PCSK9 Inhibition for : For Whom? When?

Perry J Weinstock, MD, MS, FACC, FNLA Head, Division of Director of Clinical Cardiology Cooper University Hospital Professor of Medicine Cooper Medical School of Rowan University Camden, New Jersey Disclosures

Speaker’s Bureau: , Regeneron, Aventis Objectives

• Review the role of lipids in • Understand the physiology of lipoprotein metabolism • Appreciate the evidence base of LDL-C lowering • Recognize the validity of PCSK9 monoclonal antibodies as for elevated LDL-C • Anticipate new lipid lowering goals and strategies

3

What Is Desirable ?

Cholesterol Levels Among Different Populations

Hazda Inuit Hunter- gatherer !Kung Pygmy San Adult American

50 70 90 110 130 150 170 190 210 Mean total cholesterol, mg/dL

Adapted from O’Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142–2146. Cholesterol Paradigm of Atherosclerosis

Brown and Goldstein Nobel Prize in Physiology and Medicine 1985

Familial (FH) elevated blood cholesterol dominant inheritance heterozygotes (1 in 250) 2-fold increase in LDL heart attacks at 30-40 yrs homozygotes (1 in million) 6-10-fold increase in LDL heart attacks in childhood

Hypothesis: FH is caused by defects in the regulation of the LDL receptor

Receptor-mediated Endocytosis of LDL

Lippincott Pharmacologic Therapies to Lower LDL-C

Class Drug(s) 3-Hydroxy-3-methylglutaryl (Lipitor) Coenzyme A (HMG-Co-A) (Lescol) reductase inhibitors [] (Mevacor) (Livalo) (Pravachol) (Crestor) (Zocor) sequestrants Cholestyramine (Questran) (Welchol) (Colestid) Cholesterol absorption inhibitor (Zetia)

Nicotinic acid

Dietary adjuncts Soluble fiber Soy protein Stanol esters Proprotein Convertase Subtilisin (Praluent) Kexin 9 (PCSK9) inhibitors (Repatha)

HMG-CoA Reductase Inhibitor Trials: Chronology

1994 4S 2002 PROSPER 1995 WOSCOPS 2002 ALLHAT-LLA 1996 CARE 2002 ASCOT-LLA 1997 POST-CABG 2003 CARDS 1998 AFCAPS/TEXCAPS 2004 PROVE-IT 1998 LIPID 2004 REVERSAL 1999 AVERT 2004 A to Z 2001 MIRACL 2005 TNT 2002 HPS 2005 IDEAL 2006 ASTEROID Study Population: 2008 JUPITER

Primary prevention Acute coronary syndromes Chronic coronary heart disease What if the patient cannot achieve their LDL-C Goal on statins? Pharmacologic Therapies to Lower LDL-C

Class Drug(s) 3-Hydroxy-3-methylglutaryl Atorvastatin (Lipitor) Coenzyme A (HMG-Co-A) Fluvastatin (Lescol) reductase inhibitors [Statins] Lovastatin (Mevacor) Pitavastatin (Livalo) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) Bile acid sequestrants Cholestyramine (Questran) Colesevelam (Welchol) Colestipol (Colestid) Cholesterol absorption inhibitor Ezetimibe (Zetia)

Nicotinic acid Niacin

Dietary adjuncts Soluble fiber Soy protein Stanol esters Proprotein Convertase Subtilisin Alirocumab (Praluent) Kexin 9 (PCSK9) inhibitors Evolocumab (Repatha) PCSK9 Gain-of-Function (GOF) and Loss-of-Function (LOF) Mutations1-4

GOF Mutation LOF Mutation ↓LDLR levels ↑LDLR levels ↓LDL clearance ↑LDL clearance

↑LDL ↓LDL

For illustration purposes only. LDL=low-density lipoprotein; LDLR=low-density lipoprotein receptor. Adapted from: 1. Catapano AL, Papadopoulos N. Atherosclerosis. 2013;228(1):18-28; 2. Farnier M. Arch Cardiovasc Dis. 2014;107(1):58-66; 3. Costet P, et al. Trends Biochem Sci. 2008;33(9):426-434; 4. Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177. PCSK9 Physiology and Inhibition by Injection

PCSK9

PCSK9 LDLR LDL-C ANTIBODY LDLR LDL-C

LDL-C=low-density lipoprotein cholesterol; LDLR=low-density lipoprotein receptor; PCSK9=proprotein convertase subtilisin/kexin type 9.. PCSK9 Inhibitors (Monoclonal Antibodies)

Alirocumab (Praluent) Evolocumab (Repatha)

PCSK9 Inhibitors: Alirocumab (Praluent) Evolocumab (Repatha)

• Large molecules (monoclonal antibodies) • Injected SQ • Must be refrigerated • Very potent on top of therapy • Very expensive • Emerging outcomes data

Background

• Prior intravascular ultrasound (IVUS) trials have shown that statins slow progression or induce regression of coronary disease in proportion to the magnitude of LDL-C reduction.

• No other LDL-lowering therapy has shown regression in an IVUS trial.

• The lowest LDL-C achieved in prior trials was approximately 60 mg/dL. Effects of lower levels remain unknown.

• PCSK9 inhibitors incrementally lower LDL-C when added to statins, allowing achievement of very low LDL-C levels, however, no data exist describing effects on progression. 968 patients at 197 global centers with symptomatic CAD and other high risk features. Coronary angiography showing 20-50% stenosis in a target vessel

Stable, optimized statin dose for 4 weeks with LDL-C >80 mg/dL or 60-80 mg with additional high risk features

Intravascular ultrasound via motorized pullback at 0.5 mm/sec through >40 mm segment

Statin 18 months Statin plus monthly SC monotherapy treatment evolocumab 420 mg

61 patients did not 61 patients did not complete complete 423 statin completers 423 evolocumab completers

Follow-up IVUS of originally imaged “target” vessel (n=846) Change in LDL-Cholesterol During Treatment

Mean LDL-C 93.0 mg/dL

Change from baseline 3.9% 90 mg/dL

Mean LDL-C 36.6 mg/dL

Change from baseline -59.8% 29 mg/dL Secondary Endpoint: Total Atheroma Volume

P = NS

P < 0.0001

P <0.0001

Statin Statin- monotherapy evolocumab Mean On-Treatment LDL-C vs. Change in PAV

Locally Weighted Polynomial Regression (LOESS) Plot with 95% confidence limits Change Percent Atheroma Volume (%) Volume Atheroma Percent Change

On-Treatment LDL-C (mg/dL) GLAGOV Conclusions

• In statin-treated patients with symptomatic coronary disease, addition of evolocumab, 420 mg monthly for 18 months:

– Achieved LDL-C levels averaging 36.6 mg/dL compared with 93 mg/dL for a statin alone.

– Produced regression, mean change in PAV of -0.95% compared with +0.05% in statin-only patients, (P<0.0001).

– Induced regression in a greater percentage of patients, 64% vs. 47% (P<.0.0001).

• Post hoc analysis showed a incremental benefit for combination therapy at LDL-C levels as low as 20 mg/dL Is Ultra Low LDL a Biologically Reasonable Target? A Receptor-Mediated Pathway for Cholesterol Homeostasis Michael S. Brown and Joseph Goldstein

Adapted from Nobel Prize Lecture, Stockholm, Sweden, 1985. Science 1986;232:34-52. Sabatine MS, et al. N Engl J Med. 2017 Mar 17. [Epub ahead of print]34 Study Objective

To investigate the clinical efficacy and safety of evolocumab when added to high- or moderate- intensity statin therapy in patients with clinically evident atherosclerotic cardiovascular disease (ASCVD)

35 Eligibility Criteria

Inclusion Criteria Exclusion Criteria • 40-85 years of age • MI or stroke within previous 4 weeks • Clinically evident ASCVD, defined as a history • NYHA class III or IV, or last known LVEF < 30% of myocardial infarction (MI), nonhemorrhagic • Known hemorrhagic stroke at any time stroke, or symptomatic peripheral artery • Uncontrolled or recurrent ventricular disease (PAD) tachycardia • Fasting LDL-C ≥ 70 mg/dL or a non-HDL-C ≥ • Planned or expected cardiac surgery or 100 mg/dL while taking an optimized regimen revascularization within 3 months after of lipid-lowering therapy, defined as at least randomization atorvastatin 20 mg daily or its equivalent ± ezetimibe • Uncontrolled hypertension • At least 1 major risk factor or at least 2 minor • Prior use of PCSK9 inhibition treatment other risk factors than evolocumab or use of evolocumab < 12 weeks prior to final lipid screening • Severe renal dysfunction (eGFR < 20 mL/min/1.73m2 at final screening) • Active disease or hepatic dysfunction (AST or ALT > 3 x ULN at final screening)

36 Study Design

37 Study Endpoints

Primary Efficacy Endpoint – Major cardiovascular events, defined as the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization

Key Secondary Efficacy Endpoint – Composite of cardiovascular death, MI, or stroke

Safety Endpoints – Adverse events – Development of anti-evolocumab antibodies (binding and neutralizing)

38 LDL-C Levels

39 Primary Endpoint

40 Key Secondary Efficacy Endpoint

41 Safety: Adverse Events

42 Study Conclusions

• When added to statin therapy, evolocumab lowered LDL cholesterol levels by 59% from baseline compared to placebo, from a median of 92 mg/dL to 30 mg/dL •  risk of the primary composite endpoint by 15% and  risk of the key secondary endpoint by 20% • Magnitude of risk reduction shown to increase over time • No effect of additional LDL-C lowering on cardiovascular death or all-cause mortality • Injection-site reactions were significantly higher in the evolocumab group compared to the placebo group

43 New Indication

FDA Approves Evolocumab to Prevent CV Events

December 01, 2017

After , the US Food and Drug Administration (FDA) has approved a supplemental application for evolocumab (Repatha), making it the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor indicated to prevent MI, stroke, and coronary revascularization in adults with established cardiovascular disease (CVD). The FDA also approved evolocumab as an adjunct to diet, alone or in combination with other lipid-lowering therapies such as statins, for the treatment of adults with primary hyperlipidemia to reduce LDL cholesterol.

What about Alirocumab?

Implications for the Future

• New LDL targets in high risk patients with cardiovascular disease  (2017 AACE guidelines already target LDL < 55mg/dl)

• Earlier identification of patients with primary hyperlipidemia

• Must consider therapy beyond statins in appropriate patients

Thank You Cooper University Hospital Cooper University Hospital Camden Health Sciences Campus

Cooper Medical School of Rowan University Questions?