Pamphlets promote International Pompe Day at the 2019 Muscular Dystrophy Association Conference in Orlando, Florida. (Credit: Larry Luxner)

Researchers are racing to develop a gene therapy for Pompe disease, even as Sanofi Genzyme prepares to market avalglucosidase alfa-ngpt (Nexviazyme®) for patients at least 1 year old with the late-onset version of the illness.

Until the US Food and Drug Administration approved avalglucosidase alfa on August 6, 2021, the only other drug cleared to treat this rare degenerative muscle and neurological disorder was alglucosidase alfa (Lumizyme®), which was also developed by Sanofi Genzyme in 2006 for late-onset Pompe and is sold in the European Union as Myozyme®.

In the late 1990s and early 2000s, the Muscular Dystrophy Association funded the work of Duke University researcher Y.T. Chen, who sought to create a cell line to produce the enzyme missing in Pompe — known as acid alfa glucosidase (GAA) — isolate it, then infuse it back into patients who couldn’t make it themselves because of their genetic defect.


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Sharon Hesterlee, PhD, chief research officer at the Muscular Dystrophy Association (MDA). Credit: MDA

“That’s how the original concept was developed,” said Sharon Hesterlee, PhD, executive vice president and chief research officer at the MDA, which since its inception in 1950 has funded more than $1 billion in research to cure some 40 neuromuscular diseases, including Pompe.

“The approved drugs that are on the market now, Myozyme and Lumizyme, are both based on this concept of producing the enzyme in the cell line and then giving it to the patients,” said Dr. Hesterlee, who estimates the MDA has contributed at least $5 million over the years to Pompe disease research alone.

The newly approved therapy differs from the older one in that it contains more mannose 6-phosphate (M6P) in order to bind to the mannose 6-phosphate receptor, meaning the enzyme replacement therapy (ERT) can be absorbed into cells more efficiently.

“It’s next-generation, which I suspect is why it’s called the ‘next viazyme,” Dr. Hesterlee said. “The drug itself, you can’t say it was a home run, but it might have some better attributes. It is at least as good as Lumizyme, and possibly better from a safety and lung function standpoint.”

MDA chief medical officer and Pompe expert Barry Byrne, MD, said “efforts to develop next-generation therapies for Pompe began almost as soon as the first drug was approved,” because evidence pointed to the potential for a recombinant ERT for Pompe, which affects about 3500 Americans.

“In its early iterations, this product was called neoGAA, which had improved on the ability of the protein to target muscle cells in particular,” said Dr. Byrne, director of the University of Florida’s Powell Gene Therapy Center in Gainesville. “Now, over the course of many years when this form of second‑generation enzyme, avalglucosidase, was studied, Genzyme was able to advance those several studies now through late phase studies that have led to marketing approval of neoGAA or avalglucosidase alfa.”

Yet gene therapy is going to be the best alternative for Pompe patients in the long run, Dr. Hesterlee said.

“The enzyme replacement does have side effects and it has to be administered by infusion for the lifetime of the patient,” she said. “Gene therapy, on the other hand, may have a more effective, long-lasting benefit.”

Barry Byrne, MD, director of the University of Florida’s Powell Gene Therapy Center in Gainesville, holds up a model of an adeno-associated virus (AAV) vector used in gene therapy. Credit: Larry Luxner

Dr. Byrne, who’s spent the past 20 years studying Pompe and other neuromuscular diseases, agrees.

“The initiatives we began many years ago towards gene therapy for Pompe have evolved from local regional administration to systemic administration for both the infantile form and the late-onset form of Pompe,” he explained. 

“We’ve done several studies here at the University of Florida with a small number of patients enrolled in a study which both assesses the effect of gene therapy on breathing function, and a more recent study that investigates the ability to receive multiple doses of AAV [adeno-associated virus], which will be very important for an early onset myopathy like Pompe, where, in order to sustain the effect over the lifespan, a redosing strategy is needed.”

This is crucial because, as Dr. Byrne said, the body responds to any viral pathogen or viral vector such as AAV by making antibodies, limiting its effectiveness. That’s why candidates for gene therapy cannot have detectable amounts of antibodies to AAV.

“The ability to re‑administer AAV requires that we anticipate the immune response and use a specific regimen that allows for a limited period where the body wouldn’t respond to the AAV to allow the gene therapy agent to get to where it’s needed and deliver the therapeutic genes,” Dr. Byrne said. “Then it’s possible after that to receive AAV in the future. Without that preventative treatment, antibodies develop against the vector — which would prohibit a future use.”