What Role do the New PCSK9Inhibitors Have in Lipid Lowering

Treatment?Jennifer G. Robinson, MD, MPH

Professor, Departments of Epidemiology & MedicineDirector, Prevention Intervention Center

University of IowaIowa City, Iowa

Disclosures

Vice-Chair, 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterolto Reduce Atherosclerotic Cardiovascular Disease in Adults

Member, 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk

Received in the past year:

Research grants to the institution: Amarin, Amgen, Astra-Zeneca, Eli Lilly,Esai, Glaxo-Smith Kline, Merck, Pfizer, Regeneron/Sanofi, Takeda

Consultant : Akcea/Ionis, Amgen, Eli Lilly, Esperion, Merck, Pfizer,Regeneron/Sanofi

Proprotein Convertase Subtilisin-like/kexin type 9 (PCSK9) Targetsthe LDL-Receptor for Lysosomal Degradation

LDL=low-density lipoprotein; LDL-R=LDL receptor; mAb=monoclonal antibody; PCSK9=proprotein convertase subtilisin/kinexin type 9; SREBP-2=sterol regulatoryelement-binding protein-2.Adapted from: Catapano AL, Papadopoulos N. Atherosclerosis 2013;228:18–28.

PCSK9 Inhibitory Monoclonal Antibodies Increase LDL-Receptor Expression

LDL=low-density lipoprotein; LDL-R=LDL receptor; mAb=monoclonal antibody; PCSK9=proprotein convertase subtilisin/kinexin type 9; SREBP-2=sterol regulatoryelement-binding protein-2.Adapted from: Catapano AL, Papadopoulos N. Atherosclerosis 2013;228:18–28.

PCSK-9 Monoclonal Antibody (mAb) IndicationsAlirocumab & Evolocumab

• Use as an adjunct to diet and maximally tolerated statin therapy in patientswho require additional LDL-C lowering:• Adults with heterozygous familial hypercholesterolemia• Adults with clinical cardiovascular disease

Evolocumab

Sanofi Aventis, Regeneron Pharmaceuticals Inc. Praluent (alirocumab injection) PI.. July 2015. http://products.sanofi.us/praluent/praluent.pdf.Amgen. Repatha (evolocumab) injection PI. August 2015. http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf

Evolocumab

• Patients with homozygous familial hypercholesterolemia on statins,ezetimibe, and/or LDL apheresis

•

The FDA further noted as a limitation of use that the effect of alirocumab orevolocumab on cardiovascular morbidity and mortality has not yet beendetermined.

LDL-C lowering efficacy of PCSK-9 mAbsBackground statin therapy

Alirocumab 75mg q2W

Alirocumab75/150 mg q2W

Alirocumab 150mg q2W

Evolocumab 140mg q2W

Evolocumab 420mg q4W

-48%-54%

-63% -61% -60%

-47% -46%

-62%

-71%

-63%

Heterozygous Familial Hypercholesterolemia Clinical ASCVD

Alirocumab prescribing information, July 2015. https://www.praluenthcp.com/ Accessed 10/29/15.Evolovumab prescribing information, September 2015. pi.amgen.com/united_states/repatha/repatha_pi_hcp. Accessed 10/29/15; Kereiakes D, et al. Am J Cardiol2015;169:906-915; Robinson JG, et al. NEJM 2015;372:1489-1499.

Achieved LDL-C with PCSK-9 mAbs

HeFH Added to background statin/lipid-lowering therapyODYSSEY FH I & II – Alirocumab 75/150 mg LDL-C -51-58%

Statin/LLT+ Alirocumab Mean LDL-C 135-154 mg/dl 69 mg/dl

RUTHERFORD 2 - Evolocumab 140 mg q2W or 420 mg q4W LDL-C -60-66%

Statin/LLT + Evolocumab Mean LDL-C 150-162 mg/dl 67-69 mg/dl

High CV Risk Added to background statin therapyLAPLACE-2 – Evolocumab: High risk LDL-C >70 mg/dl

Randomized to moderate or high intensity statinRe-randomized to Evolocumab (140 mg q2W vs 420 q4W)or placebo X 12 weeks

LDL-C -63-64% vs placeboModerate intensity statin + Evolocumab Mean LDL-C 115-124 mg/dl

39-49 mg/dlHigh intensity statin + Evolocumab Mean LDL-C 89-94 mg/dl 33-35 mg/dl

Robinson JG, et al. JAMA 2014; 311: 1870-1882; Kastelein JJP, et al. Eur Heart J 2015; 10.1093/eurheartj/ehv370; Raal et al. Lancet 2015; 385: 331-40

LDL-C lowering efficacy of PCSK-9 mAbsMonotherapy

EzetimibeAlirocumab75/150 mg Ezetimibe

Evolocumab140 mg q2W

Evolocumab420 mg q4W

-20%

-53%

-18%

-57% -56%

Roth E,et al. Int J Cardiol, 2014; 176: 55-61.Koren M, et al. J Am Coll Cardiol 2014; 63, 2531-2540.

Effect on Other Blood Lipids and ProteinsDESCARTES 52 weeks: Evolocumab 420 mg Q4W

52 0

-10

0

10

Pe

rce

nt

chan

gefr

om

bas

elin

e

-22

-44

-50

-29-34

-12

-60

-50

-40

-30

-20

-10

Pe

rce

nt

chan

gefr

om

bas

elin

e

Baseline 38 nmol/L 87 mg/dL 124 mg/dL 20 mg/dL 177 mg/dL 105 mg/dL 53 mg/dL 152 mg/dL 1.0 mg/dL(median) (mean) (mean) (mean) (mean) (median) (mean) (mean) (median)

Apo B=apoliporotein B; HDL-C=high-density lipoprotein cholesterol; hs-CRP= high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein(a); VLDL-C=very low density liporotein cholesterol.Blom DJ, et al. New Eng J Med. 2014; 370:1809-1819.

Safety of PCSK9 mAbsODYSSEY LONGTERMPlacebo vs Alirocumab150 mg Q2W, 80 weeks

DESCARTESPlacebo vs Evolocumab420 mg, 52 weeks

OSLER I & IIStandard careEvolocumab420 mg Q4W or 140 mgQ2W, 11 months

Adverse eventsInjection site reactions4.2% vs. 5.9%; P=0.10

Injection site reaction5.0% vs 5.7%

Injection site reactionsNA vs 4.3%4.2% vs. 5.9%; P=0.10

Mylagia2.9% vs. 5.4%; P=0.006Neurocognitive AEs0.5% vs 1.2%; P=0.17Opthalmologic AEs1.9% vs 2.9%; P=0.65

5.0% vs 5.7%Mylagia3.0% vs 4.0%URIs6.3% vs 9.3%ALT > 3X ULN1.0% vs 0.8%

NA vs 4.3%Muscle AEs6.0% vs 6.4%Neurocognitive AEs0.3% vs 0.9%

Post hoc CVD events “Exploratory” CVD events

3.3% vs 1.7%HR 0.52 (0.31-0.90;P=0.02)

2.18% vs 0.95%HR 0.47 (0.28-0.78; p=0.003)

AEs=adverse events; ALT=alanine aminotransferase; CVD=cardiovascular disease; HR=hazard ratio; Q2W=every 2 weeks; Q4W=every 4 weeks; SC=standard care;ULN=upper limit of normal; URIs=upper respiratory infections.Robinson JG, et al. N Engl J Med 2015;372:1489-1499; Blom DJ, et al. N Engl J Med 2014; 370: 1809-1819; Sabatine MS, et al. N Engl J Med 2015;372:1500-1509.

PCSK9 mAbs: Preliminary data - CVD event reductionODYSSEY LONG TERM – Alirocumab 150

mg q2WMean 80 week follow-up

OSLER – Evolocumab 140q2W/420 q4W

Mean 11 month follow-up

HR 0.52(95% CI 0.31-0.90)

HR 0.47(95% CI 0.28-

FromFrom N Engl J MedN Engl J Med,, Sabatine MS et alSabatine MS et al, Efficacy and, Efficacy andsafety of evolocumab in reducing lipids andsafety of evolocumab in reducing lipids andcardiovascular events, 372, 1500cardiovascular events, 372, 1500--1509.1509.

FromFrom N Engl J MedN Engl J Med,, Robinson JG et alRobinson JG et al, Efficacy and, Efficacy andsafety of alirocumab in reducing lipids andsafety of alirocumab in reducing lipids andcardiovascular events, 372, 1489cardiovascular events, 372, 1489--1499.1499.

CVD=cardiovascular disease; HR=hazard ratio; PCSK9=proprotein convertase subtilisin/kexin Type 9.

(95% CI 0.31-0.90)Nominal P =0.02

(95% CI 0.28-0.78)P=0.003

Magnitude of PCSK-9 mAb CV Risk Reduction &Longer-term Safety Awaits CV Outcomes Trials

Alirocumab N

MinLDL-C

(mg/dL) Evolocumab N

MinLDL-C

(mg/dL) Bococizumab N

MinLDL-C

(mg/dL)

ODYSSEY ACS CVDSPIRE-1

CVDHR PP12,000

≥70 &<100ODYSSEY

OUTCOMESACS

18,000≥70 FOURIER

CVD27,500

≥70

SPIRE-112,000

<100

SPIRE-2CVD

HR PP6300

>100

ClinicalTrials.gov. http://clinicaltrials.gov. Accessed November 2015.

PCSK9 mAbs in clinical practicePCSK9 mAbs in clinical practice

2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD RiskMajor recommendations for initiating statin therapy based on

patient’s level of RISK

I AI A

I AI A

I BI B

I AI A

IIaIIa BB

Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934

4.9 mmol/L

2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD Risk

Major recommendations for initiating statin therapy based onpatient’s level of RISK (cont)

I BI B

IIbIIb CC

I AI A IIaIIa BB

IIaIIa BB

Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934.

2013 ACC/AHA Cholesterol Guideline to Reduce ASCVD RiskMonitoring Therapeutic Response and Adherence

*

I AI A

IIaIIa BB

If baseline LDL-Cunknown, may use LDL-C<100 mg/dl

High intensity statin >50% LDL-CMod intensity statin 30-<50% LDL-C

Regularlymeasure lipid

panel

Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934

**

Nonstatinsshown toreduce ASCVDevents in RCTspreferred

IIaIIa BB

<100 mg/dl

Nonstatins

Shown to reduce CVD events added to background statintherapy

•Ezetimibe•IMPROVE-IT 2015•IMPROVE-IT 2015

•PCSK9 monoclonal antibodies•Preliminary – ODYSSEY LONG TERM & OSLER•CV outcomes RCTs pending

Cannon, C.P., et al., NEJM 2015. 372(25): p. 2387-2397; Robinson, J.G., et al., NEJM 2015. 372(16): p. 1489-1499.Sabatine, M.S., et al., NEJM 2015. 372(16):p. 1500-1509;

Not clearly shown to reduce CVD events added tobackground moderate intensity statin therapy

•Niacin (harmful in diabetic subgroup)

Nonstatins

•Niacin (harmful in diabetic subgroup)

•Fenofibrate (trend to benefit low HDL-C/high TG butharmful in women)

The HPS2-THRIVE Collaborative Group, NEJM 2014. 371: p. 203-2012; The ACCORD Study Group, N Engl J Med, 2010. 362: p. 1563-1574; The AIM-HIGHInvestigators, N Engl J Med, 2011. 365: p. 2255-2267.

ACC nonstatin clinical pathway – LDL-C thresholdsfor considering nonstatin therapy

Lloyd-Jones D, et al. JACC 2016; 68: 92-125

ACC nonstatin clinical pathway - Clinical ASCVD with comorbidities (2)

Lloyd-Jones D, et al. JACC 2016; 68: 92-125

How can patients be betteridentified for addednonstatin therapy?nonstatin therapy?

Robinson JG, et al. J Am Coll Cardiol 2016 in press

Ezetimibe, PCSK-9 mAbs and the CTT Statin line

ODYSSEY LONGTERM12248

ODYSSEY pooled

OSLER I & II12048JUPITER

10850

CTT Collaboration. Lancet 2005; 366:1267-78; Cannon CP, et al. NEJM 2015;372:2387-2397; Robinson JG, et al. NEJM 2015;372:1489-1499; Robinson JG, et al. AHA Scientific Sessions2014, Chicago IL. Nov 2014; Sabatine MS, et al. NEJM 2015;372:1500-1509

IMPROVE-IT ezetimibe major CVD7054

IMPROVE-IT ezetimibe hard CVD

Very high risk groups>30% 10-year ASCVD risk ON statin therapy in RCTs

• Clinical ASCVD + Diabetes

• Clinical ASCVD + Chronic kidney disease

• Clinical ASCVD with poorly controlled risk factors

• Recent acute coronary syndrome (<3 months)• Recent acute coronary syndrome (<3 months)

• Clinical ASCVD + primary LDL-C >190 mg/dl or familialhypercholesterolemia

• Clinical ASCVD with multiple recurrent events*

• Clinical ASCVD with elevated lipoprotein (a)*

Robinson JG, et al. J Am Coll Cardiol 2016 in press; *Lloyd-Jones DL, et al. ACC expert nonstatin pathway. JACC 68: 92-125.

Very high risk (>30% 10-year ASCVD risk)

5-year NNT to prevent 1 ASCVD event

Initial LDL-CEzetimibe

LDL-C 20%

PCSK9 mAb

LDL-C50%

PCSK9 mAb

65%

190 mg/dl 32 13 10

160 mg/dl 38 15 12160 mg/dl 38 15 12

130 mg/dl 47 19 15

100 mg/dl 61 25 19

70 mg/dl 88 35 27

Robinson JG, et al. J Am Coll Cardiol 2016 in press; Steel N. Br Med J 2000; 1446-15447

Reasonable NNT thresholds: Physicians: NNT < 50 Patients: NNT <30

PCSK9 mAbsStatin intolerant patientsStatin intolerant patients

Muscle symptoms in statin intolerant patientsODYSSEY ALTERNATIVE – Alirocumab double-blind RCT

33%

41%

46%

24%22%

78%toleratedblinded

atorvastatin20 mg

8%

24%

7%

16%

20%22%

2%

Placebo Alirocumab Ezetimibe Atorvastatin 20 mg Open labelAlirocumab

Any musculoskeletal symptoms Musculoskeletal symptoms leading to discontinuation

98%tolerated

open-labelalirocumab

Moriarity PM, et al. J Clin Lipidol. 2015;9:758-69.

Muscle symptoms in statin intolerant patientsGAUSS-3– Evolocumab double-blind RCT – mean intolerant >2 statinsTime to muscle symptoms resulting study drug discontinuation

Phase A1: Nocebo effect “Power of expectation” Phase A2: ≈20% truly intolerant?

Phase B: Ezetimibe 29% vs Evolocumab 21% DC due to intolerable muscle symptomsNissen et al. JAMA 2016; 315(15):1580-1590

Maximize statin therapy

• Same rate of muscle & other adverse events in statintrials

• Most patients with statin-related symptoms cantolerate blinded statin therapytolerate blinded statin therapy

• Clinician needs to believe statins are safe and effectiveto convince the patient

• Statins reduce nonfatal & fatal coronary & stroke events• Statins reduce total mortality in 1 & 2 prevention

Stone NJ, Robinson JG, Lichtenstein AH, et al.. J Am Coll Cardiol. 2014;63(25, Part B):2889-2934; Nissen et al. JAMA 2016; 315(15):1580-1590; Moriarity PM, etal. J Clin Lipidol. 2015;9:758-69

Lower might be better

It matters how you get thereIt matters how you get thereand in whom

Robinson, J.G.. Eur Heart J 2016. 37(17): p. 1380-1383.