Abstract Background Diabetes (DM) is associated with increased risk of macro/microvascular disease and cognitive decline. Inflammation and vascular calcification may be contributing factors. Bromodomain and extraterminal (BET) proteins coordinate gene transcription and modify the transcriptional response to hyperglycemia, and inflammation. Apabetalone competitively and selectively inhibits binding between BET proteins and acetyl-lysine marks on histone tails: normalizing transcriptional profiles to physiological levels; reducing in vitro alkaline phosphatase (ALP) transcription and in vivo plasma ALP in a dose-dependent manner. Phase 2 trials with apabetalone show improved renal function in the chronic kidney disease (CKD) subgroups. Furthermore, treatment showed a 55% reduction in CVD events with more pronounced benefit among patients with DM, low HDL-cholesterol (HDL-C) and high sensitivity C-reactive protein (hsCRP). Methods The double-blind, placebo controlled phase 3 BETonMACE trial is testing the hypothesis that apabetalone 100 mg b.i.d., added to standard care, reduces major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction or stroke) in patients with DM, acute coronary syndrome (ACS) within the preceding 7–90 days, low HDL-C (<40 mg/dL in men; <45 mg/dL in women), and estimated glomerular filtration rate (eGFR) >30 mL/min/1.7m2. The trial will continue until at least 250 MACE, providing 80% power to detect a 30% reduction. Secondary endpoints include changes in eGFR in patients with baseline eGFR 30 to <60 mL/min/1.7m2, inflammatory markers, lipids, and ALP. In addition the Montreal Cognition Assessment (MoCA) test was performed in patients ≥70 years of age at baseline and annually. Results Enrollment of 2425 patients across 13 countries and 195 centers is now complete. Baseline characteristics [median (IQR)] include LDL-C 65.0 (36) mg/dL, HDL-C 33.0 (7) mg/dL, HbA1c 7.3 (2.3) %, hsCRP 2.8 (4.9) mg/L, mean blood pressure 129/76 mmHg, and CKD in 266 patients (10.8%). Background care was based on guideline recommendations. Diabetes medications include metformin (79%), insulin (36%), sulfonylureas (28%), DPP4 inhibitors (11%), SGLT2 inhibitors (9.7%) and GLP1 receptor agonists (0.3%). The CKD subpopulation vs. total population differed significantly from the whole population with regard to age (71 vs. 62 y. o.), male sex (58% vs. 75%), history of hypertension (46% vs. 88%), history of stroke (1.5% vs. 7.5%), and current smokers (6.1% vs. 13%). In the 70 year and older (n=466, 19%) population 54% (n=243) showed a baseline MoCA score 25 and lower suggesting cognitive impairment. Summary The BETonMACE trial is testing the hypothesis that selective BET-inhibition with apabetalone, added to established, evidence-based treatment, reduces MACE in high-risk patients with DM, recent ACS, and low HDL-C. The study will also assess apabetalone's effect on renal function and cognition.

Abstract Background Despite established treatments, patients with type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS) are at higher risk of ischemic cardiovascular (CV) events and hospitalization for heart failure (HHF) compared to those without T2DM. LDL-C lowering or use of GLP-1 agonists predominantly affects ischemic CV events, with little effect on HHF. Conversely, treatment with SGLT-2 inhibitors reduces HHF, with less effect on ischemic CV events. Preclinical studies indicate that bromodomain and extra-terminal (BET) proteins coordinate gene transcription for pathways that promote atherothrombotic events as well as heart failure. We assessed the clinical effect of apabetalone (APB), a novel BET protein inhibitor, on a composite of non-fatal ischemic CV events, HHF, and CV death in a post hoc analysis of the BETonMACE trial Methods BETonMACE was a double-blind, placebo-controlled phase 3 study in patients with T2DM and recent acute coronary syndrome receiving standard of care risk factor management. In 13 countries, 2425 patients were enrolled. We conducted a time-to-event analysis for first adjudicated CV death or non-fatal MI, stroke, or HHF using a log-rank test and Cox proportional hazards model. Results At baseline median age was 62 years, 25.6% were female, 87.6% white, and use of high intensity statin, ACE inhibitors/ angiotensin II blockers, dual antiplatelet therapy and beta blocker were 90, 88, 92 and 91% respectively. A total of 312 subjects had an endpoint event, with 139 (11.5%) patients in the ABP group and 173 (14.3%) among PBO (HR 0.78, 95% CI 0.63–0.98, p=0.03, Figure). At 26 months, the absolute risk reduction was 3.2% and number needed to treat was 31. Numerically favorable HRs were observed for each component endpoint except for stroke (Table). Conclusion This present analysis suggests that BET inhibition with APB may be a novel pathway through which to reduce both HHF and ischemic CV events in high risk patients with T2DM thus impacting broader clinical outcomes with potentially large benefits for patients and healthcare systems. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Resverlogix Corp

Abstract Background/Introduction Both major adverse cardiovascular events (MACE) and non-alcoholic fatty-liver disease (NAFLD) are highly prevalent in patients with high BMI and long-standing type 2 diabetes (T2DM). NAFLD is characterized by an augmented hepatic inflammation and fat deposition and is strongly associated with metabolic syndrome. Patients with NAFLD are at an increased risk of cardiovascular (CV) events, and MACE is the leading cause of death for patients with NAFLD. Apabetalone (APB) is a novel selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. In the Phase 3 BETonMACE trial treatment of 2,425 T2DM patients post ACS with APB, resulted in hazard ratios (HR) of 0.82 (p=0.11) for the primary endpoint of ischemic MACE (CV death, non-fatal MI or stroke) and 0.59 (p=0.03) for the secondary endpoint of heart failure hospitalization (HFH) vs placebo (PBO). Transient elevations of alanine aminotransferase greater than 5xULN occurred in 3.3% of APB treated patients. Purpose In this exploratory post hoc analysis of BETonMACE we evaluated risk modification for a composite of MACE+HFH by APB based on the Angulo NAFLD fibrosis score (FS) using 6 variables (age, BMI, hyperglycemia/diabetes, AST/ALT ratio, platelet count, and albumin). The NAFLD FS categorizes individuals into groups that correlate with differing levels of fibrosis in biopsy studies: (FS F0-F2, no significant fibrosis; FS ID, indeterminant; and FS F3-F4, significant fibrosis). Methods Baseline characteristics and blood measurements were used to determine NAFLD FS at baseline. The incidence of MACE+HHF was compared between treatment groups. Results Based on FS, there were 618 pts were classified as FS F0-F2 (n=328 APB, n=290 PBO), 1,440 pts were classified as FS ID (n=708 APB, n=732 PBO) and 289 pts were classified as FS F3-F4 (n=144 APB, n=145). MACE+HHF in the PBO group was higher in FS ID and FS F3-F4 compared to FS F0-F2 (17.2% vs 15.0% vs 9.7%) and therefore the former two groups were combined into an elevated risk FS+ group. FS+ pts were older (63 vs 56), had longer duration of T2DM (9.0 vs 7.3 yrs), and higher BMI (30.8 vs 28.6) compared to FS- pts. Overall, APB was associated with fewer MACE+HHF (HR 0.78, 95% CI 0.60–1.01, p=0.06) compared to PBO in the FS+ pts with adjustment for age, duration of T2DM and BMI. Conclusions Patients with T2DM and ACS may share common risk factors with patients with NAFLD. Apabetalone appears to exert a favorable effect on MACE in patients with risk factors for NAFLD. Whether apabetalone has a modulatory effect on the development and progression of NAFLD is an important question requiring further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Resverlogix Corp.