OC-04 | The chronopharmacology of atogepant in migraine prevention: a real-world evaluation of influence of timing of administration on effectiveness and tolerability

Luigi Francesco Iannone,^1,2 Gabriele Sebastianelli,³ Flavia Lo Castro,² Federico De Santis,⁴ Michele Corrado,⁵ Marilena Marcosano,^6,7 Raffaele Ornello,⁴ Licia Grazzi,⁸ Danilo Antonio Montisano,⁸ Francesco De Cesaris,⁹ Antonio Munafò,⁹ Gianluca Avino,¹⁰ Michele Trimboli,¹¹ Maria Albanese,¹² Antonio Russo,¹³ Giorgio Dalla Volta,¹⁴ Marina Romozzi,¹⁵ Paola Merlo,¹⁶ Luisa Fofi,^6,7 Alberto Doretti,¹⁷ Gloria Vaghi,⁵ Francesca Pistoia,⁴ Delfina Ferrandi,¹⁸ Stefania Battistini,¹⁹ Gianluca Coppola,³ Simona Sacco,⁴ Simona Guerzoni,² Claudia Altamura,^6,7 Fabrizio Vernieri,^6,7 On behalf of the Italian Headache Registry (RICe) Study Group | ¹Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia; ²Pharmacology and Clinical Metabolic Toxicology-Headache Center and Drug Abuse-Laboratory of Clinical Pharmacology and Pharmacogenomics, AOU Policlinico di Modena; ³Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina; ⁴Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila; ⁵Department of Brain and Behavioral Sciences, University of Pavia; Headache Science and Neurorehabilitation Unit, IRCCS Mondino Foundation, Pavia; ⁶Headache Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Roma; ⁷Neurology Unit, Università Campus Bio-Medico di Roma; ⁸Neuroalgology Unit and Headache Center, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; ⁹Headache center and Clinical Pharmacology, AOU Careggi, Florence; ¹⁰SOC Neurologia, Ospedale di Prato; ¹¹Azienda Ospedaliera-universitaria "Renato Dulbecco", Catanzaro; ¹²Università Roma Tor Vergata, Roma; ¹³Università della Campania "Luigi Vanvitelli", Napoli; ¹⁴U.O Neurologia, Istituto Clinico Città di Brescia, Gruppo San Donato, Brescia; ¹⁵Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy; ¹⁶UO di Neurologia, Humanitas Gavazzeni, Bergamo; ¹⁷Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano; ¹⁸Neurology Department, Azienda Ospedaliero Universitaria, Santi Antonio e Biagio e Cesare Arrigo, Alessandria; ¹⁹Department of Medical, Surgical and Neurological Sciences, University of Siena, Italy

Background: To evaluate whether the timing of atogepant administration can influence its tolerability and effectiveness over a 12-week period in patients with episodic (EM) and chronic migraine (CM) in a real-world setting.

Methods: This study is a post-hoc analysis of the first 12 weeks of the STAR study, a real-world, prospective, multicenter study conducted in Italy to evaluate the effectiveness of atogepant 60 mg for migraine prevention. Demographic and clinical data were collected at baseline (T0) and after 12 weeks (T3) since the first atogepant administration. Patients were divided into two groups according to the time of atogepant administration (morning or evening). Differences in changes in monthly headache days (MHDs), monthly migraine days (MMDs), and patient-reported outcome measures (PROMs) were evaluated between the two groups as measures of effectiveness. Differences in rate and types of adverse events (AEs) were investigated as measures of tolerability. Linear mixed-effects models (LMMs) for repeated measures were used. 

Results: A total of 81 patients (86% females, mean age 50.8±13.7 years) were included. At T3, a significant reduction was observed in both MMDs (from 16.6 to 9.7, p<0.001) and MHDs (from 19.2 to 10.7, p<0.001), with 60% of patients achieving a 50% response rate at T3 (reduction in MMDs≥50%). AEs were reported by 43% of patients. Atogepant was taken in the morning by 57% and in the evening by 43% of patients. No differences emerged in MMD, MHD, frequency, or type of AEs between the two groups (morning vs. evening). Although evening users had a higher disability burden at baseline (MIDAS score = 70.0 vs 39.9), they presented a higher decrease in MIDAS scores from T0 to T3 (F(1,63) = 6.29, P = 0.015), reaching similar scores to morning users at T3 (25.1 vs. 23.9, respectively).

Conclusion: Atogepant significantly reduced migraine burden over 12 weeks in a real-world setting. While the timing of administration (morning vs. evening) did not influence its effectiveness or tolerability, a modest yet statistically significant effect was observed on the magnitude of reduction of the MIDAS score. Whether this change in the delta of MIDAS score is due to a pharmacodynamic effect induced by the evening administration or to a ceiling effect of the drug effectiveness, i.e., reaching a certain threshold after which further improvements are difficult to obtain, is yet to be determined. Long-term and dedicated studies are needed to evaluate and confirm these findings.