Migalastat HCl Produces Stable Renal Function in Fabry Disease

At the Lysosomal Disease Network World Symposium in Miami, Florida, Amicus Therapeutics presented preliminary data from a phase II trial of the novel oral drug Amigal (migalastat HCl), which is being investigated as a treatment for Fabry disease. Like Gaucher disease, Fabry disease is a lysosomal storage disorder (LSD) caused by inherited genetic mutations that result in deficiencies of an enzyme required to metabolize lipids. The missing or deficient enzyme in Fabry disease is called ceramide trihexosidase or alpha-galactosidase-A (alpha-Gal-A). As a result, globotriasylceramide (GL-3) accumulates to harmful levels in the eyes, kidneys, autonomic nervous system, and cardiovascular system. Females are carriers of the disease, which is inherited by their male offspring. Women who are carriers, however, may also have mild to severe symptoms of the disorder.

Enzyme replacement therapy (ERT) with agalsidase alpha (Replagal) or agalsidase beta (Fabrazyme) has been shown to slow progression of the disease, which is incurable. Other medications are frequently prescribed to address some of Fabry's more troubling symptoms. Some patients may also require dialysis or kidney transplantation. Individuals with Fabry disease have a lifelong increased risk of stroke, heart attack, and heart disease. While Fabry is estimated to affect only 5000 to 10,000 people, some researchers say the condition is significantly under diagnosed.

Migalastat HCl works by selectively binding to alpha-Gal A and stabilizing the enzyme. This allows the enzyme to make its way to the lysosomes, where it works to break down GL-3. The FDA has granted orphan designation to Amigal in the United States.

The initial phase II study enrolled 26 patients who received 12 or 24 weeks of ERT with migalastat HCl. A separate long-term extension study enrolled 23 patients with Fabry disease. In total, 15 patients have completed 2 to 3 years of treatment with migalastat HCl and 8 have been treated for more than 3 years. Currently, 21 individuals remain in the extension study.

Derralynn Hughes, MA, DPhil, Hematology Department, Royal Free & University College Medical School, London, England, presented data from the trial, which is designed to evaluate renal function using estimated glomerular filtration rate (eGFR) and proteinuria. Hughes reported that eGFR had remained stable after 2 to 3 years of follow-up for all patients in the extension study, with an average rate of change in responders to migalastat HCl of +2.0 mL/min/1.73 m². A trend toward reduced proteinuria was also observed in these responders. "The additional renal function data with migalastat from the ongoing extension study are encouraging," Hughes said. "The eGFR results were particularly of interest, as the data at this point in the study compare favorably to the previously published eGFR literature in untreated and ERT-treated Fabry patients."

The results led to initiation of a phase III trial in 2009, with enrollment expected to be completed by the end of 2010. The company hopes to have preliminary data in mid-2011. They are also conducting preclinical studies that combine migalastat HCl with ERT to treat mouse models of Fabry disease.