Pompe disease treatment

Last updated Nov. 18, 2024, by Marisa Wexler, MS
Fact-checked by José Lopes, PhD

Pompe disease treatment typically requires a multidisciplinary healthcare team, including neurologists, cardiologists, and respiratory therapists, among others. Currently, enzyme replacement therapy (ERT) is standard practice for the treatment of Pompe disease.

The disease, also known as glycogen storage disease type 2 (GSD2), is caused by mutations in both copies of the GAA gene (meaning it is inherited in an autosomal recessive fashion), which provides instructions for making an enzyme called alpha-glucosidase (GAA). ERT provides Pompe patients with an engineered version of GAA to replace the missing or nonworking enzyme.

Supportive therapy can also be prescribed by healthcare providers to help manage specific Pompe disease symptoms. Options include physical therapy to make muscles stronger and improve a person’s overall physical condition, as well as occupational therapy and speech therapy.

Enzyme replacement therapies

ERT is the only type of treatment approved to date for Pompe disease. As the name implies, ERT involves therapeutically administering a working version of the GAA enzyme. Dysfunction of the GAA enzyme in Pompe disease causes a toxic buildup of a complex sugar molecule called glycogen in the body’s cells, especially muscle cells, which ultimately gives rise to progressive muscle weakness and other disease symptoms.

Three ERT products, Lumizyme, Nexviazyme, and the combination therapy Pombiliti + Opfolda, are approved by the U.S. Food and Drug Administration (FDA) as a treatment for Pompe disease.

People with Pompe disease can be divided based on cross-reactive immunologic material (CRIM) status, or their ability to make the GAA enzyme. Specifically, patients who cannot make any GAA are said to be CRIM-negative, while those who can make some GAA enzyme — even though it does not function properly — are CRIM-positive.

Generally, ERT is less effective for CRIM-negative patients, because their bodies can mistake the therapeutic enzyme for an infectious invader. This leads to an immune response that interferes with the replacement therapy. Additional immune-modulating therapies may be given to help increase ERT efficacy in CRIM-negative individuals.

Lumizyme

Lumizyme (alglucosidase alfa) — sold under the brand name Myozyme outside the U.S. — was the first ERT approved for Pompe disease. Clinical trials have shown the therapy can ease breathing and improve motor function for Pompe patients. The therapy is administered via infusion into the bloodstream every other week.

Marketed by Sanofi, Lumizyme is approved to treat all types of Pompe disease in the U.S., as well as in other markets, including Canada and the European Union.

Read more on Lumizyme

Nexviazyme

Nexviazyme (avalglucosidase alfa) is a next-generation ERT designed to deliver the GAA enzyme to muscle cells more efficiently than Lumizyme. Like Lumizyme, Nexvizayme has been shown to improve motor and respiratory function in Pompe clinical trials.

The next-generation treatment also is sold by Sanofi and given via intravenous (into-the-vein) infusion every other week.

In the U.S., Nexviazyme is approved to treat late-onset Pompe disease in patients ages 1 year and older. The therapy also is approved in other markets, though the specific type(s) and age ranges vary in different places.

Read more on Nexviazyme

ERT plus enzyme stabilizer

Another approved therapy for Pompe disease is the combination approach, Pombiliti + Opfolda. Marketed by Amicus Therapeutics, this two-part therapy contains a version of the GAA enzyme called cipaglucosidase alfa (Pombiliti) alongside an enzyme stabilizer called miglustat (Opfolda).

In a Phase 3 clinical trial involving adults with late-onset Pompe disease, AT-GAA outperformed Lumizyme at increasing walking ability and preserving lung function.

Previously known as AT-GAA, this combination treatment has also been approved for adults with late-onset Pompe disease in the European Union and in the U.K.

Read more on Pombiliti + Opfolda

Supportive therapies

ERT is designed to slow the progression of Pompe disease by addressing its root cause. In addition, a number of other supportive interventions can help Pompe patients maximize their ability to function in day-to-day life. Most Pompe disease therapies are given over the long term.

Physical therapy

Consisting of exercises and stretching, physical therapy can help improve muscle strength, reduce muscle contractures, and preserve mobility. A physical therapist also can offer guidance about managing day-to-day symptoms. Among topics patients can discuss with a physical therapist are strategies for avoiding falls and recommendations about mobility devices or other adaptive equipment.

Speech therapy

Weakness in facial muscles can cause the speech of individuals with Pompe disease to sound slurry and nasal, and some patients may have difficulty making themselves understood. Respiratory problems or the use of ventilation also can complicate speaking ability. Speech therapy can help people with Pompe to better communicate by working to improve verbal abilities, as well as finding other strategies for patients to convey their wants and needs. This type of therapy also can help improve patients’ ability to swallow.

Respiratory therapy

Weakness in the muscles needed to push air in and out of the lungs can cause breathing problems in Pompe disease. Respiratory therapy aims to improve patients’ breathing abilities through exercises that strengthen these muscles. Such therapy also helps patients in developing strategies to ease breathing, like learning techniques to clear respiratory secretions.

Occupational therapy

The goal of occupational therapy in Pompe disease is to develop strategies that make it easier to cope with the genetic disorder in day-to-day life. This may involve using supportive devices like walkers and doing hand exercises to maintain dexterity. Sometimes, simply finding new ways to do activities that have become more difficult than they once were can be helpful for patients in daily life.

Additional treatments and supportive devices

In addition to ERT and forms of supportive therapy, children and adults with Pompe disease may also benefit from other approaches, including diet, supplements, and assistive devices:

• Diet. It is generally recommended Pompe patients follow a dietitian’s plan to ensure they are meeting their nutritional needs. A diet high in protein and low in carbohydrates is recommended. Nutritional supplements also may be suggested. For infants and older individuals with difficulty swallowing, a feeding tube may be used to ensure the patient is getting enough nutrition.
• Supplements. Many patients with Pompe develop weakened bones, known as osteoporosis. Supplements of calcium, vitamin D, and bisphosphonates may be recommended for these individuals.
• Assistive devices. Canes, walkers, and wheelchairs can make it easier for people with difficulty walking to get around independently. Orthopedic devices, such as braces on the legs, can help support function and prevent further worsening of problems like permanent muscle contractions, called contractures.

Experimental therapies

A number of experimental therapies for Pompe disease are being developed. These range from treatments focused on alleviating disease symptoms to those that aim to address the underlying cause of the disease.

Gene therapy

The aim of Pompe disease gene therapy is to deliver a healthy copy of the GAA gene to the body’s cells, allowing them to produce a functional GAA enzyme. Several experimental gene therapies are being explored in Pompe, including:

• AT845
• rAAV1-CMV-hGAA
• rAAV9-DES-hGAA
• ACT-101.

Substrate reduction therapy

Symptoms of Pompe disease are driven by the toxic buildup of glycogen inside of cells. Substrate reduction therapy is an experimental approach that aims to slow this buildup by blocking the production of glycogen.

An investigational substrate reduction therapy called MZE001, licensed by Shionogi from Maze Therapeutics, is in early clinical testing in healthy volunteers.

ABX1100, another experimental substrate reduction treatment by Aro Biotherapeutics, will be tested in a Phase 1b study in adults with late-onset Pompe disease.

Chaperone therapy

For an enzyme such as GAA to work, it must fold properly to form a specific 3-D shape. Chaperone therapy uses small molecules called chaperones that bind to the dysfunctional GAA enzyme, helping it to fold correctly so as to restore normal enzyme activity.

Because pharmacological chaperones can work by boosting the stability and functionality of the GAA enzyme, these medications may not work as well for some patients. For example, chaperone therapy alone would not be expected to benefit individuals with mutations that lead to no GAA enzyme being produced at all, as there would be no enzyme for the chaperone to act on. It’s estimated that 10%-15% of people with Pompe disease have mutations that are directly amenable to chaperone therapy.

Chaperone therapy in Pompe disease is being investigated as an independent therapeutic approach. It has already been approved as a complementary approach to ERT — in which the chaperone can bind to the functional GAA enzyme provided to the body by ERT — in the combination treatment Pombiliti + Opfolda.

Stimulation of lysosomal exocytosis

Lysosomes are cellular structures that act like recycling centers in cells, facilitating the breakdown of complex molecules into simpler components that can be reused. Normally, glycogen is broken down by the GAA enzyme inside of lysosomes. In Pompe disease, however, the lack of functional enzyme leads glycogen to build up inside of these cellular structures.

Lysosomal exocytosis is a process in which lysosomes can “dock” at the membrane of a cell, and then dump their cargo outside of the cell. Activating this process has been explored as a potential treatment strategy for Pompe disease in preclinical models.

Is there a cure for Pompe disease?

There is not a cure for Pompe disease. However, enzyme replacement therapy can slow the disease’s progression and improve patients’ ability to function.

Will treatment increase life expectancy?

Increases in Pompe disease life expectancy with treatment have been seen in people with Pompe relative to what would be expected without treatment. However, specific survival outcomes vary widely, depending on the type and severity of the disease and the timing of ERT. In general, starting ERT earlier is tied to better survival outcomes.

Without treatment, babies with classic infantile-onset Pompe disease will typically die in the first year or two of life. Early ERT can extend lifespan considerably for some patients, though the disease remains life-threatening and many individuals will require ventilation to help them breathe.

A 2023 study assessing 64 patients in France with classic infantile-onset Pompe disease found that ERT with Myozyme improved survival, as those receiving the treatment survived till a median age of 25 months, compared with 8 months among those untreated.

Notably, the first ERT clinical trials were started in the late 1990s, so the oldest surviving patients have recently reached adulthood, and longer-term outcomes remain to be seen.

Lifespan in untreated late-onset Pompe disease can range widely depending on when symptoms appear, how quickly they progress, rate of respiratory failure, and other coexisting disorders. A 2016 review study with data from 438 patients found that treatment with Lumizyme reduced the mortality rate by nearly five times relative to patients who didn’t receive the treatment.

Does Pompe disease type affect treatment plan?

Pompe disease is commonly classified into three types. ERT treatment regimens are different for the classic infantile-onset form of the disease and later-onset forms. In some markets, individual ERT medications may be approved only for certain Pompe types and not others.

For classic infantile-onset Pompe disease treatment, children are recommended to start on ERT as soon as possible after receiving a Pompe disease diagnosis.

Regarding late-onset Pompe disease treatment, it is recommended ERT be initiated as soon as the patient shows detectable signs of muscle weakness. Follow-up assessments of patients on this type of therapy are recommended every six months.

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