Timely ERT, Regular Monitoring Recommended for Fabry Adults in Guideline Report

Personalized care with timely treatment and regular monitoring should be given to adults with Fabry disease to prevent irreversible tissue damage and organ failure, a study reported.

Researchers gathered and analyzed recently proposed recommendations for the management and treatment of adults with Fabry disease in a review study titled “Fabry disease revisited: Management and treatment recommendations for adult patients,” published in the journal Molecular Genetics and Metabolism.

The study focused on recent advances in monitoring and therapeutic strategies — updated from previous guidelines — for clinical management of multiorgan disease in adults with Fabry disease.

The guidelines put together an updated list of recommendations agreed upon by a panel of Fabry disease clinical experts, who emphasize the importance of early treatment initiation in both men and women, and a multidisciplinary team of specialized physicians providing patient-specific care.

Enzyme replacement therapy (ERT)

The study highlights the importance of the timing of enzyme replacement therapy (ERT) with Shire’s Replagal (agalsidase alfa) or Sanofi Genzyme’s Fabrazyme (agalsidase beta). Previous studies have shown that starting ERT at an earlier age provides better outcomes and prevents disease aggravation in several organs.

“Ideally, adult male patients with a classic Fabry mutation should initiate ERT promptly, regardless of Fabry symptoms, with appropriate adjunctive treatment for symptomatic management.

“Adult female patients with classic mutations should be considered for ERT if they present with symptoms suggesting major organ involvement or, if still asymptomatic, if there is laboratory, histological, or imaging evidence of injury to the major organs,” researchers wrote to summarize the experts’ recommendations.

A similar recommendation was made for patients with later-onset Fabry disease or GLA gene variants of unclear significance (VUS) —  mutations in the GLA gene cause Fabry disease — where “ERT should be considered and is appropriate once there is biochemical, histological, or imaging evidence of injury to the kidney, heart, or CNS [central nervous system] attributable to Fabry disease.” 

Periodic monitoring of anti-agalsidase antibodies in patients receiving ERT is also recommended, as these natural defense mechanisms may block the effectiveness of ERT treatment and lead to dose adjustment.

Choosing between Replagal or Fabrazyme should be done according to the dose necessary to optimize clinical outcomes, “given the biochemical similarity of the products, the five-fold difference in the labeled doses (and related difference in infusion duration), and the need for effective early treatment to prevent or mitigate disease progression,” researchers wrote.

Researchers emphasize that “it is inappropriate to manage active clinical symptoms of Fabry disease with only symptomatic therapies such as pain relief, as these do not target the underlying Fabry disease pathogenesis.

“Preventative measures (e.g., stroke prophylaxis with an antithrombotic agent) and lifestyle modifications (e.g., avoiding extremes of temperature) are also important considerations for patient care and should be considered in addition to symptomatic treatments,” they wrote.

The authors said Fabry experts have not yet gained sufficient clinical experience to make recommendations about the use of Amicus Therapeutics’ Galafold (migalastat) treatment (approved in Canada and some countries in Europe for patients with “amenable” GLA mutations), with variations in patients’ characteristics in the available clinical trials preventing solid conclusions.

Monitoring each organ potentially affected by the disease should be thoroughly evaluated at diagnosis, and patients on ERT should receive regular assessments of therapy effectiveness in all affected organ systems. A tissue biopsy, especially of the kidney, can serve as a potential marker to assess disease progression.

Female patients

The team adds that adult female patients without signs or symptoms of Fabry disease should be monitored regularly for evidence of organ involvement. In those with later-onset mutations, initial evaluation may be normal and longer intervals between disease-monitoring tests may be considered.

Clinical vigilance and regular monitoring are essential, as an absence of symptoms at baseline or at follow-up assessment does not preclude subsequent development of organ complications, researchers noted.

Although most female patients have normal pregnancies, clinicians should pay attention to signs such as high protein levels in urine as they may be aggravated during pregnancy. Additional recommendations for pregnancy and lactation in women with Fabry disease are provided here.

Genetic screening and counseling

On average, following a Fabry diagnosis, there are at least five family members diagnosed with the disease. Therefore, clinical and genetic screening in family members at risk is critically important once a patient has been diagnosed.

Accordingly, genetic counseling for patients and their families and partners by a Fabry disease expert is important to enable all involved members to better understand and cope with the disease.

“Treatment and follow-up assessments to evaluate treatment responses should ideally be supervised by a physician experienced in the management of patients with Fabry disease, with input from sub-specialists who also have Fabry disease experience, as part of a multidisciplinary clinical team that includes a neurologist, nephrologist, cardiologist, medical geneticist, genetic counselor, psychologist, and nurse,” researchers wrote.

“The long-term management of adult patients with Fabry disease should involve timely ERT, regular assessment of disease progression in all patients, and the use of appropriate adjunctive therapies by a multidisciplinary care team to assist in the management of organ-specific complications,” they concluded.

Recommendations for the cessation of treatment were not included in the study, as the clinical consequences of stopping treatment, compared with continuing ERT, still needs to be clarified.