Are the PCSK9 Inhibitors the Panacea of Atherosclerosis Treatment? Slim Jim Revise 5/9/2018 Are the PCSK9 Inhibitors the Panacea of Atherosclerosis Treatment? Effects on Lipid Lowering and Beyond Evan A Stein MD PhD Director Emeritus, Metabolic & Atherosclerosis Research Center Disclosures Have received consulting fees related to development of PCSK9 inhibitors from Amgen, Regeneron/Sanofi, Genentech/Roche and BMS and other LDL drugs from AstraZeneca, Catabasis, CymaBay and Gemphire. Lipid Advisory Panel for CVS/Caremark 1

Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice What we know Extensive clinical trials with two mAbs, evolocumab and alirocumab, resulted in FDA marketing approval in late summer of 2015 for use as follows; along with diet and maximally tolerated statin therapy in adults with heterozygous FH or ASCVD, who need additional lowering of LDL cholesterol Both drugs have shown maximal and stable 60% reductions in LDL-C once all PCSK9 is bound (140 to 150 mg Q2W or 420 mg Q4W) and less reduction and more variability with incomplete suppression at lower doses Same reduction when added to diet alone, low and maximal dose statin or statin plus ezetimibe; in patients with HeFH and nonFH; pts adverse to statins Homozygous FH patients respond about half as well to evolocumab, with mean reductions in LDL-C of 31% to high doses, 420 mg Q4W In addition to LDL-C reductions there is robust 25-30% decrease in Lp(a) Preliminary and exploratory analysis of CVD events are encouraging

Heterozyg Fam Hyperchol OSLER Program Mono- therapy Hyperchol on a statin Statin- Intol Heterozyg Fam Hyperchol Other Phase 2 trials MENDEL-1 (n=406) LAPLACE-TIMI 57 (n=629) GAUSS-1 (n=157) RUTHERFORD-1 (n=167) YUKAWA-1 (n=310) 4465 patients (74%) elected to enroll into OSLER extension study program 1324 from Ph2 trials into OSLER-1 3141 from Ph3 trials into OSLER-2 Eligible if medically stable and on study drug Phase 3 trials MENDEL-2 (n=614) LAPLACE-2 (n=1896) GAUSS-2 (n=307) RUTHERFORD-2 (n=320) DESCARTES (n=901) THOMAS-1 (n=149) THOMAS-2 (n=165) Evolocumab plus standard of care (n=2976) Standard of care alone (n=1489) Randomized 2:1 Irrespective of treatment assignment in parent study Median follow-up of 11.1 months (IQR 11.0-12.8) 7% discontinued evolocumab early 96% completed follow-up

Evolocumab OSLER Trial: Cumulative Incidence of Cardiovascular Events¶ 1 2 30 60 90 120 150 180 210 240 270 300 330 365 HR 0.47 95% CI 0.28-0.78 P=0.003 Composite Endpoint: Death, MI, UA  hosp, coronary revasc, stroke, TIA, or CHF  hosp 3 Days since Randomization Cumulative Incidence (%) Evolocumab plus standard of care (N=2976) Standard of care alone (N=1489) 0.95%* 2.18%** *29/2976 **31/1489 Figure 2 Cumulative Incidence of Cardiovascular Events. Included among the cardiovascular events were death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and hospitalization for heart failure. Cardiovascular events were reported in 29 of 2976 patients in the evolocumab group (Kaplan–Meier 1-year event rate, 0.95%) and in 31 of 1489 patients in the standard-therapy group (Kaplan–Meier 1-year event rate, 2.18%). The inset shows the same data on an expanded y axis. The P value was calculated with the use of a log-rank test. ¶CVD clinical outcomes (prespecified, exploratory): adjudicated by TIMI Study Group CEC, blinded to treatment Included death, myocardial infarction, unstable angina requiring hospitalization, revascularization, stroke or transient ischemic attack and Heart failure requiring hospitalization Sabatine MS et al. N Engl J Med 2015;372:1500-1509

ODYSSEY LONG TERM Study Design Follow-up (8 weeks) Double-blind treatment (18 months) Adults with HeFH or at high CV-risk On maximally tolerated statin  other LLT LDL-C ≥70 mg/dL (1.81 mmol/L) N=1553 Alirocumab 150 mg Q2W SC (single 1 mL injection using prefilled syringe for self-administration) R N=788 Placebo Q2W SC W4 W12 W24 W52 W64 W78 Assessments W0 W8 W16 W36 Primary efficacy endpoint [Adapted from Figure S1. Study Design – see online Supplementary Appendix – permission may be required depending on use of this slide set] This slide set describes ODYSSEY LONG TERM, a multinational, phase 3, randomized, double-blind, placebo-controlled, parallel-group study conducted in 320 centers located in 27 countries in Africa, Europe, Canada, USA and South America. Adult patients (aged ≥18 years) were eligible if they had heterozygous familial hypercholesterolemia (diagnosis by genotyping or clinical criteria) or established coronary heart disease or a coronary heart disease risk equivalent and LDL-C level ≥70 mg/dL (1.8 mmol/L) or more at the time of screening. In addition, all patients were required to be receiving a maximally tolerated dose of statin (that is either high-dose statin [40‒80 mg of atorvastatin, 20‒40 mg of rosuvastatin, or 80 mg of simvastatin daily] or a lower statin dose or less potent statin if high-dose statin was not tolerated), with or without other LLT, for ≥4 weeks before screening (6 weeks for fenofibrate). Following a screening period of 3 weeks, eligible patients were randomized (2:1 ratio) to receive either alirocumab 150 mg or placebo Q2W for 78 weeks (as well as their baseline statin therapy ±other LLT). Alirocumab and placebo injections were given subcutaneously in a 1 mL injection volume provided as a pre-filled syringe. A Therapeutic Lifestyle Changes diet (as per Adult Treatment Panel III of the National Cholesterol Education Program or equivalent) was to be maintained for the duration of the study. [[Source for slide: Robinson JG et al. N Eng J Med 2015. 372:1489-99: Supplementary Appendix Figure S1 (page 51) Source for slide notes: Main publication, page 2, column 1 ‘Study Design and Oversight’; column 2, highlighted text in ‘Study Population’ and ‘Study Procedures’ sections]] CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; Q2W, every 2 weeks; SC, subcutaneous; W, week. ClinicalTrials.gov identifier: NCT01507831. Robinson JG et al. NEJM 2015; 372:1489-99.

Cumulative Probability of Event Alirocumab: ODYSSEY Long-term Cumulative Incidence of Cardiovascular Events¶ Time (weeks) 0.06 0.02 0.04 52 78 86 0.03 0.05 0.01 Placebo Alirocumab* Cumulative Probability of Event 64 12 24 36 Cox model analysis HR = 0.52 (95% CI, 0.31-0.90) Nominal P-value = .02 *27/1550 **26/788 3.3%** 1.7%* Figure 2 Cumulative Incidence of Cardiovascular Events. Included among the cardiovascular events were death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and hospitalization for heart failure. Cardiovascular events were reported in 29 of 2976 patients in the evolocumab group (Kaplan–Meier 1-year event rate, 0.95%) and in 31 of 1489 patients in the standard-therapy group (Kaplan–Meier 1-year event rate, 2.18%). The inset shows the same data on an expanded y axis. The P value was calculated with the use of a log-rank test. ¶post-hoc analysis not specified in the study protocol - included cardiovascular event categories which comprise the endpoint in ODYSSEY Outcomes (Study to Evaluate the Effect of Alirocumab on the Occurrence of Cardiovascular Events in Patients Who Have Experienced an Acute Coronary Syndrome). Robinson JG et al. N Engl J Med 2015;372:1489-1499

RELATIONSHIP BETWEEN MACE AND ACHIEVED LDL-C IN PHASE 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL* HR 0.76, [95% CI: 0.63-0.91] per 39 mg/dL reduction; p=0.0025 Conclusion: a continuous relationship between 24% lower MACE risk and 39 mg/dL lower on-Rx LDL-C was observed without limit, even down to mean level of 25 mg/dL *ODYSSEY FH I, FH II, HIGH FH, LONG TERM, COMBO I, COMBO II, OPTIONS I, OPTIONS II, ALTERNATIVE and MONO studies: median time to events 36 wks 4974 patients treated with ALI, placebo or EZE experienced a total of 104 CVD events Ray et al https://doi.org/10.1161/CIRCULATIONAHA.116.024604 Originally published October 24, 2016

RELATIONSHIP BETWEEN MACE AND ACHIEVED LDL-C IN PHASE 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL* LDL-C % reduction was inversely correlated with CVD rates (HR 0.71 [0.57 to 0.89] per additional 50% LDL-C reduction; p=0.003 Conclusion: a continuous relationship between lower MACE risk and Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (HR 0.71 [0.57 to 0.89] per additional 50% reduction from baseline; P=0.003) *ODYSSEY FH I, FH II, HIGH FH, LONG TERM, COMBO I, COMBO II, OPTIONS I, OPTIONS II, ALTERNATIVE and MONO studies: median time to event 36 wks. 4974 patients treated with ALI, placebo or EZE experienced a total of 104 CVD events Ray et al https://doi.org/10.1161/CIRCULATIONAHA.116.024604 Originally published October 24, 2016

GLAGOV: Post Hoc Relationship Between Achieved LDL-C Level and Change in Percent Atheroma Volume Shaded area represents 95% confidence intervals Curve truncated at 20 and 110 mg/dL owing to the small number of values outside that range. Nicholls SJ et al JAMA Published online November 15, 2016 doi:10.1001/jama.2016.16951

GLAGOV: Cardiovascular Events* *adjudicated by clinical events committee blinded to treatment assignment a Total number of cardiovascular events included 2 events occurring during the period between the last scheduled visit and the end of safety assessment period. Nicholls SJ et al JAMA Published online November 15, 2016 doi:10.1001/jama.2016.16951

Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice What remains to be known Confirmation of CVD benefit – 2 large outcome trials in progress with first and largest to report out at ACC March 17, 2017 Long term safety of both drug and low/very low LDL-C

PCSK9 Inhibitor CVD Outcomes Trials Evolocumab Alirocumab Sponsor Amgen Sanofi / Regeneron Trial FOURIER ODYSSEY Outcomes Sample size 27,500 18,000 Patients MI, stroke or PAD 4-52 wks post-ACS Statin Atorva ≥20 mg or equiv Evid-based med Rx Dose mAb 420 mg QM or 140 mg Q2W 75 mg Q2W (titrate to 150mg) LDL-C mg/dL(mmol/L) ≥70 (≥1.8) Baseline LDL-C 91.5 mg/dL (2.37 mmol/L) ? PCSK9i Dosing Q2W or Q4W Q2W Endpoint 1: CV death, MI, stroke, revasc or hosp for UA, *Key 2: CV death, MI, or stroke CHD death, MI, ischemic stroke, or hosp for UA Recruitment Status Completed June 2015 Completed Nov 2015 Completion 2016 1/2018 *The trial is planned to continue until 1630 patients experience the secondary endpoint www.clinicaltrials.gov [accessed September 6, 2016]

FOURIER CVD Outcomes Trial: Meets Primary and Key Secondary Endpoint* Feb 2, 2017: http://www.amgen.com/media/news-releases/2017/02/amgen-announces-repatha-evolocumab-significantly-reduced-the-risk-of-cardiovascular-events-in-fourier-outcomes-study/ FOURIER CVD Outcomes Trial: Meets Primary and Key Secondary Endpoint* *planned to terminate when 1630 patients achieve the 2ndary endpoint

Evolocumab: Rapid Progress in Humans from proof-of-concept in humans to regulatory approval and confirmation of CVD reduction 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Phase 3 trials complete for 2 mAbs, BLA* filed and CVD outcome trials started First subjects treated with PCSK9 mAb in SAD studies 1st MAD phase 1b trials with PCSK9 mAb started including FH, nonFH, statin Rx 1st publications MAD POC in FH, nonFH on statin or diet Phase 2 trials published for alirocumab and evolocumab; phase 3 started Early data on CVD benefit Marketing approval USA/Europe FOURIER CVD outcome POSITIVE *BLA – Biologics licensing application Stein: PCSK9 Clinical Development Timeline 2017

Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice What remains to be known Confirmation of CVD benefit – 2 large outcome trials in progress with first and largest to report out at ACC March 17, 2017 Long term safety of both drug and low/very low LDL-C

Osler: Adverse Events by Achieved LDL-C Evolocumab subjects stratified by minimum achieved LDL-C All EvoMab (n=2976) SOC Alone (n=1489) <25 mg/dL (n=773) 25 to <40 mg/dL (n=759) <40 mg/dL (n=1532) ≥40 mg/dL (n=1426) Adverse Events (%) Any 70.0 68.1 69.1 70.1 69.2 64.8 Serious 7.6 6.9 7.2 7.8 7.5 Muscle-related 4.9 7.1 6.0 6.4 Neurocognitive 0.5 1.2 0.8 1.0 0.9 0.3 Lab results (%) ALT/AST >3×ULN 1.3 CK >5×ULN 0.4 0.7 0.6 Sabatine MS et al. N Engl J Med 2015;372:1500-1509

ODYSSEY LONG TERM Study: Neurocognitive TEAEs: Safety Analysis    Alirocumab (N=1550)  Alirocumab with 2 consecutive LDL-C <25 mg/dL (N = 575)  Placebo (N=788) Neurocognitive disorders - no. of patients (%)* 18 (1.2) 3 (0.5) 4 (0.5) Amnesia 5 (0.3) Memory impairment 4 (0.3) 1 (0.1) Confusional state 1 (0.2) Confusion postoperative 1 (<0.1) Dementia Disorientation Disturbance in attention Frontotemporal dementia Reading disorder Transient global amnesia Vascular encephalopathy Robinson JG, et al. N Engl J Med. 2015;372:1489-99 – appendix Table S6.

Feb 2, 2017: http://www.amgen.com/media/news-releases/2017/02/amgen-announces-repatha-evolocumab-significantly-reduced-the-risk-of-cardiovascular-events-in-fourier-outcomes-study/ The EBBINGHAUS cognitive function trial conducted in FOURIER patients also achieved its primary endpoint, demonstrating that Repatha was non-inferior to placebo for the effect on cognitive function.

Adverse Experience Summary in Patients with LDL-C values <25 mg/dL, <15 mg/dL and >25 mg/dL in Global Safety Pool Alirocumab Briefing Document: Endocrine & Metabolic Advisory Committee Meeting [accessed Sept 14, 2015] http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM449865.pdf

Adjusted rate of any TEAE by average LDL-C during treatment period: From pool of phase 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL* Conclusion: “The present Phase 3 clinical trial analyses provide further data regarding the overall safety of alirocumab and lower LDL-C levels not being associated with an increase in total adverse events” *ODYSSEY FH I, FH II, HIGH FH, LONG TERM, COMBO I, COMBO II, OPTIONS I, OPTIONS II, ALTERNATIVE and MONO studies: 4974 patients treated with ALI, placebo or EZE. Median time to event 36 weeks Ray et al https://doi.org/10.1161/CIRCULATIONAHA.116.024604 Originally published October 24, 2016

Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice Conclusion: Patients achieving very low LDL-C levels (<25 mg/dL and even <15 mg/dL) do not show any increase in clinical or laboratory side effects compared to those with higher LDL-C or control groups The CVD event and IVUS data shows potential additional benefit from low (~40 mg/dL; 1 mmol/L) and very low LDL-C (25 mg/dL;0.4 mmol/L) and increased CVD events when LDL-C remains elevated Based on current evidence the real safety concern is under treatment of LDL-C, not too low LDL-C! Safety and benefit data for very low LDL-C based on increased LDL clearance via upregulation of the LDL receptor (statins, ezetimibe and PCSK9 inhibition), plus unreliability of Friedewald LDL-C when LDL-C <50 mg/dL suggest eliminating lower limit for LDL-C (as for hsCRP).

How low should we reduce LDL-C? Brown MS, Goldstein JL: Science 1986; 232: 34–47