On September 28, 2023, the FDA approved cipaglucosidase alfa-atga (Pombiliti; Amicus Therapeutics), a hydrolytic lysosomal glycogen-specific enzyme, combined with miglustat (Opfolda; Amicus Therapeutics), an enzyme stabilizer, for the treatment of late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) in adults weighing ≥88 lb whose disease has not improved after receiving their current enzyme replacement therapy (ERT).
The FDA previously granted cipaglucosidase alfa-atga plus miglustat a breakthrough therapy designation.
Cipaglucosidase alfa-atga combined with miglustat is a unique 2-component therapy. Cipaglucosidase alfa-atga is a recombinant human GAA enzyme that is naturally expressed with high levels of bis-mannose 6-phosphate, which is designed to increase its uptake into muscle cells. Once in muscle cells, cipaglucosidase alfa-atga can be properly processed into its most active and mature form to break down glycogen. Miglustat is an enzyme stabilizer designed to stabilize cipaglucosidase alfa-atga in the blood.
“The Pompe community continues to face unmet need and limited treatment options. This two-component therapy is an important new treatment for those adults living with late-onset Pompe disease and not improving on current therapies. I am encouraged by the evidence generated over many years of clinical research studying this therapy for ERT-experienced patients living with late-onset Pompe disease,” stated Tahseen Mozaffar, MD, Director of the Division of Neuromuscular Diseases in the Department of Neurology, School of Medicine, University of California, Irvine (UCI), and Director of the UCI Health ALS and Neuromuscular Center, in a press release.
The approval of cipaglucosidase alfa-atga for the treatment of Pompe disease in adults was based on results of the randomized, double-blind, phase 3 PROPEL clinical trial (NCT03729362). Eligible participants were aged ≥18 years with late-onset Pompe disease and had been receiving alglucosidase alfa for ≥2 years or were ERT naïve. A total of 125 patients were randomized to intravenous (IV) cipaglucosidase alfa-atga 20 mg/kg plus oral miglustat or to alglucosidase alfa 20 mg/kg IV plus oral placebo once every 2 weeks for 52 weeks. At week 52, the mean change from baseline in 6-minute walk distance was 20.8 m (standard error [SE], 4.6) in the cipaglucosidase alfa-atga plus miglustat group compared with 7.2 m (SE, 6.6) in the alglucosidase alfa plus placebo group using the last observation carried forward (between-group difference, 13.6 m [95% confidence interval, −2.8 to 29.9]).
The most common (≥5%) adverse events with cipaglucosidase alfa-atga are headache, diarrhea, fatigue, nausea, abdominal pain, and pyrexia. The prescribing information for cipaglucosidase alfa-atga includes a black box warning about the risk for severe hypersensitivity and infusion-associated reactions and the risk for acute cardiorespiratory failure in susceptible patients.
The recommended starting dose of cipaglucosidase alfa-atga is 20 mg/kg of actual body weight administered every other week as an IV infusion over approximately 4 hours. The infusion of cipaglucosidase alfa-atga should start approximately 1 hour after the oral administration of miglustat.