OBJECTIVES: There have been no head-to-head studies comparing avalglucosidase alfa (AVA), approved in multiple countries worldwide, and cipaglucosidase alfa plus migulstat (Cipa+mig), which is currently under review by health authorities. A recent indirect treatment comparison (ITC) by Fu et al. included single-arm studies into an anchored network of randomized controlled trials (RCT) and produced incoherent results that contradict direct evidence from both COMET and PROPEL phase 3 studies. Our study aimed to estimate the relative efficacy of AVA vs. Cipa+mig in LOPD patients using ITC with robust methodology.

METHODS: Anchored and un-anchored simulated treatment comparisons (STCs) were conducted, adjusting for differences in prognostic factors and treatment effect modifiers. Enzyme replacement therapy (ERT)-naive patient analyses used data from COMET (NCT02782741) (AVA, n=51 and alglucosidase alfa [ALGLU], n=49) and PROPEL (NCT03729362) (Cipa+mig, n=20 and [ALGLU], n=7). ERT-experienced patient analyses used AVA data (n=59) from COMET-OLE (open-label-extension) and NEO-1 (NCT01898364)/EXT (NCT02032524), and Cipa+mig data (n=81) from PROPEL plus ATB20002 (cohorts I and IV). Changes from baseline at week 52 in forced vital capacity percent predicted (FVCpp), maximal inspiratory pressure (MIPpp), maximal expiratory pressure (MEPpp), and 6-minute walk test (6MWT) (meters) were compared.

RESULTS: In ERT-naive patients, AVA was favorable vs. Cipa+mig for FVCpp (4.69; 95% confidence interval (CI): [−3.22, 12.61]), MIPpp (1.29; [−27.38, 29.96]), MEPpp (2.32; [−24.75, 29.4]) and 6MWT (41.88; [−5.46, 89.22]). In ERT-experienced patients, AVA was favorable vs. Cipa+mig for FVCpp (1.16; [−1.88, 4.19]), MIPpp (4.24; [−4.93, 13.41]), and 6MWT (7.67; [−21.67, 37.02]), with a statistically significant MEPpp result (8.62; [0.02, 17.21]).

CONCLUSIONS: Our STCs suggest better outcomes with AVA vs. Cipa+mig. STCs’ strength lies in using the best methodology for each subpopulation. The uncertainty of each comparison correctly reflects the available data. Ongoing real-world experience with AVA among ERT-experienced patients from managed access programs and registries will provide additional evidence.