The US Food and Drug Administration (FDA) has approved migalastat (Galafold, Amicus Therapeutics) for adults with Fabry disease and a genetic mutation determined to be amenable to treatment with the drug on the basis of in vitro assay data.
Migalastat is the first oral medicine for Fabry disease and the first new therapy approved to treat this rare disease in the United States in more than 15 years. Migalastat is a 123-mg capsule taken once every other day, at the same time of day.
Fabry disease is a rare inherited X-linked lysosomal disorder caused by a deficiency of the enzyme α-galactosidase A (GLA). This deficiency leads to the buildup of globotriaosylceramide (GL-3) in blood vessels, kidneys, heart, nerves, and other organs, increasing the risk for kidney failure, myocardial infarction, stroke, and other problems. In the United States, an estimated 3000 people have Fabry disease.
"Thus far, treatment of Fabry disease has involved replacing the missing enzyme that causes the particular type of fat buildup in this disease. Galafold differs from enzyme replacement in that it increases the activity of the body's deficient enzyme," Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research, said in a news release.
The efficacy of migalastat was demonstrated in a placebo-controlled trial in 45 adults with Fabry disease. In the trial, patients treated with migalastat over 6 months had a greater reduction in GL-3 in blood vessels of the kidneys than did patients receiving placebo.
The safety of the drug was studied in four clinical trials involving a total of 139 patients with Fabry disease.
The most common side effects related to migalastat were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia.
The FDA approved migalastat for 348 amenable GLA variants. The drug received priority review and had orphan drug status.
"Today is a long-awaited day of celebration for all of us living with and advocating for people with Fabry disease, especially those who have participated in the development of Galafold in the United States," Jack Johnson, founder and executive director, Fabry Support & Information Group, said in a company news release.
"With the FDA approval of Galafold, certain members of the US Fabry disease patient community finally have a second treatment option. Through their unwavering commitment and scientific innovation, Amicus has provided a much-needed new treatment option for many Fabry patients," said Johnson.
The company said it will begin shipping the drug to a limited distribution network in the coming week. Reuters is reporting that Amicus has set an average annual price of $315,000 for the drug. Amicus Assist, a service that will provide product assistance and support to patients to help gain access to the drug, will also be initiated immediately. In addition to the United States, migalastat is approved in Australia, Canada, the European Union, Israel, Japan, South Korea, and Switzerland and is pending approval in Taiwan.
Hughes DA, Nicholls K, Shankar SP, Sunder-Plassmann G, Koeller D, Nedd K, Vockley G, Hamazaki T, Lachmann R, Ohashi T, Olivotto I, Sakai N, Deegan P, Dimmock D, Eyskens F, Germain DP, Goker-Alpan O, Hachulla E, Jovanovic A, Lourenco CM, Narita I, Thomas M, Wilcox WR, Bichet DG, Schiffmann R, Ludington E, Viereck C, Kirk J, Yu J, Johnson F, Boudes P, Benjamin ER, Lockhart DJ, Barlow C, Skuban N, Castelli JP, Barth J, Feldt-Rasmussen U. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet. 2017
Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.
The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.
Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.
Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.
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