Efficacy of avalglucosidase alfa on forced vital capacity percent predicted in treatment-naïve patients with late-onset Pompe disease: A pooled analysis of clinical trials.

Background: The efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG.
Methods: Data from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG. Regression analyses using mixed models with repeated measures consistent with those pre-specified in COMET were performed post-hoc. Analyses were adjusted for trials and differences in baseline characteristics. Four models were developed: Model 1 considered all trials; Model 2 included Phase 3 trials; Model 3 included Phase 3 trials and was adjusted for baseline ventilation use; Model 4 included COMET and NEO1/NEO-EXT (i.e., AVA trials only).
Results: Overall, 100 randomized patients from COMET (AVA, n  = 51, ALG, n  = 49), 60 from LOTS (ALG arm only), and three patients from NEO1/NEO-EXT (who received open-label AVA only) were considered for analysis. Mean age at enrollment was similar across trials (45.3-50.3 years); however, patients from LOTS had a longer mean duration of disease versus COMET and NEO1/NEO-EXT trials (9.0 years and 0.5-2.2 years, respectively) and younger mean age at diagnosis (36.2 years and 44.7-48.6 years, respectively). Least squares mean (95% confidence interval) improvement from baseline in FVCpp at Week 49-52 for AVA versus ALG was 2.43 (-0.13; 4.99) for COMET ( n  = 98); 2.31 (0.06; 4.57) for Model 1 ( n  = 160); 2.43 (0.21; 4.65) for Model 2 ( n  = 157); 2.80 (0.54; 5.05) for Model 3 ( n  = 154); and 2.27 (-0.30; 4.45) for Model 4 ( n  = 101).
Conclusions: Models 1 to 3, which had an increased sample size versus COMET, demonstrated a nominally significant effect on FVCpp favoring AVA versus ALG after 1 year of treatment, consistent with results from COMET.
Competing Interests: TM has participated in advisory boards for AbbVie, Alexion, Amicus, Argenx, Audentes, Maze Therapeutics, Momenta, Ra-Pharmaceuticals, Sanofi, Sarepta Therapeutics, Spark Therapeutics, UCB, Ultragenyx, and Zogenix, and Speaker's bureau for Sanofi; and has received research funding from Alexion, Amicus, Argenx, Audentes, Bristol Myers-Squibb, Cartesian, Grifols, Momenta, Ra-Pharmaceuticals, Sanofi, Spark Therapeutics, UCB, and Valerion. JM, KAH, TZ, and LP are employees and may hold stock and/or stock options in Sanofi. MP: was an employee of Sanofi at the time of study participation and may still hold stock and/or stock options, and is currently employed as the Global Medical Lead for Early Indications and New Programs – Rare Diseases at UCB. LRF was an employee of Sanofi at the time the research took place and is now an employee of Aixial, a contract research organization working with Sanofi. He holds stock in Sanofi. PS and IP are employees of Evidera, part of ThermoFisher Scientific. VS has received consulting fees from Novartis Gene Therapies, Roche, Sanofi, Sarepta Therapeutics, and Vertex Pharmaceuticals, and honoraria from Sanofi; and has conducted contracted research for Sanofi and Sarepta Therapeutics.
(© 2024 The Authors. Published by Elsevier Inc.)