Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial


Priya S. Kishnani, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
Jordi Diaz-Manera, Newcastle University John Walton Muscular Dystrophy Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom.
Antonio Toscano, Department of Clinical and Experimental Medicine, Reference Center for Rare Neuromuscular Disorders, University of Messina, Messina, Italy.
Paula R. Clemens, Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Shafeeq Ladha, Gregory W. Fulton ALS and Neuromuscular Center, Barrow Neurological Institute, Phoenix, Arizona.Follow
Kenneth I. Berger, Division of Pulmonary, Critical Care and Sleep Medicine, NYU Grossman School of Medicine, New York, New York.
Hani Kushlaf, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio.
Volker Straub, Newcastle University John Walton Muscular Dystrophy Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom.
Gerson Carvalho, Instituto Chronos de Apoio à Pesquisa, Brasília, Brazil.
Tahseen Mozaffar, Department of Neurology, University of California, Irvine, Orange.
Mark Roberts, Salford Royal NHS Foundation Trust, Salford, United Kingdom.
Shahram Attarian, Referral Centre for Neuromuscular Diseases and ALS, European Reference Network Neuromuscular Diseases, Hôpital La Timone, Marseille, France.
Yin-Hsiu Chien, Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Young-Chul Choi, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea.
John W. Day, Department of Neurology, Stanford University, Stanford, California.
Sevim Erdem-Ozdamar, Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Sergey Illarioshkin, Research Center of Neurology, Moscow, Russia.
Ozlem Goker-Alpan, Lysosomal and Rare Disorders Research and Treatment Center, Fairfax, Virginia.
Anna Kostera-Pruszczyk, Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
Ans T. van der Ploeg, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Kristina An Haack, Sanofi, Chilly-Mazarin, France.
Olivier Huynh-Ba, Sanofi, Chilly-Mazarin, France.
Swathi Tammireddy, Sanofi, Cambridge, Massachusetts.
Nathan Thibault, Sanofi, Cambridge, Massachusetts.
Tianyue Zhou, Sanofi, Cambridge, Massachusetts.
Mazen M. Dimachkie, University of Kansas Medical Center, Department of Neurology, Kansas City.
Benedikt Schoser, Friedrich-Baur-Institute, Department of Neurology, LMU Klinikum, München, München, Germany.

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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.

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JAMA neurology



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