Enzyme replacement therapy and enzyme stabilizers
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Enzyme replacement therapy (ERT) is the only treatment option approved for Pompe disease. Ways to enhance the action of ERT are being investigated, including the use of enzyme stabilizers that help stabilize the functional protein/enzyme and enhance its delivery to the tissues.
Pompe disease is a lysosomal storage disorder caused by mutations in the GAA gene that provides instructions for making an enzyme called acid alpha-glucosidase, or GAA. This enzyme is normally responsible for breaking down a complex sugar molecule called glycogen in the body.
Dysfunctional or absent GAA enzyme leads to a toxic buildup of glycogen inside cells. Muscle cells, which use glycogen as a form of energy storage, are especially affected. The toxic accumulation of glycogen in cells ultimately gives rise to Pompe disease symptoms like muscle weakness.
ERT for Pompe disease
Enzyme replacement therapy, known as ERT, is a therapeutic strategy for Pompe disease that basically aims to deliver a functional version of the GAA enzyme to the body’s cells, helping to clear glycogen. There are two ERT medications available for patients in the U.S.; both are sold by Sanofi.
Lumizyme
Lumizyme (alglucosidase alfa) was the first ERT for Pompe disease to be approved in the U.S., in 2010. Outside the U.S., it’s marketed under the name Myozyme.
Nexviazyme
Nexviazyme (avalglucosidase alfa) is a next-generation treatment developed with the aim of delivering the GAA enzyme to muscle cells more effectively than Lumizyme. In the U.S., Nexviazyme is approved to treat late-onset Pompe disease in patients ages 1 and older. It’s also approved in other markets, though specific indications may differ.
Potential side effects
The specific safety profile of ERT differs from product to product. All available forms of ERT may cause allergic reactions, and also can cause a drop in heart or lung function in patients with certain underlying conditions. These potential side effects necessitate appropriate monitoring.
Lumizyme and Nexviazyme are both administered via intravenous (into-the-bloodstream) infusion every other week. Infusion-related reactions like nausea, vomiting, fever, and rash may occur; these can generally be managed by slowing the infusion and/or giving symptomatic treatment.
Less commonly, life-threatening infusion reactions like trouble breathing or swallowing have been reported in patients on ERT.
Other common ERT side effects include:
- headache
- coughing
- fatigue
- dizziness
- muscle pain
- itching, hives or abnormal skin coloration
- shortness of breath
- increased blood pressure
ERT combined with enzyme stabilizers
The combination treatment of Pombiliti (cipaglucosidase alfa) + Opfolda (miglustat) has also been approved in the U.S., EU, and U.K. This two part-therapy includes a version of the GAA enzyme, cipaglucosidase alfa (Pombiliti), and the enzyme stabilizer miglustat (Opfolda), also known as N-butyldeoxynojirimycin or NB-DNJ. It is marketed by Amicus Therapeutics and has been approved in the U.S. to treat certain adults with late-onset Pompe disease.
Existing Phase 3 trial data show that Pombiliti + Opfolda improved patients’ exercise capacity and stabilized lung function, with an efficacy profile that compared favorably to Lumizyme in some of the analyses.
Potential side effects
Pombiliti + Opfolda therapy is given via intravenous infusion (Pombiliti) and oral capsules (Opfolda). The most common side effects associated with the therapy include headache, diarrhea, fatigue, nausea, abdominal pain, and fever.
Pombiliti comes with a black box warning about the risk of life-threatening allergic reactions. There also is a black box warning about the risk of severe reactions at the site of the infusion, a risk that is higher in patients with underlying illnesses and in those who have advanced Pompe disease and compromised heart and lung function. In these patients, Pombiliti infusions may raise the risk of heart or lung failure.
ERT treatment limitations
A notable limitation of ERT concerns tissue distribution: For ERT treatments to be effective, the replacement enzyme needs to be able to get into the cells most affected by Pompe disease, particularly muscle cells. Often these products will effectively get into cells in some types of tissue, but will less effectively distribute to other tissue types. Figuring out how to ensure ERT products are effectively transported to the cells and tissues where they are most needed remains an area of ongoing research.
ERT therapies typically need to be administered by infusion into the bloodstream, which can be time-consuming and inconvenient for patients living with Pompe disease.
Can treatment increase life expectancy?
Treatment with ERT has been shown to extend life expectancy for people with Pompe disease compared with what would be expected without treatment. Specific outcomes vary widely, however, depending on the severity of the underlying disease and the timing of the ERT. Generally, earlier initiation of ERT is associated with better long-term outcomes. Since the first ERT products entered clinical testing in the late 1990s, the long-term impact of these treatments on survival outcomes remains incompletely understood.
It is still too early to say if ERT plus enzyme stabilizers can further increase life expectancy in Pompe patients.
Alternative treatment options
Enzyme replacement is the only available treatment for Pompe disease that slows the disease’s progression by targeting its underlying cause. Other experimental approaches for Pompe disease that are being explored include:
- gene therapy, which aims to deliver a healthy copy of the gene encoding GAA to the body’s cells;
- chaperone therapy, to improve the stability and functionality of the GAA enzyme;
- substrate reduction therapy, designed to reduce the toxic buildup of glycogen by blocking its production; and
- stimulation of lysosomal exocytosis, which aims to reduce glycogen levels by prompting cellular structures called lysosomes to dump glycogen outside the cell.
In addition to treatments that directly target the underlying cause, other supportive therapies — such as physical, occupational, speech, and respiratory therapies — may help improve quality of life for people with Pompe disease.
Pompe Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about ERT and enzyme stabilizers
All forms of Pompe disease are fatal, though outcomes vary substantially depending on the time of disease onset and the rate of progression — babies with infantile-onset disease usually don’t survive past infancy without treatment, while adults with late-onset disease may live for decades without any therapy. Enzyme replacement therapy has been shown to improve survival outcomes, especially if initiated early on.
The most common side effects of enzyme replacement therapy (ERT) are infusion-related reactions, which may include fatigue, headache, nausea, rash, and pain or discomfort. Serious infusion-associated reactions and allergic reactions may occur, and ERT may reduce heart or lung function in patients with some preexisting conditions. The specific safety profile of ERT depends on the particular product used.
Pombiliti + Opfolda (cipaglucosidase alfa/miglustat) is a two-component treatment that includes a version of the GAA enzime and an enzyme stabilizer. The most common side effects associated with this therapy include headache, diarrhea, fatigue, nausea, abdominal
pain, and fever.
Besides enzyme replacement therapy, the two-part therapy Pombiliti (cipaglucosidase alfa) + Opfolda (miglustat) has been approved in the U.S. to treat certain adults with late-onset Pompe disease. Other treatment strategies like gene therapy and substrate reduction therapy are being explored, but are not currently approved for Pompe disease treatment. Supportive treatments like physical and occupational therapy may help improve day-to-day life for people with Pompe, but they do not affect the progression of the underlying disease.
Pompe disease is a progressive condition, meaning that symptoms such as muscle weakness will continually worsen as time goes on. The most common life-limiting complications of the disease are respiratory failure due to damage of the muscles required for breathing, and heart disease due to damage to the heart muscle. Without treatment, babies with classic infantile-onset Pompe disease usually do not survive past age 2 due to heart and/or respiratory failure.
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