Amicus Therapeutics Moves Closer to Filing for Approval of Migalastat for Fabry Disease

Christin L. Melton, ELS

April is Fabry Disease Awareness Month.

Fabry disease is an inherited lysosomal disorder that primarily affects males. The incidence of Fabry disease is estimated at 1 in 50,000 males, but several studies in which newborns were screened for a mutation associated with late-onset Fabry disease indicate that the true incidence may be much higher.1 An estimated 5000 to 10,000 men in the United States are living with Fabry disease.2

The disorder is caused by a mutation of the GLA gene on the X chromosome, resulting in a deficiency of the enzyme α-galactosidase A (α-gal) enzyme, thereby inhibiting breakdown of a glycolipid called globotriaosylceramide.3 The excess globotriaosylceramide accumulates in the cells that line the blood vessels of the skin, kidneys, heart, and nervous system, where it causes progressive damage. Symptoms typically begin in childhood. Patients with Fabry disease may develop pain in the extremities, hypohidrosis, clouded corneas, tinnitus, hearing loss, gastrointestinal problems, angiokeratomas, progressive kidney damage, heart attack, or stroke.3 Late-onset Fabry disease is associated with milder symptoms and primarily affects the heart or kidneys. Women, who have 2 copies of the X chromosome, often have less severe symptoms or remain asymptomatic.3

The median age of survival for men with Fabry disease is 54 years compared with 62 years for women.4 Although cardiovascular disease causes more than half the deaths of men with Fabry disease, their first clinical event is usually kidney-related. More than half of women with Fabry disease also die of cardiovascular disease, and although they commonly experience renal events during their lives, cardiovascular events are more common.4

Enzyme replacement therapy (ERT) with agalsidase beta, which is administered by an infusion every 2 weeks, is standard treatment for Fabry disease.5 Some patients have experienced severe infusion reactions, however, which are a serious concern in individuals who have heart problems associated with advanced Fabry disease.5 Amicus Therapeutics in Cranbury, New Jersey, is developing a new treatment for Fabry disease called migalastat HCl. It is an oral drug intended for Fabry patients who have a specific mutation that makes them amenable to treatment with migalastat.6 Migalastat works by binding to and stabilizing molecules of endogenous α-gal  enzyme so that they are delivered to the lysosomes, where they begin breaking down globotriaosylceramide.6

Amicus conducted 2 phase 3 studies of migalastat. In Study 011, eligible patients with Fabry were randomly assigned to migalastat or placebo for 6 months, after which patients in the placebo group crossed over to the migalastat arm for 6 months.7 This was followed by an open-label extension study. At study entry, all the patients were treatment-naïve or had been off of ERT for at least 6 months. At a median of 22 months, patients taking migalastat had a significant reduction in left ventricular mass index (LVMi).8 Higher LVMi is associated with an increased risk of cardiovascular events in patients with Fabry disease.9 Persistent reductions in LVMi were observed with up to 36 months of migalastat therapy. In Study 012, patients who had been taking standard ERT for at least 12 months were randomly assigned to switch to migalastat or to continue their ERT.7 Patients who switched to migalastat had a significantly greater reduction in LVMi from baseline to 18 months than patients who continued taking ERT.8,9 In addition, the rate of Fabry-associated clinical events (a composite endpoint that included worsening of a patient’s renal, cardiac, or cerebrovascular status) was significantly lower in the migalastat arm than in the ERT arm (29% vs 44%, respectively).9

Combined, the studies included more than 400 patient-years of data. Amicus has met with a delegation from the European Medicines Agency and with the US Food and Drug Administration (FDA) to discuss the trial data and their intent to pursue regulatory approval for migalastat. Amicus announced that it plans to file a New Drug Application with the FDA, seeking accelerated approval, in the second half of 2015.7


1. Spada M, Pagliardini S, Yasuda M, et al. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79:31-40.
2. Amicus Therapeutics honors Fabry Disease Awareness Month and International Pompe Day [press release]. Published April 9, 2015. Accessed April 10, 2015.
3. National Institutes of Health. Genetics home reference: Fabry disease. Published April 6, 2015. Accessed April 10, 2015.
4. Waldek S, Patel MR, Banikazemi M, et al. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11:790-796.
5. Fabrazyme [package insert]. Genzyme Corporation: Cambridge, MA. 2010.
6. Amicus Therapeutics. Programs: Fabry disease. Published 2015. Accessed April 10, 2015.
7. Amicus Therapeutics provides positive global regulatory updates from EMA and FDA meetings for Fabry monotherapy. Published March 19, 2015. Accessed April 10, 2015.
8. Migalastat monotherapy phase 3 cardiac data [shareholder presentation]. Published January 8, 2015. Accessed April 10, 2015.
9. Amicus Therapeutics announces positive phase 3 data on cardiac and composite endpoints from Fabry monotherapy Study 012 at American Society of Nephrology [press release]. Published November 15, 2014. Accessed April 10, 2015.
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