConclusionsIn this study, combination preventive treatment for CM with onabotulinumtoxinA and atogepant was safe and generally well-tolerated. Furthermore, the addition of atogepant to those stable on onabotulinumtoxinA resulted in clinically meaningful reductions in migraine days and improvement in responder rates, suggesting a benefit of combining treatments with distinct and complementary mechanisms of action for suppression of CM.Trial RegistrationClinical Trials.gov NCT05216263.