Cardiovascular risk management: What are the strategic changes? Prof. John Deanfield University College London London, United Kingdom

40% Death Rates from All Circulatory Disease in England 1993-2011 180 A fall of 55% since baseline 160 140 Target: 40% minimum reduction from 1995-97 120 100 Death / 100,000 population 80 60 40 Immortality Guaranteed by 2026 20 1993/5 1995/7 1997/9 2001/3 2003/5 2005/7 2007/9 2009/11 2009/11 1999/2001 B/L Progress target Source: ONS (ICD9 390-459; ICD10 I00-I99)

Treatment of CVD: Residual Risk 100 Statins 40% % CV events Residual Risk 60%

CHD Impact of Early vs Late LDL Lowering Mendelian Randomisation Studies of 9 Polymorphisms in 6 Genes Ference J Am Coll Cardiol 2012; 60: 2631–9

Lifetime Risk of Death from CV Disease Berry NEJM 2012; 366: 321-329

Early intervention pays long term dividends

A reasonable next step for ATP IV? ….Consider statins for younger persons, perhaps starting at 30 in those with risk factors that convey high lifetime risk (as opposed to 10 yr risk) for CHD Pletcher JACC 2010; 56: 637-640

Benefits of further lowering of causal factors?

Coronary Heart Disease (%) LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9142X or PCSK9679X Allele No Nonsense Mutation (n=3278) 12 50th Percentile 30 P=0.008 20 8 88% 10 Frequency (%) Coronary Heart Disease (%) 50 100 150 200 250 300 PCSK9142X or PCSK9679X (N=85) 4 28% 30 20 10 No Yes PCSK9142X or PCSK9679X 50 100 150 200 250 300 Cohen NEJM 2006; 354:1264-72 LDL Cholesterol in Black Subjects (mg/dl)

PCSK9 Monoclonal AB in heFH Patients % Change in LDL-C from Baseline TC Non-HDL-C ApoB Lp(a) -10 -20 % Change in LDL-C from Baseline -30 -40 -50 -60 Stein Lancet 2012; 380: 29-36

Life Course Blood Pressure and Mortality Harvard Alumni Health Study 10 8 Survival from CVD 6 4 Normal Stage 1 hypertension Pre-hypertension Stage 2 hypertension 2 20 40 60 80 Follow up time (years) Gray JACC 2011; 58: 2396-403

4733 age 62.2 years intensive vs standard BP treatment over 4.7 years BP Treatment in Type 2 DM 4733 age 62.2 years intensive vs standard BP treatment over 4.7 years ACCORD Study Group NEJM 2010;362:1575-1585

Lifetime Risk from Blood Pressure: NICE Short-term (10-year) risk underestimates lifetime CV risk of young people with hypertension... Lifetime risk with untreated stage 1 hypertension in this age group could be substantial. Lifetime risk assessments may be a better way to inform treatment decisions and evaluate cost effectiveness of earlier drug therapy.

Need Treatments for New Targets Evidence for residual risk from other risk factors and pathways Need Treatments for New Targets

Coronary Heart Disease and HDL-C 3.5 3.0 2.5 N = 302,430 Hazard Ratio 2.0 1.5 1.0 0.8 30 40 50 60 70 80 HDL-C (mg/dL) The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000

Effect of ERN/LRPT on Major Vascular Events

Dalcetrapib in Patients With Recent ACS Schwartz NEJM 2012; 367: 2089-2099

HDL Trials:Reasons for Failure Failure of molecule -Toxicity -Potency Failure of biology -HDL not on causal pathway -Wrong pathway for drug -HDL properties may change -Wrong stage of disease

HDL : Effects on endothelial NO production in patients with CAD Healthy P<0.025 sCAD 30 ACS 20 Endothelial NO production [in % of buffer-treated cells] 10 -10 -20 25 mg/ml HDL 50 mg/ml HDL 100 mg/ml HDL Besler C et al. & Landmesser U. J Clin Invest (in press)

Dalcetrapib HDL Function Study 25 dalcetrapib treated 25 placebo-treated PLACEBO Baseline 12 wks 36 wks Serum collection HDL isolation density ultracentrifugation Endothelial Nitric Oxide production ESR spectroscopy Endothelial anti-apoptotic capacity Inhibition of caspase-3 expression Endothelial anti-inflammatory capacity Inhibition of VCAM-1 expression

Dalcetrapib and HDL Function Placebo Dalcetrapib Effect of HDL on NO production Anti-apoptotic capacity of HDL Anti-inflammatory capacity of HDL

Late-stage Drug Development Failure A major productivity limiting barrier Late-stage failure In vitro & in vivo experiments Hunan observational studies Target identification Molecule development Phase I Phase II Phase III Approval Pre-clinical development Clinical studies Cost Well-known pipeline of drug development Preclinical target and molecule discovery/validation Clinical phase Huge financial and time cost $4-11B Time Kola & Landis, Nat Rev Drug Disc. 2004 Arrowsmith, Nat Rev Drug Disc, 2011 Bunnage, Nature Chemical Biology, 2011 Arrowsmith, Nature Reviews Drug Disc, 2011 ~12yrs

In Search of Fewer independent Risk Factors Brotman Arch Intern Med. 2005; 165: 138-145

New approaches to refine target validation, safety and efficacy

RCT as an arbiter of molecule efficacy and safety, and target validity Drug intervention Genetics: natural randomisation RCT (Phase III) Sample Randomisation Placebo LDL-C unchanged CV event rate lower rate higher Protein target: HMGCR Off target Mendelian randomisation Population Random allocation of alleles HMGCR aa Genotype AA LDL-C reduced HMGCR variant (rs12916) reduce LDL-C by -0.07 mmol/L, and risk of CHD (OR of 0.94; 95%CI: 0.90, 0.98). JACC 2013 HMG-CoA red inhibitor LDL-C reduced

Finding new indications for existing medications Drug intervention (IL6R blocker licensed for Rheumatoid arthritis) Genetics: natural randomisation Population Sample Randomisation (Tocilizumab) Random allocation of IL6R alleles Protein target: IL6R Protein target: IL6R IL6R- blocker (MAB) Placebo IL6R aa IL6R AA Reduce IL6 signalling IL6 signalling unchanged Reduced IL6 signalling IL6 signalling unchanged RA disease Activity lower RA disease activity higher CV event rate lower CV event rate higher Biomarker Tocilizumab IL6R SNP IL-6  (n=1,446)  (n=29,838) CRP  (n=3,010)  (n=76,527) Fibrinogen  (n=409)  (n=52,667) Soluble IL-6R  (n=1,465)  (n=1,454) Albumin  (n=108)  (n=5,787) Haemoglobin  (n=2,072)  (n=17,898)

Finding new indications for existing medications Drug intervention (IL6R blocker licensed for Rheumatoid arthritis) Genetics: natural randomisation Sample Swerdlow, Lancet 2012 Randomisation (Tocilizumab) Protein target: IL6R IL6R- blocker (MAB) Placebo Reduce IL6 signalling IL6 signalling unchanged RA disease Activity lower RA disease activity higher Biomarker Tocilizumab IL6R SNP IL-6  (n=1,446)  (n=29,838) CRP  (n=3,010)  (n=76,527) Fibrinogen  (n=409)  (n=52,667) Soluble IL-6R  (n=1,465)  (n=1,454) Albumin  (n=108)  (n=5,787) Haemoglobin  (n=2,072)  (n=17,898)

Harmful effects of first-in-man drugs: On- vs Off-target effects CETP genetic variant recapitulates the effects of pharmacological CETP inhibition on blood lipids, but does not share the BP raising effect of torcetrapib TRG HDL No change in lipids Sample Torcetrapib Control CETP-inhibition No-CETP inhibition LDL Change in lipid traits BP (Off-target) Drug Randomisation CETP genotypes Individuals (studies) Systolic BP Mean Difference (95% CI) B1B2 v B1B1 46,412 (21) -0.27 (-0.64, 0.10) B2B2 v B1B1 29,050 (21) 0.16 (-0.28, 0.60) -2 mmHg 28

CV Risk Management: What is Needed? Opportunities from novel therapies to reduce residual CV risk Optimal approach will involve lifetime management of RFs Better strategies to refine priorotization of new drug targets needed