Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease

Abstract

Background/Aims: The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. Methods: A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m², who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. Results: Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m²) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m²) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. Conclusion: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients. This is being examined in the phase III trial BETonMACE.

Apabetalone downregulates factors and pathways associated with vascular calcification

“…In this study, we demonstrate that apabetalone suppresses TNAP expression in liver cells (Supplemental Figs. 1A-B), the major source of circulating TNAP [26], which is consistent with reduced serum ALP observed in patients receiving apabetalone [13,14]. The present study also shows that apabetalone or JQ1 attenuates TNAP gene expression, protein levels and enzyme activity in VSMCs during osteogenic transdifferentiation (Figs.…”

“…While clinical trials demonstrate apabetalone beneficially affects inflammation [15], plasma lipid profile [11], and may improve kidney function [13], data in this mechanistic study shows apabetalone also (Fig. 3A-B).…”

“…ALP in CKD patients with a history of CVD [13]. In addition to TNAP, which comprises > 90% of enzyme activity in the serum, the intestinaltype, placental-type and placental-like isozymes make up the total ALP in circulation [26].…”

“…In CVD patients, apabetalone increased high density lipoprotein (HDL) [11], which is known to counter calcification of VSMC induced by IL-6 or IL-1β in vitro [12]. In CKD patients, apabetalone had favorable effects on kidney function evaluated by estimated glomerular filtration rate [13]. Apabetalone also reduced circulating alkaline phosphatase (ALP), a robust and independent predictor of all-cause mortality that contributes to VC progression [13,14].…”

“…In CKD patients, apabetalone had favorable effects on kidney function evaluated by estimated glomerular filtration rate [13]. Apabetalone also reduced circulating alkaline phosphatase (ALP), a robust and independent predictor of all-cause mortality that contributes to VC progression [13,14]. Notably, a single dose provided to CKD patients rapidly resulted in reduction of several inflammatory cytokines, including IL-6 [15].…”