Results from the phase 3 FACETS trial showed that migalastat improved diarrhea in patients with Fabry disease.
Results from the phase 3 FACETS trial showed that migalastat improved diarrhea in patients with Fabry disease. Data from the study were recently published by the Orphanet Journal of Rare Diseases.
Fabry disease is a rare genetic disease in which the fatty substance globotriaosylceramide accumulates as the result of a deficiency in the alpha-galactosidase A (a-Gal A) enzyme. It is classified as a type of lysosomal storage disorder, and gastrointestinal symptoms, such as diarrhea, are typical characterizations of the disease.
Migalastat is a pharmacological chaperone designed to bind selectively and reversibly with high affinity to the active sites of certain mutant forms of α-galactosidase (amenable GLA mutations). It is a small molecule orally-administered drug engineered to treat the symptoms of Fabry disease in patients with amenable mutations. Migalastat has been approved in Europe.
The phase 3 FACETS trial included a 6-month randomized, double-blind, placebo-controlled portion, followed by a 6-month open-label stage with cross-over of placebo-treated patients to migalastat and a 12-month extension stage. Male and female Fabry disease patients aged 16 years to 74 years were qualified for randomization. Eligible patients also had to be naive to enzyme replacement therapy (ERT) or had to have not received ERT for at least 6 months before screening.
Stage 1 of the trial included a screening period of up to 2 months followed by a 6-month treatment period, which involved 4 visits to the clinic. In in equal proportions, patients were randomized to receive either migalastat or the placebo. All patients entered Stage 2 of the study and received migalastat in an open-label manner upon completing the 6-month double-blind phase. The Stage 2 treatment lasted for 6 months and involved 4 visits to the clinic. Additionally, patients who completed both Stage 1 and Stage 2 were offered the opportunity to enroll in an open-label treatment extension (OLE) study with migalastat.
Primary measures included the gastrointestinal symptoms rating scale (GSRS)—which consists of 15 questions that evaluate the severity of diarrhea (GSRS-D), abdominal pain, constipation, indigestion, and reflux— and the GL-3 levels in kidney peritubular capillaries.
According to the results, a significant number of patients receiving migalastat experienced an improvement in diarrhea based on a minimal, clinically important difference (MCID) of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02) after 6 months. The GL-3 levels in kidney peritubular capillaries inclusions also declined after 6 months, which correlated with diarrhea improvement. Patients more likely to experience an improvement in diarrhea if they had a reduction of > 0.1 were 5.6 times than those without (p = .031).
In conclusion, results from the study linked migalastat with a clinically significant improvement in diarrhea in Fabry disease and amenable mutations patients. Additionally, reductions in kidney globotriaosylceramide were suggested to be a useful surrogate endpoint in the prediction of the clinical benefit with migalastat in Fabry disease patients.