New Approaches to Lower LDL-C

CSIM 27 October 2016

Jacques Genest MD

Cardiovascular Health Across the Lifespan Program McGill University Health Center Disclosure J. Genest MD 2016

Advisory Board, Speaker’s Bureau, Consultant, Grants, Clinical Trials

. Merck * . Sanofi/Regeneron * . . Lilly . Novartis . Valeant . AMGEN * . Aegerion . Cerenis . RengenXBio

CADTH, CDR Stock ownership: none; INESSS Off label use: none EAS, IAS * Scientific Advisory

Relevant disclosure: IMPROVE-IT, CANTOS , CAPREE steering Committees; REVEAL , ACCELERATE, AMG145 , Sanofi, TANGO, Lilly Clinical Trials. Cell 2015:161; 161-172 Diagnosis, Prevention and Management of 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: http://dx.doi.org/10.1016/j.cjca.2016.01.003 Clinical Experience vs Randomized Clinical Trials: The Elephant in the Room regarding Goal-Inhibiting Statin Intolerance (GISI)

Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003 GAUSS-3 Statin Intolerance Comparison of Guidelines CCS 2016 EAS/ESC 2016 AHA/ACC

LDL-C Targets/Treatment Recommendations

Secondary < 2 mmol/L or < 1.8 mmol/L or High-intensity statin. prevention > 50% reduction ≥ 50% reduction (anticipate > 50% reduction) If 50% cannot be achieved, consider additional therapy. Statin Same Same Same intolerance

Primary > 50% reduction < 2.5 mmol/L High-intensity statin therapy prevention (anticipate 50% reduction) LDL > 5 mmol/L Primary < 2 mmol/L or High risk DM: ≤ 1.8 High risk DM: prevention in > 50% reduction mmol/L, or at least 50% High-intensity statin diabetes reduction Low risk DM: Low risk DM: < 2.5 mmol/L Moderate-intensity statin Primary For FRS >10%: SCORE ≥ 5% risk of fatal For PCRAE >7.5%: prevention < 2 mmol/L or CVD: Moderate- to high-intensity High risk > 50% decrease <2.5 mmol/L statin Medications for Hypercholesterolemia

Statins PCSK9 mAb CETP inh MTP inh BAR ApoB iRNA PCSK9

LDL-R A: LDL-R pathway in absence of PCSK9

LDL

apoB Lysosome Endosome Degradation

B: Intracellular PCSK9 route

PCSK9 C: Mature Extracellular PCSK9 pre-PCSK9 PCSK9 route ER TGN PCSK9 as a Target

Cohen JC, et al. NEJM 2006;354:1264 LDLR Antibody technology has evolved over past decades

Red = mouse e.g. Blue = human e.g. Bococizumab

Highly Immunogenic e.g. and

Chimeric, Still very immunogenic

Immunogenicity Can be time-consuming to create

repeated dosing possible

Fully Mouse Chimeric Humanized “Fully” Human 1st generation 2nd generation 3rd generation 4th generation

12 Nomenclature: Prefix (Pharma) C (Cardiovascular) UMAB

ODYSSEY Long-Term: Alirocumab Plus Statin Achieved a 62% Reduction in LDL-C over Placebo+Statin at 24 weeks

3.60

3.08 mmol/L 3.17 mmol/L 3.00 0.8% 3.6% ) /L 2.40 62% reduction, P<0.001 mmol (

C Absolute reduction: 1.2 mmol/L - 1.80

LDL 1.50 mmol/L 1.25 mmol/L -52.4% 1.20

Median Median -61.0%

0.60 Alirocumab + statin therapy at maximum tolerated dose ± other LLT (150 mg q2w) Placebo + statin therapy at maximum tolerated dose ± other LLT 0.00 0 4 8 12 16 24 36 52 64 78 No. of patients with data available Week Placebo 780 754 747 746 716 708 694 676 659 652 Alirocumab 1530 1473 1458 1436 1412 1386 1359 1349 1324 1269

Robinson J, et al. N Engl J Med. 2015;372(16):1489-99. ODYSSEY Long-Term: Reduction in the Rate of Cardiovascular Events- Post-hoc Analysis Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event* 0.06

Safety Analysis† 0.05 Cox model analysis HR 0.46 95% CI: 0.26 to 0.82 0.04 P<0.01 Alirocumab + max-tolerated statin ± other LLT (150 mg q2w) 0.03 Placebo + max-tolerated statin ± other LLT 54% RRR 0.02 Cumulative probability of event probability Cumulative 0.01

0.00 0 12 24 36 48 60 72 84 No. at Risk Weeks Placebo 788 776 731 703 682 667 321 127 Alirocumab 1550 1534 1446 1393 1352 1335 642 252

*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):1489-99. Ratio of LDL Lowering to CV Event Reduction with PCSK9 Inhibitors Holds True to the “LDL Hypothesis” 70%

60%

OSLER 50% ODYSSEY Long-Term 40%

30%

20% IMPROVE-IT 10% Proportional reduction in event rate (SE) rate event in reduction Proportional

0% 0.5 1.0 1.5 2.0 Reduction in LDL (mmol/L) -10%

Waters DD. Hsue PY. Circ Res. 2015;16:1643-1645. Bococizumab

Christie M. Ballantyne, et al.

Results of Bococizumab, A Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With The American Journal of Cardiology, Volume 115, Issue 9, 2015, 1212–1221 PCSK9 Outcome Trials Alirocumab Evolocumab Bococizumab

ODYSSEY Outcomes FOURIER SPIRE1 SPIRE2 Trial (secondary prevention) (secondary prevention) (secondary prevention) (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 Mar 2018 Q1Feb 2017? 2018 Aug 2017 Aug 2017 Primary • CHD death • CV death • CV death • CV death endpoint • non-fatal MI • MI • non-fatal MI • non-fatal MI • fatal and non-fatal • Stroke • non-fatal stroke • non fatal stroke ischemic stroke • hospitalization for • hospitalization for • hospitalization for • high risk UA UA UA needing urgent UA needing urgent requiring • coronary revascularization revascularization hospitalization 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 History of clinically High risk patients High risk subjects ACS evident CVD: MI, stroke • LDL-C ≥70 (1.8) and • LDL-C ≥100 (2.6) or • LDL-C ≥70 (1.8) or symptomatic PAD <100 (2.6) or and ≥1 major RF or ≥ 2 minor RFs • LDL-C ≥70 (1.8) or 73,700 patients Anti-drug antibodies (ADA): the challenge Immunogenicity: . The potential for an antigen to Anti-drug antibody induce an immune response Antibodyformation Fab (Neutralizing) . Immunogenicity against therapeutic proteins that are not in the normal human repertoire is a normal immune response. Anti-PSCK9 . Reaction to neo-antigens . Proteins are non-human . Fusion proteins create new epitopes Antibody Fc . Unusual glycosylation PCSK9 RNAi

Lancet 383;9911, 60–68 PCSK9 mAb Clinical Indications

Familial Hypercholesterolemia

ASCVD (Atherosclerotic ) not at goal despite maximally tolerated lipid-lowering therapy

Statin intolerant

CETPinh

• : off-target effects (?) increase MACE • : HDL elevation but no LDL-C lowering: no effect on MACE • : Decrease in LDL-C overestimated by Friedewald formula; effect size smaller. Concerns with prolonged terminal half-life • . Decrease in LDL-C overestimated by Friedewald formula; effect size smaller. Shorter terminal T1/2 but still prolonged • Orocetrapib (TA-8995) TULIP trial reported 2015 for Hypercholesterolemia

Statins PCSK9 mAb Ezetimibe CETP inh Fibrates Niacin MTP inh BAR ApoB iRNA Bempedoic Acid VLDL Assembly and secretion

Mipomersen

Lomatipibe

28 (Juxtapid®)

29 Lomatipide and Homozygous FH Bempedoic Acid Esperion ETC 1002

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

Extracorporeal LDL Filtration Liposorber HELP (Kaneka) (Braun) Courtoisie Dr Jean Bergeron Mean LDL-C (mmol/L) Extracorporeal LDL (HELP) Filtration Extracorporeal

1992 Apheresis

1993

Time (years) 1994

1995 +

1996 Genest J. NEJM 1999;341:490 NEJM J. Genest 1997

1998

1999 100 200 300 400 500

Mean LDL-C (mg/dL) 1989 1999

A B

C D