Challenges of enzyme replacement therapy in treating Pompe

Last updated Oct. 7, 2024, by Marisa Wexler, MS
Fact-checked by Patrícia Silva, PhD

Enzyme replacement therapy (ERT) is the only approved type of treatment that addresses the root cause of Pompe disease.

Pompe is caused by mutations that result in the dysfunction or total absence of an enzyme called acid-alpha glucosidase (GAA). A ew different types of ERTs are available, but all of them aim to give the body a functional version of the GAA enzyme.

Although ERT can be an effective therapy for slowing the progression of Pompe disease symptoms, there are notable challenges and limitations with currently available ERTs, and the response to treatment can vary substantially.

Challenges of ERTs

Challenges of ERTs range from side effects and immune reactions to difficulties with administration and getting the therapy into the cells.

Administration and tissue distribution

A few different types of ERTs are approved for Pompe disease. Some of them contain only the enzyme replacement. Others involve the enzyme being given in combination with a therapy that stabilizes the enzyme to boost its activity.

In all current ERTs, the enzyme itself needs to be given by intravenous infusion, that is, as a slow drip into the bloodstream. Infusions typically need to be administered every two weeks for the duration of the treatment, which is usually a person’s entire life. When infusions are missed or given less frequently, the therapy won’t work as well.

Each infusion typically takes a few hours to complete. Preparation and aftercare require additional time. For these reasons, getting every-other-week infusions can be an inconvenience.

Additionally, for ERT to be effective, the enzyme needs to actually get inside of your cells. Because Pompe disease affects muscles and other cells throughout the body, getting enough enzyme into all affected cells is a notable challenge.

Research is ongoing to create new methods that are better at getting the enzyme inside cells.

Side effects and safety concerns

As with any medical treatment, ERT has a risk for side effects and other adverse reactions. While specific safety profiles depend on the particular medication used, some of the common side effects associated with Pompe ERTs include:

• headache, fatigue, and dizziness
• fever or flushing
• digestive issues including nausea, vomiting, and diarrhea
• pain in the joints, muscles, and/or abdomen
• breathing problems, such as coughing or shortness of breath
• skin reactions such as hives, itching, or abnormally colored skin.

All available ERTs in the U.S. carry black box warnings noting they can cause allergic reactions, including serious reactions known as anaphylaxis, an acute, life-threatening, hypersensitivity reaction. Available ERTs also can cause infusion reactions (problematic symptoms during or just after infusions), which can in some cases be life-threatening.

Because of these risks, you should always be monitored for signs of an allergic reaction when receiving ERT infusions. Whether infusions are done at a medical center or at home, healthcare professionals overseeing the infusion should be ready to provide supportive care in case of a dangerous reaction.

ERTs also can cause a sudden worsening of lung and/or heart function in people who already have underlying problems in these organs. If you have any of these issues, you will need additional monitoring.

Immune reactions

The body’s immune system works in a black-and-white way: Anything that is a normal part of the body is to be left alone. Anything that isn’t normally part of the body is assumed to be a threat and is then attacked.

While this approach is quite effective for defending the body against infections, it also can cause problems with ERT. If the immune system isn’t able to recognize the replacement enzyme as a normal part of the body, it will launch an attack against the therapy. This can set the stage for problematic reactions and may ultimately make the ERT ineffective.

To help gauge the risk of immune reactions with ERT, clinicians and researchers use a measure called cross-reactive immunologic material (CRIM) status. Before you start on ERT, it’s recommended you undergo laboratory testing to determine your CRIM status.

If you are “CRIM positive,” it means you already have enough GAA enzyme in your body and the immune system should recognize the enzyme as part of the body. Being CRIM positive means you are unlikely to have an immune reaction with ERT.

But if you are “CRIM negative,” it means there is practically no GAA enzyme in your body. This makes it more likely your immune system will mistake a replacement enzyme for a threat and launch an immune reaction.

When you are CRIM negative, your ERT treatment will often rely on modified protocols with medicines to suppress the immune system to try to reduce the risk of problematic reactions.

Almost everyone who has late-onset Pompe disease is CRIM positive and unlikely to have immune reactions to ERT.

However, children with infantile-onset Pompe disease can be CRIM negative, so immune reactions are a much more common issue.

Long-term effects

Enzyme replacement therapy is usually long term. Once you start on ERT, you will typically continue the therapy for the rest of your life. Stopping treatment would allow the disease to progress. The exception to lifelong treatment is if there are safety issues.

There are, however, significant differences in how a person responds to ERT, which is why long-term outcomes can be highly variable.

Available data suggest the majority of people with Pompe disease who start on ERT experience some improvements in motor function in the short term. After a few months of therapy, motor function is at a new normal.

For some, the new normal may be maintained for years or even decades. But others will eventually start to experience a worsening of motor function after a few years on ERT.

Survival outcomes are also generally much better for those on ERT, but there are variations in these outcomes.

The reasons for variation in long-term outcomes with ERT are not fully understood. It isn’t completely clear whether ERT becomes less effective over time, or if the treatment is effective at slowing the progression of Pompe disease but cannot entirely halt the disease’s progression in some people.

Still, there are a few important factors that likely play a role in influencing your long-term outcomes with ERT.

Perhaps the most important factor is the type of Pompe disease a person has. Generally, infantile-onset Pompe disease is more severe than the late-onset form. And even with ERT, the long-term outcomes for children with infantile-onset disease is generally poorer than for someone with late-onset disease. Outcomes often are especially poorer in infantile-onset patients who are CRIM negative and experience an immune response against the therapy.

Another important factor influencing the long-term response to ERT is your age and how advanced the disease is when you start treatment.

As a general rule, ERT slows the progression of Pompe disease, but it is not as effective at reversing the damage that has already occurred.

So if you start on ERT when you are younger and earlier in your disease course, you are generally more likely to have a better long-term outcome than if you start on ERT at an older age or after symptoms have already substantially progressed.

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