Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks
Authors: Kishnani Priya S. , Diaz-Manera Jordi , Toscano Antonio , Clemens Paula R. , Ladha Shafeeq , Berger Kenneth I. , Kushlaf Hani , Straub Volker , Carvalho Gerson , Mozaffar Tahseen , Roberts Mark , Attarian Shahram , Chien Yin-Hsiu , Choi Young-Chul , Day John W. , Erdem-Ozdamar Sevim , Illarioshkin Sergey , Goker-Alpan Ozlem , Kostera-Pruszczyk Anna , van der Ploeg Ans T. , An Haack Kristina , Huynh-Ba Olivier , Tammireddy Swathi , Thibault Nathan , Zhou Tianyue , Dimachkie Mazen M. , Schoser Benedikt ,   COMET Investigator Group, Behin Anthony , Boentert Matthias , Carvalho Gerson , Chahin Nizar , Charrow Joel , Deegan Patrick , Durmus Tekce Hacer , Duval Fanny , Genge Angela , Gutmann Ludwig , Henderson Robert D. , Hennermann Julia B. , Hiwot Tarekegn , Hughes Derralynn , Karaa Amel , Karam Chafic , Kautzky-Willer Alexandra , Komaki Hirofumi , Laforet Pascal , Longo Nicola , Malinova Vera , Maré Ricardo , Maxit Clarisa , Mengel Eugen , Moggio Maurizio Gualtiero , Molnár Mária Judit , Mongini Tiziana Enrica , Nadaj-Pakleza Aleksandra , Nascimento Osorio Andres , Noury Jean-Baptiste , Oliveira Acary Souza Bulle , Parman Yesim , Pena Loren , Remiche Gauthier , Sciacco Monica , Shieh Perry B. Shieh , Smith Cheryl , Stulnig Thomas , Taithe Frederic , Tard Céline , Tarnopolsky Mark , Vorgerd Matthias , Whitley Chester , Young Peter , Alonso-Pérez Jorge , Altemus Patricia , Aubé-Nathier Anne-Catherine , Avelar Jennifer B.  , Bailey Carrie , Bekircan-Kurt Can Ebru , Billy Jenny , Boschi Silvia , Brown Kathryn E. , Carrera Garcia Laura , Chase Lauren , Cirne Hamilton , Danjoux Loïc , Davion Jean-Baptiste , DeArmey Stephanie , Fedotova Ekaterina , Gandolfo Eve , Grosz Zoltan , Guellec Dewi , Guettsches Anne-Katrin , Guglieri Michela , Hatcher Erin , Helms Sina , Hufgard-Leitner Miriam , Klyushnikov Sergey A. , Langton Jacqui , Linková Lenka , Mavroudakis Nicolas , Mazurová Stella , Mori Madoka , Müller-Miny Louisa , Musumeci Olimpia , Nance Christopher S. , Natera-de Benito Daniel , Neel Robert , Niizawa Gabriela A. , Noll Lauren , Ortega Erik , Pasnoor Mamatha , Pautot Vivien , Potulska-Chromik Anna , Pugliese Alessia , Questienne Claire , Ramos Lopes Margarida , Reyes-Leiva David , Riedl Michaela , Rugiero Marcelo Francisco , Salort-Campana Emmanuelle , Sgobbi Souza Paulo Victor , Sole Guilhem , Solera Luca , Souto Lopes Suzara , Specht Sabine , Statland Jeffrey , Swenson Andrea , Tan Chong Yew , Tizon Sónia , van der Beek N.A.M.E. , van Kooten Harmke A. , Wencel Marie , Wenninger Stephan , Zagnoli Fabien 
Published: April 2023

ImportanceIn 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.ObjectiveTo report avalglucosidase alfa treatment outcomes during the COMET trial extension.Design, Setting, and ParticipantsThis 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.InterventionsRandom 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 MeasuresThe 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.ResultsOf 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT02782741