Efficacy of Switching Therapy From Alglucosidase Alfa to Avalglucosidase Alfa on Respiratory Function in Participants With Late-Onset Pompe Disease: A Post Hoc Analysis From the COMET Trial

Abstract

Pompe disease (PD) is a rare, autosomal recessive neuromuscular disorder caused by a deficiency in acid α-glucosidase. In the Phase 3 COMET trial (NCT02782741), respiratory function was examined in participants with late-onset PD randomized to receive enzyme replacement therapy with alglucosidase alfa (ALG; standard of care) or avalglucosidase alfa (AVA; intervention) in the primary analysis period (PAP). The open-label extended treatment period (ETP) provided long-term data on AVA treatment. This post hoc analysis evaluated respiratory outcomes in participants who received ALG in the PAP (Weeks 0-49) and switched to AVA in the ETP (Weeks 49-145). Participants were categorized according to improvement in upright forced vital capacity percent-predicted (FVC) at Week 49. Forty-four participants were included, of whom 20 (45.5%) had ΔFVC > 0% predicted at Week 49. Among ΔFVC > 0% predicted participants, FVC improved during the PAP (estimated slope [SE]: 4.0 (1.1) %/year, p < 0.01), and was maintained following switch to AVA in the ETP (0.1 (0.8) %/year, p = 0.86). For participants with ΔFVC ≤ 0% predicted during the PAP (n = 24; estimated slope [SE]: -3.4 (1.0) %/year, p < 0.01), FVC stabilized following switch to AVA (0.3 (0.7) %/year, p = 0.70). Slopes in measures of respiratory airflow and inspiratory/expiratory muscle strength were consistent with these findings. Similar results were observed using ΔFVC ≥ 3% predicted as a measure of clinically meaningful change. This analysis demonstrates clinically meaningful maintenance in measures of lung volume (FVC) and airflow (forced expiratory volume in 1 s) after switching therapy from ALG to AVA that persists for ≥ 2 years and is independent of prior outcomes with ALG.

Keywords: Pompe disease; alglucosidase alfa; avalglucosidase alfa; forced vital capacity; respiratory outcomes.

FIGURE 1

(A) FVC, (B) FEV1, (C) MIP, and (D) MEP. LS Means values over time (up to Week 145) in mITT population who received ALG during the PAP, stratified by ΔFVC (% predicted) from study baseline to Week 49 (0% threshold), based on piecewise linear mixed model. ALG, alglucosidase alfa; FEV1, percent‐predicted forced expiratory volume; FVC, percent‐predicted upright forced vital capacity; LS, least squares; MEP, percent‐predicted maximal expiratory pressure; MIP, percent‐predicted maximal inspiratory pressure; mITT, modified intention‐to‐treat; PAP, primary analysis period; SE, standard error; ΔFVC, absolute change in FVC at Week 49 of the PAP. Participants with missing change from baseline in FVC were considered in the group of patients with a change from baseline ≤ 0%.