Connie Newman MD FACP FAMWA Adjunct Professor of Medicine New York University School of Medicine New York, NY AMWA 101 st Anniversary Meeting March 11-13, 2016

Disclosures and Conflicts of Interest None Connie Newman MD, AMWA 101st Meeting, March 2016

Myths about statins Do not work as well in women as in men Do not reduce cardiovascular disease or cardiovascular death in women Cause more side effects in women compared to men Should not be used in women for primary prevention of cardiovascular disease Elton Catherine Do Statins Work Equally for Men and Women? Times Magazine; 2010, March 29 Connie Newman MD, AMWA 101st Meeting, March 2016

Cholesterol Treatment Trialists (CTT) meta- analysis : clinical characteristics in 174,000 participants ParameterWomen N= 46,675 Men 127, 429 Mean age 65.1 yr61.8 yr Current smoker 16%20% Hypertension 60%47.5% Blood pressure 140/80138/81 History vascular disease 47 %65% Diabetes mellitus 24%18% *Cholesterol Treatment Trialists Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from participants in 27 randomized trials.Lancet 2015; 385: Connie Newman MD, AMWA 101st Meeting, March 2016

CTT 2015 meta-analysis Results Women were generally at lower CVD disease risk Statins had similar effects on 1 yr lipid levels in women & men Reduction in major vascular events per mmol/L (39 mg/dL) decrease in LDL-C was about 20%, and similar in women & men o including those at lower risk (< 10% predicted 5 yr CVD risk) Cholesterol Treatment Trialists Collaboration. Lancet 2015; 385: Connie Newman MD, AMWA 101st Meeting, March 2016 Major vascular events = Fatal or nonfatal MI or stroke and coronary revascularization

Risk reduction for major vascular events Similar in women and men Events % per year Statin or more intensive Control or less intensive Risk Reduction per 1 mmol/L reduction in LDL-C 1 mmol/L = 39 mg/dL Major vascular events: fatal or nonfatal MI or stroke, and coronary revascularization Cholesterol Treatment Trialists Collaboration. Lancet 2015; 385: Connie Newman MD, AMWA 101st Meeting, March 2016

Risk reduction for major vascular events Similar in women & men with/without vascular disease Events % per year Statin or more intensive Control or less intensive Risk Reduction per 1 mmol/L reduction in LDL-C 1 mmol/L = 39 mg/dL Cholesterol Treatment Trialists Collaboration. Lancet 2015; 385: Connie Newman MD, AMWA 101st Meeting, March 2016

CTT 2015 meta-analysis NNT number needed to treat For low 5yr risk (<10%), absolute numbers of vascular events avoided per 1,000 participants, per mmol/L reduction in LDL-C: o 9 in women o 12 in men Cholesterol Treatment Trialists Collaboration. Lancet 2015; 385: Connie Newman MD, AMWA 101st Meeting, March 2016

Monoclonal antibodies to proprotein convertase subtilisin kexin 9 Connie Newman MD, AMWA 101st Meeting, March 2016

PCSK9 Proprotein convertase subtilisin/kexin type 9 PCSK9, synthesized mainly in liver, enters the circulation, binds to LDL receptors and targets them for degradation Refs: Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. 2006, NEJM 354: ; Brown MS and Goldstein JL 2006 Science 311: ; Stein EA, Mellis S, Yancopoulos GD et al. 2012, NEJM 366: Connie Newman MD, AMWA 101st Meeting, March 2016

PCSK9 Increases degradation of LDL-C receptors Davidson M. Nature Rev Cardiol 2013; 10: ; Brautbar, A. & Ballantyne, C. M. (2011) Nat. Rev. Cardiol. doi: /nrcardio Connie Newman MD, AMWA 101st Meeting, March 2016

Mutations in PCSK9 gene Gain in function mutation causes hypercholesterolemia Loss of function mutations cause low LDL-C levels and are associated with reduced incidence of CHD o African Americans – Prevalence 2.5% associated with 40% ↓ LDL-C o Whites – Prevalence 3.2% associated with 21% ↓ LDL-C Refs: Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. 2006, NEJM 354: ; Brown MS and Goldstein JL 2006 Science 311: ; Stein EA, Mellis S, Yancopoulos GD et al. 2012, NEJM 366: Connie Newman MD, AMWA 101st Meeting, March 2016

Cohen JC. Et al. NEJM. 2006;354: NoYes PCSK9 142x or PCSK9 679X PCSK9 142x or PCSK9 679X Plasma LDL Cholesterol in Black Subjects (mg/dL) 300 No Mutation (N = 3278) 50 th Percentile F r e q uency (%) (N=85) Coronary He a rt D i sease (%) Mean 113 mg/dL Mean 100 mg/dL (-28%) 88% fewer CHD events, 15-year follow-up PCSK9 loss of function mutations in African Americans associated with low LDL-C & low prevalence of CHD events Connie Newman MD, AMWA 101st Meeting, March 2016

Development of inhibitors of PCSK9 Monoclonal antibodies to PCSK9 were the first medications developed Reduce LDL-C by % as monotherapy or in combination with a statin and/or other lipid lowering therapy (eg, ezetimibe)

Effect of PCSK9 monoclonal antibodies on LDL-C reduction Generic nameDose subcutaneous Mean % LDL-C reduction FDA Approval Alirocumab 150 mg Q 2 wk-58*July 2015 Evolocumab August 2015 CHD140 mg Q 2 wk-64† CHD420 mg Q mo-58† He FH140 mg Q 2 wk-62% He FH420 mg Q mo-56% Ho FH420 mg Q mo-22% * On maximally tolerated statin therapy; †on atorvastatin 80 mg, rosuvastatin 40 mg or simvastatin 40 mg PRALUENT ® (alirocumab) injection, US Prescribing information, Oct 2015; REPATHA™ (evolocumab) injection)US Prescribing Information Aug 2015; Ballanytne CM et al Am J Cardiol 2015; 115: Connie Newman MD, AMWA 101st Meeting, March 2016

From Jennifer Robinson MD

Sanofi Aventis, Regeneron Pharmaceuticals Inc. Praluent (alirocumab injection) PI.. July Amgen. Repatha (evolocumab) injection PI. August Alirocumab and Evolocumab Indications approved by FDA 2015 Alirocumab & Evolocumab Use as an adjunct to diet and maximally tolerated statin therapy in patients who require additional LDL-C lowering: o Adults with heterozygous familial hypercholesterolemia o Adults with clinical cardiovascular disease Evolocumab Patients with homozygous familial hypercholesterolemia on statins, ezetimibe, and/or LDL apheresis Connie Newman MD, AMWA 101st Meeting, March 2016

PCSK9 monoclonal antibodies Safety data during follow-up of years Serious hypersensitivity reactions are rare Injection site reactions in about 4-5% Myalgia in some but not all trials, 2% higher than placebo Neurocognitive events in about 1% of patients; about 0.6% greater than placebo o Amnesia, memory impairment, confusion, cognitive and attention disorders, disturbances in thinking and perception o Unclear if there is a causal relationship Robinson JG, et al. N Engl J Med 2015;372: ; Blom DJ, et al. N Engl J Med 2014; 370: ; Sabatine MS, et al. N Engl J Med 2015;372: Connie Newman MD, AMWA 101st Meeting, March 2016

Ongoing PCSK9 monoclonal antibody CVD outcomes trials PCSK9 mAbs added to lipid modifying therapy in high-risk individuals FOURIER Evolocumab: Very high risk CVD age yrs, LDL-C ≥70 mg/dL ODYSSEY OUTCOMES Alirocumab: Post-Acute coronary syndromes age ≥40 yrs Accessed July, Accessed July, Connie Newman MD, AMWA 101st Meeting, March 2016

PCSK9 Inhibitors cost nearly 100 times as much as generic atorvastatin 80 mg (2016) Annual Cost in Dollars Ezetimibe will be generic in 2017 From Accessed 26 Jan 2016 Connie Newman MD, AMWA 101st Meeting, March 2016 Annual Cost

Summary and conclusions Statins are as effective in reducing atherosclerotic CVD risk in women as in men who have the same level of ASCVD risk. Monoclonal antibodies to PCSK9, as monotherapy or added to statins, inhibit LDL-receptor degradation & ↓ LDL-C 55-60% Alirocumab & evolcumab are indicated in addition to diet & maximally tolerated statin therapy to reduce LDL-C in patients with ASCVD or heterozygous FH who require more LDL-C reduction Evolocumab is also approved for Ho FH (22% ↓LDL-C) Safety concerns thus far are injection site reactions & changes in neurocognitive function. The latter is being evaluated. Cardiovascular outcomes trials are ongoing. PCSK9, proprotein convertase subtilisin kexin 9; LDL-C, low density lipoprotein cholesterol; ASCVD atherosclerotic cardiovascular disease; He heterozygous; FH familial hypercholesterolemia; Ho homozygous Connie Newman MD, AMWA 101st Meeting March, 2016

Summary and conclusions-2 Pharmacy utilization management programs are deciding the criteria that determine which patients should be dispensed PCSK9 inhibitors The high cost of PCSK9 antibody therapy may be prohibitive for some patients PCSK9, proprotein convertase subtilisin kexin 9 Connie Newman MD, AMWA 101st Meeting March, 2016

Acknowledgements My Colleagues in the Cholesterol Treatment Trialists Collaboration J Je Connie Newman MD, AMWA 101st Meeting March, 2016 Fulcher JFulcher J, O'Connell R, Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J, Pedersen TR, Tonkin A, Davis B, Sleight P, Franzosi MG, Baigent C, Keech A, de Lemos J, Braunwald E, Blazing M, Murphy S, Downs JR, Gotto A, Clearfield M, Holdaas H, Gordon D, Davis B, Koren M, Dahlöf B, Poulter N, Sever P, Knopp RH, Fellström B, Holdaas H, Jardine A, Schmieder R, Zannad F,Goldbourt U, Kaplinsky E, Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Fuller J, Neil A, Wanner C, Krane V, Sacks F, Moyé L, Pfeffer M,Hawkins CM, Braunwald E, Kjekshus J, Wedel H, Wikstrand J, Barter P, Keech A, Tavazzi HF, Maggioni A, Tognoni RM, Franzosi MG, Maggioni A,Bloomfield H, Robins S, Collins R, Armitage J, Keech A, Parish S, Peto R, Sleight P, Pedersen TR, Ridker PM, Holman R, Meade T, Simes J, Keech A, MacMahon S, Marschner I, Tonkin A, Shaw J, Serruys PW, Nakamura H, Knatterud G, Furberg C, Byington R, Macfarlane P, Cobbe S, Ford I,Murphy M, Blauw GJ, Packard C, Shepherd J, Kjekshus J, Pedersen T, Wilhelmsen L, Braunwald E, Cannon C, Murphy S, Collins R, Armitage J,Bowman L, Parish S, Peto R, Sleight P, Baigent C, Landray M, Collins R, La Rosa J, Rossouw J, Probstfield J, Shepherd J, Cobbe S, Macfarlane P,Ford I, Flather M, Kastelein J, Newman C, Shear C, Tobert J, Varigos J, White H, Yusuf S, Barnes EH, Keech AC, Kirby A, Marschner IC, Simes J,Baigent C, Blackwell L, Collins R, Emberson J, Herrington WG, Holland LE, Mihaylova B, Reith CO'Connell RVoysey MEmberson JBlackwell LMihaylova BSimes JCollins RKirby AColhoun HBraunwald ELa Rosa JPedersen TRTonkin ADavis BSleight PFranzosi MGBaigent CKeech Ade Lemos JBraunwald EBlazing MMurphy SDowns JRGotto AClearfield MHoldaas HGordon DDavis BKoren MDahlöf BPoulter NSever PKnopp RHFellström BHoldaas HJardine ASchmieder RZannad FGoldbourt UKaplinsky EColhoun HMBetteridge DJDurrington PNHitman GAFuller JNeil AWanner CKrane VSacks FMoyé LPfeffer MHawkins CMBraunwald EKjekshus JWedel HWikstrand JBarter PKeech ATavazzi HFMaggioni ATognoni RMFranzosi MGMaggioni ABloomfield HRobins SCollins RArmitage JKeech AParish SPeto RSleight PPedersen TRRidker PMHolman RMeade TSimes JKeech AMacMahon SMarschner ITonkin AShaw JSerruys PWNakamura HKnatterud GFurberg CByington RMacfarlane PCobbe SFord IMurphy MBlauw GJPackard CShepherd JKjekshus JPedersen TWilhelmsen LBraunwald ECannon CMurphy SCollins RArmitage JBowman LParish SPeto RSleight PBaigent CLandray MCollins RLa Rosa JRossouw JProbstfield JShepherd JCobbe SMacfarlane PFord IFlather MKastelein JNewman CShear CTobert JVarigos JWhite HYusuf SBarnes EHKeech ACKirby AMarschner ICSimes JBaigent CBlackwell LCollins REmberson JHerrington WGHolland LEMihaylova BReith C Jennifer Robinson MD Jonathan Tobert MD PhD

Thank you Connie Newman MD, AMWA 101st Meeting March, 2016

Additional slides

Safety of PCSK9 mAbs ODYSSEY LONG TERM Alirocumab 150 mg Q2W vs placebo, 80 weeks DESCARTES Evolocumab 420 mg Q4W vs placebo, 52 weeks OSLER I & II Evolocumab 420 mg Q4W or 140 mg Q2W, patient preference vs standard care, 11 months Adverse events Injection site reactions 5.9% vs. 4.2%; P=0.10 Mylagia 5.4% vs 2.9%; P=0.006 Neurocognitive AEs 1.2% vs 0.5%; P=0.17 Opthalmologic AEs 1.9% 2.9% vs 1.9% ; P=0.65 Injection site reaction 5.7% vs 5.0% Mylagia 4.0% vs 3.0% URIs 9.3% vs 6.3% ALT > 3X ULN 0.8% vs 1.0% Injection site reactions 4.3% vs NA Muscle AEs 6.4% vs 6.0% Neurocognitive AEs 0.9% vs 0.3% AEs=adverse events; ALT=alanine aminotransferase; CVD=cardiovascular disease; HR=hazard ratio; Q2W=every 2 weeks; Q4W=every 4 weeks; SC=standard care; ULN=upper limit of normal; URIs=upper respiratory infections. Robinson JG, et al. N Engl J Med 2015;372: ; Blom DJ, et al. N Engl J Med 2014; 370: ; Sabatine MS, et al. N Engl J Med 2015;372: Connie Newman MD, AMWA 101st Meeting, March 2016 From Jennifer Robinson MD

Effect of PCSK9 monoclonal antibodies on LDL-C reduction Generic nameDose subcutaneous Mean % LDL-C reduction FDA Approval Alirocumab 150 mg sc Q 2 wk-58*July 2015 Evolocumab August 2015 CHD140 mg Q 2 wk-64† CHD420 mg Q mo-58† He FH140 mg sc Q 2 wk-62% He FH420 mg Q mo-56% Ho FH420 mg Q mo-22% Bococizumab (phase 2 B) 100 mg Q 12 wk / 150 mg Q 12 wk -45%* / -52%*No / Phase 3 * On maximally tolerated statin therapy; †on atorvastatin 80 mg, rosuvastatin 40 mg or simvastatin 40 mg PRALUENT ® (alirocumab) injection, US Prescribing information, Oct 2015; REPATHA™ (evolocumab) injection)US Prescribing Information Aug 2015; Ballanytne CM et al Am J Cardiol 2015; 115: Connie Newman MD, AMWA 101st Meeting, March 2016

Ongoing PCSK9 monoclonal antibody CVD outcomes trials PCSK9 mAbs added to lipid modifying therapy in high- risk individuals FOURIER Evolocumab: Very high risk CVD age yrs, LDL-C ≥70 mg/dL ODYSSEY OUTCOMES Alirocumab: Post-Acute coronary syndromes age ≥40 yrs SPIRE-1 Bococizumab: Very high risk, age≥18 yrs, LDL-C ≥70 mg/dL and <100 mg/dL SPIRE-2 Bococizumab: High risk age≥18 yrs (N=6,300) LDL C ≥100 mg/dL or non HDL C ≥130 mg/dL Accessed July, Accessed July, Accessed July, Accessed July,

2015 CTT meta-analysis comparing women & men Study design Individual patient data from 27 randomized controlled cardiovascular disease (CVD) outcome trials: o Statin vs placebo 22 trials; n= 135,000; 39,000 women o More vs less intensive statin therapy 5 trials; n=40,000; 7,600 women Comparison of major vascular events (MVE) o Fatal or nonfatal MI or stroke o Coronary revascularization procedures Cholesterol Treatment Trialists (CTT) Collaboration. Lancet 2015; 385: Connie Newman MD, AMWA 101st Meeting, March 2016