Prospects for Risk Reduction with CETP and PCSK9 Inhibitor Therapies CRT 2015, Washington, DC. Prospects for Risk Reduction with CETP and PCSK9 Inhibitor Therapies A. Michael Lincoff, M.D. Director, C5Research (Cleveland Clinic Coordinating Center for Clinical Research) Vice Chairman for Clinical Research, Lerner Research Institute Vice Chairman of Cardiovascular Medicine Professor of Medicine Heart and Vascular Institute

Speaker Disclosure – A. Michael Lincoff, MD Relationships with Industry Research Sponsors Amgen AstraZeneca Atricure Bristol-Myers Squibb (BMS) Cardiovascular Systems Centocor CSL Behring Edwards Lifesciences Early Sense Eli Lilly Ethicon Janssen Juventas Medicines Company Medtronic Novartis Omthera Orexigen Pfizer Regado Resverlogix Stemedica Cell Tech Roche / Genentech Takeda VIVUS 2

Residual Risk in Statin Trials JUPITER WOS AF/Tex LIPID CARE HPS 2o PREVENTION 1o PREVENTION HIGH RISK Percent of Events Residual Events Prevented Events

Dyslipidemia Rx Beyond Statins CETP Inhibitors PCSK9 Inhibitors

Extrahepatic Tissues (including the artery wall CETP Inhibition Liver LDL-R VLDL/LDL CE CE SR-B1 SR-B1 FC CETP CE Extrahepatic Tissues (including the artery wall Free Cholesterol LCAT HDL FC Bile Courtesy of Dr. Philip Barter, The Heart Research Institute, Sydney, Australia

Investigational Potent CETP Inhibitors Anacetrapib and Evacetrapib Changes in HDL-C and LDL-C Cannon CP, et al. NEJM 2010;363:2406. Nicholls et al. JAMA. 2011;306:2099

PCSK9 Physiology – Regulation of LDL Receptors Modified from Lose et al. Pharmacotherapy 2013;33:447.

Evolocumab – PCSK9 monoclonal Ab DESCARTES Trial – Evolocumab for 52 Weeks 905 Patients (LDL-C < 75 mg/dL) – 2:1 Randomization Evolocumab Placebo Overall Diet Alone Atorvastatin 10 mg 80 mg 80 mg + Ezetimibe 10 mg Blom. NEJM 2014;370:1809

LDL-C Lowering and Clinical Benefit CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81.

CETP and PCSK9 Inhibition The Science Behind Clinical Development Animal models Human genetic variations – GOF (“gain of function”) or LOF (“loss of function”) Associations with plasma mass or activity

Attenuates Atherosclerosis in Rabbits CETP Inhibition Attenuates Atherosclerosis in Rabbits Cholesterol-fed Japanese white rabbits JTT-705 produced 90% increase in HDL-C and 40-50% decrease in non-HDL-C Simvastatin produced 28% increase HDL-C and 70% decreased in non-HDL-C Progression of aortic atherosclerosis reduced by 70% with JTT-705 and by 80% with simvastatin Okamoto et al. Nature 2000;406:203

CETP Genotypes – Meta-Analysis Association with CETP Phenotype and Lipid Levels Thompson A, et al. JAMA 2008;299:2777.

CETP Genotypes – Meta-Analysis Odds Ratios for Coronary Disease vs Odds Ratios for HDL-C 0.95 (0.92-0.99) 0.94 (0.89-1.00) 0.95 (0.91-1.00) Thompson A, et al. JAMA 2008;299:2777.

CETP Gene Polymorphisms Genomewide Analysis – 18,245 Healthy Women Women’s Genome Health Study CETP SNP Per Allele HDL Shift (mg/dL) Incident MI HR Per Allele (Age Adjusted) Incident MI HR Per Allele (Fully Adjusted) rs708272 3.08 0.76 (0.62–0.94) 0.01 0.83 (0.66–1.04) 0.099 rs4329913 -1.03 1.34 (1.08–1.66) 0.008 1.29 (1.02–1.63) 0.031 rs1532624 3.14 0.78 (0.64–0.96) 0.018 0.83 (0.66–1.05) 0.12 rs1800775 3.09 0.82 (0.67–1.00) 0.048 0.88 (0.70–1.09) 0.24 rs7202364 1.10 0.79 (0.62–0.99) 0.045 0.76 (0.59–0.99) 0.042 rs8051691 1.09 0.79 (0.62–1.00) 0.047 0.043 Fully adjusted model controlled for age, body mass index, smoking status, hormone replacement therapy, blood pressure, diabetes, parental history of myocardial infarction before age 60 yr, LDL-C, HDL-C, and log transformed triglycerides. Ridker et al. Circ Cardiovasc Genet. 2009;2:26.

CETP Mass or Concentration Studies NOT supportive of inhibition, showing reduced risk of CV events with higher CETP levels Khera et al.1 3218 pts in PROVE-IT MI/death in highest vs lowest quartile: HR 0.81 (0.67-0.98), p = 0.027 Ritsch et al.2 3256 pts in LURIC study CV death in highest vs lowest quartile: HR 0.72 (0.55-0.95), p = 0.021 Borggreve et al.3 111 cases/116 controls in PREVEND Study CV events above vs below median (only pts with TGs below median) HR 0.46 (0.24-0.90), p = 0.03 1AJC 2010;106:451 2Circ 2010;121:366 3EHJ 2007;28:1012

PCSK9 Functional Mutations of the Protein Davignon, Dubec, Seidah. Curr Atheroscler Rep 2010;12:308.

PCSK9 PCSK9 Expression Produces LDL-Receptor Knockout Phenotype Injection of adenovirus constitutively expressing murine PCSK9 Wild Type Mice LDLR Knockout Mice Maxwell and Breslow. PNAS 2004;18:7100.

ARIC Study – 3552 Black Subjects (Y142X or C679X in ~2%) PCSK9 LOF Mutations ARIC Study – 3552 Black Subjects (Y142X or C679X in ~2%) Patients with no CHD at baseline developing CHD over 15 yr f/u 88% reduction in CHD ~40% reduction Cohen J et al. NEJM 2006;354:1264

ARIC Study – 9890 White Subjects (R46L in ~3.2%) PCSK9 LOF Mutations ARIC Study – 9890 White Subjects (R46L in ~3.2%) Patients with no CHD at baseline developing CHD over 15 yr f/u 47% reduction in CHD ~20% reduction Cohen J et al. NEJM 2006;354:1264

PCSK9 R46L LOF Mutation Meta-Analysis of 59,198 Subjects: LDL Reduction and Expected vs Observed Reduction in IHD Benn M et al. JACC 2010;55:2833

CETP and PCSK9 Inhibition Summary CETP inhibition may enhance reverse cholesterol transport to liver. Most genotypes causing reductions in CETP mass or activity (5-10%) are associated with modest increases in HDL-C (3-5%) and small decreases in CV risk (3-5%). CETP inhibitors in current trials increase HDL-C by ~100% and reduce LDL-C by ~40%: CVOTs will determine if these marked changes translate to improved CV outcomes PCSK9 is a key modulator of LDL-C levels via degradation of the LDL receptor. Loss-of-function genetic variants consistently associated with reduced levels of LDL-C and reduced risk of CV disease. PCSK9 antibodies in current CVOTs reduce LDL-C by ~60% beyond by statins: very promising potential to further improve CV outcomes.

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