The PCSK9 Inhibitor Revolution

Norman E. Lepor, MD FACCClinical Professor of Medicine-UCLA

Cedars-Sinai Heart InstituteWestside Medical Associates of Los Angeles

Disclosure Statement of Financial Interest

• Grant/Research Support

• Consulting Fees/Honoraria

• Ownership/Founder

• Amarin, Amgen, Boehringer Ingelheim, Regeneron, Sanofi, Pfizer, Gilead

• Boehringer-Ingelheim, Regeneron, Sanofi, Gilead, Gilead, Vivus, Takeda, Bristol-Myers Squibb, Pfizer, Daichi-Sankyo, Eli Lilly, Gilead

• Canady Technology

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

ASCVD Event Rates: Relation to LDL-C Levels

• Statins are currently the most effective agents for reducing LDL-C levels

– 20 million patients treated• In statin secondary prevention

trials, CHD event rates were directly proportional to on-treatment LDL-C levels

• LDL-C levels are causally related to atherosclerosis risk

• Treatments lowering LDL-C would be expected to decrease ASCVD events and mortality in proportion to LDL-C lowering

ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol.Legend to figure: 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol And Recurrent Events Trial; CHD, coronary heart disease; HPS, Heart Protection Study; LDL-C, low-density lipoprotein cholesterol; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease Trial; PROVE-IT, Pravastatin or Atorvastatin Evolution and Infection Therapy trial.O’Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142-2146.

30 50 70 90 110 130 150 170 190 210

LDL-C (mg/dL)

CHD

Eve

nts

(%)

30

25

20

15

10

5

0

y = 0.1629x – 4.6776R2 = 0.9029P < .0001

4S-P

4S-SHPS-P

LIPID-P

CARE-PLIPID-S

CARE-S

PROVE-IT-PR

PROVE-IT-AT

HPS-S

Relationship Between LDL-C and ASCVD Risk Reduction

• Hazard ratio of ASCVD primary endpoint (MACE) vs range of LDL-C levels (adjusted for age, sex, baseline LDL-C, diabetes mellitus, and prior myocardial infarction) for statin-treated patients

• Progressively lower ASCVD risk with lower LDL-C levels on treatment

ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiac events; MI, myocardial infarction.

1. Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416..

Primary endpoint: MACE: a composite of death, MI, stroke, revascularization, and unstable angina requiring hospitalization

Hazard Ratio

Referent

0.80 (0.59, 1.07)

0.67 (0.50, 0.92)

0.61 (0.40, 0.91)

>80-100

>60-80

>40-60

<40A

chie

ved

LDL

(mg/

dL)

Lower Better Higher Better

0 1 2

Evidence of Need:Looking Beyond Statins

ACS, acute coronary syndrome; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; PAD, peripheral arterial disease.*Including those with recent ACS, history of coronary events, history of ischemic stroke, and history of PAD.Ray KK et al. ISPOR 16th Annual European Congress; November 2-6, 2013; Dublin, Ireland.

Prop

ortio

n of

Pati

ents

n = 5124(5%)

n = 78,366(74%)

n = 13,353 (13%)

n = 8545(8%)

n = 105,388(100%)

Achieved LDL-C Level

Achieved LDL-C Levels by Very-High CV-Risk* Categories

IMPROVE-IT: Non-statin LDL-C Lowering Reduces CV Events

HR, 0.936 (95% CI, 0.89-0.99)P = .016

Primary Endpoint: CV death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥ 30 days), or stroke

7-year event rates

40

30

20

10

00 1 2 3 4 5 6 7

Even

t Rat

e (%

)

Time Since Randomization (y)

Cannon CP et al. N Engl J Med. Published June 3, 2015. doi: 10.1056/NEJMoa1410489.

Simvastatin monotherapy

Simvastatin–ezetimibe

What Is PCSK9?

• PCSK9 = Proprotein Convertase Substilisin/Kexin type 9

• PCSK9 targets the LDL-R for degradation by creating a PCSK9–LDL-R receptor complex1 – The LDL-R located on the hepatocyte cell surface

mediates the endocytosis of LDL-C and all atherogenic lipoproteins by recognizing ApoB and E

– PCSK9 plays a role in determining the density of LDL-R

• Will the LDL-R be recycled back to the hepatocyte cell surface after binding LDL-C followed by endocytosis, or will it undergo lysosomal degradation?

LDL-C, low-density lipoprotein cholesterol; LDL-R, low-density lipoprotein receptor.1. Lagace T et al. J Clin Invest. 2006;116:2995-3005.2. Lambert G et al. J Lipid Res. 2012;53:2515-2524.

PCSK9 Function and Physiology• PCSK9 first discovered to have lipid metabolism involvement in 20031

– Autosomal-dominant FH case determined a relation to gene encoding PCSK9

• Animal studies showed PCSK9 was involved in lipid metabolism, suggesting loss of PCSK9 function resulted in decreased LDL-C levels2

• Sequencing of the PCSK9 gene in low LDL-C individuals found subjects with loss-of-function PCSK9 mutations had 28% LDL-C level decrease vs non-mutation subjects3,4

– Relative 88% decrease in ASCVD events seen over 15 years of study follow-up4

– Gain-of-function mutations in PCSK9 reduce LDL-C receptors in the liver, resulting in high plasma levels of LDL-C1

• PCSK9 mRNA levels are responsive to cellular cholesterol levels through transcription factor SREBP-25

• Statins upregulate PCSK9 synthesis6

1. Abifadel M et al. Nat Genet. 2003;34:154-156.2. Rashid S et al. Proc Natl Acad Sci USA. 2005;5374-5379.3. Cohen J et al. Nat Genet. 2005;37:161-165.4. Cohen JC et al. N Engl J Med. 2006;354:1264-1272.5. Horton J et al. Proc Natl Acad Sci. 2003;100:12027-12032.6. Attie AD et al. Arterioscler Thromb Vasc Biol. 2004;24:1337-1339.

PCSK9 Targets LDL-R for Degradation

• PCSK9 binds to the EGF-A domain of the LDL-R, stimulating LDL-R degradation1,2

• When this complex is internalized in clathrin-coated endosomes, the LDL-R bound to PCSK9 undergoes lysosomal degradation3

EGF-A, epidermal growth factor-like repeat A; 1. Lagace TA et al. J Clin Invest. 2006;116:2995-30052. Qian YW et al. J Lipid Res. 2007;48:1488-1498.3. Seidah NG et al. Int J Biochem Cell Biol. 2008;40:1111-1125.Image from Davidson MH. http://www.medscape.org/viewarticle/763848_transcript. Accessed October 28, 2014.

PCSK9 secretionPCSK9 secretionLDLRLDLR

Lysosomal degradationLysosomal degradation

LDLR/PCSK9routed to lysosome

LDLR/PCSK9routed to lysosome

Clathrin dissociation

Clathrin dissociation

VesicleVesicle

LysosomeLysosomeAmino acids

Amino acids

LipidsLipids

EndosomeEndosome

Acidicenvironment

Acidicenvironment

LDLLDL

VesicleVesiclePCSK9PCSK9

Impact of PCSK9 mAb on LDL-R Surface Concentration

• By targeting the LDL-R, PCSK9 reduces its functional half-life and results in reducing the hepatocyte’s ability to clear LDL-C from the circulation

Image from Davidson MH. http://www.medscape.org/viewarticle/763848_transcript. Accessed October 28, 2014.

LDLLDL

VesicleVesiclePCSK9PCSK9

Lysosomal degradationLysosomal degradation

LDLR recyclingLDLR recycling

Increased LDLR surface concentration

Increased LDLR surface concentration

mAbmAb

VesicleVesicle

LDLRLDLR

Clathrin dissociation

Clathrin dissociation LysosomeLysosome

Amino acids

Amino acids

LipidsLipids

EndosomeEndosome

Acidicenvironment

Acidicenvironment

EndosomeEndosome

Mechanism of Action: Endogenous Regulation of PCSK9 Production

• In large part related to SREBP-21

• SREBP-2 is up-regulated in response to low levels of cholesterol in the key intrahepatic regulatory pools such as observed with statin therapy and other lipid-lowering treatments1,2 – Leads to up-regulation of LDL-R,

increasing uptake of LDL-C from the plasma, and the transcription of PCSK9, which leads to the degradation of the LDL-R

– Addition of a drug to inhibit PCSK9 will lead to lowering of LDL-C levels3

SREBP-2, sterol regulatory element-binding protein-2. 1. Maxwell KN et al. J Lipid Res. 2003;44:2109-2119.2. Sato R. Arch Biochem Biophys. 2010;501:177-181.3. Maxwell K, Breslow JL. Circ Res. 2012;111:274-277.Image from Maxwell K, Breslow JL. Circ Res. 2012;111:274-277.

Pcsk9 inhibitor

Population Studies: PCSK9 Loss-of-Function Mutations

ARIC, Atherosclerosis Risk in the Community; CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CHD, coronary heart disease; CIHDS, Copenhagen Ischemic Heart Disease Study; LDL-C, low-density lipoprotein cholesterol.Cohen JC et al. N Engl J Med. 2006;354:1264-1272.Benn M et al. J Am Coll Cardiol. 2010;55:2833-2842.Catapano AL, Papadopoulos N. Atherosclerosis. 2013;228(1):18-28.

PCSK9 Mutation

LDL-CReduction

CHDReduction Population

Benn et al (2010)

R46L 13% 30%

CCHS N = 10,032CGPS N = 26,013CIHDS N = 9654(Denmark)

Cohen et al (2006)

R46L

Y142X orC679X

15%

28%

47%

88%

ARIC Study (US) (black patients N = 3363; white patients N = 9524)

• Subjects with loss-of-function mutations in PCSK9 or total lack of PCSK9– Have naturally low levels of LDL-C and reduced CHD ( efficacy) – Are generally healthy with no other apparent metabolic abnormalities (

safety)

Key PCSK9 mAb Inhibitor Pharmaceuticals in Phase III Evaluation

• Key pharmaceuticals1-3

– Alirocumab (REGN727) – Evolocumab (AMG 145)– Bococizumab (RN316)

Alirocumab (REGN727; sanofi aventis, Bridgewater, NJ and Regeneron, Tarrytown, NY); bococizumab (RN316; Pfizer Inc, New York, NY; evolocumab (AMG 145; Amgen, Thousand Oaks, CA). 1. Stein EA et al. N Engl J Med. 2012;366:1108-1118.2. Dias CS et al. J Am Coll Cardiol. 2012;60:1888-1898.3. Gumbiner B. AHA Scientific Sessions; November 3-7, 2012; Los Angeles, CA.

ODYSSEY COMBO II• Objective: To evaluate the efficacy and safety

of alirocumab as add-on therapy to stable, maximally tolerated daily statin therapy vs ezetimibe in patients with hypercholesterolemia at high cardiovascular risk1-3

• Key results– Alirocumab lowered LDL-C levels

significantly more vs ezetimibe by week 24 (50.6% vs 20.7%; P < .0001) and week 52 (49.5% vs 18.3%; P <.001)

– 77% of alirocumab-treated patients achieved LDL-C levels of 70 mg/dL or lower by week 24 vs 45.6% of ezetimibe-treated patients (P < .0001)

– AEs percentage were similar between alirocumab (71.2%) and ezetimibe (67.2%) treatments

AEs, adverse events; CV, cardiovascular; ITT, intent to treat; LDL-C, low-density lipoprotein cholesterol.1. Colhoun HM et al. BMC Cardiovasc Disord. 2014;14:121-130.2. Roth EM et al. Fut Cardiol. 2014;10:183-199.3. Cannon CP et al. Eur Heart J. 2015;36:1186-1194.

ITT analysis

Most of These High CV-Risk Patients Receiving Alirocumab on Background Statin Achieved

LDL-C Goal

All Patients on Background of Maximally Tolerated Statin

PlaceboAlirocumab

Proportion of Patients Reaching LDL-C < 1.81 mmol/L (70 mg/dL)

at Week 24

Proportion of Patients Reaching LDL-C < 1.3 mmol/L (50 mg/dL) at

Week 24

P < .0001 Post hoc

% P

atien

ts

77.0%

45.6%

0

20

40

60

80

100

ODYSSEY ALTERNATIVE• Objective: To assess efficacy and safety of alirocumab in statin-intolerant subjects at

moderate to very-high ASCVD risk compared with ezetimibe1

• Study design1

– Intolerance was defined as inability to take at least two different statins because of muscle-related AEs, one at the lowest commercially available dose

– Patients first received single-blind subcutaneous and oral placebo for 4 weeks, and were withdrawn if they developed muscle-related AEs after the placebo treatment

– Continuing patients were randomized (2:2:1 ratio) to alirocumab 75 mg self-administered via single 1 mL prefilled pen every 2 weeks or ezetimibe 10 mg/day or atorvastatin 20 mg/day (statin rechallenge), for 24 weeks

– Alirocumab dose was increased to 150 mg every 2 weeks (also 1 mL) at week 12 depending on week 8 LDL-C level

– The primary endpoint is percentage change in LDL-C from baseline to week 24 by intent-to-treat analysis

• Key findings – Greater percentage reduction from baseline in LDL-C at 24 weeks with alirocumab vs

ezetimibe (45.0% vs 14.6%; P < .0001)– Rates of discontinuation due to AEs were not statistically significant between groups

AEs, adverse events; ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.1. Moriarty PM et al. Poster presentation at American Heart Association 2014 Scientific Sessions; November 17, 2014; Chicago, IL.

ODYSSEY LONG TERM Study Design

CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia; Q2W, every other week; SC, subcutaneous.ClinicalTrials.gov identifier: NCT01507831.

HeFH or High CV-risk patients

On max-tolerated statin other lipid-lowering

therapy

LDL-C ≥ 1.81 mmol/L [70 mg/dL]

HeFH or High CV-risk patients

On max-tolerated statin other lipid-lowering

therapy

LDL-C ≥ 1.81 mmol/L [70 mg/dL]

Double-blind Treatment (18 months)

n = 1553

n = 788R

Follow-up(8 weeks)

Alirocumab 150 mg Q2W SC(single 1-mL injection using prefilled syringe for self-administration)

Placebo Q2W SC

AssessmentsW0

W4

W8

W12

W16

W24

W36

W52

Primaryefficacy endpoint

Pre-specified analysisEfficacy: All patients to W52Safety: Baseline-W78 (all patients at least W52)

W64 W78

86% (2011/2341) completed 52 weeks (both treatment arms)26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) had completed 78 weeks by time of this analysisMean treatment duration: 65 weeks (both treatment arms)

ODYSSEY LONG TERM• Objective: To evaluate the long-term safety and

tolerability of alirocumab for the treatment of high and very high cardiovascular risk patients with hypercholesterolemia who are not adequately controlled on their current lipid-modifying therapy1

• Key results– At 24 weeks, mean LDL-C reduction from

baseline of 61% for alirocumab patients vs increase of 0.8% for patients on placebo (P < .0001)

– By week 24, more alirocumab patients than placebo reached LDL-C goal of ≥ 50% reduction from baseline (76% vs 2%; P < .0001), a level < 100 mg/dL in high-risk patients, or a level < 70 mg/dL in very high-risk patients (81% vs 9%; P < .0001)

– Safety results showed that AEs were similar in both arms, occurring in 78.6% and 80.6% of the alirocumab and placebo-treated patients, respectively

ITT, intent to treat; LDL-C, low-density lipoprotein chlesterol; LLT, lipid-lowering therapy.1. Roth EM et al. Fut Cardiol. 2014;10:183-199.

ITT analysis.

Most Patients Receiving Alirocumab on Background Statin ± Other LLT Achieved

LDL-C Goals

Proportion of Patients Reaching LDL-C Goal at Week 24

PlaceboAlirocumab

Very high-risk: LDL-C < 1.8 mmol/L (70 mg/dL)

High-risk: < 2.6 mmol/L (100 mg/dL)

< 1.8 mmol/L (70 mg/dL) regardless of risk

P < .0001 P < .0001

% P

atien

ts

ODYSSEY LONG TERMSignificant Reductions in Secondary Lipid Parameters at Week 24

ApoB

−52%P < .0001

Non-HDL-C

LS M

ean

(SE)

% C

hang

e Fr

om B

asel

ine

to W

eek

24

ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; Lp(a), lipoprotein(a); LS, least squares; SE, standard error.Adjusted mean (SE) shown for Lp(a).Robinson JG et al. N Engl J Med. 2015;372:1489-1499.

Lp(a)

LS mean difference vs placebo:

−54%P < .0001

−26%P < .0001

Placebo

Alirocumab

All Patients on Background of Maximally Tolerated Statin ± Other Lipid-lowering Therapy

-60

-50

-40

-30

-20

-10

0

10

7881550

7761534

7311446

7031393

6821352

6671335

321642

127252

00

No. at RiskPlaceboAlirocumab

Weeks

Mean treatment duration: 65 weeks

Placebo + max-tolerated statin ± other LLT0.10

0.08

0.06

0.04

0.02

0.0096847260483624120

Esti

mate

d P

rob

ab

ilit

y o

f Even

t

Alirocumab + max-tolerated statin ± other LLT

Cox model analysis:HR = 0.46 (95% CI: 0.26-0.82)Nominal P value = < .01

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; LLT, lipid-lowering therapy; TEAE, treatment-emergent adverse event.Same as primary endpoint of ongoing ODYSSEY OUTCOMES trial.†

†Primary endpoint for the ODYSSEY OUTCOMES trial: coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization.

Robinson JG et al. N Engl J Med. 2015;372:1489-1499.

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed

W78 visit)

ODYSSEY LONG TERM Post hoc Adjudicated Cardiovascular TEAEs

Evolocumab Phase III Trial MENDEL-2

• Objective: To assess stand-alone evolocumab treatment in patients with hyperlipidemia1

• Key results1

– Evolocumab provided more rapid and greater LDL-C lowering over 12 weeks vs placebo or ezetimibe

– Overall incidence of treatment-emergent AEs were comparable across treatment groups

MENDEL, Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels.1. Koren MJ et al. J Am Coll Cardiol. 2014;63:2531-2540.

Placebo Evolocumab monthlyEzetimibe

BL Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12

10 -

0 -

-10 -

-20 -

-30 -

-40 -

-50 -

-60 -

Placebo Evolocumab biweeklyEzetimibe

Mea

n Pe

rcen

t Cha

nge

in

LDL-

C fr

om B

asel

ine

BL Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12

10 -

0 -

-10 -

-20 -

-30 -

-40 -

-50 -

-60 -

Study drug administrationMonthlyNumber of patientsPlacebo 78 77 73 68 70Ezetimibe 77 76 70 67 69Evolocumab 153 151 147 134 136

Mea

n Pe

rcen

t Cha

nge

in

LDL-

C fr

om B

asel

ine

Study drug administration Biweekly SCNumber of patientsPlacebo 76 75 76 71 69Ezetimibe 77 77 72 68 70Evolocumab 153 146 145 143 133

Evolocumab Phase III Trial TESLA-2

• Objective: To assess the safety, tolerability, and efficacy of evolocumab and statin in HoFH patients to those on statin therapy alone (with placebo)1

• Key results1

– Vs placebo, evolocumab reduced LDL-C by 30.9% at 12 weeks– No serious AEs noted

AEs, adverse evenets; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; TESLA, Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities. 1. Raal FJ et al. Lancet. 2014; pii: S0140-6736(14)61374-X.

20 -

10 -

0 -

-10 -

-20 -

-30 -

-40 -Baseline Week 4 Week 6 Week 8 Week 12

Study weekNumber of patientsanalyzed at each visitPlacebo 16 16 15 16 15Evocolumab 33 32 28 32 29

Mea

n %

cha

nge

from

bas

elin

e in

ultr

acen

trifu

gatio

n LD

L ch

oles

tero

l

Placebo group (n=16)

Evocolumab group (n=33)

Evolocumab Phase III Trial RUTHERFORD-2

Objective: To assess and evaluate safety, tolerability, and efficacy of evolocumab dosings (140 mg Q2W, 420 mg QM) in HeFH patients1

Compared with placebo, evolocumab at both dosing schedules1

– Showed significant reduction in mean LDL-C at week 12 (Q2W: 59.2% ; QM dose: 61.3%; both P < .0001)

– Showed significant reduction in mean LDL-C at mean of weeks 10 and 12 (Q2W, 60.2%; QM 65.6%; both P < .0001)

Evolocumab was well tolerated, with similar rates of AEs vs placebo

AEs, adverse events; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; Q2W, every other week; QM, every month; RUTHERFORD, Reduction of LDL-C With PCSK9 Inhibition In Heterozygous Familial Hypercholesterolemia Disorder.1. Raal FJ et al. Lancet. 2014. pii: S0140-6736:61399-4.

BaselineWeek 2Week 8 Week 10 Week 12

Placebo every 2 weeks (n=54)

Placebo monthly (n=55)

140mg evolocumab every 2 weeks (n=110)

420mg evolocumab monthly (n=110)

Evolocumab every 2 weeks

Evolocumab monthly

..

.. .. .. ..

20

0

-20

-40

-60

-80Ch

ange

Fro

m B

asel

ine

in L

DL

Chol

este

rol

(%)

Evolocumab Phase III Trial GAUSS-2• Objective: To assess patients with

hyperlipidemia who cannot tolerate statins2

• Key results2

– Evolocumab reduced LDL-C from baseline by 53%-56%, yielding a 37%-39% treatment difference vs ezetimibe (P < .001)

– Muscular AEs occurred in 12% of evolocumab vs 23% of ezetimibe-treated patients

– Treatment-emergent AEs and laboratory abnormalities were comparable across treatment groups

AEs, adverse events; GAUSS, Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects; 1. Cho L et al. Clin Cardiol. 2014;37:131-139.2. Stroes E et al. J Am Coll Cardiol. 2014;63:2541-2548.

Time point Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 (Q2W only)

Screening and Placebo

Run-in Period

Fasting LDL-C5-10 days beforeRandomization

SubcutaneousInfection of placebo

Evolocumab 140mg SC Q2W = Placebo PO QD~ 100 subjects

Evolocumab 420mg SC QM = Placebo PO QD~ 100 subjects

Placebo SC Q2W + Ezetimibe 10 mg PO QD~ 50 subjects

Placebo SC QM + Ezetimibe 10 mg PO QD~ 50 subjects

Rand

omiz

ation

2:2

:1:1

End

of S

tudy

Maximum 6 weeks

Evolocumab or Placebo SC Q2W

Evolocumab or Placebo SC QM

Final study visit; QM End-of-study

information collected

Q2WEnd-of-study

information collected by telephone

Administration at study site Administration in non-clinic setting

Visit

Cumulative Incidence of Cardiovascular EventsIncluded 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.

Sabatine MS et al. N Engl J Med. Published March 15, 2015. doi: 10.1056/NEJMoa1500858.

No. at RiskStandard therapy 1489 1486 1481 1473 1467 1463 1458 1454 1447 1438 1428 1361 407Evolocumab 2976 2970 2962 2949 2938 2930 2920 2910 2901 2885 2871 2778 843

Days Since Randomization

100

90

80

70

60

50

40

30

20

10

0

Cum

ulati

ve In

cide

nce

(%)

0 30 60 90 120 150 180 210 240 270 300 330 365

0 30 60 90 120 150 180 210 240 270 300 330 365

Standard therapy

Evolocumab

Hazard ratio, 0.47 (95% Cl, 0.28-0.78)P = .003

3

2

1

0

Evolocumab Phase II/III Open-label Trial:Combined OSLER-1 and -2 Results

Bococizumab (RN316)Phase III Trials

• Phase III clinical trial program1,2

– SPIRE-1 Objective: To assess whether lowering LDL-C to levels well below current guideline-recommended targets will lead to further reduction in cardiovascular events; this study includes a high-risk patient population with baseline levels of LDL-C ranging from 70-100 mg/dL

– SPIRE-2 Objective: To evaluate the efficacy and safety of bococizumab in a range of high-risk patients who have not achieved LDL levels lower than 100 mg/dL despite the use of high-dose statins or who are partially or completely statin intolerant

1. http://clinicaltrials.gov/ct2/show/NCT01975376?term=SPIRE-1&rank=1.2. http://clinicaltrials.gov/ct2/show/NCT01975389?term=SPIRE-2&rank=1.

Is There a Cholesterol Level That Is Too Low?

• Reports of healthy individuals documented to have LDL-C as low as 15 mg/dL1 (due to genetic mutations)

• PCSK9 inhibitor studies are ongoing, and will determine if LDL-C lowering beyond what is observed with statin therapy provides incremental cardiovascular protection in a safe manner – LDL-C levels recommended in clinical trials may be as

low as between 25-50 mg/dL11. http://www.nytimes.com/2013/07/10/health/rare-mutation-prompts-race-for-cholesterol-drug.html?pagewanted=3&ref=ginakolata&pagewanted=all.

Overview of Safety of Alirocumab With Very Low LDL-C: A Pooled Analysis

Primary system organ class, % (n)Preferred term, % (n)

Pooled Control

(n = 1894)

Pooled Alirocumab(n = 3340)

Pooled Alirocumab ≥ 2 LDL-C < 25 mg/dL

(n = 796)

Pooled Alirocumab ≥ 2 LDL-C < 15 mg/dL

(n = 288)

Patients with any TEAE 73.7 (1396) 74.3 (2483) 68.2 (543) 67.0 (193)

Patients with any treatment-emergent SAE

13.3 (251) 13.6 (453) 13.1 (104) 9.7 (28)

Patients with any TEAE leading to death

1.0 (18) 0.4 (15) 0.4 (3) 0 (0)

Patients with any TEAE leading to permanent treatment discontinuation

6.6 (125) 6.2 (207) 3.5 (28) 4.9 (14)

Robininson J et al. Abstract presented at XVII International Symposium on Atherosclerosis; May 23-26, 2015; Amsterdam.

• Data pooled from 14 trials in the alirocumab clinical program

– 796 (23.8%) alirocumab patients achieved LDL-C < 25 mg/dL on ≥ 2 consecutive visits (approximately 70% came from ODYSSEY LONG TERM on alirocumab 150 mg Q2W)

– 288 (8.6%) alirocumab patients achieved LDL-C < 15 mg/dL on ≥ 2 consecutive visits

Summary• LDL-C reduction remains the primary target for lipid

modification to reduce cardiovascular risk• Many patients are not able to reach LDL-C treatment goals

with statins due to intolerance or resistance particularly those with HeFH

• PCSK9 inhibitors increase the functional half-life of the LDL-R, leading to increased removal of LDL-C from the circulation

• PCSK9 inhibitors are effective either as monotherapy or as an adjunct to other lipid-lowering therapies reducing LDL-C levels 50%-70% and appear to be well-tolerated and safe

Summary

• Signals are appearing in clinical trials that suggest a substantial incremental reduction of cardiovascular events with PCSK9 inhibition above and beyond those related to statins

• Large randomized clinical trials with cardiovascular events as the primary endpoint are in progress (ODYSSEY OUTCOMES, FOURIER, and SPIRE)