Insights from the First Trials in Epigenetics in Humans: What is the Way Forward? Stephen Nicholls MBBS PhD @SAHMRI_Heart
Residual Clinical Risk in Statin Trials Residual Events Prevented Events 100 80 Percent of Events 60 40 20 0 4S LIPID CARE HPS WOS AF/Tex JUPITER 2 o PREVENTION 1 o PREVENTION HIGH RISK
An Epigenetic Approach to CVD? Ac BET Ac Ac RVX-208 BET ET BD1 BD2 bromodomain Ac Ac Ac Extraterminal Domain (ET) Other transcriptional proteins Increased ApoA-I mRNA
Stimulate ApoA-I Synthesis Efflux Capacity of Serum Isolated Following 28 Days of Treatment 40 Vehicle Percent Cholesterol Efflux RVX-208 30 20 10 0 SR-BI ABCA1 ABCG1 Bailey JACC 2010; 55:2580-9
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 • Ongoing phase 3 CVOT (BETonMACE) recruiting
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
Percent Change in Biochemical Parameters No Attenuated Plaque Attenuated Plaque Characteristic P Value (n=216) (n=27) Age (years) 58.5 62.0 0.06 Males (%) 76.4 88.9 0.22 BMI (kg/m 2 ) 29.4 28.7 0.80 Hypertension (%) 79.6 77.8 0.80 Diabetes (%) 30.6 37.0 0.51 LDL-C (mg/dL) 96.0 85.0 0.07 HDL-C (mg/dL) 39.0 39.0 0.55 hsCRP (mg/L) 2.2 2.5 0.63 PAV (%) 37.5 43.8 0.007 TAV (mm 3 ) 193.6 245.0 0.005
Apabetalone Reduces ALP Activity in Phase 2 Clinical Trials
Apabetalone Reduces Osteoprotegerin Levels Plasma Osteoprotegerin: Osteoprotegerin Expression in Human Coronary Artery ASSURE trial Smooth Muscle Cells: Time Course Median Percentage Change From Baseline Fold Change mRNA relative to Day 0 15 6 ** 5 10 4 5 7,8 3 0 -6,2 2 -5 1 -10 Placebo Apabetalone 200mg 0 (n=47) daily - DMSO 5µM 25µM DMSO 5µM 25µM DMSO 5µM 25µM DMSO 5µM 25µM (n=47) 208 208 208 208 208 208 208 208 Day 0 Day 3 Day 7 Day 14 Day 21 6-months treatment
Apabetalone Reduces Expression of Factors Involved in Calcification Apabetalone downregulates expression of genes Apabetalone downregulates expression of genes related related to vascular calcification in microarrays from to vascular calcification in primary human hepatocytes whole blood treated ex-vivo (fold change) microarrays (fold change) Apabetalone downregulates expression of calcification related genes in LPS stimulated U937 macrophages
Apabetalone Downregulates Pathways Associated with Vascular Calcification in CKD Phase I, Safety & PK Study: Healthy Control Subjects (n=8) versus CKD (stage IV) Patients (n=8) treated with single 100 mg dose of Apabetalone, 12 hours post dose (Ingenuity Pathway Analysis of SOMAscan proteomic assessment) Pathways associated with VC are elevated in CKD vs controls AT BASELINE Bioinformatics (IPA) Analysis of the Plasma Proteome (SOMAscan ™) Pathway Upregulated in CKD vs controls P -value IPA z-score: 2.12 BMP signaling pathway 0.0000062 (predicted upregulation in CKD) IPA z-score: 1.89 RANK signaling in osteoclasts 0.00033 (predicted upregulation in CKD) Apabetalone downregulates pathways associated with VC in CKD patients AT 12 Hours Bioinformatics (IPA) Analysis of the Plasma Proteome (SOMAscan ™) Pathway Response to apabetalone P -value IPA z-score: -2.45 BMP signaling pathway 0.00027 (predicted downregulation) IPA z-score: -2.65 RANK signaling in osteoclasts 0.00018 (predicted downregulation) *no modulation of either pathway in controls
Apabetalone has Favorable Effects on Vascular Inflammation Apabetalone Treatment of HAEC (TNF α 3h) Apabetalone Treatment of PBMC (3h) 1,6 1,6 PARC MCP-1 1,4 1,4 MCP-1 VCAM (relative to DMSO) 1,2 1,2 (relative to DMSO) Fold Change SPP1 1 Fold Change 1 0,8 0,8 0,6 0,6 0,4 0,4 0,2 0,2 0 0 0,1 1 10 100 0,01 0,1 1 10 100 Apabetalone (uM) Apabetalone (uM) Apabetalone Treatment of Macrophage Apabetalone Treatment of Macrophage Cell Line (LPS 24h) Cell Line (LPS 3h) SPP1, 24h LPS 1,6 1,6 SPP1, Naive IL-6 1,4 1,4 MCP-1, 24h LPS (relative to DMSO) MCP-1, Naive 1,2 1,2 (relative to DMSO) Fold Change Fold Change 1 1 0,8 0,8 0,6 0,6 0,4 0,4 0,2 0,2 0 0 0 1 10 100 0,01 0,1 1 10 100 Apabetalone (uM) Apabetalone (uM) 4 Apabetalone reduces expression of PARC (CCL18), MCP-1, Apabetalone Reduces Atheroma in osteopontin (SPP1), IL-6 and VCAM-1 in blood and endothelial cells Aorta of ApoE-/- Mice (PBMCs, HAECs, U937 – resting and stimulated)
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
Apabetalone Reduces Levels of Vascular Inflammation Proteins in CVD Patients ASSURE clinical data: anti-inflammatory and plaque- stabilizing effects apabetalone Δ Placebo p-value vs p-value vs p-value vs Protein Name 200mg daily treated vs. N=47 baseline baseline placebo N=47 placebo C-reactive protein (CRP) * * * Pappalysin-1 (PAPPA) * * Vascular cell adhesion protein 1 (VCAM1) * * Serum amyloid P-component (APCS) * * apabetalone Δ Placebo p-value vs p-value vs p-value vs Protein Name 200mg daily treated vs. N=47 baseline baseline placebo N=47 placebo Stromelysin-1 (MMP3) * * Macrophage metalloelastase (MMP12) * * * = p<0.05 †p<0.10 18
Clinical Characteristics and Medication Use Placebo Apabetalone Characteristic P Value (n=242) (n=556) Age (years) 59.7 61.4 0.03 Male (%) 69.0 75.5 0.05 BMI (kg/m 2 ) 30.7 30.2 0.25 Hypertension (%) 82.6 82.4 0.93 Dyslipidemia (%) 46.7 64.4 <0.001 Prior CVD (%) 91.3 94.2 0.13 Diabetes (%) 35.1 35.1 0.99 Smoker (%) 25.2 23.6 0.62
Percent Change in Biochemical Parameters Placebo Apabetalone Characteristic P Value (n=242) (n=556) ApoA-I +2.7%*** +6.7%*** <0.001 ApoB -3.9%*** -4.6%*** 0.19 HDL-C 0% +6.5%*** <0.001 LDL-C -3.6%*** -5.0%** 0.33 Triglycerides -1.4% +3.9%* 0.54 Total HDL particles +0.5% +4.8%*** <0.001 Large HDL particles +1.7%* +23.3%*** <0.001 Total LDL particles 0% -2.2% 0.77 hsCRP -13.3%** -21.1%*** 0.04 * P<0.05, ** P<0.01 and *** P<0.001 compared with baseline
Less CV Events with Apabetalone in Pooled Phase 2 Studies 12% Apabetalone (n=556) Placebo (n=242) 9% 44% RRR p=0.0232 6% 3% 0% 0 20 40 60 80 100 120 140 160 180 200 220 Days Since Randomization 15%
Less CV Events with Apabetalone in Patients with Diabetes 15% Apabetalone Diabetics (n=195) Apabetalone Nondiabetics (n=361) Placebo Diabetics (n=85) Placebo Nondiabetics (n=157) Diabetic 12% Patients 57% RRR p=0.0181 9% 6% Non-Diabetic 3% Patients 31% RRR p=0.3037 0% 0 20 40 60 80 100 120 140 160 180 200 220 Days Since Randomization
Less CV Events with Apabetalone in Patients with Elevated CRP Levels 15% Apabetalone Elevated CRP (n=290) Apabetalone Normal CRP (n=264) Placebo Elevated CRP (n=133) Placebo Normal CRP (n=108) 12% Elevated CRP Patients 62% RRR 9% p=0.0166 6% 3% Normal CRP Patients -46% RRR p=0.7932 0% 0 20 40 60 80 100 120 140 160 180 200 220 Days Since Randomization
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