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Pena, Loren D. M.; Barohn, Richard J.; Byrne, Barry J.; Desnuelle, Claude; Goker-Alpan, Ozlem; Ladha, Shafeeq; Laforet, Pascal; Mengel, Karl Eugen; Pestronk, Alan; Pouget, Jean; Schoser, Benedikt; Straub, Volker; Trivedi, Jaya; Van Damme, Philip; Vissing, John; Young, Peter; Kacena, Katherine; Shafi, Raheel; Thurberg, Beth L.; Culm-Merdek, Kerry; van der Ploeg, Ans T. (2019): Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naive and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study. In: Neuromuscular Disorders, Vol. 29, No. 3: pp. 167-186
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This 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 alpha-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients >= 18 years, alglucosidase alfa naive (Naive) 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 Naive and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated;no deaths/life-threatening serious adverse events (SAEs). One Naive 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 Naive patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t(1/2z)similar to 1.0h). AUC was 5-6 x higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naive groups and over time. Baseline quadriceps muscle glycogen was low (similar to 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. (C) 2018 The Authors. Published by Elsevier B.V.