Galafold (migalastat) increases the activity of alpha-galactosidase A, stabilizes serum biomarkers, and improves heart function in patients with amenable Fabry disease mutations, according to clinical results.
Fabry disease is a rare genetic disorder caused by mutations in the GLA gene — located on the X chromosome — that provides instructions for the production of an enzyme called alpha-galactosidase A (alpha-GAL A). These mutations typically affect the function of alpha-GAL A, leading to the accumulation of a type of fat called globotriaosylceramide (Gb3) in several tissues and organs.
In 2016, Galafold — Amicus Therapeutics‘ oral chaperone-based therapy — was approved in Germany, followed by other European countries, and then by the U.S. in 2018. Unlike traditional enzyme replacement therapies (ERT) in which a faulty enzyme is replaced by a healthy one to compensate for its lack of activity, Galafold binds to dysfunctional forms of alpha-GAL A, stabilizing its structure and partially restoring its activity.
“Unfortunately, because (Galafold) stabilizes the patients’ endogenous alpha‐GAL A, it is not advised for patients with mutations that cause complex enzyme alterations,” the researchers wrote. Therefore, Galafold therapy is only feasible for patients with ‘amenable mutations.’
So far, no significant side effects of Galafold therapy have been reported. However, the treatment’s effectiveness and ability to improve patients’ quality of life are still unclear, because the long-term effects have not been addressed in a proper clinical setting.
In this study, researchers from the University Hospital Würzburg in Germany carried out the first long-term study to assess the effects of one-year treatment of Galafold in patients with amenable Fabry disease mutations.
The prospective, open-label, single-center study was part of the larger prospective HEAL-FABRY (NCT03362164) trial, which was designed to estimate the risks of heart disease, heart failure, and sudden death among patients with Fabry disease.
The study enrolled a total of 21 Fabry disease patients — 15 who had never been treated (naïve) and six who had been treated with ERT before switching to Galafold — with an average age of 51.7 years. From these, 14 completed the one-year follow-up.
After one year of Galafold therapy, patients showed significant improvement in alpha-GAL A activity and decreased heart enlargement associated with Fabry disease. The improvement in alpha-GAL A activity was positively associated with a reduction in heart size, but not with kidney function.
In addition, Galafold treatment decreased the amount of plasma globotriaosylsphingosine — another fat molecule that is considered a hallmark of Fabry disease — in naïve patients and stabilized the levels among those who had been treated with ERT before they switched to Galafold. Serum disease biomarkers remained stable after one year of treatment with Galafold. However, patients’ renal function decreased slightly after one year of treatment.
The “clinical impact of these observations is yet unclear,” the researchers said. “Future studies with larger patient numbers are required to confirm and further clarify these findings.”