Making War on Cholesterol with New Weapons: How Low Can We/Should We Go? Shaun Goodman

Making War on Cholesterol with New Weapons: How Low Can We/Should We Go? Shaun Goodman

Disclosures Research grant support, speaker/consulting honoraria: Sanofi and Regeneron Including ODYSSEY Outcomes trial Executive Steering Committee member and Canadian National Coordinator; Co-Director of the Canadian VIGOUR Centre (CVC; Canadian ARO) Amgen Lilly Including Guidelines Oriented Approach to Lipid lowering (GOAL) in Canada Steering Committee member; Consultant to the Canadian Heart Research Centre (CHRC; Canadian ARO) ACCELERATE and LY3015014 trials Steering Committee member AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer Additional relationships (research grant support, speaker/consulting honoraria) with commercial interests but not relevant to this presentation http://www.vigour.ualberta.ca/about/relationshipswithindustry.aspx

Proportional Reduction in Incidence of Major Coronary and Vascular Events and Mean Absolute LDL Reduction at 1 Year 50% 40% 30% Major Coronary Events n=90,056 23% proportional reduction per mmol/l LDL cholesterol reduction 50% 40% 30% Major Vascular Events 14 randomized trials 21% proportional reduction per mmol/l LDL cholesterol reduction 20% 20% 10% 10% 12% proportional reduction in 0% All-cause Mortality 0% per mmol/l LDL cholesterol reduction -10% -10% 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0 Reduction in LDL cholesterol (mmol/l) Reduction in LDL cholesterol (mmol/l) The greater the reduction in LDL, the greater the reduction in risk of major Cholesterol Treatment coronary Trialists and (CTT) vascular Collaborators events Lancet 2005;366:1267-78

Risk Assessment, Stratification & Treatment Consideration Anderson et al Can J Cardiol 2016;doi:10.1016/j.cjca.2016.07.510

LDL-Cholesterol Treatment Targets: Not Always So Easy to Hit

Risk Assessment, Stratification & Treatment Consideration Anderson et al Can J Cardiol 2016;doi:10.1016/j.cjca.2016.07.510

Persistent LDL-C Above Guideline-Recommended Target Despite Maximally Tolerated High Intensity Statin: Which Add-On Therapy Do You Choose? Lipid-Modifying Class Principal effects Other considerations Bile Acid Sequestrants LDL-C 15-20 % Fibrates Niacin LDL-C 5-20 % Lowers TG Variable effect on HDL-C LDL-C 20 % TG 40 % HDL-C 30 %? CV outcome GI intolerability, benefit may when elevate added TG to statin Colesevelam better tolerated than 1st generation BAS, has A1C lowering effect More effective at raising HDL-C when baseline TG is high No CV outcome benefit when added to statin Flushing/pruritus may limit tolerance, can cause dose-related deterioration of glycemic control No CV outcome benefit when added to statin Ezetimibe LDL-C 15-20 % Well tolerated CV outcome benefit in addition to simvastatin Adapted from Anderson et al Can J Cardiol 2013;29:151-67 and Mancini et al Can J Diabet 2013;37: S110-6

Primary Endpoint: CV Death, MI, UA Requiring Rehospitalization, Coronary Revascularization, or Stroke Pts 50 yrs hospitalized for ACS<10 days with 1 high risk feature and LDL-C >1.3 mmol/l Baseline mean 2.4 mmol/l Simvastatin 1.8 mmol/l Simva+Ezetimibe 1.4 mmol/l CV Death/Stroke/MI: 22% vs. 20%, p=0.003 Simvastatin 35% 33% Ezetimibe/ Simvastatin HR 0.94 (0.89, 0.99), p=0.016 NNT= 50 Cannon et al N Engl J Med 2015;372:2387-97

Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors The Canadian Medical Post March 26, 2013

Impact of a PCSK9 Monoclonal Antibody on LDL Receptor Expression

Statins and Other Lipid-Lowering Therapies: Impact on PCSK9 Major classes of commonly prescribed lipid-lowering medications appear to increase serum PCSK9 levels Statins cause a modest (10%-50%) upregulation of PCSK9 May explain the less than expected incremental LDL- C lowering from increasing doses of statin; i.e., ~ 6% additional LDL-C reduction with each doubling of statin dose Konrad et al Lipids Health Dis 2011;10:38

PCSK9 Inhibitors: Phase III Programs Dadu & Ballantyne et al Nat Rev Cardiol 2014;11;563-75

PCSK9 Inhibition: Dramatic and Persistent Lowering of LDL-Cholesterol Baseline LDL-C 3.10 mmol/l ~61-62% Relative, 1.8-1.9 Absolute mmol/l Reduction in LDL-C Robinson et al N Engl J Med 2015;372:1489-99 Sabatine et al N Engl J Med 2015;372:1500-9

Promising Impact on Cardiovascular Outcomes Post hoc analysis: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalization HR 0.52 (0.31-0.90) p 0.01 n=788 n=1550 Prospective exploratory analysis: CV Death, MI, Unstable angina requiring hospitalization, Coronary revascularization, Stroke/TIA, Heart failure requiring hospitalization HR 0.47 (0.28-0.78) p=0.003 n=1489 n=2976 Weeks Days Robinson et al N Engl J Med 2015;372:1489-99 Sabatine et al N Engl J Med 2015;372:1500-9

<100 mg/dl (2.6 mmol/l) <70 mg/dl (1.8 mmol/l) LDL-C Goal at 12 weeks Sabatine et al N Engl J Med 2015;372:1500-9

Alirocumab Safety Summary Pooled Alirocumab Phase 2/3 Placebo-control studies % of patients Alirocumab (N=2476) Placebo (N=1276) Treatment Emergent (TE) AEs (%) 76 76 TEAEs leading to discontinuation (%) 5 5 Any skeletal-muscle related TEAE (%) 15 15 Skeletal-muscle related TEAE leading to discontinuation (%) 0.4 0.5 Potential general allergic events 9 8 Neurocognitive events 0.8 0.7 TE diabetes and worsening of preexisting diabetes (%) 4 4 Local injection site reaction (%) 7 HR 1.48 (1.12-1.97) 5 Local injection site reaction leading to discontinuation (%) 0.2 0.4 TEAE period = time from first to last injection of study treatment + 70 days Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue n=3,752; 9 trials, median 62 (8-78) weeks duration; >4,000 patient-yrs Adapted from Jones et al J Am Coll Cardiol 2015;65:A372

PCSK9 Inhibitors vs. No PCSK9 Inhibitors 24 RCTs (n=10,159) Mean LDL-C reduction 47% (25%-70%) Event n All-cause Mortality 40 Cardiovascular Mortality Myocardial Infarction Unstable Angina Creatine Kinase Increase Serious Adverse Event 25 38 2 213 880 Events Odds Ratio & 95% CI 0.50 (0.23-1.10) p=0.084 0.45 (0.23-0.86) p=0.015 0.49 (0.26-0.93) p=0.03 0.61 (0.06-6.14) p=0.68 0.72 (0.54-0.96) p=0.026 1.01 (0.87-1.18) p=0.88 PCSK9i 1 (%) No PCSK9i 2 (%) 0.31 0.53 0.19 0.33 0.58 3 1.0 3 0.04 4 0.07 4 2.0 2.3 9.3 7.7 Tests for heterogeneity, p=ns 0.01 0.1 1 10 100 PCSK9 Inhibitor Better No PCSK9 Inhibitor Better 1 PCSK9i (n=6187) and 2 No PCSK9i (n=3972); except 3 (n=3289/1906) and 4 (n=2515/1379) Navarese et al Ann Intern Med 2015;163:40-51

PCSK9 Inhibitor CV Outcomes Trials PCSK9i Sponsor Trial Evolocumab Amgen FOURIER 1 Alirocumab Sanofi/Regeneron ODYSSEY Outcomes 2 Bococizumab Pfizer SPIRE-1/-2 3 n= Patients Statin (mg) LDL (mmol/l) Primary Endpoint Recruitment Completion 27,564 40-85 yrs+mi, isch stroke, or PAD+CV risk factor(s) atorva 20 or equiv 1.8 (or non-hdl 2.6) CV death, MI, stroke, hosp for UA, revasc June 2015 2016 18,000 4-52 wks post-acs atorva 40-80 or rosuva 20-40 1.8 (or non-hdl 2.6 or ApoB 0.8 g/l) CHD death, MI, isch stroke, hosp for UA Nov 2015 2017 17,000/11,000 High risk 1º/2º prevention atorva 40-80, rosuva 20-40, simva 40-80 or partial/comp statin intol 1.8/2.6 (or non- HDL 2.6/3.4) CV death, MI, stroke, hosp for UA + revasc ongoing/mar 2016 2018/2017 1 Sabatine et al Am Heart J 2016;173:94-101; 2 Schwartz et al Am Heart J 2014;168:682-689.e1; 3 Ridker et al Am Heart J 2016;178:135-144

Evolocumab (Repatha ) and Alirocumab (Praluent ) Primary Hyperlipidemia REPATHA and PRALUENT are indicated as an adjunct to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C). The effects of REPATHA and PRALUENT on cardiovascular morbidity and mortality have not been determined.

Who Might Receive Additional Lipid-Modifying Therapy? Patient Population FH and CAD FH not at goal Estimated number of Canadians ~10,000 ~10,000 CAD not at goal ~250,000 High risk not at goal >250,000?1,500,000 Adapted from Jacques Genest

Risk Assessment, Stratification & Treatment Consideration Anderson et al Can J Cardiol 2016;doi:10.1016/j.cjca.2016.07.510