Fabry Disease (FD) is a rare X-linked lysosomal storage disorder (LSD) caused by mutations in the GLA gene which translates into decreased activity or lack of function of the enzyme alpha-galactosidase A (α-GAL A) and accumulation of the enzymes substrate, i.e., Gb3, throughout the body. Cardiovascular and renal complications are among the leading causes of death in FD patients. RVX000222 is a BET inhibitor which modulates the expression of a variety of genes and, due to its effects on pathways downstream of substrate accumulation and reduction of major cardiac events, holds promise as a potential add-on therapy to accompany enzyme replacement therapy (ERT) in FD patients.
Fabry Disease (FD) is a rare X-linked lysosomal storage disorder (LSD) caused by mutations in the GLA gene coding for the enzyme alpha-galactosidase A (α-GAL A). As a consequence globotriaosylceramide (Gb3), the enzyme's substrate, is not metabolized efficiently. The result is progressive accumulation of Gb3 and related glycosphinglolipids, particularly in blood vessels of the skin, kidney, heart and brain, causing severe complications such as cardiomyopathy, left ventricular hypertrophy and other cardiovascular related issues, as well as renal failure and end stage renal disease, ischemic stroke and peripheral neuropathy. RVX000222 is a BET inhibitor which modulates the expression of a variety of genes; in a number of Phase 1 and 2 clinical trials RVX000222 significantly affected markers of cardiovascular disease (CVD), such as high-sensitivity C-reactive protein (hs-CRP), alkaline phosphatase, components of the complement and coagulation cascades, and markers of reverse cholesterol transport in patients with CVD. Due to its beneficial effects on several pathways downstream of Gb3 accumulation and MACE reduction, RVX000222 holds promise as a potential add-on therapy to accompany enzyme replacement therapy (ERT) in FD patients. In addition to regulating disease related pathways, RVX000222 treatment significantly affects putative markers associated with FD such as Afamin and intercellular and vascular adhesion molecules in cell cultures.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
oral, BID
Queen Elizabeth II Health Sciences Centre, Victoria General Site
Halifax, Nova Scotia, Canada
Adverse events
Adverse events in Fabry Disease patients from the screening visit until 2 weeks after treatment completion with RVX000222.
Time frame: 16 weeks
Changes in clinical laboratory parameters
Changes in chemistry and hematology laboratory test results in Fabry Disease patients throughout and at the end of treatment phase with RVX000222 relative to baseline test results.
Time frame: 12 weeks
Change in Alkaline Phosphatase
Change in serum alkaline phosphatase in Fabry Disease patients throughout and at the end of treatment phase with RVX000222 relative to baseline level.
Time frame: 12 weeks
Changes in key markers of Chronic Kidney Disease-Bone Mineral Disease (CKD-BMD)
Changes in key markers of CKD-BMD i.e. RANKL and osteoprotegerin in Fabry Disease patients throughout and at the end of treatment phase with RVX000222 relative to baseline levels.
Time frame: 12 weeks
Changes in key markers of inflammation
Changes in key markers of inflammation i.e. high-sensitivity C-Reactive Protein (hsCRP) in Fabry Disease patients throughout and at the end of treatment phase with RVX000222 relative to baseline levels.
Time frame: 12 weeks
Changes in markers of alpha-galactosidase (a-GAL A) deficiency
Changes in key markers of a-GLA A deficiency i.e. Gb3 and lyso-Gb3 in Fabry Disease patients throughout and at the end of treatment phase with RVX000222 relative to baseline level.
Time frame: 12 weeks
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Initial uptake and steady-state level of RVX000222
RVX000222 blood concentration at 4 hours after initial administration in comparison to baseline. Steady-state concentration of RVX000222 and its two principal metabolites, RVX000288 and RVX000404, throughout and at the end of treatment phase with RVX000222.
Time frame: 12 weeks