A clinical view on BET inhibition in targeting residual risk in CVD - PowerPoint PPT Presentation

A clinical view on BET inhibition in targeting residual risk in CVD and Diabetes Kausik K Ray Professor of Public Health and Consultant Cardiologist Imperial Centre for Cardiovascular Disease Prevention Imperial College London

Disclosures • Research grants : Amgen, Sanofi, Regeneron, MSD, Pfizer • Consultancy : Amgen, Sanofi, Regeneron, MSD, Pfizer, Astra Zeneca, Lilly, Medicines Company, Kowa, IONIS, Takeda, Novo Nordisk, Boehringer Ingelheim, Esperion, Cipla, Algorithm, Abbvie, Resverlogix, Cerenis

Life expectancy is reduced by ~12 years in diabetes patients with previous CVD* Modelling of Years of Life Lost by Disease Status of Participants at Baseline Compared With Those Free of Diabetes, Stroke, and MI * male, 60 years of age with history of MI or stroke 3 The Emerging Risk Factors Collaboration. JAMA . 2015;314(1):52-60.

Interventions that reduce CVD Antiplatelet therapies? Lipid lowering? Glucose lowering? Blood pressure lowering? CVD, cardiovascular disease

Lipid-lowering therapy with statins consistently reduces CV events (per 39 mg/dL lower LDL-C) Major vascular event Events (%) and prior diabetes Treatment Control RR (95% CI) Major coronary event Diabetes 776 (8.3%) 979 (10.5%) 0.78 (0.69, 0.87) No diabetes 2561 (7.2%) 3441 (9.6%) 0.77 (0.73, 0.81) Any major coronary event 3337 (7.4%) 4420 (9.8%) 0.77 (0.74, 0.80) Test for heterogeneity within subgroup: X 2 1 =0.1; P =0.8 Coronary revascularisation Diabetes 491 (5.2%) 627 (6.7%) 0.75 (0.64, 0.88) No diabetes 2129 (6.0%) 2807 (7.9%) 0.76 (0.72, 0.81) Any coronary revascularisation 2620 (5.8%) 3434 (7.6%) 0.76 (0.73, 0.80) X 2 Test for heterogeneity within subgroup: 1 =0.1; P =0.8 Stroke 407 (4.4%) 501 (5.4%) 0.79 (0.67, 0.93) Diabetes No diabetes 933 (2.7%) 116 (3.2%) 0.84 (0.76, 0.93) 1340 (3.0%) 1617 (3.7%) 0.83 (0.77, 0.88) Any stroke X 2 Test for heterogeneity within subgroup: 1 =0.8; P =0.4 Major vascular event 1465 (15.6%) 1782 (19.2%) 0.79 (0.72, 0.86) Diabetes No diabetes 4889 (13.7%) 6212 (17.4%) 0.79 (0.76, 0.82) Any major vascular event 6354 (14.1%) 7994 (17.8%) 0.79 (0.77, 0.81) Test for heterogeneity within subgroup: X 2 1 =0.0; P =0.9 1.0 1.5 0.5 Treatment better Control better RR (95% CI) CI, confidence interval; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; RR, rate ratio Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2008;371:117 – 125

10 mmHg reduction in SBP reduces all-cause mortality and macrovascular and microvascular outcomes in Type 2 diabetes • Meta-analysis of 40 large-scale, randomised, controlled trials of BP-lowering treatment including patients with diabetes (n=100,354 participants) RR (95% CI) Outcome All-cause mortality Macrovascular disease CVD CHD Stroke Heart failure Microvascular disease Renal failure Retinopathy Albuminuria 0.5 1.0 2.0 Favours BP lowering Favours control BP, blood pressure; CI, confidence interval; CVD, cardiovascular disease; CHD, coronary heart disease; RR, relative risk; SBP, systolic blood pressure Emdin CD, et al. JAMA 2015;313:603 – 615

Effect of antiplatelet therapies on CV death in patients with Type 2 diabetes may be more pronounced than in those without diabetes… TRITON-TIMI 38: Effects of clopidogrel and prasugrel on CV death, MI, and stroke through 450 days by diabetes status 1 DM No DM HR 0.70 (0.58 – 0.85), P <0.001 HR 0.86 (0.76 – 0.98), P =0.02 Clopidogrel 17.0 18 18 16 16 14 14 Primary End Point (%) Clopidogrel 10.6 12 12 10 10 Prasugrel 12.2 8 8 Prasugrel 9.2 6 6 4 4 2 2 0 0 0 50 100 150 200 250 300 350 400 450 0 50 100 150 200 250 300 350 400 450 Days Days The settings and timeframes differ between TRITON-TIMI 38 and PEGASUS-TIMI 54 CV, cardiovascular; DM, diabetes mellius; HR, hazard ratio; MI, myocardial infarction 1. Wiviott SD, et al. Circulation. 2008;118:1626 – 1636.

Newer glucose-lowering agents have been shown to improve CV outcomes in patients with Type 2 diabetes and CV disease or CV risk factors HRs for pre-specified clinical endpoints (95% CI) LEADER 3 SUSTAIN-6 4 EMPA-REG OUTCOME 1 CANVAS 2,a HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Primary efficacy endpoint 0.86 (0.74, 0.99) 0.86 (0.75, 0.97) 0.87 (0.78, 0.97) 0.74 (0.58, 0.95) Secondary efficacy endpoint 0.89 (0.78, 1.01) 0.88 (0.81, 0.96) 0.74 (0.62, 0.89) Death from any cause 0.68 (0.57, 0.82) 0.87 (0.74, 1.01) 0.85 (0.74, 0.97) 1.05 (0.74, 1.50) Death from CV causes 0.62 (0.49, 0.77) 0.87 (0.72, 1.06) 0.78 (0.66, 0.93) 0.98 (0.65, 1.48) Myocardial infarction 0.87 (0.70, 1.09) 0.85 (0.69, 1.05) 0.86 (0.73, 1.00) 0.74 (0.51, 1.08) Stroke 1.18 (0.89, 1.56) 0.90 (0.71, 1.15) 0.86 (0.71, 1.06) 0.61 (0.38, 0.99) Hospitalisation for unstable angina 0.99 (0.74, 1.34) 0.98 (0.76, 1.26) 0.82 (0.47, 1.44) 0.67 (0.52, 0.87) a hHF 0.65 (0.50, 0.85) 0.87 (0.73, 1.05) 1.11 (0.77, 1.61 Coronary revascularisation 0.86 (0.72, 1.04) 0.86 (0.72, 1.04) 0.65 (0.50, 0.86) Microvascular event 0.84 (0.73, 0.97) 0.66 (0.55, 0.79) hHF or death from CV causes excluding fatal stroke 0 1 2 0 0,5 1 1,5 0,5 1 1,5 2 0 0,5 1 1,5 Favours Favours Favours Favours Favours Favours Favours Favours empagliflozin placebo canagliflozin placebo liraglutide placebo semaglutide placebo a Difference in hHF was not considered significant due to hierarchical analysis CI, confidence interval; CV, cardiovascular; hHF, hospitalisation for heart failure; HR, hazard ratio; RCT, randomised controlled trial 1. Zinman B, et al. N Engl J Med 2015;373:2117 – 2128; 2. Neal B, et al. N Engl J Med 2017;377:644 – 657; 3. Marso SP, et al. N Engl J Med 2016;375:311 – 322; 4. Marso SP, et al. N Engl J Med 2016;375:1834 – 1844

BET and BETi Bromodomain and extra-terminal (BET) proteins Apabetalone is a selective have been implicated in a range of pathologic states BET inhibitor In perturbed states, BET proteins are more abundant APABETALONE MAY HAVE ACTIONS IN VITRO WHICH SUPPRESS THE EXPRESSION OF MULTIPLE GENES POTENTIALLY INVOLVED IN THE PATHOGENESIS OF ATHEROTHROMBOTIC EVENTS (INTERLEUKIN-6, MCP- 1, COMPLEMENT COMPONENT 9, AND THROMBIN. Modified from Belkina et al 2017

10 Downregulation of Pathways Important for Atherosclerotic CV Disease Microarrays were performed on Primary Human Hepatocytes (PHH) treated with apabetalone at and analyzed for genes (20,000+) and pathways (1,000+) affected. Blue: genes that are downregulated Black: genes not affected Yellow: genes that are upregulated Confidential 28 Aug 2016 Gilham et al Atherosclerosis 2016

Potential Mechanistic Effects Linking Apabetalone to CV Risk Reduction Complement Vascular Pathway Inflammation Reverse Coagulation Epigenetic Cholesterol Regulation Pathway Pathway Vascular Metabolism Calcification

Apabetalone in the Clinic 985 participants in completed trials 706 received treatment with apabetalone, including 576 patients with CAD and/or dyslipidemia on top of standard of care Three phase 2 studies completed in CAD patients • ASSERT: 12 weeks in 299 patients • SUSTAIN: 24 weeks in 176 patients • ASSURE: 26 weeks in 323 patients

Early Effects of Apabetalone in CAD Patients RVX-208 Placebo P Parameter 100 mg 200 mg 300 mg (n=74) Value (n=76) (n=75) (n=74) ApoA-I 0.9 0.1 3.8 5.6 0.02 HDL-C 0 3.2 6.3* 8.3** 0.02 Large HDL -0.5 11.1 20.2** 21.1*** 0.003 Small HDL 2.6 -0.4 -2.6 -4.0 0.07 α1 HDL -2.3 3.7 8.0* 8.8* 0.12 * P<0.05, ** P<0.01 and *** P<0.001compared with placebo Nicholls JACC 2010; 57:1111-9

ASSURE: Change in Percent Atheroma Volume 0.00 P=0.81† Change Percent -0.25 -0.30 Atheroma Volume P=0.23* -0.40 P=0.08* -0.50 Placebo RVX-208 * Primary endpoint: comparison from baseline † comparison between groups.

ASSURE: VH Measures of Plaque Composition 3 P=0.04 P=0.007 Percentage Change P=0.002 P=0.37 P=0.34 0 P=0.84 P=0.27 -3 P<0.001 P=0.09* P=0.46* P=0.37* P=0.04* -6 Fibrous Fibro-fatty Necrotic Calcific Expressed as LS mean change Placebo RVX-208 P values for comparison with baseline *P value for comparison with placebo

Attenuated Plaque as a Measure of Vulnerability J Pu et al. J Am Coll Cardiol 2014;63:2220-33

Apabetalone Reduces Levels of Vascular Inflammation Proteins in CVD Patients ASSERT Clinical Data : anti-inflammatory and plaque-stabilizing effects apabetalone Placebo p-value vs p-value vs Δ p-value vs Protein Name 200mg daily N=30 baseline baseline treated vs. placebo placebo N=25 C-reactive protein (CRP) * * RANTES (CCL5) * sTWEAK (TNFSF12) * * Osteopontin (SPP1) * * PARC (CCL18) * * Epiregulin (EREG) * * TNFSF14 * * Pappalysin-1 (PAPPA) * * apabetalone Placebo p-value vs p-value vs Δ p-value vs Protein Name 200mg daily N=30 baseline baseline treated vs. placebo placebo N=25 Metalloproteinase inhibitor 2 (TIMP2) * * * Metalloproteinase inhibitor 1 (TIMP1) * * * = p<0.05 †p<0.10