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

Abstract

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 (t 1/2z ∼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.

STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa

“…The fast approval of novel therapeutic options is a great unmet need for Pompe patients. According to initial interim evaluations, enzyme replacement therapy with the new modified drug avalglucosidase alfa appears to have a positive effect on lung capacity [30]. The clinical effect of recombinant alpha-glucosidase in the presence of a chaperone leading to improved stability of the ERT is in parallel under investigation [31].…”

The rapidly evolving view of lysosomal storage diseases

“…In several LSDs, the main target tissues, where the correction of enzyme activity is required to clear storage and improve pathology, are in fact the most difficult to reach (van Gelder et al , 2012). For these reasons, second‐generation recombinant enzymes with improved targeting properties or pharmacodynamics are currently under development, for example, avalglucosidase‐apha, a glycoengineered GAA, for the treatment of Pompe disease (Pena et al , 2019; Xu et al , 2019) and pegunigalsidase alfa, a PEGylated covalently cross‐linked alpha‐galactosidase A, for the treatment of Fabry disease (Schiffmann et al , 2019).…”

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

“…Neo-GAA (Avalglucosidase alfa; Sanofi Genzyme, Cambridge, MA, USA), a second-generation glycoengineered recombinant GAA with increased bis-M6P levels, was first evaluated for safety and tolerability in a now completed clinical trial (NCT01898364). The results of this Phase 1/2 open-labeled, ascending-dose (5, 10, and 20 mg/kg biweekly over the course of 24 weeks) study in previously ERT-treated (switch group) and -untreated (naïve group) LOPD patients was recently published [109]. Neo-GAA was overall well-tolerated and safe; only two of the 24 enrolled patients discontinued because of the drug-related serious adverse events.…”