EVIDENCE TO DATE EVOLOCUMAB (REPATHA)

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1 and Clinical Outcomes in Patients with Cardiovascular Disease, March CLINICAL QUESTION In patients with atherosclerotic cardiovascular disease and LDL >1.8mmol/L or non-hdl > 2.6mmol/L, how does evolocumab (either 140mg SC every 2 week or 420mg SC monthly) compare to matching placebo SC injections in reducing a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization? CONTEXT (Repatha TM ): human monoclonal ab that binds to and inhibits free Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) o PCSK9 binds to LDL receptors on hepatocytes to degradation of LDL receptors within the liver inhibiting PCSK9 LDL receptor circulating LDL Whether [] prevents cardiovascular events is uncertain. EVIDENCE TO DATE EVOLOCUMAB (REPATHA) DESCARTES 2014 : Phase 3 trial In pts (N=901) with LDL>1.94mmol/L & fasting TG<4.52mmol/L (excl. HF, recent MI, recent/planned revasc), evolocumab 420mg SC qmosx52wks, added to diet alone, ator. 10mg daily, ator. 80mg daily + ezetimibe LDLs (by %) 2 OSLER 2015 : 2 open-label RT In pts from 12 Phase 2/3 trials (N=4465), evolocumab x11.1mos + standard tx vs. standard tx alone (70% on statin) SS LDL by 58.4%. A pre-specified exploratory analysis showed SS in composite of death, MI, USA requiring hospitalization, coronary revasc., stroke, TIA, and HF hospitalization (HR: 0.47, (95% CI ), P=0.003) but trial was not powered for this outcome 3 GAUSS : 2 staged DB RCT In pts with muscle-related statin intolerance, 4-wk wash-out Stage 1 (Ator 20mgx10wk vs. x10wk) Stage 2 N=218 statin-intolerant (evolocumab qmos vs. ezetimibex24wk), evolocumab had a greater in LDL than ezetimibe (LS mean diff: 36.1%) Muscle-related AEs: ezetimibe 28.8%, evolocumab 20.7% 4 STATIN IMPROVE-IT 2015 : DB RCT In pts acutely post ACS, simvastatin 40mg daily (mod-dose statin) + ezetimibe vs simvastatin alone average LDL from 1.8 to 1.4 mmol/l and SS a composite of CV death, MI, USA requiring hospitalization, revasc. or stroke (NNT = 50/7yrs) CCS GUIDELINES 2016 We suggest that PCSK9 inhibitors be considered to lower LDL-C level for patients with atherosclerotic CVD in those not at LDL-C goal despite maximally tolerated statin doses with or without ezetimibe therapy (Conditional Recommendation; Moderate-Quality Evidence). We recommend a target LDL-C consistently <2.0mmol/L or >50% reduction of LDL-C to lower risk of CVD events and mortality for recent ACS and established coronary disease, consideration should be given to more aggressive targets (LDL-C <1.8 or >50% reduction) Methodology Study design Multi-national, double-blinded, placebo-controlled, randomized phase III trial (Feb 2013 Jun 2015) Randomization Randomized 1:1 via central computerized system, with stratification, according to final screening LDL (< 2.2 or > 2.2mmol/L) Allocation concealment Site representative will call to Voice/Web response system to assign a randomization # to subject Blinding Power Loss to follow-up Analysis Outcomes Funding Double Blinded ( matching placebo as SC injections ); Investigators, Patients, Clinical Events Committee N of 22,500 (1620 endpoint events) for 90% power to detect a 15% RRR in the key secondary endpoint with evolocumab as compared with placebo (n=5,<0.1%) vs. (n=13,<0.1%) Efficacy analysis: Intention-to-treat (ITT); Safety analysis: modified ITT Primary Outcomes: Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization Secondary outcomes: Composite of cardiovascular death, myocardial infarction or stroke Individual components of primary endpoint All-cause mortality Composite of cardiovascular death or hospitalization for heart failure Cholesterol Treatment Trialists Collaboration composite endpoint of major coronary events (coronary heart death, non-fatal MI), stroke or coronary revascularization Subsets including composite of coronary heat death, non-fatal MI, ischemic stroke or urgent coronary revascularization, composite of coronary heart death, non-fatal MI or stroke, composite of fatal or nonfatal MI or stroke AEs: Muscle-related, cataracts, injection site, allergic and neurocognitive, new onset diabetes, LFTs, CK, FBS, HbA1c and anti-evolocumab antibodies Amgen (Role: Collaborated in trial design, responsible for data collection, but no involvement in data analysis) 1

2 and Clinical Outcomes in Patients with Cardiovascular Disease, March Setting Inclusion criteria Relevant exclusion criteria I: vs. C: 1242 sites in 49 countries Study size 27,564 Average patient 40 to 85 years old Clinically evident atherosclerotic CVD (i.e. history MI, non-hemorrhagic stroke, symptomatic peripheral artery disease, or additional risk factors (see appendix below)) LDL > 1.8mmol/L, or non-hdl > 2.6mmol/L, while taking at least atorvastatin 20mg daily or equivalent + ezetimibe Within 4 wks of MI or stroke Planned cardiac surgery/revasc. w/in 3 mos NYHA III or IV HF, or last known LVEF < 30% History of hemorrhagic stroke Use of CETP inhibition treatment, mipomersen or lomitapide in previous 12 months Fibrates, except for fenofibrates are prohibited. If taking, must be on stable fenofibrate tx x 6 wks Prior use of PCSK9 inhibitors other than evolocumab or use of evoloc. in previous 12 wks LDL or plasma apheresis within previous 12 mos CK > 5x ULN egfr < 20mL/min/1.73m 2 Active liver disease or hepatic dysfunction Pregnant or breast feeding (N=13,784) (N=13,780) Demographics/History: Age 62.5 yo North America 16.6% Male 75.5% Europe 62.9% White 85% Latin America 6.6% Wt 85 kg Asia Pacific/South Africa 13.9% Atherosclerotic Disease MI Median time from MI Non-hemmorhagic stroke Median time from stroke Peripheral Artery Disease CV Risk Factors Hypertension Diabetes mellitus Current smoking Median Lipid Measure (IQR) LDL mmol/l Total Cholesterol mmol/l HDL mmol/l Triglycerides mmol/l Lipoprotein(a) nmol/l Lipid-Lowering Therapies 80.9% 3.4( ) 19.5% 3.2( ) 13.5% 80.1% 36.7% 28.0% 2.4( ) 4.3( ) 1.1( ) 1.5( ) 37 (13-166) High-intensity Statin 69.5% Moderate-intensity Statin 30.2% Low/unknown intensity Statin 0.3% Ezetimibe 5.3% Other Cardiovascular Medications Aspirin, P2Y12 inhibitor or both 92.7% Beta-blocker 75.8% ACEI/ARB, MRA or both 78.4% 81.3% 3.3( ) 19.2% 3.3( ) 12.9% 80.1% 36.5% 28.5% 2.4( ) 4.3( ) 1.1( ) 1.5( ) 37(13-164) 69.1% 30.7% 0.2% 5.2% 92.0% 75.4% 77.9% No clinically-relevant baseline between-group differences 1 o Composite (CV death, MI, stroke, hospitalization for USA or coronary revasc.) 2 o Composite (CV death, MI, stroke) PRIMARY OUTCOMES Hazard Ratio 1344 (9.8%) 1563 (11.3%) 0.85 SECONDARY OUTCOMES Hazard Ratio 816 (5.9%) 1013 (7.4%) 0.80 CV death 251 (1.8%) 240 (1.7%) 1.05 All-cause death 444 (3.2%) 426 (3.1%) 1.04 MI 468 (3.4%) 639 (4.6%) 0.73 USA hospitalization 236 (1.7%) 239 (1.7%) 0.99 Stroke 207 (1.5%) 262 (1.6%) 0.79 Ischemic Stroke/TIA 229 (1.7%) 295 (2.1%) 0.77 Coronary revasc. 759 (5.5%) 965 (7.0%) 0.78 CV death or HF hospitalization 402 (2.9%) 408 (3.0%) 0.98 CTTC composite 1271 (9.2%) q2wk % (95%CI) 61.1% ( ) LDL REDUCTION qmos % (95%CI) 56.9% ( ) Mean absolute, vs. placebo: 1.45 mmol/l (95% CI, ) 95% CI (P) (P < 0.001) 95% CI (P) (P < 0.001) (P=0.62) (P=0.54) (P<0.001) (P=0.89) (P=0.01) (P=0.003) (P<0.001) (P=0.82) (P<0.001) vs. placebo 59% (58-60%) P<0.001 : 87%: <1.8mmol/L, 67%: <1.0, 42% < 0.65 Median LDL at 48 wks: 0.78 mmol/l SAFETY OUTCOMES Absolute risk difference Any AEs (77.4%) (77.4%) 0% Serious AEs 3410 (24.8%) 3404 (24.7%) 0.1% Injection-site rxn 296 (2.1%) 219 (1.6%) 0.5% Muscle-related event 682 (5.0%) 656 (4.8%) 0.2% Rhabdomyolysis 8 (0.1%) 11 (0.1%) 0% Cataract 228 (1.7%) 242 (1.8%) 0.1% New-onset DM 677 (8.1%) 644 (7.7%) 0.4% Neurocognitive event 217 (1.6%) 202 (1.5%) 0.1% AT >3xULN 1.8% 1.8% 0% CK >5xULN 0.7% 0.7% 0% 2

3 and Clinical Outcomes in Patients with Cardiovascular Disease, March Limitations: Methods Trial enrolled a specific population o On baseline statin therapy, preferably high-intensity statin but must have been on at least the equivalent of atorvastatin 20mg daily o Excluded patients acutely post-mi (within 4 weeks) or planned revascularization/cardiac surgery o Run in period with placebo SC injections to confirm tolerance to SC administration Background lipid therapy had to be stable for at least 4 weeks o?# of pts who recently started statin and other lipid-lowering therapies Different regimens of evolocumab o Depending on patient preference, patients could be on evolocumab 420mg SC monthly or 140mg SC every 2 weeks o Comparison between two regimens: 140mg Q2W + statin mean LDL up to 77%, 420mg QM + statin mean LDL up to 67% 5 Powered for secondary efficacy outcome Funding Bias: AMGEN involved in design and data collection Results Patient Population Generalizability o Caucasian 85% male 75.5% from Europe 62.9% on high-intensity statin 69%, anti-platelet tx 92%, BB 75%, ACEI/ARB/MRA 78% o Treatment: ~90% on q2wk regimen, and compliant to treatment Median duration of Follow-up was 26 months (IQR: 22-30) o Other lipid-lowering trials follow-up have averaged approximately 5 years o Event rate ~50% higher than initially estimated led to a shorter required duration of f/u (initial plan = 4 years) Event rate predominantly MI (61%) shorter duration might have limited trial s ability to capture mortality benefit o Lacking information on long-term safety Sub-group analysis o Efficacy in 1 o outcome lost in Latin Americans, Polyvascular disease, LDL >2.37 mmol/l, in pts on ezetimibe, in pts on evolocumab q mos o Efficacy in 2 o outcome lost in Latin Americans, Polyvascular disease, in pts on ezetimibe, in pts on evolocumab q mos Patient population who switch over to monthly = possible unknown confounding factors? Compliance issues? Study s Conclusion: Inhibition of PCSK9 with evolocumab on a background of a statin therapy lowered LDL to a median of 0.86 mmol/l and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. My Conclusion and Applicability to clinical practice: For patients on a moderate to high-intensity statin with a LDL > 1.8 mmol/l and on other secondary preventative therapy for CAD, evolocumab 140mg SC every 2 weeks for 2.2 years compared to a moderate to high-intensity statin alone reduces the risk of myocardial infarction and stroke. There are no significant mortality benefits. APPENDIX I. Additional Information on Inclusion Criteria: Major Risk Factors (1 Required for inclusion): o diabetes (type 1 or type 2) o age 65 years at randomization (and 85 years at time of informed consent) o MI or non-hemorrhagic stroke within 6 months of screening o additional diagnosis of myocardial infarction or non-hemorrhagic stroke excluding qualifying MI or non-hemorrhagic stroke o current daily cigarette smoking o history of symptomatic PAD (intermittent claudication with ABI < 0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease) if eligible by MI or stroke history Minor Risk Factors (2 Required for inclusion): o history of non-mi related coronary revascularization o residual coronary artery disease with 40% stenosis in 2 large vessels o Most recent HDL-C < 40 mg/dl (1.0 mmol/l) for men and < 50 mg/dl (1.3 mmol/l) for women by central laboratory before randomization o Most recent hscrp > 2.0 mg/l by central laboratory before randomization o Most recent LDL-C 130 mg/dl (3.4 mmol/l) or non-hdl-c 160 mg/dl (4.1 mmol/l) by central laboratory before randomization o metabolic syndrome 3

4 and Clinical Outcomes in Patients with Cardiovascular Disease, March II. Study Design The study consists of 2 periods: (1) Screening, lipid stabilization, and placebo run-in period, (2) double-blind treatment and follow-up period III. Statin Intensity for FOURIER IV. Results for FOURIER 4

5 and Clinical Outcomes in Patients with Cardiovascular Disease, March IV. PCSK9 inhibitors PCSK9 Dose for inhibitor hyperlipidemia 140mg SCQ2wk (Repatha TM ) 420mg SCQmos Alirocumab (Praluent ) Bococizumab 75mg SC Q2wk (may to 150mg SC Q2wk if inadequate response within 4-8 wks) Pharmacokinetics Cost Comments Non-linear pharmacokinetics Median Tmax: 3-4 ds F: 72% Cmax: ug/ml (140mg) ug/ml (420mg) AUC: day*ug/ml (140mg) day*ug/ml (420mg) Effective half-life: days Metabolism: expected to degrade to small peptides and individual amino acids Max suppression: 4 hours Median Tmax: 3-7 ds F: 85% Cmax: ng/ml (150mg) AUC: day*mg/l (75mg) Effective half-life: days Metabolism: expected to degrade to small peptides and individual amino acids Max suppression: 4-8 hours $7844/year $7844/year Store in fridge (allow to stand at room temp for at least 30 mins prior to use) Financial Assistance Program: RepathaREADYadvance Store in fridge (allow to stand at room temp for at least 30 mins prior to use) Financial Assistance Program: MyPraulent ODYSSEY 2015 : D Phase II DB RCT, P High CV risk pts on statin, I Alirocumab 150mg SCQ2k, C O LDL -62%, post hoc analysis showed evidence of CV events (not powered) «during the conduct of these two outcomes trials bococizumab was commonly associated with the development of high-titer antidrug antibodies that resulted in substantive attenuation of LDL-cholesterol lowering over time. In addition, the trials showed that bococizumab was associated with a wide variation in LDL-cholesterol lowering, even among patients who were antibody negative.5 On the basis of the SPIRE lipid-lowering data, the sponsor elected to discontinue further development of bococizumab on November 1, 2016.» REFERENCES (1) Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, et al. and clinical outcomes in patients with cardiovascular disease. N Engl J Med Mar 17. (2) Blom DJ, Hala T, Bolognese M, Lillestol MJ, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med May 8;370(19): (3) Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med Apr 16;372(16): (4) Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. Jama Apr 19;315(15): (5) Dosing Information Repatha (evolocumab) [Internet]. Repathahcp.com [cited 12 April 2017]. Available from: 5

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