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
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 Î±-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ‰¥18 years, alglucosidase alfa naÃ¯ve (NaÃ¯ve) 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 NaÃ¯ve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One NaÃ¯ve 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 NaÃ¯ve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ˆ¼1.0 h). AUC was 5€“6 Ã— higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and NaÃ¯ve groups and over time. Baseline quadriceps muscle glycogen was low (ˆ¼6%) 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.
Medical Subject Headings
Digital Object Identifier (DOI)
Pena, Loren D.M.; Barohn, Richard J.; Byrne, Barry J.; Desnuelle, Claude; Goker-Alpan, Ozlem; Ladha, Shafeeq S.; Laforêt, 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.; and al., et, "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" (2019). Neurology Articles. 92.