Fabry disease is an inherited genetic disorder caused by mutations the GLA gene responsible for the production of an enzyme called alpha-galactosidase A. These mutations make the enzyme non-functional or only partially functional. This results in the accumulation of a fatty molecule called globotriaosylceramide (Gb3, also known as GL-3), which causes cellular damage in tissues and consequent progressive, irreversible organ damage, including damage to the nervous, cardiac, and renal systems.
Although the severity of symptoms differs from patient to patient, most require lifelong medical treatment. Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A, or gene-activated alpha-galactosidase A, is currently the most effective therapy for Fabry disease.
How Apabetalone works
Apabetalone is a selective BET (bromodomain and extra-terminal) inhibitor. BET bromodomain inhibition is a new approach that can regulate disease-causing genes. This selective inhibition produces a specific set of biological effects with potentially important benefits for patients with conditions such as high-risk cardiovascular disease, diabetes mellitus, chronic kidney disease, dialysis, Alzheimer’s disease, and Fabry disease.
Apabetalone modulates the expression of a variety of genes. Due to its beneficial effects on several biochemical pathways regulating the accumulation of Gb3, Apabetalone holds promise as a potential add-on therapy to accompany ERT in Fabry disease patients.
Apabetalone in clinical trials
In March 2017, Health Canada approved a clinical trial of apabetalone in patients with Fabry disease. This Phase 1/2 trial (NCT03228940) will evaluate the safety, tolerability, adverse effects, and changes in clinical laboratory parameters in patients taking apabetalone pills for up to 12 weeks. The trial is expected to start in April 2018 and aims to recruit 16 patients in Canada.
Apabetalone also is being studied in a Phase 3 clinical trial (NCT02586155) called BETonMACE, in high-risk cardiovascular disease patients with type 2 diabetes mellitus and low high-density lipoprotein (HDL).
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