Treatment and Medication Options for Fabry Disease

People with Fabry disease don’t produce enough of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). Without enough of this enzyme, sphingolipids, a fat-like substance, build up in blood vessels and tissues, resulting in cell abnormalities and organ dysfunction that can impact different systems in the body, especially the heart, kidneys, and brain, according to the National Fabry Disease Foundation. The skin, bones, gastrointestinal system, eyesight, and hearing can also be affected.

Fabry disease can be the classic type or late-onset, atypical type. In classic Fabry disease, symptoms appear during childhood and teenage years and get progressively worse over time.

People with late-onset Fabry disease don’t experience symptoms until their thirties or even older, and sometimes the first indication of the condition may be kidney failure or heart disease, according to UCLA Health.

There is no cure for Fabry disease; the three currently available Fabry-specific treatments are designed to slow the buildup of sphingolipids with the goal of preventing kidney disease, heart issues, or premature death and to improve quality of life.

“Early treatment in Fabry disease really guarantees the best outcome, because then we're able to decrease the risk of complications — which can be life-altering and life-ending — as much as possible, says Angelika Erwin, MD, PhD, a physician in the Center for Personalized Genetic Healthcare at Cleveland Clinic in Ohio.

The first medication to treat Fabry disease was approved only in 2003, and although early treatment has been shown to achieve better outcomes, whether or not treatment helps someone with the condition live longer isn’t yet known, according to a European expert consensus statement on treatment goals for Fabry disease, published in 2018.

In addition to the therapies approved for Fabry disease, there are also medications that aren’t Fabry-specific that can relieve pain and help with symptoms.

Recommendations for when to start therapy and which therapy is appropriate depend on a few factors: the type of Fabry disease a person has, whether they have symptoms, and a person’s genetics, says Mohamed Atta, MBBCh, MD, a professor of medicine who specializes in renal medicine at John Hopkins Medicine in Baltimore.

“Treatment typically depends on whether the patient is symptomatic or not. In the pediatric population, symptoms are often present, usually gastrointestinal symptoms such as cramps and diarrhea, pain in their feet and hands, and sometimes lack of sweating, and those can occur in both girls and boys,” says Dr. Atta.

In patients who are very young, the timing of when to start therapy may depend on symptoms and a cardiac assessment to see if Fabry disease is affecting their heart, and it can vary from patient to patient, according to guidelines published in Clinical Genetics in August 2019.

In adults with late onset of the disease, treatment is usually started after diagnosis is confirmed, which is usually after the first symptoms develop.

“In adults, usually the symptoms or the organ impact would be three big ones, the heart, kidney, and brain. People with Fabry disease who have any manifestation of the disease will definitely require therapy,” Atta confirms.

In late-onset Fabry disease, diagnosis is often made incidentally because of another issue, such as unexplained left ventricular hypertrophy (thickening of the walls of the heart’s main pumping chamber), heart failure, arrhythmias, proteinuria (protein in the urine, a sign of kidney damage), renal (kidney) failure, or stroke, according to UCLA Health.

Fabry disease is an X-linked genetic disease, meaning a child inherits the gene variant from a parent’s X chromosome. Since males have only one X chromosome, if a male child inherits the variant for Fabry disease, he will have symptoms.

But females have two X chromosomes, and it’s rare that a female child inherits the Fabry variant from both parents.

Because of this, there is a misperception, sometimes even among healthcare providers, that women are just carriers of Fabry disease, says Atta.

“While some women may be completely asymptomatic, other women can have severe manifestations and would require the same treatment as males with the condition,” he says.

There are two types of treatment that have been developed specifically for Fabry disease: enzyme replacement therapy (ERT), and oral chaperone therapy.

Enzyme replacement therapy involves taking a lab-made enzyme to replace alpha-Gal A, the enzyme that is deficient in people with Fabry disease.

The lab-made enzyme does the work of absent or defective alpha-Gal A enzyme, helping to prevent the buildup of the fatty substance in cells that takes place in Fabry disease.

Fabrazyme (agalsidase beta) was approved for adults by the U.S. Food and Drug Administration (FDA) in 2003 and children ages 2 and older in 2021.

In a real-world observational study of 82 patients, the drug helped slow the decline of renal function compared with people who didn’t receive treatment, according to a statement by Sanofi, the company who manufactures Fabrazyme.

Investigators also found that 28 percent of Fabrazyme-treated patients (14 out of 51) experienced a clinically significant event (renal, cardiac, cerebrovascular, or death) compared with 42 percent placebo-treated patients (13 out of 31).

Elfabrio (pegunigalsidase alfa-iwxj) was approved to treat adults with Fabry disease in May 2023, according to a release by Chiesi and Protalix, the makers of the drug. Elfabrio is a PEGylated enzyme, which allows for it to remain longer in the bloodstream — referred to as having a longer half-life — and also reduces immunogenicity (anti-drug antibody development) in patients.

The clinical trials didn’t establish that the extended half-life (compared with Fabrazyme) means that Elfabrio is safer or more effective than Fabrazyme, according to the company’s release.

The clinical trials for Elfabrio were non-inferiority efficacy trials in which the drug demonstrated that it was just as effective as Fabrazyme in slowing the decline of kidney function, in addition to extending drug plasma coverage (half life) and lowering immunogenicity.

However, the authors of a phase 1-2 clinical trial to evaluate the pharmacokinetics of pegunigalsidase alfa and assess efficacy, safety, and tolerability of the drug concluded that the drug “may improve the safety and clinical response to” enzyme replacement therapy in people with Fabry disease.

How Is ERT Administered?

ERT is administered via intravenous (IV) infusion every two weeks. The infusion is given every two weeks for life. If at any point ERT is stopped, the fatty substance known as globotriaosylceramide (Gb3) begins accumulating in cells again, and Fabry symptoms and damage to other organs will progress again, says Atta.

ERT infusions can be given at a hospital, doctor’s office, infusion center, or at home. It’s recommended that patients discuss which setting is best with their doctor.

Potential Problems With Enzyme Therapy

Some people experience an allergic reaction to enzyme replacement therapy for Fabry disease, which is mostly limited to fever, chills, and headache, although life-threatening reactions have also been reported, according to a paper published in January 2021 in the International Journal of Molecular Sciences. To help prevent such a reaction, you may receive an antihistamine or other medications before the infusion, according to the Cleveland Clinic.

Treatment with enzyme replacement therapy can also cause the formation of anti-drug antibodies which can make the therapy less effective, according to an paper published in August 2018 in the Journal of the American Society of Nephrology.

Whereas enzyme replacement therapy involves replacing the missing enzyme in Fabry disease, oral chaperone therapy increases the activity of the deficient enzyme.

Some GLA gene mutations cause alpha-Gal A that isn’t properly folded — a structural problem that means it can’t enter the cells’ lysosomes, where the enzyme is needed.

Galafold (migalastat), first approved by the FDA to treat adults with Fabry disease in 2018, is an oral pharmacologic chaperone that binds to misfolded alpha-Gal A in a way that repairs the structural problem, allowing the enzyme to function normally, says Atta.

“In people with Fabry disease with this mutation, the protein or the enzyme is produced, but cannot get to where it’s supposed to go; it needs help, a chaperone (hence the name) to get the enzyme where it needs to go to prevent sphingolipids from accumulating and causing damage,” he says.

The drug is only effective for people with amenable glactosidase alpha (GLA) gene variants. To be a candidate for this therapy, you need to have a mutation that causes the production of a form of defective alpha-Gal A enzyme, rather than total absence of the enzyme, says Atta.

Since genetic confirmatory testing is necessary for a diagnosis of Fabry disease, according to a paper published in 2020 in Therapeutics and Clinical Risk Management, the prescribing doctor will know if a patient is appropriate for Galafold.

People taking Galafold over a two-year period reported a stable quality of life with reductions in pain and physical limitations over time, according to a study published in February 2023 in Molecular Genetics and Metabolism.

The most common adverse drug reactions to people taking Galafold in clinical trials were headache, nasal and throat irritation, urinary tract infection, nausea, and fever.

In the United States, Galafold is approved for people ages 18 and older, while the European Medicines Agency notes that in the European Union it’s approved for children ages 12 and older.

There are two types of pain that often co-occur in classic Fabry disease, per an article in BMC Neurology: chronic nerve pain in the hands and feet, and severe, episodic pain attacks, also called “Fabry crises.”

Drugs that help control certain types of seizures in epilepsy may be prescribed to manage nerve pain in Fabry disease. These include phenytoin (Dilantin), carbamazepine (Tegretol), and gabapentin (Neurontin).

Treatment for Gastrointestinal Symptoms

Gastrointestinal (GI) symptoms can be the first symptoms of Fabry disease and can negatively impact quality of life, according to a review published in January 2022 in Gut Microbes. For some patients, ERT or chaperone therapy may help relieve GI symptoms. Other possible treatments for GI issues depend on the symptoms.

Acute Diarrhea Anti-diarrhea medications such as loperamide (Imodium) may be used.

Gastroparesis This is a condition that affects the stomach muscles and prevents proper stomach emptying, causing nausea, vomiting, and abdominal pain. Drugs that increase contractions of the stomach and upper intestines, such as metoclopramide, may be used to help empty the stomach.

Bloating and Gas Medications that help with these symptoms may be used, including simethicone (Gas X).

Upper GI Symptoms Proton pump inhibitors (PPIs) may be used to treat reflux — stomach acid entering the esophagus — and stomach pain. These include medications such as Prilosec, Nexium, and Prevacid.

Because Fabry disease can lead to serious health issues, including heart problems, kidney failure, nerve damage (peripheral neuropathy), and strokes, including transient ischemic attacks (TIA or ministrokes), other medications may be used to help delay or prevent these complications, according to UCLA Health.

Kidney Problems Blood pressure medications may be used to protect the kidneys.

Enlarged Heart, Irregular Heart Rhythms, and Heart Failure Blood thinners can help to prevent strokes or heart conditions.

Stroke Blood pressure medications can reduce stroke risk.

Hearing Loss Hearing aids may be prescribed or recommended.

Depression and Anxiety Depression and anxiety are more common in people with Fabry disease, according to a paper published in January 2020 in Orphanet Journal of Rare Diseases. These issues should be discussed with your healthcare provider so that any mood issues can be appropriately treated, says Dr. Erwin.

“Fabry disease affects the small blood vessels; there’s a higher risk of early-onset stroke and early-onset cardiac complications, like heart attacks,” says Erwin.

In addition to taking medication for Fabry disease, it’s important to decrease all of the other risk factors that we all have, and those include smoking, she says.

“We also want to make sure that we control the cholesterol and high blood pressure, and so a heart-healthy diet is recommended, and regular exercise as much as possible,” says Erwin.

There may be some regional differences depending on where patients are and who their closest Fabry disease specialist is, says Erwin. “I think the most common scenario is that a medical geneticist directs the care and keeps all the threads together,” she says.

Clinical or medical geneticists are doctors who care for patients in clinical settings and often carry out research related to patient care. They hold American Board of Medical Genetics and Genomics (ABMGG) certification in the specialty of clinical genetics and genomics and have broad training in the evaluation, diagnosis, management, and treatment of inherited conditions in patients across all ages from birth to adulthood. Because inherited conditions can include a lot of different body systems, clinical geneticists work at the intersection of many other medical specialties.

“Medical geneticists are really directing the care, and we typically see patients at least once a year and oversee or coordinate enzyme replacement therapy, if that is the treatment they’ve been prescribed,” says Erwin. This includes both children and adults, she adds.

They are also “the ones who make sure that patients see the cardiologist (who specializes in treating the heart) on a regular basis, and we also monitor lab results to decide when the patient needs to begin seeing other types of doctors to manage the complications of the disease,” says Erwin.

The medical team involved in treating a person with Fabry disease may also include the following:

Nephrologist, a doctor who specializes in kidney conditions.

Endocrinologist, a doctor who specializes in treating diabetes and osteoporosis.

Neurologist, a doctor who manages disorders of the brain and spinal cord.

Transplant hepatologist, a doctor who helps manage an organ transplant, such as a kidney transplant or a heart transplant.

Pain management specialist, a doctor who evaluates and manages chronic pain.

Dermatologist, a doctor who specializes in treating the skin.

Ophthalmologist, a specialist who treats disorders and diseases of the eye.

Gastroenterologist, a type of doctor who treats gastrointestinal (GI) issues.

Audiologist, a specialist who treats issues with hearing.

Physical therapist, a specialist who can tailor movement and exercise for specific health conditions.

Dietitian, a specialist who can recommend a healthy diet as well as what types of foods to limit or avoid.

Psychiatrist, psychologist, or other mental health professional, professionals who can manage issues such as depression or anxiety.

According to the Cleveland Clinic, you should call your healthcare provider if you have Fabry disease and experience:

• Chest pain, irregular heartbeat, shortness of breath, or signs of heart attack
• Excessive swelling or fluid retention
• Extreme dizziness, vision problems, or signs of stroke
• Hearing loss
• Severe abdominal pain or diarrhea

There are several preclinical and clinical trials underway for gene therapy to treat Fabry disease, per the American Society of Gene and Cell Therapy. If successful, this could potentially be a one-time treatment that would slow or stop the progression of the disease by introducing a working GLA gene that would provide instructions to the cells to make more of the alpha-galactosidase A (alpha-Gal A).

If you have Fabry disease and are interested in participating in a clinical trial, talk with your physician. More information about the types of clinical trials can be found at the National Fabry Disease Foundation.