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PCSK9 Inhibition: LDL Lowering

PCSK9 inhibitors New option for dyslipidemia. PCSK9 Inhibition: LDL Lowering. Alireza Esteghamati,MD November 2018. Agenda. Residual risk after Statin PCCSK9 Inhibitors physiology & mechanism of action PCSK-9 Inhibitor trials: FOURIER, ODYSSEY , GLAGOV

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PCSK9 Inhibition: LDL Lowering

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  1. PCSK9 inhibitorsNew option for dyslipidemia PCSK9 Inhibition: LDL Lowering Alireza Esteghamati,MD November 2018

  2. Agenda • Residual risk after Statin • PCCSK9 Inhibitors physiology & mechanism of action • PCSK-9 Inhibitor trials: FOURIER, ODYSSEY , GLAGOV • ADA , AACE, AHA Guideline based indications

  3. Efficacy of Lipid-Lowering Drug Treatment for Diabetic and Nondiabetic PatientsMeta-Analysis of Randomized Controlled Trials

  4. In Real World Data, Many Very High Risk CHD Patients Do Not Achieve LDL-C Targets InternationalAnalysis of 17 Guidelinesand42Observational Studies Patients(VeryHighRisk)NotAchieving NCEP-ATP-IIIGuidelines LDL-CLevelTarget,<70mg/dL(1.81mmol/L) MiddleEast/Asia Europe US Global 96.0 100 87.9 84.8 68.1 78.0 77.0 80 70.0 16.9 60 NotAchieving Goals(%) 40 20 0 Waters etal.,2009 Gomez- Belda etal.,2006 (N= 211, Spain) Arafa etal.,2013 (N= 533, ArabianGulf Countries) Chan etal.,2012 (N= 655, China [HongKong]) Wong etal.,2013a (N= 225, US) Wang etal.,2014 (N= 501, Taiwan) Persell etal.,2006 (N= 655, US) Munawar etal.,2013 (N= 290, Indonesia) (N= 2,334,US, Canada,Mexico, Brazil,Spain, Netherlands, France,Taiwan, Korea) *VeryhighriskdefinedaspatientswithCHDorwhohadtwoormoreCVDriskfactors,CHDrisk-equivalentconditions,or diabetes; Notes:Treated anduntreatedpatients.TheN representspatientsathighrisk,asubsetofthetotalnumberofpatientsstudied. LDL-C= low-densitylipoproteincholesterol;NCEP-ATP-III=NationalCholesterolEducationProgram–AdultTreatmentPanelIII; US =UnitedStates. MitchellS, etal. BMCCardiovascDisord.2016;16:74.

  5. Even With Addition of Ezetimibe, Many ASCVD Patients Do Not Achieve LDL-C Goal LDL-CTarget*AttainmentAfterAddingEzetimibeto StatinTherapyforPatients WithBaselineLDL-C>100mg/dL(>2.6mmol/L)AfterStatins† AchievedLDL-C <70mg/dL(1.8mmol/L) DidNotAchieveLDL-C<70 mg/dL(1.8 mmol/L) 100% Patients: N =1,309 ASCVD of HeFH 90day Follow-up: Assessedfor achievementof LDL-C <70mg/dL (<1.8mmol/L) 86% 93% 80% 60% 40% 20% 14% 7% 0% ASCVD,BaselineLDL-C100–129mg/dL (2.6mmol/L)(n=286) ASCVD,BaselineLDL-C 130mg/dL(3.4mmol/L)(n=305) *Iftargetdefinedas<70 mg/dL(1.8mmol/L);†The extenttowhichpatients werereceivingmaximallytoleratedstatintherapy was not availableinthedata. ASVCD = atheroscleroticcardiovasculardisease;LDL-C =low-densitylipoproteincholesterol. Menzinet al.JMCP2017.

  6. Residual CV Risk Exists Even in Those CHD Patients Receiving Treatment With High-Intensity Statins Incidenceof MajorCVDEventsandLevels of LDL-CinPatientsReceiving Moderate-orHigh-IntensityStatinTherapy1-3 Moderate-intensitystatintherapy High-intensitystatintherapy 40 26.3 35 30 25 22.4 13.7 12 20 PatientsExperiencing MajorCVDEvents(%) 15 10.9 8.7 10 5 0 PROVE IT-TIMI221 4,162 IDEAL2 8,888 TNT3 10,001 N LDL-C,*mg/dL LDL-C,*mmol/L 95 2.46 62 1.60 104 2.69 81 2.09 101 2.61 77 1.99 Meanor medianLDL-C aftertreatment. CV = cardiovascular;CVD=cardiovasculardisease;LDL-C= low-densitylipoproteincholesterol. 1.CannonCP,et al. N EnglJMed.2004;350:1495-1504.2.PedersonTR,etal.JAMA.2005;294:2437-2445. 3.LaRosaJC, etal. N EnglJMed.2005;352:1425-1435.

  7. What should we do in the next step? What is PCSK9? It’s a protein that regulates cholesterol metabolism

  8. Proprotein convertases • Proprotein convertases are a family of enzymes involved in converting precursors of secretory proteins, such as hormones, enzymes and receptors, into bioactive molecules at their intended target tissue. • These enzymes are part of regulatory pathways that help the body to maintain homeostasis

  9. PCSK9 • PCSK9 (proproteinconvertasesubtilisin/kexin type 9) was first described in 2003 • In its active form, PCSK9 regulates cell surface receptors, in particular the LDL receptor. • The enzyme encoded by the PCSK9 gene is primarily expressed in the liver.

  10. Proproteinconvertasesubtilisin/kexin type 9 (PCSK9) Is a Key Regulator of LDL-R Recycling • PCSK9 mediates degradation of the LDL-R by interacting with the extracellular domain and targeting the receptor for degradation1 • PCSK9 is highly expressed in the liver, small intestine, and kidney4 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S177. 2. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. 3. Zhang DW, et al. J Biol Chem. 2007;282:18602-18612. 4. Lopez D. BiochimBiophysActa. 2008;1781:184-191.

  11. PCSK9 inhibitors • Are monoclonal antibodies • Target and inactivate PCSK9 in the liver • Dramatically decrease LDL-C

  12. PCSK9 InhibitionRapid Progress From Discovery to Clinic • Adenoviral  expression in mice • PCSK9 KO mouse  LDL-C • PCSK9 LOF mutations found with 28%  LDL-C and 88%  CHD risk • Humans null for PCSK9 have LDL-C ~15 mg/dL • First subject treated with PCSK9 mAb • First patients with FH & nonFH treated with PCSK9 mAb • PCSK9 (NARC-1) discovered • PCSK9 GOF mutations associated with ADH  LDL-C in mice and non-human primates treated with anti-PCSK9 mAb Plasma PCSK9 binds to LDLr First publication POC in patients 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012 Seidah NG. Proc Natl Acad Sci USA 2003;100(3):928-33, Abifadel M. Nat Genet 2003;34(2):154-6, Maxwell KN. Proc Natl Acad Sci USA 2004;101(18):7100-5, Rashid S. Proc Natl Acad Sci USA 2005;102(15):5374-79, Lagace TA et al. JCI 2006;116:2995-3005 Cohen JC. N Engl J Med 2006;354(12):1264-72, Zhao Z. AmJ Hum Genet 2006;79(3):514-23, Hooper AJ. Atherosclerosis 2007;193(2):445-8, Chan JC. Proc Natl Acad Sci USA 2009;106(24):9820-5; Stein et al N Engl J Med 2012;366:1108-18

  13. Timeline of development

  14. Population StudiesPCSK9 Loss-of-Function Mutations

  15. The PCSK9 Variant Story

  16. Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels • PCSK9 Loss of Function (LOF) = More LDL-Rs2,4,5 • 1-3% of population6,7 PCSK9 Gain of Function (GOF) = Less LDL-Rs1,3,5 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S177. 2. Lakoski SG, et al. J ClinEndocrinolMetab. 2009;94:2537-2543. 3. Abifadel M, et al. Hum Mutat. 2009;30:520-529. 4. Cohen J, et al. Nat Genet. 2005;37:161-165. 5. Steinberg D, et al. PNAS. 2009;106:9546-9547. 6. Cohen JC, et al. N Engl J Med. 2006;354:1264-1272. 7. Benn M, et al. J Am CollCardiol. 2010;55:2833-2842.

  17. LDL: Lower is Better IMPROVE-IT S40/E10 Adapted from Raymond, Cleveland Clin J Med, Jan, 2014

  18. PCSK9 TRIALSDM & Non DM

  19. Evolocumab Mechanism of Action • Fully humanized monoclonal antibody Image available from: https://www.repathahcp.com/

  20. PCSK9 Inhibitors PCSK9 inhibitors are highly effective lipid-lowering agents that can dramatically lower circulating LDL. • Currently, two PCSK9 inhibitors: • Alirocumab (Praluent, Sanofi/Regeneron) • Evolocumab (Repatha, Amgen) have been approved by FDA and are available for clinical use.

  21. Evolocumab • In meta-analysis from three phase 3 studies evolocumab has also shown favorable changes in lipid profile in diabetic patients • Prespecified analysis of diabetics from the pivotal FOURIER trial sheds light on the effect of evolocumab on outcomes in diabetics.

  22. Evolocumab FOURIER trial • 11031 diabetics (40%) • 16533 non-diabetics with stable ASCVD and deranged lipid profiles • On statin therapy • Median of 2.2 years Found that it similarly reduced the primary composite endpoint of CV death, stroke, MI, hospitalization of angina, or coronary revascularization in • Diabetics(HR 0.83, 95% CI 0.75–0.93) • Non-diabetics(HR 0.87 95% CI 0.79–0.96) • Importantly, the trial showed no increase in new-onset diabetes or glycemic derangements with PCSK9 inhibition.

  23. PCSK9 Inhibitors & DM

  24. Alirocumab A pooled analysis of 5 placebo-controlled phase 3 trials of alirocumab showed that : • it reduced LDL as significantly in patients with type 2 diabetes compared to non-diabetics with a similar safety profile as well. • This analysis of diabetics with mixed dyslipidemia treated with 150 mg of alirocumab every 2 weeks for 24 weeks resulted in : • 57% reduction in LDL • 47% reduction in non-HDL cholesterol, similar to non-diabetics.

  25. Alirocumab The most common adverse effect was: • Upper respiratory tract infection (5%) • Injection site reaction (3%) • Overall rate was similar between diabetics and non-diabetics. • Beneficial improvements in lipid profile have also been shown in • ODYSSEY DM-DYSLIPIDEMIA • ODYSSEY DM INSULIN • ODYSSEY COMB II.

  26. PCSK9 Inhibitors & DM

  27. BACKGROUND • Patients who have had an ACS are at high risk for recurrent ischemic cardiovascular events. • We sought to determine whether alirocumab, would improve cardiovascular outcomes after an ACS in patients receiving high-intensity statin therapy.

  28. Alirocumab ODYSSEY OUTCOMES • Included 18,924 patients with abnormal lipid profiles on maximally tolerated statin therapy who had an ACS within the last 12 months. • Of this population, 29% (n = 4971) had diabetes. • Goal of trial was an LDL between 25 and 50 mg/dLand those with LDL < 15 mg/dL has therapy down titrated or stopped.

  29. ODYSSEY OUTCOMES Median follow-up of 2.8 years • LDL in the alirocumab group was 53.3 mg/dL • compared with 101.4 mg/ dLin placebo arm. • The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).

  30. Alirocumab resulted in a reduced composite primary end point of first occurrence of coronary heart disease death, nonfatal MI, unstable angina requiring hospitalization, or ischemic stroke of 9.5% vs. 11.1% in the placebo arm (HR 0.85, 95% CI 0.78–0.93, p = 0.0003).

  31. Alirocumab • There was also a reduction in the secondary endpoint of all-cause mortality (3.55% vs. 4.1%, p = 0.03). • These reductions were more marked in patients with a baseline LDL > 100 mg/dL. • These promising data show that PCSK9 inhibition achieved through either alirocumab or evolocumab can play an important role in reducing residual risk in selected diabetics at high risk.

  32. PCSK9 Inhibitors & DM

  33. Inclisiran • Inclisiran is a small interfering RNA designed to target PCSK9 messenger RNA. • In ORION-1, a multicenter phase 2 randomized double-blind placebo controlled trial of 501 patients with ASCVD or ASCVD equivalent on maximally tolerated statin therapy • Single dose of injectable inclisiranresulted in an LDL mean reduction of 27.9 (42% reduction) • Two doses led to a reduction of 35.5 (53% reduction) at 180 days.

  34. Inclisiran • Serious side effects occurred in 11% of patients receiving inclisiran and 8% receiving placebo. • Injection site reactions occurred in 5% of patients and were most common. • Of these patients, 67 (14%) had diabetes, and these patients experienced similar LDL reductions without any worsening in glycemic profile. • While more data is required, these initial reports are encouraging.

  35. FOURIERFurther cardiovascular OUtcomesResearch with PCSK9 Inhibition in subjects with Elevated Risk MS Sabatine, RP Giugliano, AC Keech, N Honarpour,SM Wasserman, PS Sever, and TR Pedersen,for the FOURIER Steering Committee & Investigators American College of Cardiology – 66th Annual Scientific Session Late-Breaking Clinical Trial March 17, 2017 SC-MEA-AMG145-00095 Mar 17

  36. FOURIER Trial: Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated Risk • This randomized, double-blind, placebo-controlled trial investigated the effects of adding evolocumab to high-intensity statin therapy compared with high-intensity statins alone. • Study results included data for over 27,500 individuals with clinically evident atherosclerotic disease and LDL-C ≥70 mg/dL and non-HDL-C ≥100 mg/dL; mean patient follow-up was 2.2 years. • All study participants were receiving statin therapy with or without ezetimibe, and the evolocumab and placebo groups had the same LDL-C (92 mg/dL). Abbreviations:; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction.SabatineMS, et al. NEJM. 2017; epub ahead of print.

  37. TrialDesign 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomaticPAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (±ezetimibe) LDL-C ≥70 mg/dL (1.8 mmol/L)or non-HDL-C ≥100 mg/dL (2.6mmol/L) RANDOMIZED DOUBLEBLIND EvolocumabSC 140 mg Q2W or 420 mgQM PlaceboSC Q2W orQM Follow-up Q 12 weeks; Median f/up 2.2yrs Primary Endpoint: CVD/MI/Stroke/UA/Coronary Revasc Key Secondary Endpoint:CVD/MI/Stroke Sabatine MS et al. Am Heart J2016;173:94-101

  38. Study Endpoints Primary Efficacy Endpoint • Major cardiovascular events, defined as the composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization Key Secondary Efficacy Endpoint • Composite of CV death, MI, or stroke Safety Endpoints • Adverse events • Development of anti-evolocumab antibodies (binding and neutralizing)

  39. FOURIER Evolocumab StudyLDL-C Levels Over time No. at Risk Abbreviations:FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol. Sabatine MS, et al. NEJM. 2017; epub ahead of print.

  40. Summary of Effects of PCSK9iEvolocumab • LDL-C by 59% down to a median of 30mg/dl • CV outcomes in patients onstatin • Safe andwell-tolerated HR 0.85 (0.79-0.92) P<0.0001 100 Placebo 14.6 15 HR 0.80 (0.73-0.88) P<0.0001 80 12.6 59%reduction P<0.00001 LDLCholesterol(mg/dl) KM Rate(%)at3Years 9.9 60 10 7.9 Absolute 56mg/dl 40 5 Evolocumab (median 30 mg/dl, IQR 19-46mg/dl) 20 0 0 CVD, MI,stroke CVD, MI,stroke UA, correvasc 0 24 48 72 96 120144168 Weeks afterrandomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard MedicalSchool Sabatine MS et al. NEJM2017;376:1713-22

  41. FOURIER: CV Outcome FOURIER: CV Outcomes SabatineMS, et al . NEJM. [published online ahead of print March 17, 2017].

  42. FOURIER Evolocumab Study Endpoints Cumulative rates for the key secondary efficacy endpoint (Composite of cardiovascular death, MI, or stroke) Cumulative event rates for the primary efficacy endpoint (Composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) Abbreviations:FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; MI, myocardial infarction. Sabatine MS, et al. NEJM. 2017; epub ahead of print.

  43. FOURIER: LDL Cholestrol In patients with baseline LDL-C ≤ 70 mg/dL FOURIER: LDL CholesterolIn patients with baseline LDL-C≤70 mg/dL • FOURIER subanalysis in several thousand patients who had baseline LDL-C ≤ 70 mg/dL or non-HDL ≤ 100 mg/dL Courtesy of Marc S. Sabatine, MD, MPH- National Lipid Association Conference 2017.

  44. FOURIER: LDL Cholestrol In patients with baseline LDL-C ≤ 70 mg/dL FOURIER: Clinical OutcomesIn patients with baseline LDL-C<70 mg/dL Courtesy of Marc S. Sabatine, MD, MPH- National Lipid Association Conference 2017.

  45. FOURIER Primary and Secondary Endpoints • At 26 months, extremely tight lipid control with evolocumab led to • 15% decrease in risk for the primary composite endpoint • 20% decrease in risk for a secondary composite endpoint • Beyond the second year of follow-up, the risk reduction increased to • 20% for the primary endpoint • 25% for the secondary endpoint Abbreviations:FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. Sabatine MS, et al. NEJM. 2017; epub ahead of print.

  46. FOURIER Primary and Secondary Endpoints • For singular endpoints at 26 months, very tight lipid control reduced the risk of • MI by 27% • stroke by 21% • coronary revascularization by 22% Abbreviations:FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. Sabatine MS, et al. NEJM. 2017; epub ahead of print.

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