ESC abstracts are available for the three conference presentations (no abstracts for symposium). Interesting abstract on the neutrophil to lymphcyte ratio (notice the first author). This is new analysis on the SUSTAIN/ASSURE samples. Looks like Ewelina is presenting the Phase 1 renal trial SOMAscan proteomic data that we've seen before. The abstract by D.S. Shishikura seems similar to the one presented a few weeks ago at the Australian conference.

Abstract P6483: Apabetalone (RVX-208) impacts key biomarkers and pathways associated with cardiovascular disease in patients with severe renal impairment

Authors: E. Kulikowski1, S. Wasiak1, L. Tsujikawa1, D. Gilham1, C. Halliday1, B. Rakai1, R. Jahagirdar1, K. Kalantar-Zadeh2, M. Sweeney3, J. Johansson3, N. Wong1, R. Robson4, 1Resverlogix Corp. - Calgary - Canada, 2University of California at Irvine - Irvine - United States of America, 3Resverlogix Corp. - San Francisco - United States of America, 4Christchurch Clinical Studies Trust - Christchurch - New Zealand,

Introduction: Apabetalone is a first-in-class orally active bromodomain and extraterminal (BET) inhibitor associated with a reduction in major adverse cardiac events (MACE) in patients with cardiovascular disease (CVD) from phase 2 clinical trials. Apabetalone has previously been shown to downregulate markers of atherosclerosis and vascular inflammation, which may explain its effects on MACE. Chronic kidney disease (CKD) is associated with a progressive loss of renal function and a high risk of CVD.

Purpose: To determine the effect of apabetalone on levels of circulating proteins and pathways that contribute to cardiovascular complications in CKD, in a phase 1, open-label, parallel group study of patients with impaired kidney function.

Methods: Eight subjects with stage 4 CKD not on dialysis (mean eGFR=20 ml/min/1.73m2) and eight age-, gender-, and BMI-matched subjects (mean eGFR=78.5 ml/min/1.73m2) received a single 100 mg oral dose of apabetalone. Plasma samples were collected at multiple time points over a period of 48 hours for pharmacokinetic (PK) analysis and at 12 hours post dose for proteomic analysis using the SOMAscan® 1.3K platform. Proteomics data were analysed with Ingenuity® Pathway Analysis (IPA) software to identify pathways dysregulated in CKD patients compared to matched controls, and the effect of apabetalone treatment on those pathways.

Results: Apabetalone PK parameters were similar in controls and CKD patients. At baseline, plasma proteomics showed enrichment of markers that correlate with progression of CKD, as compared to matched controls, including cystatin C and b2 microglobulin (3-fold and 5-fold enrichment, respectively, p<0.001). Accordingly, pathway analysis of CKD plasma proteome at baseline showed an upregulation of pathways that underlie CVD in CKD patients such as the inflammatory response, atherosclerosis, thrombosis and calcification, when compared to controls. These pathways were robustly and significantly downregulated in CKD patients by apabetalone 12h post dose. In the CKD group, apabetalone treatment also reduced the abundance of circulating CVD markers involved in vascular inflammation, atherosclerosis, fibrosis, vascular calcification, complement activation and hemostasis including CRP, IL-6, TNFα, IL-1, ICAM-1, VCAM-1, L-selectin, E-selectin, MMP-3, MMP-10, fibronectin, osteopontin, C3 and C5 active fragments, plasminogen activator inhibitor-1, D-dimer and P-selectin (p<0.05).

Conclusions: In stage 4 CKD patients, a single oral dose of apabetalone rapidly reduces circulating markers and molecular pathways linked to progression of renal disease and accompanying CVD complications. The potential impact of chronic treatment with apabetalone on biomarkers, renal function and CVD outcomes in patients with impaired kidney function is currently being studied in a subpopulation of the phase 3 BETonMACE CVD outcomes trial.

Abstract P1769: Lowering the neutrophil to lymphocyte ratio by the BET inhibitor, apabetalone: potential implications for cardiovascular events in high risk patients

Authors: S. Nicholls1, E. Kulikowski2, C. Halliday2, K. Lebioda2, J. Johansson2, M. Sweeney2, K. Kalantar-Zadeh3, 1South Australian Health and Medical Research Institute - Adelaide - Australia, 2Resverlogix Corp. - Calgary - Canada, 3University of California at Irvine - Irvine - United States of America,

Background: In addition to traditional inflammatory markers, the neutrophil to lymphocyte ratio (NLR) has been identified as a marker of systemic inflammation. Higher NLR has been associated with adverse clinical outcomes and is predictive of incident events in patients with CVD, diabetes and CKD. Apabetalone selectively inhibits the second ligand domain in bromodomain and extra terminal (BET) proteins, which are epigenetic readers of acetylated lysine marks on histone tails. Apabetalone modifies inflammatory pathways implicated in vascular disease and reduces incidence of major adverse cardiovascular events (MACE: death, non-fatal myocardial infarction and hospitalization for cardiovascular causes) in pooled data from phase 2 studies (SUSTAIN & ASSURE, n=499).

Purpose: To evaluate the impact of apabetalone treatment on the NLR and its association with MACE.

Methods: Neutrophil and lymphocyte counts were collected in the haematology panels during two phase 2 trials: SUSTAIN and ASSURE, which compared the effects of treatment with apabetalone 200 mg bid (n=331) and placebo (n=168) for up to 26 weeks on circulating cardiovascular biomarkers and atherosclerotic plaque in patients with established CVD (n=499).

Results: During the course of the trials, patients that experienced a MACE (n=36) were identified to have a higher baseline NLR compared with those patients who did not experience a MACE (n=463; 2.8 vs. 2.4, p<0.05). After 3 months of treatment, reductions in the NLR were observed with apabetalone treatment compared to placebo (-8.0%, p<0.001 vs baseline in apabetalone group and -1.0%, ns vs baseline in placebo group). The NLR improvement was sustained at 6 months (-7.5%, p<0.001 vs baseline in apabetalone group and -3.5%, ns vs baseline in placebo group). Consistently, in the diabetes patients in the phase 2 studies (n=127 in apabetalone group; n=65 in placebo group), similar reductions in the NLR were observed with apabetalone treatment compared to placebo (-7.0%, p<0.10 vs baseline in apabetalone group and +6.3%, ns vs baseline after 6 months of treatment).

Conclusions: Baseline NLR levels were higher in patients with established CVD that experienced a MACE during the 6 months SUSTAIN and ASSURE apabetalone intervention studies. Apabetalone treatment in these studies reduced NLR in the all and in the diabetes subpopulation highlighting its impact on inflammatory pathways implicated in CVD, and supports previously published anti-inflammatory effects observed with apabetalone treatment. The effect of apabetalone on reducing MACE outcomes is being evaluated in the ongoing phase 3 BETonMACE study.

Abstract P1104: The effect of apabetalone on attenuated coronary atherosclerotic plaque: insights from the ASSURE trial

Authors: D.S. Shishikura1, Y.K. Kataoka1, S.H. Honda1, K.T. Takata1, S.K. Kim1, J.A. Andrews1, P.J.P. Psaltis1, J.J. Johansson2, N.W. Wong2, S.J.N. Nicholls1, 1South Australian Health and Medical Research Institute, Heart Health - Adelaide - Australia, 2Resverlogix Corporation - Calgary - Canada,

Background: Apabetalone, the first selective bromodomain and extra-terminal (BET) inhibitor, modulates lipid and inflammatory pathways implicated in atherosclerosis. The impact of apabetalone on attenuated plaque (AP), a measure of vulnerability, is unknown.

Methods: The ApoA-1 Synthesis Stimulation and intravascular Ultrasound for coronary atheroma Regression Evaluation (ASSURE) study employed serial IVUS measures of coronary atheroma in 281 patients treated with RVX-208 or placebo for 26 weeks. Attenuated plaque (AP) was measured at baseline and follow-up. Factors associated with changes in AP were investigated.

Results: AP was observed in 31 (11%) patients. The apabetalone group demonstrated reductions in AP length by 1 mm (P=0.03), AP arc by 37.0o (P=0.004) and the AP index (API) by 34.6 mmo (P=0.02). The change in API correlated with the on-treatment HDL particle concentration (r=-0.50, P=0.007), but not HDL-C (r=-0.20, P=0.36) or apoA-1 (r=-0.20, P=0.25). Multivariable analysis revealed that on-treatment concentrations of HDL (P=0.03) and VLDL (P=0.01) particle concentrations independently associated changes in API.

Conclusions: Apabetalone may have a potential beneficial effect on ultrasonic measures of vulnerable atherosclerotic plaque, which may relate to its favorable effects on circulating HDL particle concentrations. The clinical implications are currently being investigated in large cardiovascular outcome trials.