Prof. John J.P. Kastelein, MD PhD FESC Dept. of Vascular Medicine Academic Medical Center / University of Amsterdam The Netherlands
Disclosures Dr. Kastelein consults with and speaks for biotechnological as well as pharmaceutical companies that develop molecules that influence lipoprotein metabolism and / or inflammation to prevent CVD, including Regeneron, Sanofi, Amgen, Pfizer, Eli Lilly, Iosis, AstraZeneca, CSL Behring, Cerenis, Esperion, The Medicines Company, Kowa, Affiris, UniQure, Madrigal Pharmaceuticals, Akcea Therapeutics, Staten Biotech, Akarna, Corvidia and Gemphire 2
BET Protein Guides Basal Transcription Complex Along Gene BRD4 BET Protein 4 (BRD4) Confidential 3 28 Aug 2016 Nature Reviews Molecular Cell Biology 13, 543-547
Apabetalone Is A Selective Inhibitor of BET Proteins Apabetalone (RVX-208) A Nucleosome BET Protein Acetylated Lysine Histone Tail Core Histones Apabetalone selectively inhibits BD2 2 bromodomains (BD1 & BD2) are present in each BET protein to read acetylated lysine 58-159 349-461 600-678 1362 1 BD1 BD2 ET Confidential 4 28 Aug 2016
Effects on Gene Activity: Apabetalone (selective) vs. JQ-1 (pan) BET inhibitors Regulated genes Dose 1 Dose 2 (+)-JQ1 JQ-1 RVX208 RVX208 PAN PAN BD2 BD2 specific gene expression differs from pan inhibitor PNAS, 2013 110 (49):19754-9. Confidential 5 28 Aug 2016
Beneficial Effects of Apabetalone on Inflammation Apabetalone Treatment of Macrophage Apabetalone Treatment of HAEC* (TNF α 3h) Cell Line (LPS 3h) 1,6 1,6 MCP-1 IL-6 1,4 1,4 (relative to DMSO) VCAM Fold Change 1,2 1,2 (relative to DMSO) Fold Change 1 1 0,8 0,8 0,6 0,6 0,4 0,4 0,2 0,2 0 0 0,01 0,1 1 10 100 0,01 0,1 1 10 100 Apabetalone (uM) Apabetalone (uM) *Human Aortic Endothelial Cells Confidential 6 28 Aug 2016
Apabetalone Reduces Atheroma in Aorta of ApoE-/- Mice Chow High Fat (42% kcal) Diet Chow: TD 2016 +/- apabetalone WK 19 WK 9 WK 33 WK 8 Animal HF Diet Chow Diet Necropsy Arrival Aortic sinus Whole aorta Placebo Apabetalone 20 Whole aorta of -31% of -40% (p<0.016) 15 11.081-607-040 (p<0.045) Plaque/whole area (%) +/- SE 15.081-608-519 10 Aortic sinus 5 8.092-895-111 0 16.040-776-379 Placebo Placebo Apabetalone Apabetalone (150 mg/kg) (150 mg/kg) 7 Confidential 28 Aug 2016 Jahagirdar et al, Atherosclerosis 2015
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 8 Confidential 28 Aug 2016 Gilham et al Atherosclerosis 2016
Apabetalone in the Clinic • 985 subjects have participated in completed trials • 706 received treatment with apabetalone including 576 patients with CAD and/or dyslipidemia on top of standard of care therapy • Three Phase 2 studies in patients with CAD have been completed: • 12-week (ASSERT) enrolled 299 patients • 24-week (SUSTAIN) enrolled 176 patients • 26-week (ASSURE) enrolled 323 patients • On going Phase 3 CVOT (BETonMACE) currently has ~ 600 patients 9 Confidential 28 Aug 2016
Combined Phase 2 Six Month Studies Patient Demographics Parameter Placebo (n=168) apabetalone (n=331) Age, (years) 57.2 58.7 Male, n (%) 113 (67.3) 249 (75.2) Hypertension, n (%) 136 (81.0) 260 (78.5) Diabetes, n (%) 65 (38.7) 127 (38.4) Prior myocardial infarction, n (%) 44 (26.1) 117 (35.3) Concomitant Medication Use Prior statin use, n (%) 116 (69.0) 268 (81.0) Aspirin, n (%) 125 (74.4) 263 (79.5) Beta blocker, n (%) 90 (53.6) 227 (68.6) ACE inhibitor, n (%) 71 (42.3) 131 (39.6) Source: RVX data on file – ASSURE and SUSTAIN SAFETY Population. Confidential 10 28 Aug 2016
Clinical Analysis of Vascular Inflammation in CVD Patients in ASSURE Study (n=94) Placebo Apabetalone Treatment p-value vs Protein Name Gene Symbol 200mg Difference placebo (n=47) (n=47) C-reactive protein CRP -22.3 -43.6 -21.3 0.02 Tumor necrosis factor receptor TNFRSF11B 7.8 -6.2 -14.0 0.003 superfamily Vascular cell adhesion protein 1 VCAM1 5.7 -6.4 -12.2 0.005 Interleukin-6 receptor subunit alpha IL6R -0.1 -9.3 -9.1 0.01 Fibronectin FN1 -19.8 14.3 34.1 0.04 Patients treated with apabetalone experienced reductions in inflammatory biomarkers, consistent with preclinical observations Confidential 11 28 Aug 2016
Apabetalone Reduces Levels of Complement and Coagulation Components in ASSURE Patients (n=94) Protein Name Gene Symbol Placebo Apabetalone Treatment p-value vs (n=47) 200mg Difference placebo (n=47) C5a anaphylatoxin C5 22.7 -28.7 -51.4 0.0001 Complement Complement component C6 C6 0.9 -15.3 -16.1 0.002 Complement C2 C2 4.2 -6.7 -10.9 0.0002 Complement C5 C5 -0.9 -11.7 -10.8 0.0001 Coagulation Coagulation factor Xa F10 7.4 -1.0 -8.5 0.005 Coagulation Factor XI F11 4.1 0.1 -4.0 0.03 Thrombin F2 -17.6 -3.0 14.6 0.02 Coagulation Factor V F5 4.6 -0.9 -5.6 0.08 Patients treated with apabetalone experienced reductions in complement and coagulation proteins. No increase in the incidence of infections, infestations or bleeding events has been observed. Confidential 12
Apabetalone Biomarker Changes Accompanied by MACE Reduction in Phase 2 Studies MACE: Major Adverse Cardiac Events Note: Patients were censored at 30 including: death, days after the last dose of study myocardial infarction, medication. stroke, coronary Source: RVX data on file – ASSURE and revascularization, SUSTAIN Safety Population. Log-Rank hospitalization for test for between group comparison acute coronary syndrome or heart failure 13
Apabetalone Adverse Events • Across the three studies (ASSERT/SUSTAIN/ASSURE) most common AEs were similar to placebo: • gastrointestinal disorders (nausea, diarrhea, and constipation) • infections (upper respiratory tract infection, sinusitis, and bronchitis) • With few exceptions these findings were mild and moderate in severity • Most clinically significant adverse event is raised hepatic transaminases 14 Confidential 28 Aug 2016
Hepatic Adverse Events • Hepatic profile of apabetalone evaluated in detail • Incidence of transaminases >3X ULN 7-8% • No cases of Hy’s law or serious hepatic injury to date in >1000 subjects • Raised transaminases resolve rapidly (approx 15 days for 5X to <ULN) • More data to be obtained from BETonMACE study to further delineate both early and long term hepatic safety 15 Confidential 28 Aug 2016
BETonMACE CV Outcomes Study Design 2,400 + subjects atorvastatin safety follow-up apabetalone 200mg daily + standard of care with T2DM and • double blinded rosuvastatin • 1-2 week statin run-in placebo + standard of care safety follow-up run-in standard of care includes 20-80 mg atorvastatin or 10-40 mg rosuvastatin 1-2 weeks treatment duration up to 104 weeks 4-16 weeks screening randomization (1:1) end of treatment The study is an event-based trial and continues until 250 events have occurred. Confidential 16 28 Aug 2016
BETonMACE CV Outcomes Study Design Primary Endpoint Key inclusion criteria Time from randomization to the first • T2DM occurrence of adjudication-confirmed triple o HbA1c > 6.5% or history of diabetes MACE defined as a composite endpoint of medications CV Death, Non-fatal MI, and Stroke. • CAD event 7 days - 90 days prior to Visit 1 o MI, UA or PCI • HDL < 1.04 for males and < 1.17 for females Secondary Endpoint Time from randomization to the first occurrence of adjudication-confirmed MACE Primary Objective including revascularization and UA To evaluate if treatment with apabetalone as Changes in apoA-I, apoB, LDL-C, HDL-C, compared to placebo increases time to the first and TG occurrence of triple MACE. Triple MACE is defined Changes in HbA1c, fasting glucose, and as a composite endpoint of CV death, non-fatal MI, fasting insulin and stroke. Changes in ALP and eGFR Confidential 17 28 Aug 2016
Apabetalone and BETonMACE 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 • Current recruitment ~ 600 patients The details of the trial can be found at www.clinicaltrials.gov Confidential 18 28 Aug 2016
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