FDA Approves Cipaglucosidase Alfa and Miglustat as First Two-Component Therapy for Pompe Disease


In a phase 3 setting, the 2-component therapy showed positive trends or clinically meaningful improvements on motor and respiratory functions compared with previously approved enzyme replacement therapy.

Tahseen Mazaffar, MD, director of the division of neuromuscular diseases in the department of neurology at the School of Medicine at UC Irvine

Tahseen Mazaffar, MD

The FDA has approved Amicus Therapeutics’ combination of cipaglucosidase alfa-atga (Pombiliti) and miglustat (Opfolda) as the first and only 2-component treatment for patients with late-onset Pompe disease (LOPD). This new therapy, which was already previously approved in the European Union and United Kingdom, is indicated for adults with the disease weighing at least 40 kg and who are not improving on their current enzyme replacement therapy (ERT).

The design of the 2-component therapy is unique. Cipaglucosidase alfa is a recombinant alpha-glucosidase (GAA) enzyme naturally expressed with high levels of bis-Mannose 6-Phosphate, designed for increased uptake into muscle cells. Once in the cell, this enzyme can be properly processed into its most active and mature form to break down glycogen, while the second part, miglustat, stabilizes the enzyme in the blood.

"The Pompe community continues to face unmet need and limited treatment options,” Tahseen Mazaffar, MD, director of the division of neuromuscular diseases in the department of neurology at the School of Medicine at UC Irvine, said in a statement. “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.”

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Mozaffar was an investigator on the phase 3 PROPEL study (NCT03729362), the supportive trial to the approval and only trial in LOPD to study ERT-experienced participants in a controlled setting. The study, conducted between 2018 and 2019, featured 125 patients who were randomly assigned to cipaglucosidase alfa plus miglustat (n = 85) or alglucosidase alfa plus placebo (n = 40). Two patients in the active treatment group ended up not receiving any dose because of an absence of genotype confirmation of LOPD and were excluded.

Top Clinical Takeaways

  1. The approval of Pombiliti and Opfolda addresses the unmet needs and limited treatment options for late-onset Pompe disease, providing a valuable alternative for patients.
  2. Results from the phase 3 PROPEL study show the potential benefits of cipaglucosidase alfa/miglustat, offering eligible late-onset Pompe disease patients in the U.S. access to improved treatment options.
  3. Clinical research demonstrated promising results, including improved 6-minute walk distance and forced vital capacity, making it a significant advancement for the LOPD community in the United States.

Published in Neurology, data at week 52 showed a 14 m mean improvement in 6-minute walk distance (6MWD) with cipaglucosidase alfa/miglustat vs approved ERT therapy but did not reach statistical superiority (P = .072). Cipaglucosidase alfa/miglustat achieved a nominally statistically significant and clinically meaningful 3% mean improvement in percentage predicted forced vital capacity (FVC) for superiority over approved therapy (P = .023). Outcomes consistently favored cipaglucosidase alfa/miglustat in all subgroups for the overall and ERT-experienced populations, regardless of baseline 6MWD and percentage predicted FVC.2

"Today’s FDA approval is an extremely important step and acknowledges the potential of Pombiliti and Opfolda,” investigator Priya Kishnani, MD, professor of pediatrics and chief of medical genetics at Duke University School of Medicine, said in a statement.1 "I am grateful that eligible patients with late-onset Pompe disease in the U.S. will now have access to additional treatment options."

1. Amicus Therapeutics announces FDA approval and launch of new treatment for Pompe disease. News release. September 28, 2023. Accessed September 29, 2023. https://www.globenewswire.com/news-release/2023/09/28/2751407/15991/en/Amicus-Therapeutics-Announces-FDA-Approval-and-Launch-of-New-Treatment-for-Pompe-Disease.html
2. Mozaffar T, Bratkovic D, Byrne B, et al. Cipaglucosidase alfa/miglustat versus algucosidas alfa/placebo in late-onset Pompe disease (LOPD): PROPEL study subgroup analyses. Neurology. 2022;98(18 suppl).
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