AT-GAA’s Conceivable Benefits for Pompe Disease and the Need for More Options


Barry J. Byrne, MD, PhD, the associate chair of pediatrics and director of the Powell Gene Therapy Center at the University of Florida; and the chief medical advisor to the Muscular Dystrophy Association, offered his perspective on the upcoming FDA decision on AT-GAA (Amicus Pharma).

Barry J. Byrne, MD, PhD, associate chair of pediatrics, and director, Powell Gene Therapy Center, University of Florida; and chief medical advisor, Muscular Dystrophy Association

Barry J. Byrne, MD, PhD

Later this year, the FDA is set to make a decision on a two-part combination therapy for late-onset Pompe disease (LOPD), developed by Amicus Pharma, called AT-GAA. The agency is set to review the therapy’s new drug application by the end of October 2022, opening the door for a potential new option for physicians who treat this rare disease.

AT-GAA consists of cipaglucosidase alfa, a novel rhGAA with enhanced glycosylation for improved uptake and processing, and miglustat, an enzyme stabilizer. The investigational therapy was assessed in a phase 3 trial, called PROPEL (NCT03729362), comparing it to alglucosidase alfa (Lumizyme; Sanofi) and placebo in adults with LOPD. Those data, which included 65 participants who were enzyme-replacement therapy (ERT)-experienced and 20 who were ERT-naïve assigned to AT-GAA, and 30 who were ERT-experienced and 8 who were ERT-naïve assigned to alglucosidase alfa.1

At week 52, those in the AT-GAA group showed clinical improvement on 6-minute walk distance (mean change, 20.8 m; SD, 7.2) compared with alglucosidase (mean change, 7.6 m; SD, 6.6) but this did not achieve statistical significance (P = .072). A statistically significant improvement in percent predicted forced vital capacity (sitting) was observed in the AT-GAA group (–0.9 change; SD, 0.7) compared with the alglucosidase group (–4.0 change; SD, 0.8; P = .023).1

To find out more about what role this new therapy might play in the care paradigm ahead of the looming FDA decision, as well as to check on the state of care for LOPD, NeurologyLive® reached out to Barry J. Byrne, MD, PhD, associate chair of pediatrics, and director, Powell Gene Therapy Center, University of Florida; and chief medical advisor, Muscular Dystrophy Association.

NeurologyLive®: What impact could the approval of an agent like AT-GAA have on the landscape of treatment for Pompe disease?

Barry J. Byrne, MD, PhD: The use of miglustat in combination with cipaglucosidase alfa as a 2-component therapy has the potential to increase the efficacy of ERT for patients with Pompe disease. The value in the combination is that miglustat is able to stabilize the ERT in the blood and allow for greater activity of the enzyme inside the cell. Having multiple therapeutic products to evaluate will be important to providers and patients in choosing the best regimen for them.

How does AT-GAA compare to other therapies for Pompe based on what we know about its clinical development? Are there any advantages to its administration or approach?

AT-GAA has been evaluated in 5 different groups that reflect the variety of Pompe patients who have been clinically identified. The findings so far show improved function in patients who switch from conventional therapy to AT-GAA. The greatest improvement is in those who were not previously treated with ERT. Similar findings are observed in tests of respiratory function and biomarkers of disease severity.

How would you describe the current state of care for Pompe disease? Are there major gaps in care or education that new options might help address?

Pompe patients are now mostly identified by newborn screening which was developed to identify the early-onset or infantile-onset Pompe disease patients. In addition to offering early diagnosis for those who are most severely affected, the process of screening identifies children who are pre-symptomatic and have late-onset Pompe disease. The challenge of early diagnosis of late-onset Pompe disease patients is that infants with Pompe disease may be asymptomatic for up to 20 years and there is no clear guidance on when and how to initiate therapy in this setting. Expectations for children who received this early diagnosis are altered in the family unit and the risk of those differences have to be evaluated in the context of early diagnosis that avoids a prolonged period of searching for the cause of diffuse and non-specific findings that may be overlooked in early life. Ongoing evaluation of the natural history of an early childhood diagnosis of late-onset Pompe will help to correlate specific genotypes with disease severity.

Transcript edited for clarity.

1. Mozaffar T, Bratkovic D, Byrne B, et al. Efficacy and safety of cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo in late-onset Pompe disease (LOPD): A phase 3 trial (PROPEL). Presented at MDA Clinical and Scientific Conference 2021; March 15-18. Poster 129.
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