New Study Explores Variability in ERT Outcomes

Enzyme replacement therapy (ERT) may not effectively manage all aspects of Fabry disease in all patients, particularly when started at more advanced ages, a new study indicates.

The findings highlight the need to start treatment early, its researchers said.

The study, “Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy,” was published in Molecular Genetics and Metabolism Reports.

Fabry disease is caused by a lack of alpha-galactosidase A, due to mutations in the gene that provides instructions for making that enzyme. The loss of alpha-galactosidase A causes a molecule called globotriaosylceramide (GL-3) to build up within cells, which causes damage to organs.

ERT and chaperone therapy are the two standard-of-care treatments for Fabry disease. As the name suggests, ERT involves administering an enzyme that can replace the missing alpha-galactosidase A. In the U.S., Fabrazyme (agalsidase beta) is the only approved ERT for Fabry disease; another ERT, Replagal (agalsidase alpha), has been approved in other countries.

In the new study, researchers reported long-term outcomes for 26 Fabry disease patients who were treated in an outpatient clinic at the University of California, Irvine.

“The aim of this study is to present the variable molecular and clinical features in a cohort of FD [Fabry disease] patients on ERT, treatment outcomes across organ systems, and highlight patients with previously unreported variants, to help improve treatment options and patient care,” the researchers wrote.

Of the 26 patients, there were 13 males and 13 females, with ages ranging from 10 to 68 years. Most of the patients (20) were on ERT; age at starting  ERT ranged from 6 to 65 years.

In 17 patients with available data, ERT treatment substantially reduced GL-3 levels by an average of 0.25 micrograms/mL per year.

Half of the patients had evidence of kidney disease, such as abnormally high levels of protein in the urine. Some individuals on ERT had apparently stable kidney function. However, in the overall group, levels of creatinine (a marker of kidney dysfunction) tended to increase over time, whereas estimated glomerular filtration rate (eGFR, a measurement of kidney function) tended to decrease. In other words, even with ERT, kidney function tended to steadily decline over time.

About three-quarters of the patients had neuropathic pain (pain caused by damage to the nervous system). In patients with available data, pain — as measured by various validated questionnaires — tended to be inconsistent or worsen over time, even with ERT treatment. This was associated with worsening physical function.

Gastrointestinal symptoms, such as abdominal pain and diarrhea, were reported by about two-thirds of the patients. Generally, these symptoms either eased or remained stable with ERT treatment.

About one-third of patients had notable mental health problems, such as depression and anxiety. In general, ERT treatment did not substantially affect mental health.

“While ERT was shown to be effective in clearing plasma GL-3 and, in many patients maintaining serum creatinine and eGFR within normal limits in this cohort, we identified that many patients continued to have impairment of their renal [kidney] function and health-related quality of life despite standard of care management,” the researchers concluded.

The researchers noted that, in many of the patients, ERT was begun relatively late in life. They highlighted that one child in the group, who was started on ERT at an early age, experienced a substantial improvement of pain symptoms.

“We believe earlier initiation of ERT is required to limit deterioration of the major organs,” the researchers wrote.

A major limitation of this study, according to the researchers, was that because most of the patients were on long-term ERT it wasn’t feasible to do comparisons between individuals who were or were not receiving such treatment.