Miglustat

This review describes the mechanism and clinical data for miglustat as the first‑in‑class enzyme stabilizer for cipaglucosidase alfa in late‑onset Pompe disease. Cipaglucosidase alfa, a second‑generation recombinant human acid α‑glucosidase enriched with bis‑mannose‑6‑phosphate N‑glycans, overcomes challenges in cellular uptake and lysosomal processing. Co‑administered miglustat stabilizes the enzyme in the bloodstream, enhancing exposure and tissue availability. Preclinical and clinical studies show that miglustat improves functional outcomes and biomarker levels compared to cipaglucosidase alfa alone. The once‑every‑2‑weeks regimen is well tolerated, with fewer gastrointestinal events than daily high‑dose miglustat used for other diseases. Miglustat is a critical component of this novel treatment approach for late‑onset Pompe disease.

Fig. 1 Miglustat-induced increase in cipaglucosidase alfa exposure improved glycogen clearance in Gaa KO mice. (Hopkin RJ, et al., 2026)

An open‑label extension study assessed the long‑term safety and efficacy of cipaglucosidase alfa plus miglustat (cipa+mig) in 118 adults with late‑onset Pompe disease following the phase III PROPEL trial. At 104 weeks, the cipa+mig group (continuous treatment) maintained improvements in 6‑minute walk distance (mean +3.1% predicted) and stabilization of forced vital capacity (-0.6% predicted), with improved biomarkers (CK and Hex4). The switch group (from alglucosidase alfa to cipa+mig) showed comparable or better outcomes. Three patients discontinued due to infusion‑associated reactions. No new safety signals emerged. Cipa+mig treatment up to 2 years was well tolerated with durable efficacy, supporting long‑term benefits.

Fig. 2 Patient disposition. (Schoser B, et al., 2024)