Introduction to Pompe Disease 

Pompe disease is a rare and complex disease in which a build-up of sugars called glycogen builds up in your body’s cells, causing progressive weakness in the heart and muscles. 

It is not well understood to what extent the disease reduces the patient’s life span.¹ Pompe disease is typically seen in adults between 19-79 years. It is caused by mutations in the GAA gene, responsible for breaking down glycogen (used for energy).

Pompe disease is also known as glycogen storage disease type II or acid maltase deficiency. It is an autosomal recessive disorder, meaning that two copies of the mutated gene must be present for the disease to develop.

There are two types of Pompe disease depending on the symptoms and the age at which the individual develops this disease:

• An infantile-onset type is where people develop Pompe disease as infants and are typically the most severely affected. The symptoms can begin as early as 4 months. If the infant does not receive treatment, their condition can get progressively worse and most babies may not reach their first birthday.
• Another type is late-onset where the symptoms can begin in childhood or into adulthood. Typically a milder form of the infantile-onset type. It is very rare to see the heart affected as it is usually the muscles that get progressively weaker.

Before the introduction of enzyme replacement therapy (ERT) for Pompe disease in 2006, respiratory support was the only way of managing Pompe disease. Many clinical trials have now proven the effectiveness of ERT and have shown it can improve survival and muscle function.¹

In this article, we will describe how ERT works to treat Pompe disease.

Understanding Enzyme Replacement Therapy (ERT) 

Mechanism of Action of ERT for Pompe Disease 

Enzyme replacement therapy (ERT) is a treatment used to treat chronic disorders where there is a lack of essential enzymes needed for the proper function of the human body. ERT works by replacing the missing or deficient enzymes. It is typically done through IV infusions and directly administrated through the bloodstream. These replacement enzymes are genetically modified from human or animal tissue.²

Other conditions that require ERT include Fabry disease and Gaucher disease.

How the deficient enzyme affects the body 

The GAA gene (alpha-glucosidase) produces an enzyme called acid alpha-glucosidase. It is stored in lysosomes that act like recycling centres within cells. They help break down a sugar called glycogen into glucose, which is the main source of energy for most cells. 

If you’re deficient in the acid alpha-glucosidase enzyme, the cells are unable to convert glycogen into glucose leading to a buildup that damages your muscles and your heart. Infants affected by Pompe disease may have breathing problems or struggle to gain weight as a result of this enzyme deficiency. 

Administration and Treatment Protocol 

The treatment is administrated intravenously. The recommended dosage is 20mg/kg every other week but some patients receive 40mg/kg if their condition is declining, despite treatment with 20mg/kg.  

Patient management and monitoring during ERT 

You will be supervised by a healthcare professional who has experience managing patients with Pompe disease or other inherited neuromuscular diseases. You may be able to receive treatment at home if you’re able to tolerate the infusions well and have no recent history of severe infusion-associated reactions (headaches, fever, chills, flushing, nausea etc.).⁵ 

Potential side effects or adverse reactions

When you begin treatment, you may have infusion-related reactions which can be managed by slowing the infusion or giving supportive treatment. You will be carefully monitored by your healthcare provider  (i.e., your doctors and nurses).

Goals and benefits of ERT for patients

The effectiveness of ERT may vary from person to person. Your doctor will discuss what to expect with the course of the treatment. You may require additional care like a feeding tube or occupational therapy depending on the severity of your condition. 

The aim of ERT for patients with Pompe disease is to:

• slow disease progression
• improve muscle function
• maintain the normal function of the heart
• reduce glycogen buildup 

With early detection and treatment, you should expect to see better management of your condition. 

Development and Approval of ERT for Pompe Disease 

The development of ERT began in 1963. As early as the 1990s, recombinant human alpha-glucosidase ERT was developed. ERT has been available for Pompe disease for 17 years, with great responses to the treatment.

The treatment has improved motor and heart function and generally slowed disease progression. However, it’s far from being a cure as the disease continues to progress over time in some patients.³

The first clinical trial to prove the effectiveness of recombinant human alpha-glucosidase ERT from rabbit milk was published in 2001.⁴ Patients with classic infantile-onset Pompe disease were involved in this study and received different doses of ERT ranging from 15-40mg/kg every other week. The authors noted an improvement in motor and heart function.⁴ 

Based on the findings of many clinical trials of ERT after the first trial in 2001, ERT with Myozyme (which contains the active ingredient alglucosidase alfa) was approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2006. 

Other drugs include Avaglucosidare alfa-ngpt (Nexviazyme©) and ​​Lumizyme©.

Regulatory approval and market availability

A recent ERT drug called cipagulocidase alfa was approved for the treatment of late-onset Pompe disease in the EU on 27th March 2023. It is used in combination with migulastat, an enzyme stabiliser. It is recommended to have 20mg/kg every two weeks.⁵

Effectiveness and Efficacy of ERT 

Studies and evidence supporting the effectiveness of ERT

The response can vary from person to person but it is generally effective and can slow the progression of the disease. To test the effectiveness of ERT, many studies used a 6-minute walking test, and a quality-of-life questionnaire and measured the time on ventilation. The results found that ERT improved in all outcomes.⁶ 

Limitations or challenges associated with ERT

A limitation associated with ERT is the distribution of the therapy in the tissues that are most affected by Pompe disease. A challenge in research is that it may not distribute effectively to other tissue types. Discovering how to direct ERT drugs to the cells or tissues where it is affected by Pompe disease remains an area of ongoing research.

As ERT is administered via IV infusions, this can also be time-consuming and inconvenient for patients.

Cost and Access to ERT 

ERT can be very expensive especially as you require lifelong treatment. It’s important to understand the specific financial support options available in your country or region. You can discuss this with your healthcare professionals, patient advocacy groups, and insurance providers to explore your options.

Future Directions and Ongoing Research

The impact of ERT in patients with Pompe disease has been positive, with the disease progressing at a slower rate in patients. Currently, there are ongoing clinical trials in patients with Pompe disease.⁵ ERT may likely be combined with a more effective therapy like gene therapy which could potentially improve the outcome and the nature of the disease.³ Early timing and accurate diagnosis of Pompe disease is important and will lead to improvement in patient care. 

Summary

Pompe disease is a rare and progressive disorder that weakens the muscles. It is caused by a mutation in the GAA gene, responsible for breaking down glycogen into glucose. Treating infants with Pompe disease brings challenges in healthcare practice as the condition is generally severe. Some people may develop the disease in childhood or adulthood. This is described as late-onset Pompe disease and is a milder form of infantile-onset type.

The primary treatment shown to slow disease progression is enzyme replacement therapy. Many patients have shown improved motor function and quality of life following treatment with ERT. Most ERT drugs are administrated through IV infusion and given a dosage of 20mg/kg every other week or weekly. Living with Pompe disease can seriously affect the quality of life of patients, especially as it’s required to receive lifelong treatments and can be extremely costly.

This area of research is ongoing with the potential to see ERT being combined with gene therapy in the future.