Fernando-Cruz Foundation Symposium, Hospital Clinico San ... · Rashid S et al. PNAS 2005;102:5374–5379. Role of PCSK9 in regulation of the surface expression of LDL receptors LDL

M. John Chapman BSc (Hons), Ph.D., D.Sc., FESC

Director Emeritus, INSERM,

Research Professor, University of Pierre and Marie Curie

Past-President, European Atherosclerosis Society

Pitié-Salpetriere University Hospital,

Paris, France

Fernando-Cruz Foundation Symposium,

Hospital Clinico San Carlos, Madrid 2015

Management of Hypercholesterolemia beyond Statins :

ODYSSEY and OSLER Trials

PCSK9 Inhibitors:

From Target Discovery to Phase III to the Clinic

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

PCSK9 (NARC-1) discovered

PCSK9 GOF mutations

associated with ADH*

PCSK9 LOF Mutations found with 28% LDL-C and 88% CHD risk

Humans null for PCSK9 have LDL-C ~15 mg/dL

Plasma PCSK9 binds to LDL-R

First Patientswith FH

/ non-FH treated with PCSK9i mAb

1st FDA / EMEA PCSK9i filing

Adenoviral expression in mice

PCSK9 KO mouse LDL-C

First subject treated with PCSK9 mAb

LDL-C in mice andnon-human primates treated

with anti-PCSK9 mAb

First publication

POC in patients

* ADH: Autosomal Dominant Hypercholesterolemia; Seidah NG. Proc Natl Acad Sci US 2003;100(3):928-33, Abifadel M. Nat Genet 2003;34(2):154-6, Maxwell KN. Proc Natl Acad Sci US 2004;101(18):7100-5, Rashid S. Proc Natl Acad Sci US 2005;102(15):5374-79, Lagace TA et al. JCI 2006;116:2995-3005 Cohen JC. N Engl J Med 2006;354(12):1264-72, Zhao Z. Am J Hum Genet 2006;79(3):514-23, Hooper AJ. Atherosderosis 2007;193(2):445-8, Chan JC. Proc Natl Acad Sci US 2009;106(24):9820-5: Stein et at N Engl J Med 2012;366:1108-18;Stein modified from Swergold, Regeneron.

• Cell membrane component

• Steroid hormone precursor

• Vitamin D precursor

• Bile acid precursor

• LXR agonist (oxysterols)

CHOLESTEROL

NY-160626.038/020131YlsjoLS1

CHOLESTEROL HOMEOSTASIS

WHOLE BODY

ExcretionDietary

Cholesterol

Biliary

Cholesterol

Intestine Liver

Peripheral

Tissue

Cholesterol

Pool

Synthesis

Cholesterol

Pool

Synthesis

Cholesterol

Pool

Synthesis

Skin

Cholesterol

Pool

Synthesis

Cholesterol

Pool

Synthesis

Endocrine

Glands

CM

VLDL LDL

nascentHDL HDL

Biliary

Cholesterol

600 mg/j

Bile

Acids

400 mg/j

Steroïd

Hormones

50 mg/j

Skin

Sterols

85 mg/j

NPC1L1

NPC1L1

Inflammation- macrophages

- T lymphocytes

- mast cells

Courtesy: Erling Falk

Thin cap

Cholesterol

crystals

Thin cap, rupture-prone atherosclerotic plaque

Lipid-rich core

LDL is causalin the pathophysiology of atherosclerotic vascular

disease

•INTERHEART

•Familial hypercholesterolemia

•RCTs with statins and cholesterol absorption inhibition

•Mendelian randomisation studies

•PCSK9 genetics

•Origin of Plaque components

•Modulation of Plaque composition and size by Statins

EXONS

DOMAINS

Ligand binding

(292 aa)

Epidermal growth

factor precursor

homology

(400 aa)

O-linked sugars

(58 aa)

Cytoplasmic

(50 aa)

DOMAINS

Ligand binding

(292 aa)

NH2

COOH

Membrane-

spanning

(22 aa)

2 3 4 5 6

I II III V VI VIIIV

A

B

C

Control of plasma LDL- cholesterol levels:

Key role of the cellular LDL receptor

http://www.iemrams.spb.ru/english/molgen/fh-en/domain-e.htm. [Accessed 6 August 2015]

LDLR

ER Golgi

Coated vesicle

Endosome(H+)

Lysosome(H+)

Recyclingvesicle

Plasma LDL degradation by the LDL Receptor pathway

Coated pit

LDL

Which factors principally control

levels of LDL receptor activity in the liver ?

Control of hepatic LDL-Receptor activity

- Intracellular levels of cholesterol

(reflecting uptake of cholesterol contained in LDL,

VLDL and chylomicron remnants, and HDL), endogenous

cholesterol synthesis, cholesterol conversion to bile acids, and

excretion of bile acids and biliary cholesterol)

via the SREBP pathway

- PCSK9

- the IDOL pathway

Control of hepatic LDL-Receptor activity

- Intracellular levels of cholesterol

(reflecting uptake of cholesterol contained in LDL,

VLDL and chylomicron remnants, and HDL), endogenous

cholesterol synthesis, cholesterol conversion to bile acids, and

excretion of bile acids and biliary cholesterol)

via the SREBP pathway

- PCSK9

- the IDOL pathway

What is PCSK9 ?

How was PCSK9 identified as a key

gene in cholesterol homeostasis ?

What is PCSK9?

• Expressed in liver, kidney, intestine

• Undergoes autocatalytic cleavage in the ER to active conformation

• Appears to play the role of an intracellular protein chaperone

http://www.genecards.org/cgi-bin/carddisp.pl?gene=PCSK9/. [Accessed 19 July 2011]

Abifadel M, et al. Nature Genet 2003;34:154–6.

Abifadel M, et al. Hum Mutat 2009;30:520–9.

Chromosome:

• 1p32.3

Gene:

• 12 exons

• cDNA 3617 bp

Protein:

• 692 amino acids

Horton JD, et al. Trends Biochem Sci 2007;32:71–7.

Chen SN, et al JACC 2005;45:1611–9.

A PCSK9 GAIN-of-Function mutation causes

Autosomal Dominant Hypercholesterolaemia

Abifadel M, et al. Nat Genet 2003;34:154–6.

Affected family members with:

• Total cholesterol in 90th percentile

• Tendon xanthomas

• CHD

• Early MI

• Stroke

Absence of PCSK9 Leads to Marked Increase in LDL-R

PCSK9 knockout mice : hepatic LDL-R levels

Immunoblot Immunofluorescence against LDL-R

PCSK9 decreases number of LDL-R : LDL-C

Rashid S et al. PNAS 2005;102:5374–5379

Role of PCSK9 in regulation of

the surface expression of LDL receptors

LDL particles

LDL-R

PCSK9 secretion

PCSK9 routes LDL-R for lysosomal degradation

LDL-R recycling blocked

Chan JC, et al. Proc Natl Acad Sci USA 2009;106:9820–5..

Regulation of PCSK9 is dynamic

1. Horton JD, et al. J Lipid Res. 2009;50:S172–7.

2. Lopez D. Biochem Biophys Acta 2008;1781:184–91.

3. Abifadel M, et al. Hum Mutat. 2009;30: supplementary information.

4. Abifadel M, et al. In: Toth PP. The Year in Lipid Disorders. Vol. 2. Oxford, UK: Atlas Medical Publishing Ltd. 2010:3–23.

5. Miao et al, ATVB. 2015;35:1589-1596.

• Dietary and cellular cholesterol4

• Bile acids3,4

Plasma PCSK9 levelDownregulates PCSK9

Upregulates PCSK9

• Cholesterol depletion2,3

• SREBP2 1,3,4

• Statins3,4

Is there a major flaw In the MOA of

statins ?

Mechanism of statin-mediated upregulationof the LDLR gene via SREBP2

Statin SREBP2

LDLRLysosomal

degradation

LDL-C

Hepatocyte

Mechanism of statin-mediated upregulation

of the LDLR and PCSK9 genes via SREBP2

Statin SREBP2

LDLR PCSK9Lysosomal

degradation

LDL-C

Hepatocyte

Adapted from Konrad RJ et al. Lipids Health Dis 2011;10:38.

PCSK9

How do genetic mutations/variants in

PCSK9 relate to LDL-C levels and CV risk ?

Can PCSK9 be targeted to reduce LDL-C

and CVD ?

Genetic variants of PCSK9 exert

distinct roles in regulating LDL-C levels

PCSK9 Gain of Function

= Less LDLRs

PCSK9 Loss of Function

= More LDLRs

Already in JC

presentation but I will

get better picture

quality for both

PCSK9 secretion

Plasma

Lysosomal degradation of LDLR Recycling of LDLR

Golgi apparatus

Nucleus

Gain-of-functionmutation

Plasma

Loss-of-functionmutation

Gain-of-function PCSK9 Loss-of-function PCSK9

Control 105

D35Y

L108R

S127R

F216L

R218S

D374Y

249

266

287

227

216

350

Poirier S, Mayer G. Drug Des Devel Ther 2013;7:1135–48.

RARE

Elevated LDL-C levels in patients

with GAIN-of-Function PCSK9 mutations

Poirier S, Mayer G. Drug Des Devel Ther 2013;7:1135–48.

Control

R46L

R97

G106R

Y142X

C679X

86

58

89

53

68

105

FREQUENT

Low LDL-C levels in patients

with LOSS-of-Function PCSK9 mutations

Loss-of-Function PCSK9 mutations are associated

with low LDL-C and low prevalence of CHD events

Adapted from Cohen JC et al. N Engl J Med 2006;354:1264–72.

30

20

10

09.7%

PCSK9142x or

PCSK9679X

No Yes

12

8

4

0

0 50 100 150 200 250 300

30

20

10

00 50 100 150 200 250 300

No nonsense

mutation(n = 3278)

50th Percentile

Plasma LDL-C in black subjects (mg/dL)

Fre

qu

en

cy (

%)

1.2%

PCSK9142x or

PCSK9679X

(n=85)

Coro

na

ry H

ea

rt D

ise

ase

(%

)

Mean 138 mg/dL

Mean 100 mg/dL

(-28%)

88% reduction in risk of CHD

events during 15-year follow-up

• Individuals who completely lack PCSK9 and

have very low LDL-C levels are healthy

• Therefore, inhibition of PCSK9 may be

a safe pharmacologic approach

to dyslipidaemia management

Bind plasma PCSK9

• Monoclonal antibodies

− Evolocumab, now EMEA approved (Amgen)

− Alirocumab, now FDA approved (Regeneron/Sanofi)

− Bococizumab (Pfizer)

• Adnectins (Adnexis/BMS)

Reduce PCSK9 synthesis

• siRNA (Alnylam)

Approaches to reducing PCSK9 interaction with the LDLR

Lambert G, et al. J Lipid Res. 2012. 53: 2515–24.

http://www.lilly.com/SiteCollectionDocuments/Pipeline/Clinical%20Development%20Pipeline/index.html. [Accessed 6 August 2015]

Impact of an anti-PCSK9 monoclonal antibody on LDL-R

expression

Chan JC, et al. Proc Natl Acad Sci USA 2009;106:9820–5.

LDLR recycling

LDLR PCSK9

Increased LDLR surface concentration

Anti-PCSK9 mAb

Alirocumab: Dynamic Relationship Between mAb Levels, PCSK9 and LDL-C

-70

-60

-50

-40

-30

-20

-10

0

0

20

40

60

80

100

120

140

160

180

200

0 500 1000 1500 2000 2500

LD

L-C

mean %

change

2 W

Total alirocumab

Free PCSK9

LDL-CFre

e/tota

l P

CS

K9 C

onc. (n

g/m

L)

Tota

l alir

ocum

ab (

ng/m

L)

X 0

.01

Time (hours)

Stein EA et al. New Engl J Med 2012;366:1108–18.

Familial Hypercholesterolemia (HeFH and HoFH)• LDL-C levels often far from goal, even with potent statins

and combination therapies • Life-long exposure to high LDL-C; considered high risk

even w/o additional risk factors

High CV Risk Patients• Patients not at LDL-C goal with currently available LLT

(even high doses of potent statins) and persistent high risk

Statin Intolerant Patients • LDL-C levels often far from goal, due to intolerance• Patients unable to tolerate at least 2 statins, including

one at the lowest dose

The CV Risk Pyramid :

Greatest clinical needs

Metabolic

syndrome

Chronic

kidney

disease

(SHARP)

Type 2

diabetes

Ischaemic

Stroke

Acute Coronary

Syndromes

Very high and

high risk

Dyslipidaemic

patient

populations

Stable;

Unstable

CAD

Non-FH

hyperchol

Chapman, MJ. Unpublished.

FH

Auto-immune

disorders

Overview of ODYSSEY Phase 3 Clinical Trial Program

ODYSSEY FH II (NCT01709500; CL1112)

LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL

N=250; 18 months

14 global phase 3 trials including >23,500 patients across >2,000 study centers

HeFH population HC in high CV risk population Additional populations

ODYSSEY HIGH FH (NCT01617655; EFC12732)

LDL-C ≥160 mg/dL

N=105; 18 months

ODYSSEY ALTERNATIVE (NCT01709513; CL1119)

Patients with defined statin intolerance


N=250; 6 months

ODYSSEY OPTIONS II (NCT01730053; CL1118)

Patients not at goal on moderate dose rosuvastatin


N=300; 6 months

ODYSSEY MONO (NCT01644474; EFC11716)

Patients on no background LMTs

LDL-C ≥100 mg/dL

N=100; 6 months

ODYSSEY OPTIONS I (NCT01730040; CL1110)

Patients not at goal on moderate dose atorvastatin


N=350; 6 months

ODYSSEY COMBO I (NCT01644175; EFC11568)


N=306; 12 months

ODYSSEY FH I (NCT01623115; EFC12492)

LDL-C ≥ 70 mg/dL OR LDL-C ≥100 mg/dL

N=471; 18 months

ODYSSEY LONG TERM (NCT01507831; LTS11717)

LDL-C ≥70 mg/dL

N=2,100; 18 months

ODYSSEY OUTCOMES (NCT01663402; EFC11570)

LDL-C ≥70 mg/dL

N=18,000; 64 months

Add-on to max-tolerated statin

(± other LMT)


(± other LMT)

*ODYSSEY COMBO II (NCT01644188; EFC11569)


N=660; 24 months

FH=familial hypercholesterolemia; HC=hypercholesterolemia; LMT=lipid-modifying therapy; OLE=open-label extension.

*For the ODYSSEY COMBO II other LMT not allowed at entry.

ClinicalTrials.gov. ODYSSEY Phase 3 Trials. http://clinicaltrials.gov. Accessed February 12, 2014.

ODYSSEY CHOICE I (NCT01926782; CL1308)


N=700; 12 months

ODYSSEY CHOICE II (NCT02023879; EFC13786)

Patients not treated with a statin


N=200; 6 months

ODYSSEY OLE (NCT01954394; LTS 13463)

Open-label study for FH from EFC 12492,

CL 1112, EFC 12732 or LTS 11717

N≥1000; 30 months

Evolocumab Clinical Trial Program

33

Program to

Reduce LDL-C and

Cardiovascular

Outcomes

Following

Inhibition of

PCSK9

In Different

Populations

(Latin):

•To advance

•To make progress

Evolocumab’s PROFICIO clinical trial program addresses key areas of

unmet need in the management of dyslipidaemia

HeFH, heterozygous hypercholesterolaemia; HoFH, homozygous hypercholesterolaemia. Clintrials.gov. * Amgen data on file.

Combinationtherapy

Statin intolerant

Monotherapy

HeFH

Long-term safety and efficacy

Open-labelextension

HoFH/ Severe FH

SecondaryPrevention

Atherosclerosis

Phase 2(n=631)

Phase 3(n=2067)

Phase 2(n=411)

Phase 3(n=615)

Phase 2(n=160)

Phase 3(n=331)

Phase 2(n=168)

Phase 2(n=1104)

Phase 3(n=3671)*

Phase 3(n=905)

Phase 3(n=27,564)

Phase 3(n=970)

Phase 2/3(n=300)

Phase 2/3(n=58)

NeurocognitionPhase 3

(n=1971)*

Phase 3(n=511)*

Phase 3(n=307)

Completedtrials

>35,000 patients

SPIRE Phase 3 Bococizumab Clinical Development ProgrammeUnmet Needs in the Management of CVD in High Risk Patients

SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events) N=~30,000

SPIRE HR (n=300)

On statinHigh risk of CV event

LDL-C ≥70 or ≥100 mg/dL

SPIRE LDL (n=1,932)

On statinHigh risk of CV event

LDL-C ≥70 mg/dL

SPIRE FH (n=300)

HeFH (genetic diagnosis or Simon Broome Criteria),

LDL >70 mg/dL

SPIRE Lipid Lowering Studies SPIRE CV Outcome Studies

SPIRE LL (n=690)

On statinHigh / very high risk of

CV eventLDL-C ≥100 mg/dL

SPIRE SI (n=150)

Statin intolerantLDL-C ≥70 mg/dL

SPIRE-1 (n=17,000)

High Risk Primary and Secondary Prevention

LDL-C ≥70 to <100 mg/dLon statins (or statin

intolerant)

SPIRE-2 (n=9,000)

High Risk Primary and Secondary PreventionLDL-C ≥100 mg/dL on

statins (or statin intolerant)

NCT#: https://clinicaltrials.gov

SPIRE HR: NCT01968954

SPIRE LDL: NCT01968967

SPIRE HF: NCT01968980

SPIRE-LL: NCT02100514

SPIRE-SI: NCT02135029

SPIRE-1: NCT01975376

SPIRE-2: NCT01975389Studies on PCSK9 Inhibition and the

Reduction of Vascular Events

https://clinicaltrials.gov/

Overview of ODYSSEY Phase 3 Clinical Trial Program

ODYSSEY FH II (NCT01709500; CL1112)


N=250; 18 months

14 global phase 3 trials including >23,500 patients across >2,000 study centers

HeFH population HC in high CV risk population Additional populations

ODYSSEY HIGH FH (NCT01617655; EFC12732)

LDL-C ≥160 mg/dL

N=105; 18 months

ODYSSEY ALTERNATIVE (NCT01709513; CL1119)

Patients with defined statin intolerance


N=250; 6 months

ODYSSEY OPTIONS II (NCT01730053; CL1118)

Patients not at goal on moderate dose rosuvastatin


N=300; 6 months

ODYSSEY MONO (NCT01644474; EFC11716)

Patients on no background LMTs

LDL-C ≥100 mg/dL

N=100; 6 months

ODYSSEY OPTIONS I (NCT01730040; CL1110)

Patients not at goal on moderate dose atorvastatin


N=350; 6 months

ODYSSEY COMBO I (NCT01644175; EFC11568)


N=306; 12 months

ODYSSEY FH I (NCT01623115; EFC12492)

LDL-C ≥ 70 mg/dL OR LDL-C ≥100 mg/dL

N=471; 18 months

ODYSSEY LONG TERM (NCT01507831; LTS11717)

LDL-C ≥70 mg/dL

N=2,100; 18 months

ODYSSEY OUTCOMES (NCT01663402; EFC11570)

LDL-C ≥70 mg/dL

N=18,000; 64 months


(± other LMT)


(± other LMT)

*ODYSSEY COMBO II (NCT01644188; EFC11569)


N=660; 24 months

FH=familial hypercholesterolemia; HC=hypercholesterolemia; LMT=lipid-modifying therapy; OLE=open-label extension.

*For the ODYSSEY COMBO II other LMT not allowed at entry.

ClinicalTrials.gov. ODYSSEY Phase 3 Trials. http://clinicaltrials.gov. Accessed February 12, 2014.

ODYSSEY CHOICE I (NCT01926782; CL1308)


N=700; 12 months

ODYSSEY CHOICE II (NCT02023879; EFC13786)

Patients not treated with a statin


N=200; 6 months

ODYSSEY OLE (NCT01954394; LTS 13463)

Open-label study for FH from EFC 12492,

CL 1112, EFC 12732 or LTS 11717

N≥1000; 30 months

Clinicaltrials.gov identifiers: ODYSSEY FH I: NCT01623115; ODYSSEY FH II: NCT01709500.

Placebo Q2W SC

R

n=323 (FH I); n=167 (FH II)

n=163 (FH I); n=82 (FH II)

HeFH patients on

max tolerated statin

± other lipid-

lowering therapy

OLE

/8 w

eek F

U

Alirocumab 75 mg Q2W SC with potential ↑ to 150 mg Q2W SC(single 1-mL injection using prefilled pen for self-administration)

AssessmentsW0 W8 W16 W36

W52

Double-Blind Treatment Period (78 Weeks)

Primaryefficacy endpoint

W64

W4 W12 W24 W78

LDL-C ≥1.81 mmol/L

[70 mg/dL]

(history of CVD)

or

2.59 mmol/L

[100 mg/dL]

(no history of CVD)

Dose ↑ if LDL-C >70 mg/dL

at W8

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

Per-protocol dose ↑ possible based

on pre-specified LDL-C level

ODYSSEY FH I and FH II Study Design

Kastelein, ESC 2014

†Patients should receive either rosuvastatin 20-40 mg, atorvastatin 40-80 mg daily, or simvastatin 80

mg daily unless not tolerated and/or appropriate other dose given according to the judgement of the

investigator.

‡High-intensity statin: atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily.

Lipid Medication and LDL-C at Baseline

Any statin†, % (n) 100% 100% 100% 100%

High-intensity statin‡, % (n) 80.8% (261) 82.8% (135) 86.2% (144) 87.8% (72)

Ezetimibe, % (n) 55.7% (180) 59.5% (97) 67.1% (112) 64.6% (53)

LDL-C, mean (SD), mmol/L

[mg/dL]

3.7 (1.3)

[144.7 (51.2)]

3.7 (1.2)

[144.4 (46.8)]

3.5 (1.1)

[134.6 (41.3)]

3.5 (1.1)

[134.0 (41.6)]

All patients on background

of max-tolerated statin ±

other lipid-lowering

therapy

FH I FH II

Alirocumab

(N=323)

Placebo

(N=163)

Alirocumab

(N=167)

Placebo

(N=82)

Kastelein, ESC 2014

Alirocumab Significantly Reduced LDL-C from

Baseline to Week 24 versus Placebo

LS

me

an

(S

E)

% c

ha

ng

e f

rom

ba

se

lin

e t

o W

ee

k 2

4

LS mean

difference (SE)

vs. placebo:

N=163

Alirocumab

N=322

−57.9% (2.7)

P<0.0001

N=81N=166

−51.4% (3.4)

P<0.0001

FH IPlacebo

FH II

43.4%

had dose

increase

at W12

38.6%

had dose

increase

at W12

Primary Endpoint: % Change from Baseline to Week 24 in LDL-C

Intent-to-treat (ITT) Analysis Kastelein, ESC 2014




Combinationtherapy

Statin intolerant

Monotherapy

HeFH


Open-labelextension

HoFH/ Severe FH

SecondaryPrevention

Atherosclerosis

Phase 2(n=631)

Phase 3(n=2067)

Phase 2(n=411)

Phase 3(n=615)

Phase 2(n=160)

Phase 3(n=331)

Phase 2(n=168)

Phase 2(n=1104)

Phase 3(n=3671)*

Phase 3(n=905)

Phase 3(n=27,564)

Phase 3(n=970)

Phase 2/3(n=300)

Phase 2/3(n=58)


(n=1971)*

Phase 3(n=511)*

Phase 3(n=307)

Completedtrials

>35,000 patients

Evolocumab Q2W or QM:

consistent LDL-C reductions across different studies

Results are for the mean of weeks 10 and 12 except for DESCARTES, which are for week 52.MENDEL-2: Koren MJ, et al. J Am Coll Cardiol 2014;63:2531–40; LAPLACE-2: Robinson JG, et al. JAMA 2014;311:1870–82; RUTHERFORD-2: Raal FJ, et al.

Lancet 2015;385:331–40; DESCARTES: Blom DJ, et al. N Engl J Med 2014;370:1809–19; GAUSS-2: Stroes E, et al. J Am Coll Cardiol 2014;63:2541–8.

MonotxMENDEL-2

N=614

MonotxMENDEL-2

N=614

CombotxLAPLACE-2

N=1896

HeFHRUTHERFORD-2

N=329

SIGAUSS-2N=307

Long TermDESCARTES

N=901

CombotxLAPLACE-2

N=1896

Evolocumab 140 mg Q2W Evolocumab 420 mg QM

Treatment difference for

% change from baseline

in LDL-C

Evolocumab vs placebo:consistent reduction in LDL-C, Q2W and QM

Evolocumab vs ezetimibe:consistent reduction in LDL-C, Q2W and QM




Combinationtherapy

Statin intolerant

Monotherapy

HeFH


Open-labelextension

HoFH/ Severe FH

SecondaryPrevention

Atherosclerosis

Phase 2(n=631)

Phase 3(n=2067)

Phase 2(n=411)

Phase 3(n=615)

Phase 2(n=160)

Phase 3(n=331)

Phase 2(n=168)

Phase 2(n=1104)

Phase 3(n=3671)*

Phase 3(n=905)

Phase 3(n=27,564)

Phase 3(n=970)

Phase 2/3(n=300)

Phase 2/3(n=58)


(n=1971)*

Phase 3(n=511)*

Phase 3(n=307)

Completedtrials

>35,000 patients

Figure 2

Raal FJ et al. Lancet 2015; 385: 331–40

Efficacy of LDL-C lowering by Evolocumab in heterozygous FH patients : RUTHERFORD-2

Evolocumab 140 mg Q2W Evolocumab 420 mg QM

Raal FJ, et al. Lancet 2014; doi.org/10.1016/S0140-6736(14)61399-4 and supplementary material.

45

On treamentresidual

LDL= 280 mg/dL

46Raal et al ISA 2015

TAUSSIG

Cuchel et al, EHJ 2014




Combinationtherapy

Statin intolerant

Monotherapy

HeFH


Open-labelextension

HoFH/ Severe FH

SecondaryPrevention

Atherosclerosis

Phase 2(n=631)

Phase 3(n=2067)

Phase 2(n=411)

Phase 3(n=615)

Phase 2(n=160)

Phase 3(n=331)

Phase 2(n=168)

Phase 2(n=1104)

Phase 3(n=3671)*

Phase 3(n=905)

Phase 3(n=27,564)

Phase 3(n=970)

Phase 2/3(n=300)

Phase 2/3(n=58)


(n=1971)*

Phase 3(n=511)*

Phase 3(n=307)

Completedtrials

>35,000 patients

Sabatine et al. N Engl J Med 2015; March 15: online

OSLER Program

LAPLACE-TIMI 57

(n=629)

MENDEL-1

(n=406)

GAUSS-1

(n=157)

RUTHERFORD-1

(n=167)

LAPLACE-2

(n=1896)

MENDEL-2

(n=614)

GAUSS-2

(n=307)

RUTHERFORD-2

(n=329)

YUKAWA-1

(n=307)

THOMAS-1

(n=149)

THOMAS-2

(n=164)

DESCARTES

(n=901)

Phase 2

trials

Phase 3

trials

MONO-

THERAPY

HYPERCHOL

ON A STATIN

STATIN-

INTOL

HETEROZYG

FAM HYPERCHOL

OTHER

Median follow-up of 11.1 months (IQR 11.0-12.8)

7% discontinued evolocumab early

96% completed follow-up

Evolocumab

plus standard of care

(n=2976)

Standard of care alone

(n=1489)

Randomized2:1

Irrespective of treatment assignment

in parent study

4465 patients (74%) elected to enroll

into OSLER extension study program1324 from Ph2 trials into OSLER-1

3141 from Ph3 trials into OSLER-2

Eligible if medically stable

and on study drug

Trial Sponsor: Amgen


LDL Cholesterol

Evolocumab plus standard of care


61% reduction (95%CI 59-63%), P<0.0001

Absolute reduction: 73 mg/dL (95%CI 71-76%)

N=4465 N=1258 N=4259 N=4204 N=1243 N=3727

(Parent study) (OSLER)


Other Lipid Parameters

52% in Non-HDL-C

5.9

-46.1-50

-40

-30

-20

-10

0

10

Chan

ge fr

om

Bas

elin

e (%

)

P<0.001

47% in ApoB

5.5

-41.7-50

-40

-30

-20

-10

0

10

Chan

ge fr

om

Bas

elin

e (%

)

P<0.001

26% in Lp(a)

0.0

-25.5-30

-25

-20

-15

-10

-5

0

5

Chan

ge fr

om

Bas

elin

e (%

)

P<0.001

13% in Triglycerides

3.5

-9.1

-15

-10

-5

0

5

10

Chan

ge fr

om

Bas

elin

e (%

)

P<0.001

7% in HDL-C 4% in ApoA1

1.7

8.7

0

2

4

6

8

10

Chan

ge fr

om

Bas

elin

e (%

)

2.6

6.8

0

1

2

3

4

5

6

7

8

Chan

ge fr

om

Bas

elin

e (%

)

P<0.001P<0.001


Evolocumab plus standard of careWeek 12 data; values are means

except for TG and Lp(a) which are medians

Evolocumab 140 mg Q2W or 420 mg Q4W:

Effect of Baseline TG on TG response

N 1228 429 137

TG <150 mg/dL TG 150-250 mg/dL TG >250 mg/dL

Mean TG 99.2 mg/dL Mean TG 186.8 mg/dL Mean TG 328.7 mg/dL

Mean

% C

han

ge f

rom

Baselin

e

With permission from Dr E. Stein


Cardiovascular Outcomes

0

1

2

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

HR 0.47

95% CI 0.28-0.78

P=0.003

Composite Endpoint: Death, MI, UA hosp,

coronary revasc, stroke, TIA, or CHF hosp

Evolocumab plus standard of care(N=2976)

Standard of care alone(N=1489)

0.95%

2.18%

3

Days since Randomization

Cu

mu

lati

ve

In

cid

en

ce

(%

)

788

1550

776

1534

731

1446

703

1393

682

1352

667

1335

321

642

127

252

0

0

No. at Risk

Placebo

Alirocumab

Weeks

Mean treatment

duration: 65 weeks

Placebo + max-tolerated statin ± other LLT0.10

0.08

0.06

0.04

0.02

0.00

96847260483624120

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 to 0.82)

Nominal p-value = <0.01

†Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic

stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy

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)

Post-hoc Adjudicated Cardiovascular TEAEs (Same as primary endpoint of ongoing ODYSSEY OUTCOMES trial†)

Robinson et al. N Enl J Med 2015; March 15: online

0

50

100

150

200

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

Cu

mu

lati

ve L

DL-

C (

mm

ol)

Years Age

HOZ Untreated Treat at 10yrs Non FH Treat at 18yrs

35yrs

53yrs

48yrs

55yr

12.5yrs

Start high dose statin

Start lowdose statin

Threshold

for CHD

Female sex

Smoking

Hypertension

Diabetes

Triglycerides

HDL-C

Lipoprotein(a)

Without FH

Homozygous FH Heterozygous FH

Age in years

Nordestgaard et al, EHJ 2013; EAS Consensus Panel

Coronary disease & death before age 20

Untreated coronary disease before age 55/60


Safety

Evolocumab

+ stnd of care

(N=2976)

Standard of

care alone

(N=1489)

Adverse events (%)

Any 69.2 64.8

Serious 7.5 7.5

Leading to discontinuation of evolocumab 2.4 n/a

Injection-site reactions 4.3 n/a

Muscle-related 6.4 6.0

Neurocognitive 0.9 0.3

Laboratory results (%)

ALT or AST >3×ULN 1.0 1.2

Creatine kinase >5×ULN 0.6 1.2


Adverse Events by Achieved LDL-C

Evolocumab subjects stratified by

minimum achieved LDL-C All

EvoMab

(n=2976)

Stnd of

Care

Alone

(n=1489)

<25

mg/dL

(n=773)

25 to <40

mg/dL

(n=759)

<40

mg/dL

(n=1532)

≥40

mg/dL

(n=1426)

Adverse Events (%)

Any 70.0 68.1 69.1 70.1 69.2 64.8

Serious 7.6 6.9 7.2 7.8 7.5 7.5

Muscle-related 4.9 7.1 6.0 6.9 6.4 6.0

Neurocognitive 0.5 1.2 0.8 1.0 0.9 0.3

Lab results (%)

ALT/AST >3×ULN 0.9 0.8 0.8 1.3 1.0 1.2

CK >5×ULN 0.4 0.9 0.7 0.5 0.6 1.2

Phase 3 Trials: Alirocumab, Evolocumab, Bococizumab

EUHQ-NP-145-0715-109452

References to support data: see slide notes No head-to-head studies available. No direct study comparison intended. This overview is intended to be used for scientific illustrative purposes only.

Patient Pop’n Evolocumab (PROFICIO program) Alirocumab (ODYSSEY program) Bococizumab (SPIRE program)

Trial N Dur’n (m)Predicted Pt

Exposure (Y)

Min B/L

LDL-C

(mg/dL)

TrialN Dur’n (m)

Predicted

Pt

Exposure

(Y)

Min B/L LDL-

C (mg/dL)Trial N Dur’n (m)

Predicted

Pt

Exposure

(Y)

Min B/L LDL-

C (mg/dL)

HeFHRUTHERFORD-2 327 3 51 ≥100

FH I 471 18 471 ≥70

FH 300 12 200 >70FH II 250 18 250 ≥70

HAUSER (paeds) 150 6 50 ≥130 HIGH FH 105 18 105 ≥160

HoFHTESLA 50 3 8 ≥130

.TAUSSIG (OL) 300 60 1000 ≥100

Combo Therapy LAPLACE-2 1896 3 258 ≥80

COMBO I 316 12 209 ≥ 70 HR 600 12 400 >70

COMBO II 720 24 958 ≥70

OPTIONS I 345 6 51 ≥70 LDL 1932 12 1288 >70

OPTIONS II 300 6 150 ≥70

Monotherapy MENDEL-2 614 3 71 ≥100 MONO 103 6 24 ≥70 AI 300 3 50 ≥70

Statin IntoleranceGAUSS-2 307 3 47 None

ALTERNATIVE 314 6 47 ≥70 SI 150 6 23 ≥70

GAUSS-3 511 36 984 None

Long termDESCARTES 901 12 600 ≥75 LONG-TERM 2341 18 2341 ≥70

LL 690 12 460 ≥100

OSLER-2 (OL) 3671 24 5904 None OLE (OL) 1200 28 2800 None

Atheroma GLAGOV 970 18 970 ≥60

Totals Patients 10462 Predicted Pt Yrs ~ 9943 Patients 5465 Predicted Pt Yrs ~ 7302 Patients 3972 Predicted Pt Yrs ~ 2421

CVD Outcomes FOURIER 27,564 Event driven NA ≥70 OUTCOMES 18,000Event

drivenNA ≥70

SPIRE-1 17,000Event

drivenNA ≥70 & <100

SPIRE-2 9,000Event

drivenNA ≥100

Neurocognitive

eventsEBBINGHAUS 1971 in

FOURIER

End of

FOURIERN/A ≥70

†For Predicted Pt Exposure, where randomization is unknown, assumed 2:1 in favour of active comparator; ‡Assumed 1:1:1 random ization; §Patients from 4 studies: FH1, FH2, High FH and Long-term.

PCSK9 mAb Outcomes Trials

59

StudyFOURIER

ODYSSEY

OUTCOMESSPIRE-1 SPIRE-2

Who? Patients aged 40-

85 with history of

clinically evident

CVD at high risk for

recurrent event

Patients aged ≥40

hospitalized for

ACS recently (<52

weeks)

Background lipid lowering treatment and

at high risk of a CV event

N 27,500 18,000 17,000 9000

Primary

endpt

Time to CV death,

MI, hospitalization

for UA, stroke, or

coronary revasc,

whichever occurs

first

Time to CHD

death, any non-

fatal MI, fatal and

non-fatal ischemic

stroke,

hospitalization for

UA

Confirmed major cardiovascular event

[CV death, non- fatal MI, non-fatal

stroke, and hospitalization for UA

needing urgent revascularization]

LDL-C ≥70 mg/dL (or non-

HDL-C ≥100

mg/dL)

≥70 mg/dL ≥70 and <100

mg/dL (or non-

HDL-C ≥100 mg/dL

and <130 mg/dL)

≥100 mg/dL (or

non HDL C ≥130

mg/dL)

PCSK9 Education and Research Forumis the major, globally-recognized academic resource

of independent knowledge

of PCSK9 science

and its translation to therapeutic innovation.

Register at www.pcsk9forum.org

OSLER-1: Phase 2 programmeOpen-label Study of Long-term Evaluation Against LDL-C

Patients with hyperlipidaemia and mixed

dyslipidaemia

• Completed a qualifying

evolocumab Phase 2

parent study

• Eligible if medically

stable and on study drug

• Age ≥ 18 to ≤ 75 years

• n=1104

R

A

N

D

O

M

I

Z

E

D

Evolocumab 420 mg

QM + standard of care

(n=736)


(n=368)

2:1, irrespective

of treatment

assignment in

parent study

1

At Week 52, patients in the evolocumab +

SOC group achieved an LDL-C reduction of

52% (SE, 1%)

Koren et al. Circulation 2014;129:234–43.

OSLER subpopulations:

patients with T2DM, IFG or MetS

Presented by Henry RR, et al. American

Association of Clinical Endocrinologists, Las

Vegas, NV. May 2014.

Disease categorization (parent-study baseline):

• T2DM (n=72): By patient history

• IFG (n=95): No T2DM, but presence of FPG ≥ 110 mg/dL

and < 126 mg/dL

• MetS (n=291): No T2DM, and presence of ≥ 3 IDF

criteria

1

OSLER: Conclusions

In patients with T2DM, IFG or MetS:

• Evolocumab (420 mg monthly) treatment

reduced LDL-C by up to 52% (P < 0.001) at week 52

– Reductions were comparable to those observed in patients

without these three conditions

• Evolocumab dosed monthly demonstrated encouraging

safety and tolerability at 1 year of treatment




1

Time course of plasma levels of FPG and HbA1C




1

135

125

115

105

95

85

135

125

115

105

95

85

135

125

115

105

95

85

135

125

115

105

95

85

Med

ian

FP

G (

mg

/dL

)

7.5

7

6.5

6

5.5

5

7.5

7

6.5

6

5.5

5

7.5

7

6.5

6

5.5

5

7.5

7

6.5

6

5.5

5

Patients

with

T2DM

Patients

with MetS

Patients

with IFG

Patients

without

MetS, IFG

or T2DM

Med

ian

Hb

A1c (

%)

PCSK9 inhibition :

The Future

1) Cardiovascular outcomes in Phase III trials

2) Impact on atherosclerotic vascular disease (AVD)

3) Impact of TGRL, remnant and Lp(a) lowering, and possibly

HDL raising, on progression of AVD and CV events

3) Long term, real life, safety data from post-marketing

surveillance

4) Evaluation of efficacy in other patient populations at high risk