New Approaches to Lower LDL-C

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1 New Approaches to Lower LDL-C CSIM 27 October 2016 Jacques Genest MD Cardiovascular Health Across the Lifespan Program McGill University Health Center

2 Disclosure J. Genest MD 2016 Advisory Board, Speaker s Bureau, Consultant, Grants, Clinical Trials Merck * Pfizer Novartis AMGEN * Cerenis Sanofi/Regeneron * Lilly Valeant Aegerion RengenXBio CADTH, CDR INESSS EAS, IAS Stock ownership: none; Off label use: none * Scientific Advisory Relevant disclosure: IMPROVE-IT, CANTOS, CAPREE steering Committees; REVEAL, ACCELERATE, AMG145, Sanofi, TANGO, Lilly Clinical Trials.

3 Cell 2015:161;

4 Diagnosis, Prevention and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016) G.B. John Mancini, MD, Steven Baker, MD, Jean Bergeron, MD, David Fitchett, MD, Jiri Frohlich, MD, Jacques Genest, MD, Milan Gupta, MD, Robert A. Hegele, MD, Dominic Ng, MD, Glen J. Pearson, PharmD, Janet Pope, MD, A. Yashar Tashakkor, MD Mancini et al, DOI:

5 Clinical Experience vs Randomized Clinical Trials: The Elephant in the Room regarding Goal-Inhibiting Statin Intolerance (GISI) Mancini et al, DOI:

6 GAUSS-3 Statin Intolerance

7 Comparison of Guidelines CCS 2016 EAS/ESC 2016 AHA/ACC LDL-C Targets/Treatment Recommendations Secondary prevention Statin intolerance < 2 mmol/l or > 50% reduction < 1.8 mmol/l or 50% reduction High-intensity statin. (anticipate > 50% reduction) If 50% cannot be achieved, consider additional therapy. Same Same Same Primary prevention LDL > 5 mmol/l Primary prevention in diabetes Primary prevention High risk > 50% reduction < 2.5 mmol/l High-intensity statin therapy (anticipate 50% reduction) < 2 mmol/l or > 50% reduction For FRS >10%: < 2 mmol/l or > 50% decrease High risk DM: 1.8 mmol/l, or at least 50% reduction Low risk DM: < 2.5 mmol/l SCORE 5% risk of fatal CVD: <2.5 mmol/l High risk DM: High-intensity statin Low risk DM: Moderate-intensity statin For PCRAE >7.5%: Moderate- to high-intensity statin

8 Medications for Hypercholesterolemia Statins Ezetimibe Fibrates Niacin BAR PCSK9 mab CETP inh MTP inh ApoB irna Bempedoic Acid

9 PCSK9 LDL-R A: LDL-R pathway in absence of PCSK9 LDL Degradation Lysosome Endosome apob B: Intracellular PCSK9 route PCSK9 pre-pcsk9 C: Extracellular PCSK9 route Mature PCSK9 ER TGN

10 PCSK9 as a Target Cohen JC, et al. NEJM 2006;354:1264

11 LDLR

12 Antibody technology has evolved over past decades Immunogenicity Highly Immunogenic e.g. Abciximab Chimeric, Still very immunogenic e.g. Bococizumab Can be time-consuming to create Red = mouse Blue = human e.g. Evolocumab and Alirocumab repeated dosing possible Fully Mouse 1 st generation Chimeric 2 nd generation Humanized 3 rd generation Fully Human 4 th generation Nomenclature: Prefix (Pharma) C (Cardiovascular) UMAB 12

13

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17 ODYSSEY Long-Term: Alirocumab Plus Statin Achieved a 62% Reduction in LDL-C over Placebo+Statin at 24 weeks mmol/l 3.17 mmol/l 0.8% 3.6% Median LDL-C (mmol/l) % reduction, P<0.001 Absolute reduction: 1.2 mmol/l 1.25 mmol/l -61.0% 1.50 mmol/l -52.4% 0.60 Alirocumab + statin therapy at maximum tolerated dose ± other LLT (150 mg q2w) Placebo + statin therapy at maximum tolerated dose ± other LLT No. of patients with data available Week Placebo Alirocumab Robinson J, et al. N Engl J Med. 2015;372(16):

18 ODYSSEY Long-Term: Reduction in the Rate of Cardiovascular Events- Post-hoc Analysis Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event 0.06 Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event* Cumulative probability of event Safety Analysis Cox model analysis HR % CI: 0.26 to 0.82 P<0.01 Alirocumab + max-tolerated statin ± other LLT (150 mg q2w) Placebo + max-tolerated statin ± other LLT 54% RRR 0.00 No. at Risk Placebo Alirocumab Weeks *Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalization. LLT, lipid-lowering therapy 52 weeks for all patients continuing treatment, incl. 607 patients who completed W78 visit Robinson J, et al. N Engl J Med. 2015;372(16):

19 Ratio of LDL Lowering to CV Event Reduction with PCSK9 Inhibitors Holds True to the LDL Hypothesis 70% 60% Proportional reduction in event rate (SE) 50% 40% 30% 20% 10% IMPROVE-IT ODYSSEY Long-Term OSLER 0% -10% Reduction in LDL cholesterol (mmol/l) Waters DD. Hsue PY. Circ Res. 2015;16:

20 Bococizumab Christie M. Ballantyne, et al. Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With Hypercholesterolemia The American Journal of Cardiology, Volume 115, Issue 9, 2015,

21 PCSK9 Outcome Trials Alirocumab Evolocumab Bococizumab Trial ODYSSEY Outcomes (secondary prevention) FOURIER (secondary prevention) SPIRE1 (secondary prevention) SPIRE2 (primary prevention) No of patients 18,600 27,500 17,000 10,600 Dosage s/c, Q2W s/c, Q2W or Q4W s/c, Q2W s/c, Q2W Start date Oct 2012 Jan 2013 Oct 2013 Oct 2013 Expected End date Q1 2017? Primary endpoint Mar 2018 Feb 2018 Aug 2017 Aug 2017 CHD death non-fatal MI fatal and non-fatal ischemic stroke high risk UA requiring hospitalization CV death MI Stroke hospitalization for UA coronary revascularization CV death non-fatal MI non-fatal stroke hospitalization for UA needing urgent revascularization CV death non-fatal MI non fatal stroke hospitalization for UA needing urgent revascularization Duration Up to Month 64 Up to 5 years Up to Month 60 Up to Month 60 Population Patients 4 to 52 wks post High risk patients ACS LDL-C 70 (1.8) and LDL-C 70 (1.8) <100 (2.6) or History of clinically evident CVD: MI, stroke or symptomatic PAD and 1 major RF or 2 minor RFs LDL-C 70 (1.8) or High risk subjects LDL-C 100 (2.6) or 73,700 patients

22 Anti-drug antibodies (ADA): the challenge Immunogenicity: The potential for an antigen to induce an immune response Immunogenicity against therapeutic proteins that are not in the normal human repertoire is a normal immune response. Reaction to neo-antigens Proteins are non-human Fusion proteins create new epitopes Unusual glycosylation Anti-drug antibody formation Antibody Fab (Neutralizing) Anti-PSCK9 Antibody Fc

23 PCSK9 RNAi Lancet 383;9911, 60 68

24 PCSK9 mab Clinical Indications Familial Hypercholesterolemia ASCVD (Atherosclerotic Cardiovascular Disease) not at goal despite maximally tolerated lipid-lowering therapy Statin intolerant

25

26 CETPinh Torcetrapib: off-target effects (?) increase MACE Dalcetrapib: HDL elevation but no LDL-C lowering: no effect on MACE Anacetrapib: Decrease in LDL-C overestimated by Friedewald formula; effect size smaller. Concerns with prolonged terminal half-life Evacetrapib. Decrease in LDL-C overestimated by Friedewald formula; effect size smaller. Shorter terminal T 1/2 but still prolonged Orocetrapib (TA-8995) TULIP trial reported 2015

27 Medications for Hypercholesterolemia Statins Ezetimibe Fibrates Niacin BAR PCSK9 mab CETP inh MTP inh ApoB irna Bempedoic Acid

28 VLDL Assembly and secretion Mipomersen Lomatipibe 28

29 (Juxtapid ) 29

30 Lomatipide and Homozygous FH

31 Bempedoic Acid Esperion ETC 1002 Bempedoic acid inhibits ATP-citrate lyase (ACL)

32 Bempedoic Acid Esperion ETC 1002

33 In Conclusion PCSK9 inhibitors hold great promise for the treatment of severe LDL-C elevation Clinical trials are underway to determine if PCSK9inh reduce ASCVD CETPinh (Anacetrapib) is tested in the REVEAL trial and results are expected in 2017

34

35 Extracorporeal LDL Filtration

36 Liposorber (Kaneka) HELP (Braun)

37 Courtoisie Dr Jean Bergeron

38 Extracorporeal LDL Filtration (HELP) Mean LDL-C (mmol/l) Apheresis + Atorvastatin Mean LDL-C (mg/dl) Time (years) Genest J. NEJM 1999;341:490

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