Galafold Improves GI Symptoms in Patients with Fabry Disease, Study Shows

Galafold (migalastat) significantly reduces diarrhea in patients with Fabry disease and “amenable” mutations — that can respond to Galafold treatment — according to a recent analysis of the FACETS study’s results.

This result supports previous evidence from the same trial showing that Galafold improves gastrointestinal symptoms, including diarrhea, reflux, and indigestion, in patients with Fabry disease.

The study, “Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial,” was published in the Orphanet Journal of Rare Diseases.

Fabry disease is caused by mutations in the α-galactosidase A (GLA) gene that result in absent or markedly reduced GLA enzymatic activity. This deficiency leads to an accumulation of GLA’s major target molecule, globotriaosylceramide (Gb3), throughout the body, including the kidneys.

Gastrointestinal symptoms are reported by at least half of Fabry disease patients, and have been associated with a significant reduction in patients’ quality of life. The most common gastrointestinal symptoms in Fabry disease are abdominal pain, diarrhea, nausea, vomiting, and constipation.

Galafold, developed by Amicus Therapeutics, works by restoring enzymatic activity of specific mutant forms of the GLA enzyme in people carrying so-called “amenable” GLA mutations, who account for 35-50 percent of Fabry patients worldwide.

Positive results from two Phase 3 pivotal studies — the FACETS trial (NCT00925301) and the ATTRACT study (NCT01218659) — led to the approval of Galafold in the European Union, Switzerland, Israel, Australia, Canada, Japan, and South Korea for the treatment of Fabry disease in patients 16 years and older with “amenable” mutations.

The FDA has granted orphan drug, fast track designations, and priority review to Galafold, which are meant to speed up a treatment’s development, regulatory review, and the FDA’s decision.

The FACETS study consisted of a six-month randomized, double-blind, placebo-controlled phase, followed by a six-month open-label phase where all patients received Galafold, and a one-year extension phase. Galafold’s safety and effectiveness were assessed throughout the trial.

The study included 50 individuals, aged 16 to 74, with Fabry disease and “amenable” mutations who had not received enzyme replacement therapy. Participants were initially randomized to receive either 150 mg of Galafold (28 patients) or a placebo (22 patients), every other day for six months.

Improvements in gastrointestinal symptoms were assessed through the patient-reported Gastrointestinal Symptom Rating Scale (GSRS).

Previous results from the FACETS study, published in the New England Journal of Medicine, showed that by the end of the study’s first phase (six months), diarrhea — in all patients — and reflux — among patients with symptoms at baseline — were improved significantly.

Significant reductions at the end of the trial (after two years) also were observed regarding diarrhea and indigestion in patients with or without baseline symptoms. Constipation symptoms also were reduced, but without statistical significance.

Now, researchers further analyzed patients’ improvements regarding diarrhea during the first six months of the FACETS study, using the minimal clinically important difference (MCID) scores. These are patient-derived scores that reflect changes in a clinical intervention that are meaningful for the patient.

Among participants of the FACETS study, 28 (56%) reported diarrhea symptoms at baseline.

After six months, significantly more patients receiving Galafold (43%) experienced a clinically relevant improvement in diarrhea, compared to those receiving placebo (11%). Among those with diarrhea symptoms at baseline, 71% of Galafold-treated patients showed improvements, compared to 20% of patients receiving placebo.

Researchers also found that diarrhea improvement was associated with a reduction in Gb3 accumulation in the kidney. Patients with a reduction in kidney Gb3 bigger than 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without.

These findings showed that Galafold treatment was associated with a “clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations,” researchers wrote.

They also noted that reductions in kidney Gb3 may be a potential indicator/predictor of clinical benefits of Galafold in patients with Fabry disease.