Preparing for a Novel Era in

CV Prevention:

Where do PCSK9 Inhibitors Fit

in Lipid Management

Prof. John J.P. Kastelein, MD PhD FESC

Dept. of Vascular Medicine

Academic Medical Center / University of Amsterdam

The Netherlands

2

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, Iosis, AstraZeneca, CSL Behring,

Cerenis, Esperion, The Medicines Company, Kowa, Affiris,

UniQure, Madrigal Pharmaceuticals, Akcea Therapeutics, Staten

Biotech, Akarna, Corvidia and Gemphire

3

PCSK9: Protein and Function

PCSK9: The Chaperone

(Binds to the LDLR)

EGFA

domain

PCSK9 LDLR

CHRD

Prodomain

Catalytic

domain

Seidah et al. (2014) Circ Res

Endocytosis

5

PCSK9: Target for

Pharmacotherapy?

SPIRE Phase 3 Bococizumab

Clinical Development

6

PCSK9 Inhibitors

7

High risk, high LDL-C

Statin Intolerance

Familial Hypercholesterolemia

Familial Hypercholesterolemia

Familial Hypercholesterolemia

10Ray and Hovingh, Eur Heart J. 2016; 37: 1395-97

Number of Publications on FH per year

11

Heterozygous Familial Hypercholesterolemia Patients

are at greater risk from their LDL than other individuals with

similar LDL-C (Khera et al, JACC 2016; 67: 2578)

are rearly diagnosed before they suffer from their first

coronary event at age 44 (Krogh et al, Eur Heart J. 2016; 17: 1398)

have a post-ACS hazard ratio of 3.5 for a secondary event (Nanchen et al, Eur Heart J. 2015; 36: 2438)

are only receiving high-dose statin therapy in 75% of cases (Pijlman et al, Atherosclerosis 2009; 1: 189)

seldom reach the LDL-C guideline target of <70 mg/dl (Nanchen et

al, Circulation 2016; in press)

All of the above leads to their death from a recurent event at a

mean age of 60 (Krogh et al, Eur Heart J. 2016; 17: 1398)

Novel Insights in the Diagnosis and

Management of FH to date.

PCSK9 Inhibitors in the Management of FH

12

FH I, 78 weeks

Alirocumab, n=323

Placebo, n=163

FH II, 78 weeks

Alirocumab, n=167

Placebo, n=82

HIGH FH, 78 weeks

Alirocumab, n=72

Placebo, n=35

Patients with HeFH

Alirocumab, n=276

Placebo, n=139

SPIRE FH (n=300)

HeFH (genetic diagnosis

or Simon Broome

Criteria),

LDL >70 mg/dl

Alirocumab Bococizumab Evolocumab

In total: 1634 heFH patients

The RUTHERFORD-2 Study: Evolocumab

Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (NCT20110117)

Design: A 12-week, randomized, double-blind, placebo-controlled, multicenter phase 3 study

Objective:To evaluate the efficacy and safety of evolocumab(AMG 145) 140 mg Q2W and 420 mg QM administered subcutaneously in a large cohort of HeFH patients unable to achieve an LDL-C < 100 mg/dL despite statin therapy with or without ezetimibe

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

-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

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

Raal et al, Lancet 2014;385:331-40

0

10

20

30

40

50

60

70

80

90

0

10

20

30

40

50

60

70

80

90

RUTHERFORD-2: LDL-C Goal Achievement

< 70 mg/dL

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

Raal et al, Lancet 2014;385:331-40

The Odyssey Program: Alirocumab Efficacy

and Safety in 1257 heFH Patients

17Kastelein, Eur Heart J. 2015; 36: 2996-3003

18

-43,6

-57,1

5,41,1

-48,8

-55,0

7,1

1,3

-60

-50

-40

-30

-20

-10

0

10

LS

mean

(S

E)

% c

han

ge f

rom

baselin

e t

o W

eek 1

2/W

eek

24 i

n L

DL

-C

Pool of FH I & II studies Pool of LONG TERM (HeFH

patients only) and HIGH FH

Kastelein, Eur Heart J. 2015; 36: 2996-3003

Week 12

Week 24

Alirocumab 75/150 mg Q2W† (n=488)

Week 12

Week 24Placebo (n=244)

Week 12

Week 24Alirocumab 150 mg Q2W (n=346)

Week 12

Week 24Placebo (n=174)

-49.0% -58.1% -56.4%-55.8%

LDL-C Reduction with Alirocumab at Week 24

was Similar in Both Pooled Study Groups

19

0

20

40

60

80

100

120

140

160

180

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80

Alirocumab 150 mg Q2W (n=345) Placebo (n=174)

ΔW24†:

-57.1 (2.4)%

versus placebo

(P<0.0001)

LS

mean

LD

L-C

level

(SE

), m

mo

l/L

Study Week

Kastelein, Eur Heart J. 2015; 36: 2996-3003

Mean Calculated LDL-C Levels Pool of LONG TERM (HeFH patients only) and HIGH FH

20

Week 12

Week 24Alirocumab 75/150 mg Q2W‡ (n=488)

Kastelein, Eur Heart J. 2015; 36: 2996-3003

Odyssey ProgramPool of FH I & II Studies: Goal Achievement

LDL-C Levels in FH: From a Lethal Disorder

to a Manageable Dislipidemia

21Kastelein, Nat. Rev. Cardiol. 2014; 11:629-31

Conclusions

22

The current management of heFH can be summarizedby: too little, too late (Hovingh & Kastelein, Circulation2016, in press)

The future looks a lot brighter: both Evolocumab & Alirocumab therapy, on top of statins / ezetimibe, offers goal attainment hitherto impossible