More Positive Cardiac Outcomes in Amicus Fabry Studies

James Radke

More encouraging results from Amicus Therapeutics’ Fabry clinical trials were announced today.

Fabry disease is a lysosomal disorder caused by deficiency of an enzyme called α-galactosidase A that leads to progressive accumulation of globotriaosylceramide (GL-3). This accumulation leads to a variety of symptoms, including  pain, kidney failure, and increased risk of heart disorders and stroke. The leading cause of death in patients with Fabry disease is from cardiovascular disease.  The new data from Amicus’ phase III studies indicate their drug candidate migalastat significantly improves cardiac measures.

More specifically, In Study 011 and Study 041, previously untreated patients with amenable mutations* showed a statistically significant decrease in left ventricular mass index (LVMi) following treatment with migalastat for up to 36 months (average of 22 months). LVMi is a measure of cardiac hypertrophy, an increase in the size of the heart that has been associated with an increased risk of cardiac events in Fabry patients.

John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics, Inc. stated,

"The effects of migalastat on Fabry patients with amenable mutations continue to be very profound. For the first time we are able to show that migalastat can lead to a reduction in LVMi in Fabry patients who are ERT-treatment naive. These new data add to the positive cardiac effects that we showed in the ERT switch Study 012. Migalastat has now demonstrated a beneficial effect on LVMi in untreated Fabry patients for up to 36 months, which is twice as long of a treatment period as we previously reported in ERT switch patients from Study 012. What is perhaps most important in these results is that after 18 months we continue to see further significant reductions in cardiac mass. These data therefore strongly suggest that migalastat has a persistent and increasing positive effect on LVMi over longer periods of time. We believe that this positive effect is related to migalastat's unique mechanism of action, which is very distinct from currently approved therapies. The cardiac data from both of our Phase 3 studies, in addition to the favorable results on disease substrate reduction and stabilization of kidney function that we previously reported, represent a very compelling data package as we prepare to seek global approval of migalastat monotherapy."

Left Ventricular Mass Index (LVMi) (g/m2) in Phase 3 Study 011+041
-- Change from Baseline to Last Available Time Point


Migalastat Baseline Mean
(% abnormal)

Migalastat Change
(Mean, 95% CI)

Study 011 and 041
(Avg 22 months)

97.5 g/m2

-8.0 g/m2
(-13.5, -2.5)

Study 011 was a Phase III study designed to measure the reduction of GL-3 following treatment with migalastat in patietns with Fabry disease who were naive to treatment or had not received enzyme relacement therapy. Numerous secondary outcomes were also measured, including renal function and LVMi, as secondary endpoints. The 24-month study began with a 6-month double-blind, placebo-controlled treatment period, after which all patients were treated with migalastat for a 6-month open-label follow-up period and a subsequent 12-month open-label extension phase. Positive 12- and 24-month data on substrate reduction as well as renal function were previously reported.  Upon completion, patients were eligible to roll over into a separate extension Study (Study 041) to continue migalastat.

Similar results have also been observed earlier in the company’s ‘Study 012’ that compared migalastat to enzyme replacement therapy in patients with Fabry disease.

Amicus expects to submit a marketing application for migalastat monotherapy in Europe, and is scheduled to meet with the European Medicines Agency in the fourth quarter of this year. Amicus also plans to meet with the  U.S. Food and Drug Administration (FDA) in the first quarter of 2015 to discuss the data and determine the fastest U.S. registration pathway for migalastat. Currently, the only approved medication in the United States for patients with Fabry disease is the enzyme replacement therapy, Fabrazyme. Shire's Replagal is available in other countries (as is Fabrazyme).

*Amenable mutations are defined as having an absolute increase of 3% of wild type alpha-Gal A enzyme activity and a relative increase of 20% when exposed to migalastat in a cell-based in vitro assay. All patients enrolled in Study 011 and Study 012 had amenable mutations in the clinical trial HEK assay available at study initiation ("clinical trial assay"). Following the completion of enrollment, a GLP HEK assay was developed with a third party to measure the criteria for amenability with more quality control and rigor. However, approximately 10% of mutations in the HEK database switched categorization between "amenable" and "non-amenable" when moving from the clinical trial assay to the GLP HEK assay. Therefore there were changes in categorization from amenable to non-amenable in 17 patients in Study 011, and in 4 patients in Study 012.  Overall based on results from mutations tested in the GLP HEK assay, Amicus continues to believe that approximately 30% to 50% of the Fabry population have mutations that are amenable to migalastat.
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