BarcelonaAugust 30, 2014

Innovations in lipid management:Evolving insights and implications from PCSK9 research

Prof. John Kastelein, MDAcademic Medical Center

Amsterdam, The Netherlands

EBAC ACCREDITED EDUCATIONAL PROGRAMME HELD DURING THE ESC CONGRESS 2014

Validation of PCSK9 as a Novel Target for CVD Prevention and it’s

Role in the Management of FH

Presented - August 30, 2014

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Disclosures

Dr. Kastelein consults with and speaks for biotechnological

as well as pharmaceutical companies that develop

molecules that influence lipoprotein metabolism and / or

inflammation to prevent CVD, including Regeneron,

Sanofi, Amgen, Pfizer, Eli Lilly, Isis, Genzyme, Aegerion, Dezima

Pharmaceuticals, AstraZeneca, Omthera, CSL Behring,

Cerenis, Esperion, Catabasis, The Medicines Company,

Novartis, Boehringer Ingelheim, MSD, UniQure, Vivus

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New Approaches to LDL Reduction

What is in development?

• Cholesterol Absorption Inhibitors

• Squalene Synthase (SSI) inhibitors

• Apo B mRNA antisense drugs

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors

• Thyroxin Receptor Agonists

• PCSK9 Inhibitors

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Familial Hypercholesterolemia

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Familial Hypercholesterolemia

Mabuchi H et al. Circulation 1989;79:225–232.

6

FH Patients at LDL Goal

Alirocumab Phase I studies

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8

The Use of a PCSK9 Monoclonal AB

in heFH Patients

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The Use of a PCSK9 Monoclonal AB

in heFH Patients: Results

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The Use of a PCSK9 Monoclonal AB

in heFH Patients: Results

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The Use of a PCSK9 Monoclonal AB

in heFH Patients: Safety

The Addition of Evolocumab (AMG 145)

Allows the Majority of Heterozygous Familial

Hypercholesterolemic Patients to Achieve

Low-density Lipoprotein Cholesterol Goals

– Results from the Phase 3 Randomized,

Double-blind, Placebo-controlled StudyFrederick Raal,1 Robert Dufour,2 Traci Turner,3 Fernando Civeira,4 Lesley Burgess,5

Gisle Langslet,6 Russell Scott,7 Anders G. Olsson,8 David Sullivan,9

Gerard K. Hovingh,10 Bertrand Cariou,11 Ioanna Gouni-Berthold,12

Ransi Somaratne,13 Ian Bridges,14 Rob Scott,13 Scott M. Wasserman,13 and Daniel Gaudet15 for the RUTHERFORD-2 Investigators

1Carbohydrate & Lipid Metabolism Research Unit, University of Witwatersrand, Johannesburg, South Africa; 2Institut de Recherches Cliniquesde Montreal, Universite de Montreal, Quebec, Canada; 3Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA; 4Hospital

Universitario Miguel Servet, Zaragoza, Spain; 5TREAD Research, Cardiology Unit, Department of Internal Medicine, University of Stellenbosch, Parow, South Africa; 6Lipid Clinic, Oslo University Hospital, Oslo, Norway; 7Lipid and Diabetes Research Group, Christchurch, New Zealand; 8Linkoping University and Stockholm Heart Center, Stockholm, Sweden; 9Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia; 10Academisch Medisch Centrum, Vascular Medicine, Amsterdam, The Netherlands; 11Institut du

Thorax, Nantes University Hospital, Nantes, France; 12Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany; 13Amgen Inc., Thousand Oaks, CA, USA; 14Amgen Ltd, Uxbridge, United Kingdom; 15ECOGENE-21, Dyslipidemia,

Diabetes and Atherosclerosis Research Group, Department of Medicine, Université de Montréal, Chicoutimi, Québec, Canada

March 29, 2014, Featured Clinical Research Session 400

American College of Cardiology, Washington DC

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RUTHERFORD-2 Study Design

Screening

Period

with

Placebo

Injection

Evolocumab 140 mg SC Q2W

N = 111a

Placebo SC QM

N = 55

Placebo SC Q2W

N = 55a

Ra

nd

om

iza

tio

n

Day 1 Week 2 Week 4b Week 6b Week 8 Week 10 Week 12 Week 14cMax. 6 weeks

Evolocumab or placebo SC Q2W

Evolocumab or placebo SC QM

Evolocumab 420 mg SC QM

N = 110

En

d o

f S

tud

y

2:2:1:1

a N’s are number of patients randomized. One patient in each of the placebo Q2W and evolocumab Q2W groups did not receive any

doses of the study drug and were not included in the analysesb Injections at weeks 4 and 6 were done at homec Week 14 was a follow-up call for Q2W patients to capture adverse events and concomitant medications

Q2W, biweekly; QM, monthly; SC, subcutaneous

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-70

-60

-50

-40

-30

-20

-10

0

10

20

-70

-60

-50

-40

-30

-20

-10

0

10

20

RUTHERFORD-2: Mean % Change in LDL-Ca from Baseline

to the Mean of Weeks 10 and 12, and Week 12 Alone

Weeks 10 and 12

aDetermined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 40 mg/dL or

triglyceride levels were > 400 mg/dLbP < 0.001; placebo-adjusted treatment difference analyzed using repeated measures model which included treatment group, stratification

factors (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates

LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly; SE, standard error

Ad

jus

ted

Me

an

Pe

rcen

t C

ha

ng

e ±

SE

fro

m

Bas

eli

ne

Placebo Q2W (N = 54)

Placebo QM (N = 55)

Evolocumab 140 mg Q2W (N = 110)

Evolocumab 420 mg QM (N = 110)

–1%

–60%b

–61%

2%

–64%

–66%b –60%b –61%b

–1%

5%

–56%–61%

Week 12

15

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

RUTHERFORD-2: LDL-Ca Goal Achievement

< 70 mg/dL

aDetermined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 40 mg/dL or triglyceride

levels were > 400 mg/dLbP < 0.001; analyzed using CMH test, stratified by the stratification factors

LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly

Pro

po

rtio

n o

f P

ati

en

ts (

%)

2%

67%

80%

2% 2%

68%

2%

63%

Placebo Q2W (N = 54)

Placebo QM (N = 55)

Evolocumab 140 mg Q2W (N = 110)

Evolocumab 420 mg QM (N = 110)

61%b65%b

79%b

66%b

Weeks 10 and 12 Week 12

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RUTHERFORD-2: Key Laboratory Results

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; ULN, upper limit of normal

Laboratory ResultsPlacebo(N = 109)

Evolocumab (N = 220)

ALT or AST > 3 × ULN at any

post-baseline visit, %0.0 0.0

CK > 5 × ULN at any

post-baseline visit, %1.8 0.0

CK > 10 × ULN at any

post-baseline visit, %0.9 0.0

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Primary endpoint: % change from baseline in ultracentrifugation LDL-C at week 12

Study drug administration

*Randomization stratified by screening LDL-C (<10.9 mmol/L or ≥10.9 mmol/L). †Week 2 and week 10 study visits were optional.

SC = subcutaneous; QM = every 4 weeks; LDL-C = low-density lipoprotein

cholesterol

Screening

period

Fasting LDL-C

5–10 days

before

randomization

Ra

nd

om

iza

tio

n*

2:1

En

d o

f S

tud

y

Placebo SC QM

(N = 17)

Evolocumab 420 mg SC QM

(N = 33)

Day 1 Week 2† Week 4 Week 6 Week 8 Week 10† Week 12Visits:

Dosing QM:

Trial Evaluating Evolocumab, a PCSK9 Antibody, in Patients with

Homozygous FH (TESLA part B): a Global, Phase 3, Randomized,

Double-blind, Placebo-controlled Trial: Study Design

Raal et al Presented EAS Madrid May

2014

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TESLA part B: LDL-C Lowering by Type of

MutationPercent Change from Baseline in UC LDL-C at Week 12, Mean (SE)

Mutation Status N Placebo Evolocumab

420 mg QM

Treatment

Difference

All 49 7.9 (5.3) -23.1 (3.8) -30.9 (6.4)*

LDLR

Defective/any† 28 11.2 (5.1) -29.6 (3.4) -40.8 (6.1)‡

Defective/defective 13 15.1 (7.3) -31.8 (5.8) -46.9 (9.4)‡

Negative/defective 9 3.5 (5.8) -21.0 (4.0) -24.5 (7.0)§

Unclassifiedǁ 22 3.8 (11.7) -17.9 (8.8) -21.7 (13.9)

Median (Q1, Q3) 7.2 (0.0, 9.9) -39.2 (-48.8, -14.6) -

Negative/negative 1 - 10.3 -

LDLR Heterozygous 1 - -55.7 -

Apolipoprotein B 2 -10.8, 13.1 - -

ARH 1 - 3.5 -

Data are least squares (LS) mean for groups with sufficient data; otherwise actual value at week 12. LS mean is from the

repeated measures model, which includes treatment group, screening LDL, scheduled visit and the interaction of

treatment with scheduled visit as covariates. *Adjusted P-value < 0.001; †Receptor defective in at least one of two

affected alleles. ‡ Nominal P-value < 0.001; §Nominal P-value = 0.013; ǁFunction of one or both LDLR mutations is

unknown (includes 6 patients from the defective/any group).Raal et al Presented EAS Madrid May

2014

LDL Cholesterol: A Moving Target in FH

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