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

Mazen M. Dimachkie*, Richard J. Barohn, Barry Byrne, Ozlem Goker-Alpan, Priya S. Kishnani, Shafeeq Ladha, Pascal Laforêt, Karl Eugen Mengel, Loren D.M. Peña, Sabrina Sacconi, Volker Straub, Jaya Trivedi, Philip Van Damme, Ans T. Van Der Ploeg, John Vissing, Peter Young, Kristina An Haack, Meredith Foster, Jane M. Gilbert, Patrick MiossecOlivier Vitse, Tianyue Zhou, Benedikt Schoser

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background and ObjectivesPompe 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.MethodsNEO1 participants with LOPD, either treatment naive (Naive 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 prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.ResultsTwenty-four participants enrolled in NEO1 (Naive 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 antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of-0.473 per year (-1.188 to 0.242) and-0.648 per year (-1.061 to-0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of-0.701 per year (-1.571 to 0.169) and-0.846 per year (-1.567 to-0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged <45 years at NEO1 enrollment in both the Naive and Switch Groups.DiscussionAvalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.Classification of EvidenceThis 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. First participant enrollment: NEO1-August 19, 2013; NEO-EXT-February 27, 2014.

Original languageEnglish
Pages (from-to)E536-E548
JournalNeurology
Volume99
Issue number5
Early online date26 May 2022
DOIs
Publication statusPublished - 2 Aug 2022

Bibliographical note

Funding Information:
M.M. Dimachkie serves or recently served as a consultant—Amazentis, argenx, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, Momenta, NuFactor, Octapharma, RaPharma/UCB, Roivant Sciences Inc., RMS Medical, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Third Rock, and UCB Biopharma—and received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, BioMarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, UCB Biopharma/RaPharma, Viromed/Helixmith, and TMA. R.J. Barohn: consulting fees—NuFactor and Momenta Pharmaceutical; contracted research—FDA Office of Orphan Products Development, NIH, Orphazyme, PCORI, PTC Therapeutics, Ra Pharma, and Sanofi Genzyme. B. Byrne: advisory board—Sanofi Genzyme. O. Goker-Alpan: advisory board—Amicus, BioMarin, Sanofi Genzyme, and Takeda; consulting fees—Amicus, BioMarin, Sanofi Genzyme, Shire HGT, and Takeda; contracted research—Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi Genzyme, and Takeda; and speaker's bureau—Sanofi Genzyme and Takeda. P.S. Kishnani: advisory board—Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies; consulting fees—Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharma, and Asklepios BioPharmaceutical, Inc. (AskBio); contracted research—Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics; honoraria—Sanofi Genzyme, Maze Therapeutics, Asklepios Biopharmaceutical, Inc. (AskBio), and Amicus Therapeutics; ownership interest less than 5% (stocks, stock options, or other ownership interest excluding diversified mutual funds)—Asklepios Biopharmaceutical, Inc. (AskBio) and Maze Therapeutics; and travel expenses—Sanofi Genzyme and Amicus Therapeutics. S. Ladha: advisory board—Sanofi Genzyme; consulting fees—Sanofi Genzyme; contracted research—Sanofi Genzyme; and speaker's bureau—Sanofi Genzyme. P. Laforêt: advisory board—Sanofi Genzyme and Spark Therapeutics; consulting fees—Sanofi Genzyme; contracted research—Sanofi Genzyme; honoraria—BioMarin, Sanofi Genzyme, and Spark Therapeutics; and travel expenses—Sanofi Genzyme, Amicus Therapeutics, and Spark Therapeutics. K.E. Mengel: advisory board—Actelion, Sanofi Genzyme, Takeda Shire, and Amicus; consulting fees—Orphazyme and Prevail; and contracted research—Orphazyme, Sanofi Genzyme, Shire, Idorsia, and Takeda Shire. L.D.M Peña: advisory board—AveXis Inc; consulting fees—AveXis Inc.; contracted research—Shire Takeda, Chiesi, and ModernaTx; Fees for Non-CME/CE Services Received Directly from a Commercial Interest or their Agents—Castle IRB; speaker's bureau—France Foundation; and travel expenses—France Foundation. S. Sacconi: advisory board—Alnylam Pharmaceuticals, Biogen, BioMarin, and Sanofi Genzyme; consulting fees—Alnylam Pharmaceuticals, Biogen, BioMarin, Sanofi Genzyme, AEC partners, BresMed, Sanofi-Aventis France, and argenx BV; contracted research—AFM; and travel expenses—Biogen, BioMarin, and Sanofi Genzyme. V. Straub: consulting fees—AveXis Inc, Exonics Therapeutics, Roche, Sanofi Genzyme, and Sarepta Therapeutics; contracted research—Sanofi Genzyme and Ultragenyx; and honoraria—Sanofi Genzyme. J. Trivedi: contracted research—Sanofi Genzyme. P. Van Damme: advisory board—Biogen, Alexion Pharmaceuticals, Ferrer, QurAlis, and argenx. A.T. van der Ploeg: advisory board—Amicus, BioMarin, Sanofi Genzyme, and Spark Therapeutics; consulting fees—Amicus, BioMarin, Sanofi Genzyme, and Spark Therapeutics; and contracted research—Amicus, BioMarin, Sanofi Genzyme, and Spark Therapeutics. J. Vissing: advisory board—argenx, Roche, Viela Bio, Biogen, Amicus Therapeutics, PTC Therapeutics, Sanofi Genzyme, Ultragenyx Pharmaceutical, Fulcrum Therapeutics, ML Bio Solutions, Sarepta Therapeutics, Novartis Pharma AG, Stealth Biotherapeutics, Zogenix, Regeneron, and Lupin Limited; consulting fees—argenx, Roche, Viela Bio, Biogen, Amicus Therapeutics, PTC Therapeutics, Sanofi Genzyme, Ultragenyx Pharmaceutical, Fulcrum Therapeutics, ML Bio Solutions, Sarepta Therapeutics, Novartis Pharma AG, Stealth Biotherapeutics, Zogenix, Regeneron, and Lupin Limited; contracted research—argenx, Amicus Therapeutics, PTC Therapeutics, Sanofi Genzyme, Novartis Pharma AG, Stealth Biotherapeutics, UCB Pharma, and Genethon; employee/salary—Edgewise; and travel expenses—argenx, Roche, Viela Bio, Biogen, Sanofi Genzyme, ML Bio Solutions, and Sarepta Therapeutics. P. Young: advisory board—Biogen, BioMarin, Medice, Sanofi Genzyme, and Vanda; honoraria—Biogen, BioMarin, Löwenstein Medical, Medice, Sanofi Genzyme, UCB, and Vanda; and speaker's bureau—Biogen, BioMarin, Löwenstein Medical, Medice, Sanofi Genzyme, UCB, and Vanda. K. An Haack: employee/salary—Sanofi Genzyme (spouse: employee/salary—Sanofi Genzyme). M. Foster: employee/salary—Sanofi Genzyme; ownership interest less than 5% (stocks, stock options, or other ownership interest excluding diversified mutual funds)—Sanofi Genzyme. J.M. Gilbert: employee/salary—Elevate Medical Affairs (contracted by Sanofi Genzyme for publication support services). P. Miossec: employee/salary—Sanofi Genzyme; ownership interest less than 5% (stocks, stock options, or other ownership interest excluding diversified mutual funds)—Sanofi Genzyme. O. Vitse: employee/salary—Sanofi Genzyme; ownership interest less than 5% (stocks, stock options, or other ownership interest excluding diversified mutual funds)—Sanofi Genzyme. T. Zhou: employee/salary—Sanofi Genzyme; ownership interest less than 5% (stocks, stock options, or other ownership interest excluding diversified mutual funds)—Sanofi Genzyme. B. Schoser: advisory board—Amicus, Alexion, Audentes, Dyne, Lupin, Sanofi Genzyme, and UCB; contracted research—Amicus and Sanofi Genzyme; honoraria—Kedrion; and travel expenses—Sanofi Genzyme. Go to Neurology.org/N for full disclosures.

Funding Information:
The Article Processing Charge was funded by Sanofi.

Publisher Copyright:
© American Academy of Neurology.

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