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

Kausik K Ray Professor of Public Health and Consultant Cardiologist Imperial Centre for Cardiovascular Disease Prevention Imperial College London

A clinical view on BET inhibition in targeting residual risk in CVD and Diabetes

• 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

Disclosures

Life expectancy is reduced by ~12 years in diabetes patients with previous CVD*

3

* male, 60 years of age with history of MI or stroke

Modelling of Years of Life Lost by Disease Status of Participants at Baseline Compared With Those Free of Diabetes, Stroke, and MI The Emerging Risk Factors Collaboration.

• JAMA. 2015;314(1):52-60.

Lipid lowering?

Interventions that reduce CVD

Blood pressure lowering? Antiplatelet therapies? Glucose lowering?

CVD, cardiovascular disease

Lipid-lowering therapy with statins consistently reduces CV events (per 39 mg/dL lower LDL-C)

CI, confidence interval; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; RR, rate ratio Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2008;371:117–125

Major vascular event and prior diabetes

1.0 1.5

Treatment Control Events (%) Major coronary event Diabetes No diabetes Any major coronary event Test for heterogeneity within subgroup: Coronary revascularisation Diabetes No diabetes Any coronary revascularisation Test for heterogeneity within subgroup: Stroke Diabetes No diabetes Any stroke Test for heterogeneity within subgroup: Major vascular event Diabetes No diabetes Test for heterogeneity within subgroup: Any major vascular event 776 (8.3%) 2561 (7.2%) 3337 (7.4%) X2

1=0.1; P=0.8

491 (5.2%) 2129 (6.0%) 2620 (5.8%) X2

1=0.1; P=0.8

407 (4.4%) 933 (2.7%) 1340 (3.0%) X2

1=0.8; P=0.4

1465 (15.6%) 4889 (13.7%) 6354 (14.1%) X2

1=0.0; P=0.9

979 (10.5%) 3441 (9.6%) 4420 (9.8%) 627 (6.7%) 2807 (7.9%) 3434 (7.6%) 501 (5.4%) 116 (3.2%) 1617 (3.7%) 1782 (19.2%) 6212 (17.4%) 7994 (17.8%) 0.78 (0.69, 0.87) 0.77 (0.73, 0.81) 0.77 (0.74, 0.80) 0.75 (0.64, 0.88) 0.76 (0.72, 0.81) 0.76 (0.73, 0.80) 0.79 (0.67, 0.93) 0.84 (0.76, 0.93) 0.83 (0.77, 0.88) 0.79 (0.72, 0.86) 0.79 (0.76, 0.82) 0.79 (0.77, 0.81) RR (95% CI)

Treatment better Control better

0.5

RR (95% CI)

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)

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

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

RR (95% CI)

Effect of antiplatelet therapies on CV death in patients with Type 2 diabetes may be more pronounced than in those without diabetes…

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.

TRITON-TIMI 38: Effects of clopidogrel and prasugrel on CV death, MI, and stroke through 450 days by diabetes status1

DM No DM

HR 0.70 (0.58–0.85), P<0.001 HR 0.86 (0.76–0.98), P=0.02 Clopidogrel 10.6 Prasugrel 9.2 Clopidogrel 17.0 Prasugrel 12.2

Days

Days

18 16 14 12 10 8 6 4 2

Primary End Point (%)

50 100 150 200 250 300 350 400 450 18 16 14 12 10 8 6 4 2 50 100 150 200 250 300 350 400 450

Newer glucose-lowering agents have been shown to improve CV

• utcomes in patients with Type 2 diabetes and CV disease or CV

risk factors

1 2

Primary efficacy endpoint Secondary efficacy endpoint Death from any cause Death from CV causes Myocardial infarction Stroke Hospitalisation for unstable angina Coronary revascularisation Microvascular event hHF or death from CV causes excluding fatal stroke 0.86 (0.74, 0.99) 0.89 (0.78, 1.01) 0.68 (0.57, 0.82) 0.62 (0.49, 0.77) 0.87 (0.70, 1.09) 1.18 (0.89, 1.56) 0.65 (0.50, 0.85) 0.86 (0.72, 1.04) 0.66 (0.55, 0.79) 0.99 (0.74, 1.34) HR (95% CI)

HRs for pre-specified clinical endpoints (95% CI)

0,5 1 1,5 2 Favours placebo Favours empagliflozin Favours placebo Favours liraglutide

EMPA-REG OUTCOME1 LEADER3 SUSTAIN-64

hHF 0.87 (0.78, 0.97) 0.88 (0.81, 0.96) 0.85 (0.74, 0.97) 0.78 (0.66, 0.93) 0.86 (0.73, 1.00) 0.86 (0.71, 1.06) 0.87 (0.73, 1.05) 0.86 (0.72, 1.04) 0.84 (0.73, 0.97) 0.98 (0.76, 1.26) HR (95% CI)

0,5 1 1,5 Favours placebo Favours semaglutide

0.74 (0.58, 0.95) 0.74 (0.62, 0.89) 1.05 (0.74, 1.50) 0.98 (0.65, 1.48) 0.74 (0.51, 1.08) 0.61 (0.38, 0.99) 1.11 (0.77, 1.61 0.65 (0.50, 0.86) 0.82 (0.47, 1.44) HR (95% CI)

0,5 1 1,5 Favours placebo Favours canagliflozin

CANVAS2,a

0.86 (0.75, 0.97) 0.87 (0.74, 1.01) 0.87 (0.72, 1.06) 0.85 (0.69, 1.05) 0.90 (0.71, 1.15) 0.67 (0.52, 0.87)a HR (95% CI)

aDifference 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

Modified from Belkina et al 2017 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.

Bromodomain and extra-terminal (BET) proteins have been implicated in a range of pathologic states

In perturbed states, BET proteins are more abundant

Apabetalone is a selective BET inhibitor

BET and BETi

Downregulation of Pathways Important for Atherosclerotic CV Disease

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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 Gilham et al Atherosclerosis 2016

Confidential 28 Aug 2016

Potential Mechanistic Effects Linking Apabetalone to CV Risk Reduction

Vascular Inflammation Reverse Cholesterol Pathway Metabolism Vascular

Calcification

Coagulation Pathway Complement Pathway

Epigenetic Regulation

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

Parameter Placebo (n=74) RVX-208 P Value 100 mg (n=76) 200 mg (n=75) 300 mg (n=74) ApoA-I 0.9 0.1 3.8 5.6 0.02 HDL-C 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

Placebo RVX-208

• 0.50
• 0.25

0.00

P=0.81†

• 0.30

P=0.23*

• 0.40

P=0.08*

Change Percent Atheroma Volume

ASSURE: Change in Percent Atheroma Volume

* Primary endpoint: comparison from baseline † comparison between groups.

• 6
• 3

3

Percentage Change

Fibrous Calcific Necrotic Fibro-fatty

P=0.002 P=0.34 P=0.007 P=0.37 P=0.84 P<0.001 P=0.04 P=0.27 P=0.04* P=0.09* P=0.37* P=0.46*

ASSURE: VH Measures of Plaque Composition

Placebo RVX-208

Expressed as LS mean change 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

Protein Name Placebo N=30 p-value vs baseline apabetalone 200mg daily N=25 p-value vs baseline Δ treated vs. placebo p-value vs placebo Metalloproteinase inhibitor 2 (TIMP2) * * * Metalloproteinase inhibitor 1 (TIMP1) * * Protein Name Placebo N=30 p-value vs baseline apabetalone 200mg daily N=25 p-value vs baseline Δ treated vs. placebo p-value vs placebo C-reactive protein (CRP) * * RANTES (CCL5) * sTWEAK (TNFSF12) * * Osteopontin (SPP1) * * PARC (CCL18) * * Epiregulin (EREG) * * TNFSF14 * * Pappalysin-1 (PAPPA) * *

ASSERT Clinical Data : anti-inflammatory and plaque-stabilizing effects

Apabetalone Reduces Levels of Vascular Inflammation Proteins in CVD Patients

* = p<0.05 †p<0.10

Apabetalone Reduces Levels of Vascular Inflammation Proteins in CVD Patients

Protein Name Placebo N=47 p-value vs baseline apabetalone 200mg daily N=47 p-value vs baseline Δ treated vs. placebo p-value vs placebo C-reactive protein (CRP) * * * Pappalysin-1 (PAPPA) * * Vascular cell adhesion protein 1 (VCAM1) * * Serum amyloid P-component (APCS) * * Protein Name Placebo N=47 p-value vs baseline apabetalone 200mg daily N=47 p-value vs baseline Δ treated vs. placebo p-value vs placebo Stromelysin-1 (MMP3) * * Macrophage metalloelastase (MMP12) * *

ASSURE clinical data: anti-inflammatory and plaque-stabilizing effects 18

* = p<0.05 †p<0.10

Less CV Events with Apabetalone in Pooled Phase 2 Studies

44% RRR p=0.0232 0% 3% 6% 9% 12% 20 40 60 80 100 120 140 160 180 200 220 Days Since Randomization Apabetalone (n=556) Placebo (n=242) 15%

Less CV Events with Apabetalone in Patients with Diabetes

Diabetic Patients 57% RRR p=0.0181 Non-Diabetic Patients 31% RRR p=0.3037 0% 3% 6% 9% 12% 15% 20 40 60 80 100 120 140 160 180 200 220 Days Since Randomization Apabetalone Diabetics (n=195) Apabetalone Nondiabetics (n=361) Placebo Diabetics (n=85) Placebo Nondiabetics (n=157)

Less CV Events with Apabetalone in Patients with Elevated CRP Levels

Elevated CRP Patients 62% RRR p=0.0166 Normal CRP Patients

• 46% RRR

p=0.7932 0% 3% 6% 9% 12% 15% 20 40 60 80 100 120 140 160 180 200 220 Days Since Randomization Apabetalone Elevated CRP (n=290) Apabetalone Normal CRP (n=264) Placebo Elevated CRP (n=133) Placebo Normal CRP (n=108)

BETonMACE

2,400 + subjects

• double blinded
• 1-2 week statin run-in

atorvastatin and rosuvastatin run-in apabetalone 200mg daily + standard of care placebo + standard of care safety follow-up safety follow-up standard of care includes 20-80 mg atorvastatin

• r 10-40 mg rosuvastatin

screening 1-2 weeks treatment duration up to 104 weeks 4-16 weeks randomization (1:1) end of treatment The study is an event-based trial and continues until 250 events have occurred.

Key inclusion criteria

• T2DM
• HbA1c > 6.5% or history of diabetes

medications

• CAD event 7 days - 90 days prior to Visit 1
• MI, UA or PCI
• HDL < 1.04 for males and < 1.17 for females

Primary Objective To evaluate if treatment with apabetalone as compared to placebo increases time to the first

• ccurrence of triple MACE. Triple MACE is defined

as a single composite endpoint of CV death or non-fatal MI or stroke. Primary Endpoint Time from randomization to the first

• ccurrence of adjudication-confirmed triple

MACE defined as a single composite endpoint of CV Death or Non-fatal MI or Stroke. Secondary Endpoint Time from randomization to the first

• ccurrence of adjudication-confirmed MACE

including revascularization and UA Changes in apoA-I, apoB, LDL-C, HDL-C, and TG Changes in HbA1c, fasting glucose, and fasting insulin Changes in ALP and eGFR

BETonMACE CV Outcomes Study

23 28 Aug 2016

Summary Apabetalone is a first in class BET-inhibitor that regulates genes and pathways that underlie development of CVD In phase 2 clinical trials, CVD event reductions were found which were most pronounced in patients with diabetes mellitus or increased inflammation BETonMACE is an ongoing pivotal phase 3 trial designed to confirm if apabetalone can prevent CVD events in post-ACS patients with T2DM and low HDL cholesterol

28 Aug 2016