Long-term Safety and Efficacy of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease


Mazen M. Dimachkie, University of Kansas Medical Center, Kansas City, KS, USA mdimachkie@kumc.edu.
Richard J. Barohn, University of Kansas Medical Center, Kansas City, KS, USA.
Barry Byrne, University of Florida, Gainesville, FL, USA.
Ozlem Goker-Alpan, LDRTC, Fairfax, VA, USA.
Priya S. Kishnani, Duke University Medical Center, Durham, NC, USA.
Shafeeq Ladha, Barrow Neurological Institute, Phoenix, AZ, USA.Follow
Pascal Laforêt, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France Service de Neurologie, Hôpital Raymond-Poincaré, Garches, AP-HP and INSERM U1179, Université Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
Karl Eugen Mengel, SphinCS GmbH, Institute of Clinical Science for LSD, Hochheim, Germany.
Loren D. Peña, Duke University Medical Center, Durham, NC, USA.
Sabrina Sacconi, Neuromuscular Diseases Centre, Department of Clinical Neurosciences, University Hospital of Nice (CHU), Nice, France.
Volker Straub, Newcastle University John Walton Muscular Dystrophy Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
Jaya Trivedi, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Philip Van Damme, KU Leuven (Catholic University of Leuven) - Department of Neurosciences, VIB - Center for Brain & Disease Research, and University Hospitals Leuven - Department of Neurology, Leuven, Belgium.
Ans T. van der Ploeg, Erasmus MC University Medical Center, Pompe Center & Center for Lysosomal and Metabolic Diseases, Rotterdam, The Netherlands.
John Vissing, Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Peter Young, Department of Neurology, Medical Park Bad Feilnbach, Germany.
Kristina An Haack, Sanofi Genzyme, Chilly-Mazarin, Franc.
Meredith Foster, Sanofi Genzyme, Cambridge, MA, USA.
Jane M. Gilbert, Elevate Medical Affairs, Horsham, UK.
Patrick Miossec, Sanofi Genzyme, Chilly-Mazarin, Franc.
Olivier Vitse, Sanofi Genzyme, Montpellier, France.
Tianyue Zhou, Sanofi Genzyme, Cambridge, MA, USA.
Benedikt Schoser, Friedrich-Baur-Institut, Department of Neurology Klinikum München, München, Germany.

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BACKGROUND AND OBJECTIVES: Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies. METHODS: NEO1 participants with LOPD, either treatment-naïve (Naïve Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week [qow]) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a pre-specified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model. RESULTS: Twenty-four participants enrolled in NEO1 (Naïve Group, n=10; Switch Group, n=14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well-tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed anti-drug antibodies without apparent impact on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity (FVC) %predicted remained stable in most participants, with slope estimates (95% confidence intervals) of -0.473/year (-1.188, 0.242) and -0.648/year (-1.061, -0.236) in the Naïve and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of -0.701/year (-1.571, 0.169) and -0.846/year (-1.567, -0.125) for the Naïve and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged <45 years at NEO1 enrollment, in both the Naïve and Switch Groups. DISCUSSION: Avalglucosidase alfa was generally well-tolerated for up to 6.5 years in adult participants with LOPD either naïve to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months. Evidence: This study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.

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