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Pompe HCP

About Pombiliti + Opfolda

What is Pombiliti® + Opfolda®?

Pombiliti® (cipaglucosidase alfa) is a novel recombinant human acid alpha-glucosidase (rhGAA) enzyme enriched with bis-mannose-6-phosphate (bis-M6P).1,2

Opfolda® (miglustat) is a small-molecule enzyme stabiliser approved in combination with Pombiliti® for the treatment of adults with a confirmed diagnosis of late-onset Pompe disease (LOPD).1,3

A next-generation therapy

Pombiliti® + Opfolda® was designed as a two-component therapy to addresses three key mechanistic challenges in delivering rhGAA to muscles.4

Pombiliti® + Opfolda® has demonstrated efficacy in the first-in-human ATB200-02 (Phase I/II) and randomised, multicentre PROPEL (Phase III) clinical trials

Learn more

Key challenges of treatment delivery

Challenge 1​ Enzyme stability5-7

Like other lysosomal enzymes, rhGAA has pH-sensitive enzyme activity and is most stable and active at the acidic pH of the lysosome. In the neutral pH of the blood, rhGAA can become less stable, so a smaller amount of active enzyme may be available to enter the muscle.

Challenge 2​ Enzyme uptake4,8,9

In healthy individuals, GAA is created inside the cell. Enzyme-replacement therapy (ERT) relies on the enzyme being taken up from​ outside the cell.

Challenge 3​​Enzyme activity8

Once in the skeletal muscle, rhGAA requires both proteolytic processing and N-glycan trimming for maximal glycogen hydrolytic activity.

How does Pombiliti + Opfolda work?

Pombiliti® + Opfolda® is a two-component therapy for adults with LOPD: a bis-M6P enriched enzyme + an oral enzyme stabiliser.1

Pombiliti®Bis-M6P enriched enzyme1,2,4​

  • Pombiliti® is a long-term ERT used in combination with the enzyme stabiliser miglustat for the treatment of adults with late-onset Pompe disease (acid a-glucosidase [GAA] deficiency).1
  • High-affinity cation-independent mannose 6-phosphate receptor (CI-MPR) binding, designed for increased uptake into muscle cells.
  • Bis-M6P has ~3000x the binding affinity of M6P.
  • Can be processed into its most active form to break down glycogen.

Opfolda®Oral enzyme stabiliser1-3​

  • Opfolda® is an enzyme stabiliser of cipaglucosidase alfa which is a long-term ERT in adults with late-onset Pompe disease (GAA deficiency).3
  • Binds selectively to Pombiliti® to minimise loss of activity in the blood​.
  • Increases the amount of active enzyme that can reach the muscle.

The in vitro and pharmacokinetic data supporting these statements cannot be translated into clinical efficacy.​

How does Pombiliti + Opfolda address the three key mechanistic challenges of treatment delivery?

Improving enzyme stability

Like other lysosomal enzymes5, rhGAA has pH-sensitive enzyme activity and is most stable and active at the acidic pH of the lysosome.6.7 In the neutral pH of the blood, rhGAA can become less stable, so a smaller amount of active enzyme may be available to enter the muscle.7 Opfolda® binds with and stabilises Pombiliti® in these unfavourable conditions, thereby increasing the levels of active enzyme available for targeting to lysosomes in muscles.2,8

Enhancing enzyme uptake

Binding to the CI-MPR is a mandatory first step in the uptake of rhGAA.4 Pombiliti® is a bis-M6P enriched enzyme, which means it has roughly 3000 times more binding affinity compared to M6P alone, which serves to enhance its cellular uptake.1,2,4

Maximising enzyme activity

Pombiliti® is fully processed via proteolysis and N-glycan trimming, yielding the most active and mature form of the GAA enzyme.1,8

PP-AT-UK-0022-0623 | October 2024
References
  1. Pombiliti® 105 mg powder for concentrate for solution for infusion. Summary of Product Characteristics.
  2. Schoser, B., Roberts, M., Byrne, B.J., et al. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidasealfa 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.
  3. Opfolda® 65 mg hard capsules. Summary of Product Characteristics.
  4. Do. H.V., Khanna, R. and Gotschall, R. Challenges in treating Pompe disease: an industry perspective. Ann Transl Med. 2019;7(13):291.
  5. Lieberman, R.L., D’aquino, J.A., Ringe, D., Petsko, G.A. Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability. Biochemistry. 2009 Jun 9;48(22):4816-27
  1. Xu, S., Lun, Y., Frascella, M., et al. Improved efficacy of a next-generation ERT in murine Pompe disease. JJCI Insight. 2019;4(5):e125358.
  2. Porto, C., Ferrara, M.C., Meli, M., et al. Pharmacological enhancement of a-glucosidase by the allosteric chaperone N-acetylcysteine. Mol Ther. 2012 Dec;20(12):2201-11.
  3. Johnson, F.K., Kang, J., Mondick, J., et al. Mechanism of action, plasma total GAA protein PK profiles and PK/PD relationships differ between cipaglucosidase alfa/miglustat and alglucosidase alfa in patients with late-onset Pompe disease. Presented at the: 18th Annual WorldSymposium (Abstract No. 166); 2022.​
  4. Selvan, N., Mehta, N., Venkateswaran, S., et al. Endolysosomal N-glycan processing is critical to attain the most active form of the enzyme acid alpha-glucosidase. J Biol Chem. 2021;296:100769. ​