Cipaglucosidase Alfa and Miglustat (Pombiliti and Opfolda)

Cipaglucosidase alfa is a recombinant enzyme-replacement drug for late-onset Pompe disease, approved only for use together with an oral enzyme stabilizer, miglustat, as a required two-component therapy. Approved by the FDA in 2023 specifically for adults whose disease had not improved on an existing enzyme-replacement therapy, it is the fourth distinct Pompe disease enzyme covered on this site — and its own pivotal trial technically missed its primary endpoint for statistical superiority, while its FDA review was separately delayed a full year for a reason that had nothing to do with its clinical data at all.

A fourth Pompe enzyme, aimed at patients already on treatment

This site's alglucosidase alfa page describes how Myozyme (2006) and Lumizyme (2010) turned once-fatal infantile Pompe disease into a treatable one, and how a newer engineered enzyme, avalglucosidase alfa (Nexviazyme), was approved in 2021 for better cellular uptake in late-onset patients. Cipaglucosidase alfa, developed by Amicus Therapeutics under the internal name ATB200 and marketed as Pombiliti, is a fourth distinct recombinant acid alpha-glucosidase (GAA) enzyme approved for Pompe disease, aimed specifically at adults with late-onset disease whose muscle strength or respiratory function has not improved despite already being on an existing enzyme-replacement therapy. Unlike the earlier Pompe drugs, cipaglucosidase alfa is not approved to be given alone: the FDA approval requires it be co-administered with miglustat (marketed as Opfolda), an oral small-molecule chaperone that stabilizes the infused enzyme in the bloodstream and is thought to reduce its breakdown before it reaches muscle cells — a two-component enzyme-plus-stabilizer approach genuinely different from how any other Pompe or lysosomal-storage-disease drug on this site is dosed.

PROPEL: a trial that missed its own primary endpoint

The pivotal evidence was PROPEL, an international, randomized, double-blind, phase 3 trial that enrolled 125 adults with late-onset Pompe disease between December 2018 and November 2019, randomizing them 2:1 to cipaglucosidase alfa plus miglustat (85 patients) or alglucosidase alfa plus an oral placebo (40 patients), dosed every two weeks for 52 weeks. The trial's single primary endpoint was change from baseline in six-minute walk distance (6MWD) at week 52: patients on cipaglucosidase alfa plus miglustat improved by a mean 20.8 meters against 7.2 meters on alglucosidase alfa, but the 13.6-meter between-group difference did not reach statistical significance, since its 95% confidence interval (-2.8 to 29.9 meters) crossed zero (Schoser B, Roberts M, Byrne BJ, Sitaraman S, Mozaffar T, Kishnani PS, et al., "Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial," Lancet Neurol 2021;20(12):1027-1037, PMID 34800400, DOI: 10.1016/S1474-4422(21)00331-8).¹ By the plain statistical standard the trial itself set out to meet, PROPEL did not succeed in its overall population — worth stating as directly as the trial's own published results do, rather than glossing over it because the drug was eventually approved anyway.

Approved anyway — on secondary evidence in the switch population

What ultimately supported approval was the totality of secondary and subgroup evidence rather than the missed primary endpoint alone. Cipaglucosidase alfa plus miglustat showed a nominally significant improvement over alglucosidase alfa in sitting percent-predicted forced vital capacity, a respiratory-function secondary endpoint, across the trial's overall population. In the pre-specified subgroup of 61 patients who had already been on enzyme-replacement therapy for at least two years before enrolling — the same population the drug is now actually approved for, patients not improving on existing treatment — 6MWD improved by an estimated 17 meters more than on alglucosidase alfa, a result that reached nominal statistical significance even though its own confidence interval (0.2 to 33 meters) barely cleared zero. The FDA's eventual approval rested on this pattern: a trial that missed its single pre-specified primary endpoint in the full population, but showed a more consistent, biologically coherent benefit specifically in the switch population the drug is now labeled to treat, together with supportive biomarker and long-term extension data.

A yearlong delay over a factory inspection, not the data

The FDA's review of cipaglucosidase alfa was separately delayed by roughly a year for a reason unrelated to any of this trial data. The agency initially set a PDUFA action date of 29 July 2022 for the cipaglucosidase alfa biologics license application, then extended it to 29 October 2022 to allow time for a required pre-license inspection of a Chinese contract manufacturing site operated by WuXi Biologics — but COVID-19 travel restrictions kept FDA inspectors from actually reaching the site before that date, and in October 2022 the agency issued a deferred-action letter putting the application on hold until the inspection could be completed, citing the inspection alone as the reason. Amicus resubmitted once the inspection was finished, and the FDA approved both Pombiliti (cipaglucosidase alfa-atga, BLA 761204) and Opfolda (miglustat, NDA 215211) together on 28 September 2023 — a real, clinically supportable drug sitting in regulatory limbo for roughly a year over pandemic-era travel restrictions on a factory inspection, not because of anything wrong with the drug itself.

Current status

Pombiliti plus Opfolda remains FDA-approved and marketed by Amicus Therapeutics, specifically for adults weighing at least 40 kg with late-onset Pompe disease not improving on their current enzyme-replacement therapy — it is not approved as a first-line or standalone treatment, and its label carries a warning for hypersensitivity reactions, including anaphylaxis, tied to the infused enzyme. Longer-term open-label follow-up data Amicus presented at the September 2025 International Congress of Inborn Errors of Metabolism reported continued improvements in muscle strength and function through four years, though that evidence comes from an open-label extension rather than a second placebo- or comparator-controlled trial. Late-onset Pompe disease patients who are not improving on their existing enzyme-replacement therapy now have a real, if narrowly targeted and imperfectly proven, FDA-approved second-line option that did not exist before 2023.