Nearly half of Fabry patients have amenable or responsive mutations to Galafold (migalastat) but show different responses to the therapy, according to a Swiss population study.
The study found that patients with higher residual activity of the alpha-galactosidase A (GLA) enzyme — which is deficient in Fabry patients — responded better to the treatment.
The findings were published in an article, “Fabry disease genotype, phenotype and migalastat amenability: Insights from a national cohort,” in the Journal of Inherited Metabolic Disease.
Fabry disease is caused by mutations in the GLA gene, which result in absent or markedly reduced GLA enzymatic activity. This deficiency leads to the damaging accumulation of two fat molecules — Gb3 and lysoGb3 — in tissues of organs such as the heart, kidneys, nervous system, eyes, and skin.
The disease can be classified as “classic” and “non-classic or late onset.” Patients with the classic form are typically men, have GLA activity lower than 3%, and multiple organ involvement early in life. Those with the late-onset form lack the classic early manifestations of the disease and frequently develop heart disease or kidney failure in their 40s or 50s.
Galafold is the first oral therapy approved for Fabry disease, and has been approved in the United States and European Union. It is a chaperone therapy that binds to dysfunctional “amenable mutant” forms of GLA, stabilizing its structure and partially restoring its activity.
A study analyzed the response of 600 GLA mutations in human cells grown in the lab to Galafold treatment, and defined amenable mutations as those showing an 1.2-fold or higher, or a 3% or more, increase in GLA activity in the presence of Galafold.
Amenable mutations are estimated to account for 35% to 50% of all Fabry patients worldwide. However, these numbers mainly come from data of patients who participated in the Galafold clinical trials, and no real-world estimations in a given country have yet been published.
In the study, researchers analyzed the genetic and clinical data of all patients diagnosed with Fabry disease in Switzerland over the last 59 years. They evaluated the proportion of each form of Fabry disease and amenable mutations, as well as the responses to Galafold treatment. This was possible because all of these patients underwent genetic and clinical analysis, treatment, and follow-up at three specialized Fabry centers.
In total, 170 adults (106 women and 64 men) from 46 families, and with 39 different GLA mutations, were diagnosed with Fabry disease. Most patients (68%) showed the classic form of the disease, and nearly half of them (48%) had amenable mutations.
These responsive mutations were found in about one-third of patients (33%) with the classic form of the disease and in all patients with late-onset disease.
In patients with amenable mutations and treated with Galafold, the increase in GLA activity was associated with the residual, or basal, activity of the enzyme before treatment. Patients with higher residual GLA activity showed greater increases with Galafold, suggesting that those patients are more likely to benefit to a greater extent from this treatment.
However, the researchers noted that there were inconsistencies between the lab data that defined GLA amenable mutations and the responses of male patients in terms of Galafold-associated increase in GLA activity.
They also emphasized that since the minimal GLA activity threshold for the development of Fabry disease has been estimated to be 30%–35% of residual levels, it is unclear whether the smallest increase in GLA activity (around 3%) — currently considered to be enough for a mutation to be classified as amenable — is clinically beneficial.
Based on the results, measurements of GLA activity before and during Galafold treatment in Fabry patients “should be introduced as standard and used as part of the clinical amenability definition and as a way to follow patients on [Galafold],” the researchers wrote.
“Further studies are required to investigate the long‐term benefits of [Galafold] therapy depending on the achieved enzyme activities in different amenable mutations,” they said.