Rare Disease Report

Pivotal Migalastat - Fabry Study Published in NEJM

AUGUST 12, 2016
James Radke, PhD
The pivotal trial with Amicus’ Migalastat to treat Fabry disease patients has been published this week in the New England Journal of Medicine.
The study led to migalastat being approved in Europe but not in the US.  The European Commission, in their assessment of migalastat,  allowed post hoc analysis of the data to be reviewed showing that a subset of people suitable for Migalastat treatment did respond to treatment.

Unfortunately the planned primary outcome measure of the study (≥50% reduction in the number of globotriaosylceramide, or GL-3, inclusions per kidney interstitial capillary) was not reached. More specifically, the drug did not show a statistically significant treatment effect in when looking at all 67 Fabry patients in the study.

However, post hoc analysis in 50 of the Fabry patients that have a mutant α-galactosidase forms suitable for targeting by migalastat did show a statistically significant treatment effect. And the FDA tends to not approve drugs when the primary endpoint is not met.
And based on that information, the EU approved the drug for those that have that suitable mutations while the FDA told Amicus that more studies are needed.   

 Study Details

Patients were randomly assigned to receive migalastat hydrochloride (150 mg) or placebo every other day for 6 months. All patients who completed the study were eligible to receive migalastat in an open-label extension.

Primary Outcome Measure Not Reached

In the 6-month primary end-point analysis (ITT population), 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response (≥50% reduction in the number of GL-3 inclusions per kidney interstitial capillary) (P = .30). The median change in interstitial capillary GL-3 from baseline was −40.8% with migalastat and −5.6% with placebo (P =.10).
In a  post hoc analysis,  prespecified analysis in 45 patients with suitable mutant α-galactosidase, 6 months of migalastat was associated with a significantly greater reduction in the mean (±SE) number of GL-3 inclusions per kidney interstitial capillary than was placebo: −0.25±0.10 versus 0.07±0.13; P = .008.
 In a press release, lead author Dominique P. Germain, MD, PhD, Division of Medical Genetics at the University of Versailles (Paris-Saclay University) and Assistance Publique - Hôpitaux de Paris stated:
“As a treating physician of Fabry disease patients for 15 years, I believe that significant unmet needs remain for these patients. Migalastat is a paradigm of precision medicine with a unique mechanism of action that was developed through a significant patient-centered research effort to first understand the genetics and mutations of the GLA gene underlying this disease and then to identify more than 250 mutations that are amenable to this chaperone therapy. As the lead author of the journal publication along with 40 colleagues from 12 different countries as co-authors, and having served as principal investigator in France for the migalastat clinical studies for the past decade, I believe that migalastat may offer a differentiated and important personalized treatment option for patients with Fabry disease who have an amenable mutation.”

What is Fabry Disease?

Fabry disease is an X-linked lysosomal storage disorder that leads to excessive deposition of globotriaosylceramide (GL-3) throughout the body. Skin, eye, kidney, heart, brain, and peripheral nervous system are highly vulnerable.
The condition is caused by deficiency of the enzyme alpha-galactosidase A (alpha-Gal A) which degrades GL-3. The accumulation of GL-3 is believed to cause a variety of symptoms, including pain, kidney failure, and increased risk of heart attack and stroke.
In the video below, Jack Johnson of the Fabry Support & Information Group (FSIG) discusses the symptoms of this rare disease.


Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat N Engl J Med 2016; 375:545-555. DOI: 10.1056/NEJMoa1510198

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