Rare Disease Report

A Subset of Fabry Patients May Respond More Favorably to Migalastat

JUNE 12, 2013

A new clinical study was published in Molecular Genetics and Metabolism examining the effects of migalastat in female patients with Fabry disease. The study by Giugliani and colleagues was  an open-label, uncontrolled, phase 2 study examining the safety and efficacy of migalastat (50 mg, 150 mg and 250 mg QOD) in 9 females with Fabry disease over a 12 week period (with extension up to 48 weeks).

One interesting aspect of this study was that it used migalastat’s unique mechanism of action -  it  facilitates the trafficking of a patient's own mutant α-Gal A to lysosomes to break down GL-3 – to perform a post hoc analysis of the data comparing patients expressing a catalytically competent α-Gal A to those who did not. The post hoc test was a  HEK-293 assay that retrospectively categorized each study patient's GLA mutation as either ‘amenable’ or ‘non-amenable’ to chaperone treatment.  According to the study, “The patients with amenable mutations seem to demonstrate greater pharmacodynamic response to migalastat HCl compared to patients with non-amenable mutations. The greatest declines in urine GL-3 were observed in the three patients with amenable GLA mutations that were treated with 150 or 250 mg migalastat HCl QOD. Additionally, these three patients all demonstrated decreases in GL-3 inclusions in kidney peritubular capillaries.”

This study has many limitations, including the fact that it only enrolled 9 patients with a large variation in baseline characteristics. As such, it is difficult to draw too many conclusions from the data and that ambiguity may not help Amicus Therapeutics in their uphill battle to get migalastat monotherapy approved for Fabry disease. However, Amicus has not given up on the drug and we look forward to seeing their phase 3 data as well as their combination therapy studies.  Whether or not those studies perform an ‘amenable vs non amenable’ comparison will also be of interest.

Fabry Disease
Fabry disease is an X-linked lysosomal storage disorder that leads to excessive deposition of glycosphingolipids throughout the body. Skin, eye, kidney, heart, brain, and peripheral nervous system are highly vulnerable. Fabry disease is often difficult to diagnose since signs and symptoms are often nonspecific. For example, common symptoms may be fatigue, neuropathy (in particular, burning extremity pain), cerebrovascular effects leading to an increased risk of stroke, tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, diarrhea etc. 

Symptoms do appear in childhood but often go undiagnosed for several years. As the disease progressive, most patients with Fabry disease die in their fourth or fifth decade due to complications arising from renal or cardiovascular problems.

Currently, Genzyme’s Fabrazyme is the only approved treatment for Fabry disease in the United States.  Fabrazyme is also approved in Europe and elsewhere, as is Shire’s Replagal.


R. Giugliani, et al., A Phase 2 study of migalastat hydrochloride in females with Fabry disease: Selection of population,safety and pharmacodynamic effects, Mol. Genet. Metab. (2013), http://dx.doi.org/10.1016/j.ymgme.2013.01.009

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