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
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.