Rare Disease Report

Fabry Patients in the Migalastat Trials Are Sicker Than Those in Other Studies

MARCH 03, 2016
Michael R. Page, PharmD, RPh
Fabry is a disease caused by a deficiency of the lysosomal alpha-galactosidase A enzyme, which results in accumulation of glycosphingolipids. This X-linked inherited disorder affects the brain, heart, and kidneys, and may result in premature mortality. More than 800 types of mutations have been linked with the GLA gene, the majority (approximately 60%) of which are missense mutations. Although both males and females are affected, females tend to have less severe disease, as half of somatic cells in a female with Fabry are genetically normal.
Migalastat is a small molecule drug taken orally every other day. Mechanistically, migalastat is thought to increase the physical stability of the alpha-galactosidase A enzyme, improving lysosomal trafficking and cellular activity. However, only a portion of Fabry patients (30% to 50%) have mutations of the alpha-galactosidase A enzyme that respond to migalastat. Those mutations can be determined by an in vitro assay.
In the AT1001-011 (FACETS) double-blind randomized placebo-controlled study of migalastat, 57 patients were randomized in a 1:1 ratio to received migalastat 150 mg or placebo every other day for a 6-month double-blind period, followed by a 6-month open-label phase, and an optional 12-month extension phase. Patients included males and females aged 16 to 74 years with Fabry and a GLA mutation amenable to treatment with migalastat. Patients were required to be enzyme replacement therapy (ERT)-naïve or to have withdrawn ERT for a minimum of 6 months. Patients were required to meet criteria for renal parameters (>30 mL/min/1.73 m2), and to have urinary globotriaosylceramide (GL-3) levels at least 4 times the upper limit of normal in a 24-hour urine collection test. Patients taking renin-angiotensin-aldosterone system antagonists were required to be in a stable dose of therapy for at least 4 weeks before the screening phase of the trial.
In a similar trial, known as AT1001-012 (ATTRACT), patients were stratified by gender and proteinuria (≥1 gram/24 h [high], or <0.1 g/22 h [low]). A total of 59 patients were randomized in a 3:2 ratio to received migalastat 150 mg or placebo every other day. Inclusion and exclusion criteria were virtually identical to those of the FACETS trial, except that patients were required to have been using ERT for at least 1 year prior to the baseline visit, with a stable dose in the 3 months prior to baseline assessment, and a high treatment adherence rate (80% or higher).
A total of 268 amenable mutations were identified in patients enrolled in FACETS and ATTRACT, and phenotypes were assessed for nonclassical or classical disease, with classical disease presenting with early-onset disease and low residual alpha-galactosidase A enzyme activity in males, elevated levels of lyso-Gb3, and disease of multiple organs or organ systems. Nearly two-thirds (64%) of patients enrolled in FACETS and ATTRACT presented with the classical phenotype, resulting in high rates of significant baseline disease severity in cardiac, central nervous system, neuropathic, renal, and gastrointestinal involvement. The vast majority (91%) of patients enrolled in either trial had disease involvement of 2 or more organ systems.
In the FACETS clinical trial, renal involvement was present in 90% of patients, and more than half of patients had cardiac and central nervous system involvement (52% and 54% of patients, respectively). Similarly, in ATTRACT, CNS involvement was present in more than half (52%) of patients, and up to three-fourths showed renal involvement (75%) or cardiac involvement (72%).
Investigators concluded that the ATTRACT and FACETS clinical trials showed a high rate of multi-organ involvement comparable to those observed in prior registry trials, such as the Fabry outcomes survey and the Fabry registry.


Hughes D, Michet DG, Germain DP, et al. Phenotype of Fabry disease in patients with mutations amenable to migalastat. Poster 137. Presented at: WORLDSymposium 2016, San Diego, California.

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