Background: Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for GAA production.
Objectives: We report initial analyses of safety and bioactivity of the first (low-dose) cohort (n=3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). The primary study objective is to evaluate the safety of AAV8-LSPhGAA in adult subjects as assessed by the incidence of adverse events (AEs), serious AEs (SAEs), and clinical laboratory abnormalities. Secondary objectives include six-minute walk test distance (6MWT), forced vital capacity (FVC), serum GAA activity, and muscle GAA activity and glycogen content.
Methods: Eligible subjects had LOPD, no detectable anti-AAV8 neutralizing antibodies, >12 months stable ERT dosing, and ability to walk at least 100 meters on the 6MWT. Subjects continued bi-weekly ERT until ERT withdrawal at Week 26 based on the detection of quantifiable serum GAA activity from AAV8-LSPhGAA and the absence of clinically significant declines in FVC or 6MWT performance.
Results: All subjects demonstrated sustained serum GAA levels from 101% to 235% above baseline trough activity two weeks following the preceding ERT dose which confirmed bioactivity as GAA is not normally secreted into the blood. There were no treatment-related SAEs and laboratory assessments supported the safety of AAV8-LSPhGAA. No subject had elevated serum alanine aminotransferase, reflecting an absence of anti-AAV8 T-cell responses. Although there were no treatment-related SAEs, one subject experienced two moderate severity treatment-related AEs (headache). At Week 24 all subjects met criteria for ERT withdrawal. Subsequently, all subjects met criteria to remain off ERT at Weeks 52 and 104, although one subject opted to resume ERT at Week 97. Muscle biopsy at Week 24 revealed a large decrease (-40%) in muscle glycogen content for one subject. At Week 52 muscle GAA activity for the cohort was significantly increased in comparison with baseline (p<0.05). One subject had a 10-fold increase from 2.8% to 28% of normal, the second increased from 19% to 44% of normal, and the third increased from 56% to 94% of normal.
Conclusions: Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.