Enzyme replacement therapy for Fabry disease

Last updated April 26, 2024, by Lindsey Shapiro, PhD
Fact-checked by Ana de Barros, PhD

Enzyme replacement therapy (ERT) plays a critical role in the management of Fabry disease, a rare genetic disorder characterized by alpha-galactosidase A (GLA) deficiency or the absence of this enzyme.

The alpha-Gal A enzyme is important for breaking down fatty molecules such as globotriaosylceramide (Gb3) inside cells, and its loss in Fabry disease causes those molecules to accumulate to toxic levels inside cells, leading to organ damage mainly in the heart, kidneys, and nervous system.

Used for more than two decades as a mainstay Fabry disease treatment, ERT is one of the two main approaches for managing Fabry. It works by delivering a functional alpha-Gal A enzyme to patients to address the underlying cause of the disorder, which is expected to slow or prevent the progression of organ damage that characterizes the disease.

How does enzyme replacement therapy work?

ERT is commonly used for genetic disorders caused by enzyme deficiencies, such as Fabry disease. It involves regular administrations of the missing or deficient enzyme, usually through an infusion into the bloodstream, to ensure patients have enough levels of the functional enzyme to perform the molecular reactions that are impaired.

In Fabry, ERT is designed to temporarily provide patients with a working version of alpha-Gal A to reduce the toxic accumulation of Gb3 and other fatty molecules that would normally be degraded by the body’s own enzyme.

By reducing Gb3 buildup, the approach can improve heart health and kidney function, help with pain management, and ease several other Fabry disease symptoms.

Because the body still cannot produce a functional alpha-Gal A, and the infused enzyme usually lasts only a few hours in circulation, patients will require lifelong ERT infusions to maintain appropriate alpha-Gal A levels in the body.

Still, ERT can be given to patients with all types of mutations, a clear advantage in comparison with chaperone therapy, the other main type of Fabry disease treatment. Chaperone therapy works by stabilizing the abnormal enzyme to boost its function, and thus is available only for patients with disease-causing mutations that result in a functional but unstable enzyme.

Enzyme replacement therapy for Fabry disease

It’s generally recommended that ERT is started as early as possible in the course of the disease, ideally before irreversible organ damage.

In people diagnosed with classic Fabry disease, which manifests in childhood or adolescence, treatment guidelines suggest ERT should be started promptly in all male patients even if they don’t have any symptoms yet. Female patients, however, should only receive replacement therapy if they experience symptoms or have clinical signs of major organ involvement.

Among those with non-classic, or late-onset Fabry disease, ERT may be considered for all patients who exhibit early signs of their kidneys, heart, or nervous system being affected, even in the absence of typical Fabry symptoms.

However, regardless of sex or disease type, patients with advanced Fabry disease, end-stage organ damage, or severe cognitive decline may not be candidates for ERT.

Types of enzyme replacement therapy for Fabry disease

Currently, Fabrazyme (agalsidase beta) and Elfabrio (pegunigalsidase alfa) are the only two ERTs approved for Fabry disease in the U.S. A third enzyme replacement therapy called agalsidase alfa is also approved for Fabry in several countries worldwide, where it is under the brand name Replagal, but this medication is not cleared for use in the U.S.

Agalsidase alfa and agalsidase beta (Fabrazyme) have both been approved for Fabry disease patients since the early 2000s, while Elfabrio became available more recently, in 2023.

All three are given via into-the-vein, or intravenous, infusions every other week. The specific dosage is calculated based on the patient’s body weight and the medication being used.

Fabrazyme

Fabrazyme, the first Fabry disease ERT to gain approval in the U.S., is indicated for adults and children, 2 and older, with confirmed Fabry disease. Marketed by Sanofi, it contains a lab-made version of the alpha-Gal A enzyme that’s produced in hamster ovary cells.

Elfabrio

Elfabrio, developed by Chiesi Global Rare Diseases, is approved in the U.S. and Europe for adults with confirmed Fabry disease. It works by delivering a version of alpha-Gal A, made with a plant cell-based system, with a chemical modification called PEGylation that makes the enzyme more stable in the bloodstream.

Agalsidase alfa (not approved in the U.S.)

Agalsidase alfa is not approved in the U.S., but is approved in several countries globally. In Europe, the medication is indicated for children and adults with a confirmed diagnosis of Fabry disease. Developed by Takeda, it contains a lab-made alpha-Gal A enzyme that’s produced by genetically engineered human cells.

Potential side effects or complications

Allergic reactions, in some cases severe, are possible complications of currently available ERTs for Fabry disease. Patients should be closely monitored and, if such a reaction occurs, treatment may need to be slowed or stopped and appropriate supportive care administered.

Infusion-related reactions occurring during or shortly after ERT infusions are also common. These may include symptoms such as gastrointestinal issues, itching or burning sensations, chills, shortness of breath, or low blood pressure.

Patients may sometimes be given medications before the ERT infusion to prevent such reactions, and those with compromised cardiac function should be closely monitored due to a higher risk of complications from infusion reactions.

Some Fabry disease patients who receive ERT may develop antibodies against the supplied alpha-Gal A enzyme. The risk of allergic or infusion-related reactions may be more common in these individuals.

Other side effects reported in clinical trials of ERT for Fabry disease include but are not limited to:

• sinus inflammation
• cold-like symptoms
• upper respiratory tract infections
• headache
• fatigue
• diarrhea
• nausea
• pain in the limbs or back
• chills
• fever
• cough
• tingling or burning sensations
• swelling in the limbs
• dizziness
• rash.

The specific side effect profile of enzyme replacement therapies will depend on which particular product is administered. Patients should talk with their healthcare team if they experience any unexpected or severe reactions to their prescribed therapy.

Fabry 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.