Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks
Priya S. Kishnani, Jordi Díaz‐Manera, António Toscano, Paula R. Clemens, Shafeeq Ladha, Kenneth I. Berger, Hani Kushlaf, Volker Straub, Gérson Carvalho, Tahseen Mozaffar, Mark Roberts, Shahram Attarian, Yin‐Hsiu Chien, Young‐Chul Choi, John W. Day, Sevim Erdem‐Özdamar, С. Н. Иллариошкин, Özlem Göker-Alpan, Anna Kostera‐Pruszczyk, Ans T. van der Ploeg, Kristina An Haack, Olivier Huynh‐Ba, Swathi Tammireddy, Nathan Thibault, Tianyue Zhou, Mazen M. Dimachkie, Benedikt Schoser, COMET Investigator Group, Anthony Béhin, Matthias Boentert, Gérson Carvalho, Nizar Chahin, Joel Charrow, Patrick Deegan, Hacer Durmuş Tekçe, Fanny Duval, Angela Genge, Ludwig Gutmann, Robert D. Henderson, Julia B. Hennermann, Tarekegn Hiwot, Derralynn Hughes, Amel Karaa, Chafic Karam, Alexandra Kautzky‐Willer, Hirofumi Komaki, Pascal Laforêt, Nicola Longo, Vĕra Malinová, Ricardo Maré, Clarisa Maxit, Eugen Mengel, Maurizio Moggio, Mária Judit Molnár, Tiziana Mongini, Aleksandra Nadaj‐Pakleza, A. Nascimento Osorio, Jean‐Baptiste Noury, Acary Souza Bullé Oliveira, Yeşim Parman, Loren Peña, Gauthier Remiche, Monica Sciacco, Perry B. Shieh, Cheryl J. Smith, Thomas M. Stulnig, Frédéric Taithe, Céline Tard, Mark A. Tarnopolsky, Matthias Vorgerd, Chester B. Whitley, Peter Young, Jorge Alonso‐Pérez, Patricia Altemus, Anne-Catherine Aubé-Nathier, Jennifer Avelar, Carrie Bailey, Can Ebru Bekircan‐Kurt, Jenny Billy, Silvia Boschi, Kathryn E. Brown, Laura Carrera‐García, Lauren Chase, Hamilton Cirne, Loïc Danjoux, Jean‐Baptiste Davion, Stephanie DeArmey, E. Yu. Fedotova, Eve Gandolfo, Zoltán Grosz, Dewi Guellec, Anne-Katrin Guettsches, Michela Guglieri, Erin Hatcher, Sina Helms, Miriam Hufgard‐Leitner, S. A. Klyushnikov, Jacqui Langton, Lenka Linková, Nicolas Mavroudakis
Abstract
Importance: In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa. Objective: To report avalglucosidase alfa treatment outcomes during the COMET trial extension. Design, Setting, and Participants: This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021. Interventions: Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week. Main Outcomes and Measures: The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed. Results: Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched. Conclusions and Relevance: In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed. Trial Registration: ClinicalTrials.gov Identifier: NCT02782741.