New biologics for the treatment of atherosclerosis and the...

New biologics for the treatment

of atherosclerosis and the

safety thereof

Derick RaalFCP(SA), FRCP, FRCPC, Cert Endo, MMED, PHD

Head, Division of Endocrinology & Metabolism

Director, Carbohydrate and Lipid Metabolism Research Unit

Faculty of Health Sciences, University of the Witwatersrand

Presenter Disclosure Information

Frederick J. Raal

FCP(SA), FRCP, FRCPC, Cert Endo, MMed(Wits), PhD

Professor Raal has received research grants, honoraria, or consulting fees for

professional input and/or delivered lectures from Pfizer Pharmaceuticals, Merck,

Sanofi, Regeneron, Amgen and The Medicines Company.

Decline in deaths from cardiovascular disease in relation to scientific advances

Nagel. N Eng J Med 2012;366:54-63

600

500

400

300

200

100

0

1950 1960 1970 1980 1990 2000 2010 2020

Year

De

ath

s p

er

10

0 0

00

po

pu

latio

n

1954First

open-heart procedure(Gibbon)

1972NHBPEP

1961Risk

factors defined

1958Coronary

arteriography developed

(Sones)

1962Firstβ-blocker developed (Black)

1969First

description of CABG

(Favolaro)

1976First HMG

CoA reductase inhibitor

described (Endo)

1961Coronary care unit

developed (Julian) 1979

Coronary angioplasty developed (Grunfeld)

1976First

implantable cardioverter defibrillator developed (Mirowski)

1985 TIMI 1

1983 CASS

1986 GISSI andISIS-Z

1985 NCEP

2002 ALLHAT

1993 Superiority of

primary PCI vs fibrinolysis in

acute MI noted

2002 Efficacy of

drug-eluting vs bare-metal

stents determined

1992 SAVE

2007 Benefit of

cardiac resin-chronization

therapy in heart failure

demonstrated

2009 Deep gene sequencing for responsiveness to CV drugs performed

2009 Genomwide association in early onset MI described

2009 Left ventricular assist device as destination therapy in advanced heart failure shown to be effective

Cardiovascular disease

is the leading cause

of death worldwide

1 in every 2.4 deaths

> 17 million people worldwide every year

Murray CJL, Lopez AD, eds.The Global Burden of Disease; Boston: Harvard School of Public Health;1996

Atherosclerosis

Hypertension Smoking

Obesity Diabetesmellitus

DYSLIPIDAEMIA

Cholesterol, particularly

LDL- cholesterol is the pivotal risk factor

for atherosclerosis

Relative concentration of ApoB containing lipoproteins in normolipidaemic individuals

LDL

VLDL

IDL remnants

Lipoprotein(a)

Ference et al. Eur Heart J 2017;38:2459-2472

LDL/HDL

Current smoking

Diabetes

Hypertension

Abdominal obesity

Psychosocial

Fruit & veg daily

Exercise

Alcohol intake

Odds Ratio

3.25

2.87

2.37

1.91

1.62

2.57

0.70

0.86

0.91

INTERHEART: Nine modifiable risk factors

predict 90% of acute myocardial infarction

N = 30 000

(262 sites across

52 countries)

Salim Yusuf Lancet 2004;364: 937-52

50%

40%

30%

20%

10%

0%

-10%

40%

50%

30%

20%

10%

0%

-10%

Pro

po

rtio

na

l re

du

ction in e

ve

nt ra

te (

SE

)

0.5 1.5 2

0.5 1 1.5 2

1

Major vascular events

Major coronary events

For every 1 mmol/L reduction in

LDL cholesterol there is :

a) a 21 -24 % reduction in major

CAD or vascular events

b) a 12% reduction in overall

mortality

CTT Collaborators Lancet 2005;366:1267-99; n=90000

CTT Collaborators Lancet 2010;376:1670-81; n=170000

Relation between proportional

reduction in incidence of major

CAD and vascular events and

mean absolute reduction in

LDL cholesterol at 1 year

N= 170 000 subjects from 26 statin trials

80

60

40

20

0

Va

scu

lar

eve

nt fo

r p

rim

ary

en

dp

oin

t (p

er

10

00

pe

rson

ye

ars

)

75

64

28

19

25

15

77

68

27 26

75

64

27

21

Those with diabetes but no CVDallocated to placebo

Those with diabetes & CVDallocated to statin

Those with diabetes & CVDallocated to placebo

Those with diabetes but no CVDallocated to statin

HPS CARDS ASPEN CTTC

RRR with statin (%) 18 33 37 18 3 20 27

RRR with statin(events/1000 person years) 14 9 9 14 1 15 7

Residual risk despite statin(events/1000 person years) 64 19 15 66 26 61 21

With CVD No CVD No CVD With CVD With CVDNo CVD No CVD

STATINS ARE EFFECTIVE IN CAD PREVENTION BUT

DO NOT ELIMINATE THE RISK

“Residual Risk”

LDL –cholesterol/remnant deposition

Nordestgaard and Langsted. J Lipid Res 2016;57:1953-75

Stenosis

through wound

healing

(fibrosis)

Thrombosis

Atherosclerosis

Tailored therapy in atherosclerotic cardiovascular disease

Known atherosclerotic

cardiovascular disease

High intensity statin +/- ezetimibe

“Residual Cholesterol Risk”

LDL-C highLp(a)/ hsCRP low

Additional LDL-C reduction

“Residual Inflammatory Risk”

LDL-C lowLp(a)/ hsCRP high

Additional inflammation reduction

“Residual Thrombotic Risk”


Additional antiplatelet & anticoagulant therapy

Ridker P, ESC Barcelona 2017

15

10

5

-50%

10-20%

5-10%

55 - 70 %

reduction

In LDL-C

LDL-C

mmol/L

Reduction in LDL-C in FH with combination lipid-lowering therapy

Adapted from Nordestgaard B.G. et al. Eur Heart J 2013;34:3478-3490 and Hovingh G.K et al. Eur Heart J 2013;34, 962–971

100

80

60

40

20

01 2 3 4 65 7 8 9 10

LDL-C target

(mmol/L)

Att

ain

men

t o

f ta

rget

(%)

N=1249

Proportion of FH patients on LDL-C targets for different treatment goals

Pijlman AH, Atherosclerosis 2010;209:189-94

Emerging therapies for severe hypercholesterolaemia

While statins and ezetimibe constitute first-line therapy, they provide

less than optimal LDL-C reduction in severe FH

in particular HoFH requires combination therapy: high-dose statin,

ezetimibe, with or without apheresis

Emerging therapies

PPAR delta agonists

Acetyl CoA carboxylase

inhibitor (Gemcabene)

ACL/AMP kinase modulator

(ETC-1002 or Bempedoic acid)

ANGPTL3 inhibitors

Others e.g. CETP–inhibitors,

probucol

AAV-8 LDLR gene

replacement therapy

New therapies

Mipomersen (apoB inhibitor)

Lomitapide (MTP inhibitor)

PCSK9 inhibitors

Therapies for severe FH:

Stein EA, Raal FJ. Curr Cardiol Reports 2015;17:1-11

PCSK9-inhibitors

Rapid progress from discovery to clinic

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

First subjects treated

with PCSK9 mAb in

SAD studies

*BLA – Biologics licensing application; SAD – single ascending dose, MAD – multiple ascending dose

First MAD phase 1b

trials with PCSK9 mAb

started including FH,

non-FH, statin Rx Phase 2 trials in-progress

published for REGN727

including FH, Q2W/Q4W

dosing

Phase 2 trials

published for

AMG145 including

HoFH, Statin intol,

Q2W/Q4W

Phase 3 trials

complete for 2 mAbs,

BLA* filed and CVD

outcome trials started

1st publications MAD

in FH, nonFH on

statin or diet

Early data on

CVD benefit

Marketing

approval

USA/Europe

Seidah. Circ Res 2014:114:1022-36

In 2003 Marianne Abifadel from Lebanon described two gain-of-function mutations in the PCSK9 gene which resulted in a FH phenotype.

Modified from Bergeron et al. Circulation. 2015;132:1648-66

Pharmaceutical approaches targeting PCSK9

Approach

mAbs

Mimetic peptides

Adnectin

siRNA

Small molecules

Advantages

Highly selective

Less dosing frequencies

No serious adverse reactions

Highly selective

Easier production than mAbs

Selective

Easier & less costly production than mAbs

Highly selective

Oral administration

Low cost

Disadvantages

IV or subcutaneous

admin.

High cost

Short shelf life

Injection administration

Short half-life

IV or subcutaneous administration

Less selective

Greater likelihood of side effects

Compound

Alirocumab/ REGN7272/ SAR236553

Evolocumab/ AMG145

SX-PCK9

EGF-A peptide

BMS-962476

Inclisiran/ ALN-PCS (IV)

ALN-PCSsc (sub)

SBC-1 & SBC-1

Development stage

FDA approved July 24, 2015

Preclinical

Preclinical

Phase I completed

Phase I completed

Phase II recruiting

Preclinical completed

Company

Sanofi/Regeneron

Serometrix

Merck & Co

BMS-Adnexus

Alnylam Pharmaceuticals;

Medicines Company

Shifa Biomedical Corp

FDA approved Aug 27, 2015

Amgen

Pfizer/Genetech

Genentech/Roche

Development stopped in Nov 2016

Phase II

Bococizumab/ RN-316/ PFO4950615

RG7652(MPSK3169A)

LDL

EndocytosisRecycling of LDL-R

LDL receptor

mAb

LDL-R synthesis

Clathrin-coated vesicle

Endoplasmic reticulum

Nucleus SREBP Hepatocyte Lysosome

Endosome

Golgi apparatus

PCSK9 processing/

export siRNA or ASO

modified from Hovingh G K, et al. Eur Heart J 2013;34:962-71

Catabolism of LDL, the role of PCSK9

LDL

Endocytosis

LDL receptor

Endosome

Lysosome

Clathrin-coated vesicle

Hepatocyte

LDL-R synthesis

Endoplasmic reticulum

Nucleus SREBP

Golgi apparatus

PCSK9 processing/

export

Catabolism of LDL, the role of PCSK9 and antibody to PCSK9

modified from Hovingh G K, et al. Eur Heart J 2013;34:962-71

Stein E. N Engl J Med 2012;366:1108-18

Mean percent change from baseline in LDL-C values among healthy volunteers in single-dose studies

Subcutaneous administration of Alirocumab

-60

-50

-40

-30

-20

-10

0

10

20

-70

Me

an

ch

an

ge f

rom

ba

se

lin

e in

LD

L-C

(%

)

85 106

Study Day

Placebo 50 mg 100 mg 150 mg 250 mg

8443292215118421

PCSK9 Inhibitor CVD Outcomes Trials

www.clinicaltrials.gov (accessed September 6, 2017)

Sponsor

Trial

Sample size

Patients

Statin

LDL-C (mmol/L)

PCSK9i Dosing

Endpoint

Recruitment status

Completion

Evolocumab

Amgen

FOURIER

27,500

MI, stroke or PAD

Atorva ≥20 mg or equiv

≥1.8

Q2W or Q4W

Completed June 2015

ACC 2017

1º: CV death, MI stroke, revasc. or hosp for UA

Key 2º: CV death, MI or stroke

Alirocumab

Sanofi / Regeneron

ODYSSEY outcomes

17,000

4052 wks post-ACS

Evid.-based med Rx

≥1.8

Q2W

Completed Dec 2015

2017/2018

CHD death, MI, ischaemic stroke, or hospital for UA

Bococizumab

Pfizer

SPIRE I SPIRE II

17,000 9,000

High risk of CV event

Lipid-lowering Rx

1.8-2.6 ≥2.6

Q2W

Discontinued

2017/2018

CV death, MI, stroke, or urgent revasc.

http://www.clinicaltrials.gov/

CV

De

ath

, M

I, S

tro

ke

,

Ho

sp

fo

r U

A o

r C

or

reva

sc

Primary endpoint

Evolocumab

Placebo

Hazard ratio 0.85

(95% CI, 0.79-0.92)

P<0.0001 12.6%

14.6%

0%

2%

4%

6%

8%

10%

12%

14%

16%

Months from Randomization

0 6 12 18 24 30 36

27,564 high-risk, stable patients with established CV disease

Sabatine et al. New Engl J Med, 2017,376:1713-22

0

Study Day

28 56

0

50

500

100

300

400

200

14 70 8442

LDL-C

Me

an C

han

ge (%

)

0

150

350

450

250

Total AMG 145 (evolocumab)

Free PCSK9

LDL-C

Fre

e P

CSK

9 c

on

cen

trat

ion

(n

g/m

L)Fr

ee

evo

locu

mab

co

nce

ntr

atio

n (

ng

/mL

x 0

.01

)

Pharmacokinetics and pharmacodynamics of

evolocumab: changes in PCSK9 and LDL-C levels

in response to evolocumab

Stein EA & Raal FJ Annu. Rev. Med. 2014. 65:417–31.

160

140

120

100

80

60

40

20

0

Model predicted time course of LDL-C after multiple evolocumab doses

Gibbs et al. J Clin Pharm. 2017;57:616

0

-20

-40

-60

-80

LD

L-C

(%

ch

an

ge

fro

m b

ase

line

)

0 2 4 6 8 10 12

Time (weeks)

280 mg QM

420 mg QM

140 mg Q2W

Whitehead et al. Nat Rev Drug Discov 2009;8:129-38

Small interfering RNA (siRNA) targeted to PCSK9: Mechanism of action

Long DNAsiRNA

Cytoplasm

Deer

AGO2

RISC

RISC assembly

Target mRNA recognition

Cleaved sense strand

Target mRNA cleavageRecycled RISC-siRNA

activated complex

Sense strand

Antisense strand

Target mRNA

5’ 3’GalNAc

GalNAc

GalNAc

Hepatic ASP

receptor

INCLISIRAN

Change in LDL-Cholesterol level in single-dose cohorts with Inclisiran

Fitzgerald K et al. N Engl J Med. 2017;376:41-51

160 180140120100806040200-80

-60

-40

-20

0

Days after dose

Me

an

ch

an

ge

fro

m b

ase

line

(%

)

Cohort

Placebo (n=6)

Inclisiran, 25 mg (n=3)





Ray et al. New Engl J Med 2017;376:1430-40

Inter-individual LDL-C lowering response to Inclisiran

Phase 2 Study

2.07

1.55

1.04

0.52

0

-0.52

-1.04

-1.55

-2.07

-2.59

-3.11

-3.63

-4.15

Cha

nge

fro

m b

ase

line in L

DL

-C (

mm

ol/L

)

2.07

1.55

1.04

0.52

0

-0.52

-1.04

-1.55

-2.07

-2.59

-3.11

-3.63

-4.15

Cha

nge

fro

m b

ase

line in L

DL

-C (

mm

ol/L

)Mean 1.66 mmol/L

Placebo group at day 180 Two-dose 300 mg Inclisiran group at day 180

LDL levels in FHFrom a lethal disorder to a manageable dyslipidaemia

Adapted from Kastelein JJP. Nat Rev Cardiol. 2014;11:629-631

11.7

10.4

9.1

7.8

6.5

5.2

3.9

2.6

1.3

0No

therapySimva 40 mg

Atorva 80 mg

Simva 40 mg

Simva 80 mg

Statin +Eze 10 mg

+ PCSK9-inhibitor

LD

L-C

levels

(m

mol/L)

Firstsynvinolin study

ASAP ENHANCE

RUTHERFORDODYSSEY I & II

TESLA, TAUSSIG

1986 2016














Ridker PM, Eur Heart J 2016;37:1720-22

IMPROVE-IT: Ezetimibe 6% RR

FOURIER/SPIRE: PCSK9 inhibition Q2W 15% RRR

Science 2015;349:237-8. Eur Heart J 2016;37:1959-67. Circ Res 2017;120:1947-57

Cholesterol crystals induce local and systemic inflammation

Experimental studies

Human studies

Monocytes and macrophages Volume expansion Intima perforation

Carotid artery Coronary artery Systemic effects

Ridker PM et al, Circulation 2012;126:2739-2748

Activation of inflammasome - “clinical utility”

NLRP3inflammasome

IL-1β

TNF

IL-6

hsCRP

target

converter

distributor

biomarker

Ridker PM et al, Circulation 2012;126:2739-2748

CANTOS: dose-dependent effects on inflammatory biomarkers and lipids (38 months)

10

0

-10

-20

-30

-40

-50

-60

-70

hsC

RP

10

0

-10

LD

C

10

0

-10

HD

C

10

0

-10

TG

30 6 9 2412 36 48Months

Pa

tie

nt ch

an

ge

fro

m b

ase

line

(m

ed

ian)

Placebo SC q 3 nth

Canakinumab 50mg SC q 3 mth



Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300

Ridker PM et al, New Engl J Med 2017;377:1119-31

CANTOS: greater risk reduction among those with greater hsCRP reduction (MACE+)

0.25

0.20

0.15

0.10

0.05

0.000 1 2 3 4 5

Follow-up years

Cu

mu

lative

in

cid

en

ce (

%)

HR 0.73

95% CI 0.63-0.83

p = 0.0001

Placebo

Canakinumab (on treatment hsCRP < median)

Canakinumab (on treatment hsCRP ≥ median)

for those with reductions

in hsCRP ≥median at 3

mths (1.8 mg/dL)

HR

1.0

0.95

0.73

(95% CI)

(referent)

(0.84-1.08)

(0.63-0.83)

P

(referent)

0.47

0.0001

CANTOS: additional outcomes (per 100 person years of exposure)

Adverse eventPlacebo

(N=3347)

50 mg

(N=2170

150 mg

(N=2284)

300 mg

(N=2263) P

Canakinumab SC q 3 months

* P-value for combined Canakinumab doses vs. placebo

Ridker PM et al, New Engl J Med 2017;377:1119-31

Any SAE

Leukopenia

Any infection

Fatal infection

Injection site reaction

Any malignancy

Fatal malignancy

Arthritis

Osteoarthritis

Gout

ALT >2x normal

Bilirubin >2x normal

12.0

0.24

2.86

0.18

0.23

1.88

0.64

3.32

1.67

0.80

1.4

0.8

11.4

0.30

3.03

0.31

0.27

1.75

0.55

2.15

1.21

0.43

1.9

1.0

11.7

0.37

3.13

0.28

0.28

1.69

0.50

2.17

1.12

0.35

1.9

0.7

12.3

0.52

3.25

0.34

0.30

1.72

0.31

2.47

1.30

0.37

2.0

0.7

0.43

0.002

0.12

0.9/0.02*

0.49

0.31

0.0007

0.002

0.04

0.0001

0.19

0.34














Ridker PM, Eur Heart J 2016;37:1720-22

IMPROVE-IT: Ezetimibe 6% RR

FOURIER/SPIRE: PCSK9 inhibition Q2W 15% RRR

CANTOS

Evidence base for Lp(a) as an independent, causal, genetic risk factor for ASCVD

1.8

1.6

1.4

1.2

1.2

0.9

0.8

Usual Lp(a) Geometric mean mg/dL

Ris

k r

atio

(95

% C

I)

Adjustment for age and sex onlyNonfatal MI and coronary death

9318 cases

0.8 1 2 4

Hazard Ratio (95% CI)

P>0.002

Lp(a)

mg/dL

>117

77-117

30-76

5-29

< 5

Multivariable and KIV-2 adjusted

Epi/Meta-analyses Mendelian Randomisation

0 25 50 75 100 125

0.0

1.0

2.0

4.0

8.0

Geometric mean Lp(a) (mg/dL)

Od

ds r

atio

fo

r co

ron

ary

dis

ea

se

0 Variant

alleles

1 Variant

allele

2 Variant

alleles

Genome-wide association

Erqou et al. JAMA 2009;302:412-23 Kamstrup et al. JAMA 2009;301:2331-9 Clarke et al. NEJM 2009;361:2518-28

Helgadottir A. Nat Genet 2016;48:634-39

0.8

0.8

1.0

1.1

1.2

1.3

APOE LDLR

APOE

LPA

Non-HDL cholesterol effect of the minor allele

(mmol/L)

CA

D O

R

Lp(a) has ¼ effect of LDL-cholesterol on ASCVD risk but the effect

is 3 fold greater per mmol/L cholesterol

Comparison of cumulative effects of Lp(a) and LDL-C on CVD

50%

40%

30%

20%

10%

0%

0 20 40 60 80 100 120

Absolute lowering of Lp(a) (mg/dL)

Red

uctio

n in

CH

D r

isk

Genetic estimates

Observational estimates

Trial estimates (predicted)

50%

40%

30%

20%

10%

0%

0 0.3 0.3 0.5 1.0

Absolute lowering of LDL-C (mmol/L)

Red

uctio

n in C

HD

ris

k

Genetic estimates

Observational estimates

Trial estimates

Exome. CHD consortium 2017, in press

Changes in Lp(a) and LDL-C with equivalent effects on CVD

1.0 mmol/L lifetime lower LDL-C

50% reduction in lifetime risk of CHD

90 – 100 mg/dL lifetime lower Lp(a)

Reconciles epidemiologic and Mendellan randomisation studies

Explains failure of lowering Lp(a) in niacin, CETP and PCSK9 randomised trials

Informs the optimal design of RCTs for potent Lp(a) lowering agents

Ference B et al. Exome. CHD consortium 2017, in press

Viney et al. ACC 2016

Phase 2 IONIS-APO(a)Rx Study - mean change in Lp(a) in placebo and patients with Lp(a) 50-175 mg/dL and >175 mg/dL

30

0

-20

-40

-60

-80

1 190

Treatment period (days)

Fasting L

p(a

), m

ean %

change fro

m

ba

se

line

(±

SE

M)

16212085/99/ET

7857432915

Placebo

Cohort A

(> 175 mg/dL)

Cohort B

(50-175 mg/dl)

ATHEROSCLEROSIS

“chronic inflammatory fibroproliferative

process which is excessive and in its

excess, this protective response has

become a disease state.”

Russell Ross; New Engl J Med 1999;340:115-126

75th Percentile of CAC score in women (A) and men (B) across populations

700

600

500

400

300

200

100

045 50 55 60 65 70 75 80 85

Age (years)

45 50 55 60 65 70 75 80 85

Age (years)

75

thP

erc

en

tile

CA

C s

co

re

1800

1600

1400

1400

1000

800

600

400

200

0Tsimane

US women (UIC)

US women (MAHI)

US white women (MESA)

Korean women

US black women (MESA)

European women (HNR)

US Hispanic women (MESA)

US Chinese women (MESA)

Japanese women

Tsimane women

US men (MAHI)

US men (UIC))

US white men (MESA)

US black men (MESA)

US Hispanic men (MESA)

European men (HNR)

Korean men

US Chinese men (MESA)

Japanese men

Tsimane men

Tsimane

A B

Kaplan H, et al. Lancet 2017;389:1730-39

CAC scores by age for US MESA and Tsimane populations

100

90

80

70

60

50

40

30

20

10

0

Pro

po

rtio

n o

f in

div

idu

als

(%

)

0%

40-44 45-54 55-64 65-74 75-84

Age group (years)

1%

6%2%

17%

8%

34%

36%

8%

19%

51%

65%72%

83%

92%

55%

75%

Tsimane

CAC = 0

MESA

CAC = 0

MESA

CAC >100

Tsimane

CAC >100

Kaplan H et al. Lancet 2017;389:1730-39

CAD in the Tsimane Tribe

Kaplan H, et al Lancet 2017;389:1730-39

Total (n=705)

Anthropometry

Proportion of men (%)

Mean weight (kg)

Height (cm)

BMI (kg/m2)

Body fat (%)

Physiology

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

Heart rate (beats/min)

Lipids

Total cholesterol (mmol/L)

LDL-C (mmol/L)

HDL-C (mmol/L)

Triglycerides (mmol/L)

ApoA (mg/dL)

ApoB (mg/dL)

ESR (mm/h)

hs-CRP (mg/dL)

50 (0.5)

58.4 (9.9)

155.7 (7.8)

24.1 (3.5)

22.1 (8.2)

116.0 (12.5)

73.4 (10.0)

65.9 (9.3)

3.9 (0.8)

2.4 (0.7)

1.0 (0.2)

1.2 (0.5)

126.0 (84.9)

97.2 (41.5)

22.0 (13.9)

3.7 (3.2)

Tuberculosis is also a disease that has

a strong inflammatory component

It is associated with :-

• Influx of macrophages and T cells

• high levels of inflammatory cytokines

• elevated CRP

However treatment of this “inflammatory disease” is

the elimination of Mycobacterium tuberculosis, the root

cause

Likewise, in atherosclerosis, inflammation

is a consequence of LDL retention in the

sub-endothelial space, not the cause

The most successful treatment of

atherothrombotic vascular disease in humans is

therefore to address the root cause,

namely LDL-cholesterol!

LDL-Cholesterol

Atherosclerotic plaque

development

Plaque expansion and acute CV event

ACCELERATING

FACTORS

Smoking

Hypertension

Diabetes

Obesity

Inflammation

LDL cholesterol is essential for the development of

atherosclerosis. Other factors are “accelerating factors”.

Can we go too low?

Lower LDL-C is better

12%

11%

10%

9%

8%

7%

6%

5%

13%

0 0.5 1.0 1.6 2.1 2.6 3.1

Achieved LDL-C (mmol/L)

Card

iova

scu

lar

de

ath

, M

I, o

r str

oke

P<0.0001

Patients divided by quartile of baseline and by treatment arm

Q3

Q1

Q2

Q4

Q1

Q2

Q3

Q4

Placebo

Evolocumab

Adapted from Sabatine et al. New Engl J Med, 2017,376:1713-22 Suppl

Clinical Efficacy and Safety of Achieving Very Low LDL Levels with the

PCSK9 Inhibitor Evolocumab in theFOURIER Outcomes Trial

RP Giugliano, TR Pedersen, AV Keech,

PS Seever, JG Park, and MS Sabatine, for the

FOURIER Steering Committee & Investigators

Presented at ESC, Barcelona, August 2017

Published in the Lancet 2017 ;390;1962-1971

Achieved LDL-C at 4 weeks

Giugliano RP, ESC Congress 2017, Barcelona August 2017

Sabatine M, et al. Lancet. 2017;390:1692-71

4

5

2

1

0

3

Pe

rce

nt o

f p

atie

nts

0 1 2 4 5 6

≥2.6

9.6%

90.4%

1.8-2.6

10%

90%

1.3-1.8

41%

59%

1.3-1.8

96.5%

3.5%

<0.8

99.6%

0.4%

LDL-C at week 4 (mmol/L)

3

LDL (mmol/L)

% Evolocumab

% Placebo

Evolocumab 0.8 (mmol/L[0.5-1.2]

32 mg/dL [21-45]Placebo 2,2 mmol/l [1.9-2.7]

87 mg/dL2.24 mmol/L [74-104]

Median [IQR] LDL-C at 4 weeks

LDL-C over time

4

3

1

00 24 48 72 96 120 144 168

4 12

2

Weeks after randomisation

Mean L

DL

-C (

mm

ol/L)


Sabatine M, et al. Lancet. 2017;390:1692-71

LDL-C at 4 weeks in mmol/L

<0.5 0.5-1.3 1.3-1.8 1.8-2.6 ≥2.6

CV death, MI or stroke

0.16

0.14

0.12

0.10

0.08

0.06

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

LDL-C (mmol/L) at 4 weeks

4.5

LDL-C

<0.5

0.5-1.4

1.3-1.8

1.8-2.6

≥2.6

Adj HR (95% CI)

0.69 (0.56-0.85)

0.75 (0.64-0.86)

0.87 (0.73-1.04)

0.90 (0.78-1.05)

referentP = 0.0001

Adju

ste

d e

vent

rate

(pro

babili

ty)

Giugliano RP, ESC Congress 2017, Barcelona August 2017Sabatine M, et al. Lancet. 2017 ;390:1692-71

Safety events - 1

25

20

15

10

5

0

% pts

SAE AE->Discon New DM Cancer Cataract

Adj P-values for trend >0.10

for each comparison


<0.5

0.5-1.3

1.3-1.8

1.8-2.6

>2.6


Sabatine M, et al. Lancet. 2017 ;390:1692-71

Safety events - 2


<0.5

0.5-1.3

1.3-1.8

1.8-2.6

>2.6

10

5

% pts

0Neurocog AST/ALT CK Non-CV death Hemor stroke


Sabatine M, et al. Lancet. 2017 ;390:1692-71

Does reducing LDL cholesterol to low and very low levels have safety concerns?

In Fourier, reduction of LDL-C with evolocumab to a median of 0.78

mmol/L, with nearly 6,000 patients <0.65 mmol/L and 2500 patients

below 0.5 mmol/L, was not associated with any major safety concerns

such as haemorrhagic stroke, cognitive impairment or cataracts

Safety and benefit data for very low LDL-C based on increased LDL

clearance via upregulation of the LDL receptor (statins, ezetimibe and

PCSK9 inhibition) suggest eliminating a lower limit for LDL-cholesterol

Based on current evidence the real safety concern is under treatment

of LDL-C, not too low LDL-C!

A quarter of a century of treating LDL-C

5.18

4.66

4.15

3.63

3.11

2.59

2.07

1.55

1.04

0.52

01994 1996-2002 1994-2005 2015 2017

LD

L-C

(m

mo

l/L

)

High is bad

Lower is better

Even lower is even better

Lowest is best

Average is not good


Goldstein & Brown. Science 1996, 272:629

Cholesterol year score and the threshold for CHD

Concept of lifetime cumulative LDL-C exposure

and vascular risk

Adapted from Horton et al. J Lipid Res. 2009;50:S172-S177

1 20 40 60 80

Age (years)

Cum

ula

tive L

DL e

xposure

High RiskHeFHHoFH Mod. Risk

Statins, ezetimibe

plus PCSK9

inhibition

Ference B. Eur Heart J 2017;38:2459-72

The mean age at the time of

randomization in the statin

trials was 63 years

Comparative CHD risk reduction of earlier and later LDL-C lowering

Ference et al. JACC 2012;25: 2631-9

1.0 mmol/L

0.5 mmol/L

0.25 mmol/L

0.125 mmol/L

Genetic studies

Statin trials

Genetic studies

Statin trials

Genetic studies

Statin trials

Genetic studies

Statin trials

0.46 (0.41-9.51)

0.76 (0.74-0.78)

0.67 (0.64-0.72)

0.87 (0.86-0.88)

0.82 (0.80-0.85)

0.93 (0.93-0.94)

0.91 (0.89-0.92)

0.96 (0.96-0.97)

8.4x10-19

8.4x10-19

8.4x10-19

8.4x10-19

0.40 0.50 0.50 0.70 0.80 0.90 1.0

Lower LDL-C

Meta-analysis

312,321

169,138

212,321

169,138

312,321

169,138

312,321

169,138

Sample size (N)

OR (95% CI) P diff.

Lauf U, Ference B. Eur Heart J 2017, in press

Expected lifetime risk reduction with 50% reduction in LDL-C beginning in early adulthood

Baseline LDL-Cmmol/L

6.5

5.0

4.0

3.5

3.0

2.5

LDL-C mmol/Lafter 50% reduction

3.25

2.5

2.0

1.75

1.5

1.25

RR for CHDa

0.08

0.14

0.21

0.26

0.31

0.38

Relative reduction in lifetime risk

92%

86%

79%

64%

69%

62%

a Based on an expected 54% reduction in lifetime risk of ASCVD per mmol/L reduction in LDL-C

Importance of Early Treatment

10 80

Age (years)

40

Age of

intervention

Age at which clinical

horizon is reached

Biologics including PCSK9 inhibitors are very promising, and potentially the most effective, approach to further reducing LDL-cholesterol, the cause of atherosclerosis

Two large CVD outcome trials are completed or soon to be completed with the Amgen (evolocumab) and Sanofi (alirocumab) monoclonal antibodies and no significant adverse effects have emerged so far

“Residual risk” may well be the result of treating “too little, too late”

Earlier intervention and more aggressive LDL-cholesterol reduction is pivotal for effective treatment and prevention of atherosclerosis

Conclusions

New biologics for the treatment of atherosclerosis and the...

Documents

Transcript of New biologics for the treatment of atherosclerosis and the...