First inhibitor of BET transcriptional regulators improves kidney function in CKD patients with CAD
Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease
Introduction and methods
Chronic kidney disease (CKD) is characterized by vascular calcification and inflammation, and there is a need for specific treatments for this condition . Apabetalone (RVX-208), an oral small molecule that targets the second bromodomain of bromodomain and extra-terminal (BET) proteins BRD2, BRD3, and BRD4, decreases atherogenesis, thrombosis and vascular inflammation, and is currently being developed for the treatment of CVD .
In this post-hoc analysis of the SUSTAIN and ASSURE studies, the effects of apabetalone on the levels of alkaline phosphatase (ALP) and the estimated glomerular filtration rate (eGFR) were evaluated, in patients with established coronary artery disease (CAD) and eGFR <60 mL/min/1.73m2.
The phase IIb SUSTAIN study evaluated the effects of apabetalone on lipid parameters in patients with documented stable CAD, while the phase IIb ASSURE trial assessed the effects of apabetalone on the progression of coronary atherosclerosis using serial intravascular ultrasound.
Both trials enrolled patients with established CVD receiving standard of care therapy, including statins, who were randomized to receive either apabetalone 100 mg b.i.d. or placebo for a period of 6 months . Out of a total of 499 subjects, 28 in the SUSTAIN study and 20 in the ASSURE study had baseline eGFR <60 mL/min/1.73 m2, and were included in this analysis. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR .
- Patients treated with apabetalone were more likely to have higher levels of creatinine (1.3 mg/dL vs 1.1 mg/ dL; P=0.002), to be male (77.1% vs 30.8%; P=0.003), and to be co-administered rosuvastatin (77.1% vs. 38.5%; P=0.02), while placebo treated patients were more likely to be co-administered atorvastatin (61.5% vs 22.9%; P=0.02).
- In the apabetalone group, ALP was reduced by 14.0% (12.0 U/L) (P<0.0001 vs baseline) compared to a reduction of 6.3% (4.5 U/L; P=0.9 vs baseline) in the placebo group. The difference between groups was significant (P=0.02).
- eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m2; P=0.04 vs baseline) and decreased by 5.8% (2.9 mL/min/1.73 m2; P=0.6 vs baseline) in the placebo group. The difference between groups was not significant (P=0.3).
- Apabetalone was well tolerated with fewer patients in the apabetalone group experiencing a serious adverse event compared to the placebo group (5/35, 14.3% compared to 2/13, 15.4%).
In a post-hoc analysis that included 48 patients, apabetalone, a potential novel therapeutic approach for the treatment of CKD and CAD, had beneficial effects on ALP and eGFR.