Pompe disease management update

For Rare Disease Day 2024, on 29 February, what is the outlook for Pompe disease management? 

Gene therapy for improving time to initiate disease-modifying therapy

A single treatment of the transgene that produces the acid α-glucosidase (GAA) enzyme could preclude biweekly enzyme replacement therapy (ERT) for Pompe disease. Most gene therapies use adeno-associated virus vectors (AAV) for single delivery;¹ lentivirus-driven correction of autologous haematopoietic stems cells and reinfusion of cells is another option.²

Substrate reduction for delaying Pompe disease onset

Substrate (glycogen) reduction, which could delay Pompe disease symptom onset, is being investigated in genetic studies.³ This form of treatment could be used as a monotherapy or in combination with ERT.

Mixed results for long-term efficacy of ERT

Infant-onset Pompe disease (IOPD)

Although standard ERT can improve overall and ventilator-free survival, and cardiac function,⁴ reduced skeletal muscle strength and cardiac arrhythmias can develop years after treatment initiation. Infants with Pompe disease who survive into childhood with a history of ERT can develop hearing loss, speech dysfunction, cognitive impairment, and gastrointestinal or respiratory dysfunction.⁵

Late-onset Pompe disease (LOPD)

For LOPD, ERT can stabilise mobility, improve skeletal and respiratory muscle strength.⁴ However, 2–3 years following ERT initiation, ERT with alglucosidase alfa can lose efficacy.^6,7 Alternate ERT, avalglucosidase alfa and cipaglucosidase alfa + miglustat, were compared to alglucosidase alfa (standard-of-care) in the COMET and PROPEL trials:^8,9

• COMET: There was improvement with avalglucosidase alfa over alglucosidase alfa for respiratory function, ambulation, functional endurance, improved safety, and health-related quality of life;⁸ Avalglucosidase alfa was FDA approved for Pompe Disease in 2021¹⁰
• PROPEL: Cipaglucosidase alfa + miglustat did not achieve statistical superiority to alglucosidase alfa + placebo for improving six-minute walk distance⁹

Investigational enzyme replacement therapies

• In treating skeletal muscle phenotypes of Pompe disease mice, targeted ERT, which uses antibody enzyme fusion proteins to target the GAA enzyme, removed more glycogen than the standard-of-care, alglucosidase alfa¹¹
• Patients with Pompe disease treated with VAL-1221, a fusion protein targeting cytoplasmic glycogen, improved the six-minute walk test more than alglucosidase alfa; serious adverse events were not associated with VAL-1221¹²

Improved delivery to target organs?

Liver-directed strategies

Liver-directed treatment for Pompe, through single intravenous (IV) infusion of the AAV-packaged transgene, targets the nucleus of liver cells for production of GAA.^13,14 This could create a ‘depot’ for GAA production for release into skeletal and cardiac tissues.²

Muscle-based approaches

In muscle-based approaches, the GAA transgene is delivered to muscle cells for production of the GAA enzyme. One study used a skeletal-muscle targeting approach, administered as an IV infusion based on the AAV vector with muscle-specific serotype and promoters.¹⁵ As only 1% of GAA produced in the liver reaches skeletal and cardiac muscle, muscle-directed AAV could improve GAA uptake in tissues. In principle, a skeletal-muscle targeting approach delivers the AAV vector to all muscle tissue; however, this could increase risk of hepatotoxicity or cardiomyopathy.²

A role for direct intramuscular injection?

Direct intramuscular (IM) injection aims to deliver the AAV vector directly to muscle fibres. A benefit of IM injection for Pompe disease is that certain muscles that are more affected, such as the diaphragm, could be targeted. However, the benefits of IM injection seem to be localised at the injection site, which may require multiple injections at different sites, imposing a higher risk for antibody development.²

References

1. Ronzitti G, Collaud F, Laforet P, Mingozzi F. Progress and challenges of gene therapy for Pompe disease. Annals Translat Med. 2019;7(13):287.
2. Stevens D, Milani-Nejad S, Mozaffar T. Pompe Disease: a Clinical, Diagnostic, and Therapeutic Overview. Curr Treat Options Neurol. 2022;24(11):573-588.
3. Tang B, Frasinyuk MS, Chikwana VM, Mahalingan KK, Morgan CA, Segvich DM, et al. Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase. J Med Chem. 2020;63(7):3538–3551.
4. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, et al. Recombinant human acid α-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurol. 2007;68(2):99–109.
5. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8(5):267–288.
6. Harlaar L, Hogrel JY, Perniconi B, Kruijshaar ME, Rizopoulos D, Taouagh N, et al. Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease. Neurol. 2019;93(19):e1756–1767.
7. Papadimas GK, Anagnostopoulos C, Xirou S, Michelakakis H, Terzis G, Mavridou I, et al. Effect of long term enzyme replacement therapy in late onset Pompe disease: A single-centre experience. Neuromuscul Disord. 2021;31(2):91–100.
8. Diaz-Manera J, Kishnani PS, Kushlaf H, Ladha S, Mozaffar T, Straub V, et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): A phase 3, randomised, multicentre trial. Lancet Neurol. 2021;20(12):1012–1026.
9. Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Laforêt P, 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.
10. FDA. Nexviazyme (avalglucosidase alfa-ngpt) Highlights of Prescribing Information. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761194s000lbl.pdf.
11. Baik AD, Calafati P, Zhang X, Aaron NA, Mehra A, Moller-Tank S, et al. Cell type-selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies. Mol Ther. 2021;29(12):3512–3524.
12. Kishnani P, Lachmann R, Mozaffar T, Walters C, Case L, Appleby M, et al. Safety and efficacy of VAL-1221, a novel fusion protein targeting cytoplasmic glycogen, in patients with late-onset Pompe disease. Mol Genet Metab. 2019;126(2):S85–86.
13. Clinicaltrials.gov. A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE). 2023. Available at: https://clinicaltrials.gov/study/NCT04093349.
14. Clinicaltrials.gov. AAV2/​8-LSPhGAA (ACTUS-101) in Late-Onset Pompe Disease. 2023. Available at: https://clinicaltrials.gov/study/NCT03533673.
15. Clinicaltrials.gov. Gene Transfer Study in Patients With Late Onset Pompe Disease (FORTIS). 2024. Available at: https://clinicaltrials.gov/study/NCT04174105?term=NCT04174105&rank=1.