These mutations cause an enzyme called alpha-galactosidase A (alpha-gal A) to become non-functional or only partially functional.
Decreased activity of alpha-gal A leads to cells accumulating fatty substances called globotriaosylceramide (Gb3 or GL-3) and lyso-Gb3 that the enzyme would normally break down. The accumulation causes cell damage in tissues throughout the body. The result is progressive, irreversible organ damage, particularly in the nervous system, heart and kidneys.
Fabry patients require lifelong treatments to manage the problems that they experience in multiple organs. Enzyme replacement therapy with recombinant human alpha-gal A (agalsidase beta) or gene-activated alpha-gal A (agalsidase alfa) is the current standard of care for Fabry disease.
How Galafold works
Galafold is what scientists call a chaperone therapy, and is the first of this class of drugs. It is designed to restore alpha-gal A activity in patients with what are known as amenable mutations. So far, 313 GLA mutations have been identified as amenable, representing between 35 and 50 percent of the Fabry population. The medicine does not work in patients with other types of mutations.
Galafold attaches to certain unstable and dysfunctional forms of alpha-gal A, stabilizing the enzyme and partially restoring its activity. This allows the enzyme to go to areas of a cell where it can break down Gb3. And this, in turn, reduces the toxic effects caused by Gb3 accumulation.
Galafold in clinical trials
Galafold has been evaluated in two Phase 3 clinical trials covering 127 patients with Fabry disease.
The FACETS study (NCT00925301) assessed its safety and effectiveness in Fabry patients with amenable GLA mutations. A key measure of its effectiveness was the number of patients who responded to it. Researchers defined response as a reduction of at least 50 percent in Gb3 deposits in patients’ kidneys. The key finding was that patients with amenable mutations responded to Galafold after six months of treatment.
Amicus’ other Phase 3 study, ATTRACT (NCT01218659), evaluated Galafold’s safety and effectiveness in Fabry disease patients with amenable GLA mutations who had been on enzyme replacement therapy. The main measure of effectiveness was whether patients’ kidney function improved after 18 months of treatment. The key finding was that Galafold was as effective as enzyme replacement therapy in stabilizing kidney function.
Based on these results, the European Commission approved Galafold as a first-line therapy for the long-term treatment of Fabry disease patients 16 years and older with an amenable mutation. Galafold is also approved in Switzerland, Israel, Australia, South Korea, and Canada. The drug has yet to be approved by the U.S. Food and Drug Administration, but in February 2018 the agency agreed to give it priority review. This means a decision is expected by August 2018.
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