Efficacy and Safety Results of the Avalglucosidase alfa Phase 3 COMET Trial in Late-Onset Pompe Disease Patients
Hani Kushlaf1, Shahram Attarian2, Joao Lindolfo Borges3, Francoise Bouhour4, Yin-Hsiu Chien5, Young-Chul Choi6, Paula Clemens7,8, John Day9, Jordi Diaz-Manera10,11,12, Sevim Erdem-Ozdamar13, Ozlem Goker-Alpan14, Sergey Illarioshkin15, Priya Kishnani16, Anna Kostera-Pruszczyk 17, Shafeeq Ladha18, Tahseen Mozaffar19, Mark Roberts20, Volker Straub21, Antonio Toscano22, Ans van der Ploeg23, Kristina An Haack24, Christopher Hug24, Olivier Huynh-Ba24, Tianyue Zhou24, Judith Johnson24, Mazen Dimachkie25, Benedikt Schoser26
1Department of Neurology & Rehabilitation Medicine and Department of Pathology & Laboratory Medicine, University of Cincinnati, 2Referral Centre for Neuromuscular Diseases and ALS, Hôpital La Timone, 3Clinical Research Center of Brazil, 4Pierre Wertheimer Hospital, 5Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, 6Gangnam Severance Hospital, Yonsei University, College of Medicine, 7Univ of Pittsburgh/ Dept of Neurology, 8Department of Veterans Affairs Medical Center, 9Stanford University School of Medicine, 10John Walton Muscular Dystrophy Research Center, Newcastle University, 11Neuromuscular Diseases Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, 12Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 13Hacettepe University Department of Neurology, 14O and O Alpan LLC, 15Research Center of Neurology, 16Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, 17Department of Neurology, Medical University of Warsaw, 18Barrow Neurological Institute, 19Department of Neurology, University of California, Irvine, 20Salford Royal NHS Foundation Trust, 21Newcastle University John Walton Muscular Dystrophy Research Centre, Newcastle Hospitals NHS Foundation Trust, 22Neurology and Neuromuscular Diseases Unit, Department of Clinical and Experimental Medicine, University of Messina, 23Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center, 24Sanofi Genzyme, 25University of Kansas Medical Center, 26Department of Neurology, Friedrich-Baur-Institute, Klinikum München
Objective:
Results (Baseline to Week 49) of the double-blinded Phase 3 COMET trial (NCT02782741/Sanofi Genzyme) comparing avalglucosidase alfa (n=51) and alglucosidase alfa (n=49) in treatment-naïve patients with late-onset Pompe disease (LOPD) are reported. 
Background:
Avalglucosidase alfa is a recombinant human GAA enzyme replacement therapy specifically designed for enhanced M6P-receptor targeting and enzyme uptake aimed at increased glycogen clearance and improvement of clinical efficacy as compared to alglucosidase alfa. 
Design/Methods:
The primary objective was to determine the effect of avalglucosidase alfa on respiratory muscle function, measured by upright forced vital capacity (FVC) %predicted. Secondary/other objectives include the effect of avalglucosidase alfa on functional endurance, inspiratory and expiratory muscle strength, lower and upper extremity muscle strength, motor function, and health-related quality of life, and safety. 
Results:
Treatment with avalglucosidase alfa resulted in greater improvements in upright FVC %predicted at all timepoints and a 2.43% greater increase in FVC %predicted compared to alglucosidase alfa at Week 49. The primary study objective, achieving statistical non-inferiority, was met (p=0.0074) and testing for superiority was borderline significant (p=0.0626). Avalglucosidase alfa treatment resulted in greater improvements in the 6-Minute Walk Test (6MWT) (meters and %predicted), with 30.01-m and 4.71% greater increases, respectively. Similarly, positive results for avalglucosidase alfa were seen for all secondary and other efficacy endpoints. Treatment-emergent adverse events (AEs) were reported in 86.3% of avalglucosidase alfa-treated and 91.8% of alglucosidase alfa-treated participants. Five participants withdrew, four due to AEs, all in the alglucosidase alfa arm. Serious AEs were reported in 8 avalglucosidase alfa-treated and 12 alglucosidase alfa-treated participants. IgG antidrug antibody responses were similar in both groups. High titers and neutralizing antibodies were more common for alglucosidase alfa.
Conclusions:
These results demonstrate substantial improvements in clinically meaningful outcome measures as well as a more favorable safety profile in patients with LOPD treated with avalglucosidase alfa compared to alglucosidase alfa.