• Neuromuscul. Disord. · Mar 2019

    Multicenter Study

    Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study.

    • Loren D M Pena, Richard J Barohn, Barry J Byrne, Claude Desnuelle, Ozlem Goker-Alpan, Shafeeq Ladha, Pascal Laforêt, Karl Eugen Mengel, Alan Pestronk, Jean Pouget, Benedikt Schoser, Volker Straub, Jaya Trivedi, Philip Van Damme, John Vissing, Peter Young, Katherine Kacena, Raheel Shafi, Beth L Thurberg, Kerry Culm-Merdek, Ans T van der Ploeg, and NEO1 Investigator Group.
    • Duke University Medical Center, Durham, NC, USA. Electronic address: Loren.Pena@cchmc.org.
    • Neuromuscul. Disord. 2019 Mar 1; 29 (3): 167-186.

    AbstractThis multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

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