Benefit of Apabetalone on Plasma Proteins in Renal Disease

Abstract

IntroductionApabetalone, a small molecule inhibitor, targets epigenetic readers termed BET proteins that contribute to gene dysregulation in human disorders. Apabetalone has in vitro and in vivo anti-inflammatory and antiatherosclerotic properties. In phase 2 clinical trials, this drug reduced the incidence of major adverse cardiac events in patients with cardiovascular disease. Chronic kidney disease is associated with a progressive loss of renal function and a high risk of cardiovascular disease. We studied the impact of apabetalone on the plasma proteome in patients with impaired kidney function.MethodsSubjects with stage 4 or 5 chronic kidney disease and matched controls received a single dose of apabetalone. Plasma was collected for pharmacokinetic analysis and for proteomics profiling using the SOMAscan 1.3k platform. Proteomics data were analyzed with Ingenuity Pathway Analysis to identify dysregulated pathways in diseased patients, which were targeted by apabetalone.ResultsAt baseline, 169 plasma proteins (adjusted P value <0.05) were differentially enriched in renally impaired patients versus control subjects, including cystatin C and β2 microglobulin, which correlate with renal function. Bioinformatics analysis of the plasma proteome revealed a significant activation of 42 pathways that control immunity and inflammation, oxidative stress, endothelial dysfunction, vascular calcification, and coagulation. At 12 hours postdose, apabetalone countered the activation of pathways associated with renal disease and reduced the abundance of disease markers, including interleukin-6, plasminogen activator inhibitor-1, and osteopontin.ConclusionThese data demonstrated plasma proteome dysregulation in renally impaired patients and the beneficial impact of apabetalone on pathways linked to chronic kidney disease and its cardiovascular complications.

Apabetalone downregulates factors and pathways associated with vascular calcification

“…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).…”

“…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]. Canonical pathway analysis of plasma proteomics predicted downregulation of IL-6 and bone morphogenetic protein signaling pathways, which both promote VC [15].…”

“…Notably, a single dose provided to CKD patients rapidly resulted in reduction of several inflammatory cytokines, including IL-6 [15]. Canonical pathway analysis of plasma proteomics predicted downregulation of IL-6 and bone morphogenetic protein signaling pathways, which both promote VC [15]. Processes involved in VC are similar to the mineralization of bone, and therefore strategies to alleviate VC could have effects on bone metabolism.…”

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

“…Apabetalone is the first BET inhibitor to be evaluated in human clinical trials for treatment of chronic disease, and has been shown to target multiple processes that underlie CVD, including reverse cholesterol transport, atherogenesis, thrombosis and vascular inflammation [9, 10]. A recent pharmacokinetic study of apabetalone treatment in patients with late stage CKD revealed that a single dose of apabetalone rapidly downregulated multiple CKD and CVD protein markers, and associated molecular pathways [11]. Moreover, in the phase II clinical studies with apabetalone, patients treated with apabetalone were less likely to experience a major adverse cardiovascular event (MACE) and experienced reductions in CKD risk factors such as ALP [9].…”

Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease

“…Apabetalone (RVX-208) is a small molecule inhibitor of BET proteins (BETi) that selectively targets the second BD (BD2) of BET proteins, reducing their transcriptional activity [9,10]. Preclinical and clinical studies have shown that apabetalone modulates the expression of proinflammatory and proatherosclerotic genes in models of atherosclerosis and in patients with coronary artery or chronic kidney disease [11][12][13][14][15][16][17]. Apabetalone also impacts the transcription of APR genes in primary human hepatocytes (PHH), including C-reactive protein (CRP) [12,13,16].…”