New Therapy Brings Hope for Late-Onset Pompe Disease

“Don’t hope for a miracle. Make one,” is the powerful tag line from Extraordinary Measures a 2010 drama film starring Brendan Fraser, Harrison Ford, and Keri Russell. The movie is inspired by the true story of John and Aileen Crowley, a couple whose lives take a turn when their two youngest children are diagnosed with Pompe disease, a rare and often fatal genetic disorder that causes progressive weakness to the heart and skeletal muscles. With the clock ticking, Crowley becomes a man with a mission and teams up with Dr. Robert Stonehill (portrayed by Harrison Ford), an unconventional scientist who may have a theoretical solution to slow the progression of Pompe. Together, they face a series of challenges, including medical trials, corporate interests, and the intricacies of medical bureaucracy. The movie showcases their extraordinary measures, sacrifices, and the lengths a parent would go to save their children.  

Pompe disease, also known as acid maltase deficiency, is caused by mutations in a gene responsible for producing an enzyme called acid alpha-glucosidase (GAA). The body uses this essential enzyme to break down glycogen, a stored form of sugar utilized by the cells for energy. Muscle cells, including those of the heart and respiratory system, rely on glycogen to power movement. Mutations in the GAA gene reduce or completely eliminate the enzyme, leading to the accumulation of glycogen inside the cells. Without treatment, the glycogen eventually builds to toxic levels, causing muscle damage. The severity of the disease and the age of onset, are both related to the degree of enzyme deficiency.  

In Extraordinary Measures, hope for the Crowley’s came from Dr. Stonehill in the form of a groundbreaking enzyme replacement therapy (ERT), which was able to slow down the progression of the disease, allowing the children’s muscles, especially the heart and lungs, to function better. While Stonehill is fictional, ERT is not. There are currently two enzyme replacement therapies available for patients with Pompe disease in the U.S., Lumizyme (alglucosidase alfa) and Nexviazyme (avalglucosidase alfa). Treatment with ERT has been shown to extend life expectancy, however, ERT is not a cure. 

The real John Crowley’s endeavors have led to significant advancements in Pompe treatment, giving hope to many suffering from the condition, and ultimately saving his children’s lives. Currently, he serves as the executive chairman and founding CEO of Amicus Therapeutics, a global biotechnology company dedicated to advancing therapies for a range of rare and devastating diseases. His children, Megan and Patrick, are now 26 and 24 years old, and continue to defy the odds thanks to their father’s determination and love and the miracles of modern medicine.  

The character of Dr. Stonehill is actually composite, incorporating the characteristics and efforts of various researchers, including Bill Canfield, M.D., a glycobiologist from the University of Oklahoma Health Sciences Center, and Muscular Dystrophy Association’s own Chief Medical Advisor, Barry Byrne, M.D., Ph.D., Associate Chair of Pediatrics and Director of the Powell Gene Therapy Center at the University of Florida. Both physicians are prominent figures in the field of Pompe research, and their work has been instrumental in advancing the understanding and treatment of the disease. 

“I had the good fortune to meet John Crowley at a National Institute of Health meeting soon after Megan and Patrick were diagnosed,” said Dr. Barry Byrne. “Completely by chance, I was seated with John and Bill Canfield at lunch and we learned of the pioneering work Bill was doing to enhance the effectiveness of GAA through protein engineering. My lab helped establish the basis for enhanced activity of highly phosphorylated GAA. Over the past 15+ years, I have been delighted to continue productive collaborations with Amicus Therapeutics to improve the lives of those living with Pompe disease.” 

Pompe disease is classified into two subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). In IOPD, symptoms typically appear during the first year of life and tend to progress very quickly. With LOPD, symptoms may not be apparent right away, and can mimic those of other disorders. LOPD is typically diagnosed in children older than 1 year of age and as late as the second to sixth decade of life, depending on when disease symptoms manifest. Individuals with LOPD may not develop any noticeable symptoms until adulthood, making it possible for someone with Pompe to go decades without being diagnosed. Even after symptoms are apparent, most patients experience a substantial diagnostic lag, which in turn delays the start of treatment. In late-onset disease, the median age at diagnosis has been reported at 38 years, with most experiencing a substantial delay between the initial onset of symptoms and the eventual diagnosis of the disorder.  

John Crowley’s mission continues as Amicus Therapeutics recently received approval in the United Kingdom for a new treatment indicated for adults with LOPD. The treatment, known as AT-GAA, is a combination product consisting of an enzyme replacement therapy, Pombiliti (cipaglucosidase alfa), and the oral enzyme stabilizer Opfolda (miglustat), which works to minimize loss of enzyme activity in the blood. Earlier this year, AT-GAA also earned full approval to treat adults with LOPD in the European Union, and is currently up for approval in the U.S., with a decision expected as early at Q4 2023. The U.S. approval could offer an exciting new option for patients living with Pompe, with potential benefits seen as early as 3 months.  

“The opportunity to have additional options for treatment of Pompe disease is always a benefit,” said Dr. Byrne. “Given the mechanism of action for the 2-component therapy, AT-GAA plus miglustat, we expect some patients to have additional benefit compared to conventional therapy. In general, there is an early response in clinical studies with changes seen in the first 12 weeks. Following the initial response, there is stabilization of muscle and respiratory function.” 

The Muscular Dystrophy Association remains hopeful for the approval of AT-GAA from Amicus Therapeutics in the coming weeks. In the meantime, MDA hosted a virtual learning webinar on Pompe disease which is available on-demand. To register click here. 

 If you have questions about this webinar or other MDA Community Education programs, please reach out to our MDA Resource Center at 1-833-ASK-MDA1 (275-6321) or  ResourceCenter@mdausa.org. 

Since its inception, the Muscular Dystrophy Association has invested more than $5 million in Pompe Disease research, including nearly $500,000 in research grants in the last five years. For more information, please visit MDA research.  For information on Pompe Disease, visit the MDA Resource Center at 1-833-ASK-MDA1 (275-6321) or  ResourceCenter@mdausa.org.