An excellent review article focused on the latest developments in Pompe disease research was recently published by Naresh K. Meena and Nina Raben from the National Institutes of Health (NIH). It details our current understanding of the pathophysiology of Pompe disease as well as an update on the latest treatments in development.

A major take-home message from the review article is that current treatment options for Pompe disease, whether infantile-onset or late-onset Pompe disease, are not as effective in the long term as once hoped. Newer treatment options that are in development will hopefully remedy that problem.

Some of the clinical pearls in the article include:

  • Thanks to the success of enzyme replacement therapy (ERT) for patients with infantile-onset Pompe disease, these patients are living longer. This has created a new phenotype of Pompe disease – one with a series of symptoms previously not associated with Pompe disease, including cognitive disabilities.
  • The hope that ERT would transform the severe infantile-onset Pompe disease to a milder late-onset type has not panned out for most infants. Despite living longer lives, they are still fraught with severe muscle weakness and many other multisystemic problems.
  • There is a large variance in persons with late-onset Pompe disease in how they respond to ERT. Some do not respond while others continue to respond to therapy for up to 8-10 years. The reason(s) why some respond to therapy and others do not is being studied but at present, it is not well understood. There are over 500 genetic mutations reported thus far.
  • The only approved therapy for Pompe disease, alglucosidase alfa, has significantly improved the course of the disease, but it is not an efficient treatment. Only 1% of the enzyme delivered into the body reaches the muscles where it is needed. Numerous treatments are in development to improve upon that delivery system, including:
    • Next generation ERT, avalglucosidase alfa (aka neoGAA) is believed to provide better uptake of the enzyme to the muscle. Data from clinical trials are showing the drug to be effective but more studies are needed to ascertain its safety and efficacy. Studies for both IOPD and LOPD are underway.
    • A second ERT treatment in development called AT-GAA, is combining an ERT with a chaperone drug to also increase the uptake of the enzyme to muscles. Two phase 3 studies are currently underway for this drug.
    • VAL-1221 combined a fusion protein with the GAA enzyme plus an anti-DNA antibody. Preclinical data did show promise but in June 2020, a phase 1/2 clinical trial was terminated.
    • Combination ERT with a beta-2 agonist was tested in late-onset Pompe disease and has shown to improve some parameters (e.g., 6 minute walk test) in a small study.
  • Numerous gene therapies are in development to not just treat Pompe disease but possible cure it or at least stop disease progression. Some of the gene therapies listed in the article that are in clinical trials include: rAAV2/1-CMV-hGA (University of Florida), rAAV9-DES-hGAA (Lacerta Therapeutics), AAV2/8-LSPhGAA (AskBio), and SPK-3006 (Spark Therapeutics).

We encourage you to read the full article.

Tagged: chaperone, clinical trials, ERT, gene therapy, NIH