Nouvelles approches pour abaisser les LDL · Kaplan-Meier Estimates for Time to First Adjudicated...

Nouvelles approches pour abaisser les LDL

Jacques Genest MD

Cardiovascular Health Across the Lifespan Program McGill University Health Center

Congrès de l’ACQ 15 octobre 2016

▪ Merck *▪ Pfizer▪ Novartis▪ AMGEN *▪ Cerenis

Disclosure J. Genest MD 2016

Relevant disclosure: IMPROVE-IT, CANTOS , CAPREE steering Committees; REVEAL , ACCELERATE, AMG145 , Sanofi, TANGO, Lilly Clinical Trials.

Advisory Board, Speaker’s Bureau, Consultant, Grants, Clinical Trials

▪ Sanofi/Regeneron *▪ Lilly▪ Valeant▪ Aegerion▪ RengenXBio

Stock ownership: none; Off label use: none* Scientific Advisory

Cell 2015:161; 161-172

Cholesterol et MCAS

▪ Causalité, ▪ Etudes Cliniques, ▪ Randomisation

Mendelienne, ▪ Cibles thérapeutiques

Nikolay Nikolaevich Anitschkow

Anichkov discovered the significance and role of cholesterol in atherosclerosis pathogenesis. In 1958, in an editorial in Annals of Internal Medicine he published his findings

Absolute effect of statin therapy onMAJOR VASCULAR EVENTS

0 1 2 3 4 5

05

1015

20

LDL cholesterol, mmol/L

Five

yea

r ris

k of

a m

ajor

vasc

ular

eve

nt, %

Control

21% relative riskreduction per mmol/LStatin

15% relative riskreduction per 0.5 mmol/LMore statin

Combined evidence:~33% relative risk reduction

per 1.5 mmol/L(0.79 x 0.85 = 0.67)

Cholesterol Treatment Trialists’ Collaborators Lancet 2012;380:581–90

Patients with Genetically Lower LDL have Correspondingly Better CV Event Reduction

10%

20%

30%

.003 .005 .078 .104 .130 .155 .181 .207 .233 .259 .285 .311 .330 .363 .389 .389 .440 .466 .492 .518 .5440

Lower LDL-C (mmol/L)

Prop

ortio

nal R

isk

Red

uctio

n (S

E) lo

g sc

ale

PCSK9 46Lrs11591147

ALLHAT-LLT

SEARCH

Pharmacologically Lower LDL-C

A to Z

Genetically Lower LDL-C

GISSI-P

NPC1L1 LDL-C ScoreHMGCR LDL-C Score

IMPROVE-IT

Combined NPC1L1 & HMGCR LDL-C Score

LDLRrs6511720

LDLRrs2228671

Ference BA, et al. J Am Coll Cardiol. 2015;65(15):1552-1561.

PCSK9rs11206510

ABCG5/8rs4299376

HMGCRrs12916

PCSK9rs2479409

NPC1L1rs217386

HMGCR LDL-C ScoreNPC1L1 LDL-C Score

Greater effect than Pharmacologically Lower LDL-C − Possibly due to Lifetime Lower LDL levels

-25%-25%

16

4

160120906750

-20%

-15%

-11%-8%

LDL-C [mg/dl]

8

12

80 12040 160

10.2

15

12

8.3 9.1

Abs

olut

e C

V R

isk

[%]

-25% -25%

Diminishing risk reduction for the same relative LDL-C lowering with lower baseline LDL-C. Calculations based on the CTT analysis (Lancet. 2005;366:1267-78).

Comparison of GuidelinesCCS 2016 EAS/ESC 2016 AHA/ACC

LDL-C Targets/Treatment Recommendations

Secondary prevention

< 2 mmol/L or > 50% reduction

< 1.8 mmol/L or ≥ 50% reduction

High-intensity statin.(anticipate > 50% reduction)If 50% cannot be achieved, consider additional therapy.

Statin intolerance

Same Same Same

Primary preventionLDL > 5 mmol/L

> 50% reduction < 2.5 mmol/L High-intensity statin therapy (anticipate 50% reduction)

Primary prevention in diabetes

< 2 mmol/L or > 50% reduction

High risk DM: ≤ 1.8 mmol/L, or at least 50% reductionLow risk DM: < 2.5 mmol/L

High risk DM: High-intensity statin Low risk DM:Moderate-intensity statin

Primary preventionHigh risk

For FRS >10%: < 2 mmol/L or > 50% decrease

SCORE ≥ 5% risk of fatal CVD:<2.5 mmol/L

For PCRAE >7.5%:Moderate- to high-intensity statin

Lignes Conductrices Canadiennes

▪ Standard de soins au Canada▪ La référence prise par le CDR

(CADTH)▪ INESSS

Medications for Hypercholesterolemia

StatinsEzetimib

eFibratesNiacinBAR

PCSK9 mAbCETP inh

MTP inhApoB iRNABempedoic Acid

Monoclonal Antibodies (mAbs) 101

Paul Ehrlich (1854-1915)

• Gram stain • Arsphenamine (first

Rx for Syphilis) • Anti-serum against

dyphteria • Concept of

“magische Kugel” –magic bullet

Nobel Prize 1908

Antibody technology has evolved over past decadesRed = mouse

Blue = human

Imm

unog

enic

ity

Fully Mouse 1st generation

Highly Immunogenic

Chimeric 2nd generation

e.g.Abciximab

Chimeric, Still very immunogenic

Humanized 3rd generation

e.g.Bococizumab

Can be time-consuming to create

“Fully” Human 4th generation

e.g.Evolocumab and Alirocumab

repeated dosing possible

14Nomenclature: Prefix (Pharma) C (Cardiovascular) UMAB

The biologics explosionTNF Inhibitors

▪ Etanercept ▪ Adalimumab ▪ Infliximab ▪ Golimumab ▪ Certolizumab

Non-TNF Biologics • Tocilizumab (IL-6) • Rituximab (B cell CD20) • Abatacept (B7-CTLA4Ig) • Anakinra (IL1) • Canakinumab IL-1β)

Emerging non-TNF Biologics •Sarilimab •Olokizumab •Clazakizumab •Sirukumab •Secukinumab •Brodalumab

(IL6R) (IL6) (IL6) (IL6) (IL-17) (IL-17R)

Emerging non-MAb Biologics •Small molecules

• Tofacitinib (JAK1/3) •Biosimilars

PCSK9

PCSK9: A Canadian Discovery

Dr. Nabil Seidah IRCM

Nature Genetics  34, 154 - 156 (2003)

Proprotein Convertase Subtilisin/Kexin Type 9

Evolutionary Conservation: Must be important

Bacillus amyloliquefaciens saccharomyces cerevisiae Homo sapiens

ER TGN

EndosomeLysosome

LDL-R

PCSK9

pre-PCSK9

A: LDL-R pathway in absence of PCSK9

B: Intracellular

PCSK9 route

C: Extracellular PCSK9 route

Mature PCSK9

LDL

apoB

PCSK9

Deg

rada

tion

PCSK9 as a Target

Cohen JC, et al. NEJM 2006;354:1264

LDLR

Clinical Data

ODYSSEY Long-Term: Alirocumab Plus Statin Achieved a 62% Reduction in LDL-C over Placebo+Statin at 24

weeks

Robinson J, et al. N Engl J Med. 2015;372(16):1489-99.

3.60

3.00

2.40

1.80

1.20

0.60

0.00

Med

ian

LDL-

C (m

mol

/L)

Week

0 4 8 12 16 24 36 52 64 78

0.8%

3.08 mmol/L 3.17 mmol/L

3.6%

1.25 mmol/L

-61.0%

1.50 mmol/L

-52.4%

Alirocumab + statin therapy at maximum tolerated dose ± other LLT (150 mg q2w)Placebo + statin therapy at maximum tolerated dose ± other LLT

PlaceboAlirocumab

7801530

7541473

7471458

7461436

7161412

7081386

6941359

6761349

6591324

6521269

No. of patients with data available

62% reduction, P<0.001Absolute reduction: 1.2 mmol/L

ODYSSEY Long-Term: Reduction in the Rate of Cardiovascular Events- Post-hoc Analysis

*Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalization. LLT, lipid-lowering therapy†

≥52 weeks for all patients continuing treatment, incl. 607 patients who completed W78 visit

Robinson J, et al. N Engl J Med. 2015;372(16):1489-99.

7881550

7761534

7311446

7031393

6821352

6671335

321642

127252

847260483624120WeeksNo. at Risk

PlaceboAlirocumab

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event

Cum

ulat

ive

prob

abili

ty o

f eve

nt

0.06

0.05

0.04

0.03

0.02

0.01

0.00

Alirocumab + max-tolerated statin ± other LLT (150 mg q2w)Placebo + max-tolerated statin ± other LLT 54% RRR

Safety Analysis† Cox model analysis HR 0.46 95% CI: 0.26 to 0.82 P<0.01

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event*

ODYSSEYLong-Term

Ratio of LDL Lowering to CV Event Reduction with PCSK9 Inhibitors Holds True to the

“LDL Hypothesis”

Waters DD. Hsue PY. Circ Res. 2015;16:1643-1645.

70%

60%

50%

40%

30%

20%

10%

0%

-10%

0.5 1.0 1.5 2.0

Prop

ortio

nal r

educ

tion

in e

vent

rate

(SE)

Reduction in LDL cholesterol (mmol/L)

OSLER

IMPROVE-IT

Am J Cardiol 2015;115:1212e1221)

Christie M. Ballantyne, et al.

Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With Hypercholesterolemia

The American Journal of Cardiology, Volume 115, Issue 9, 2015, 1212–1221

Bococizumab

Figure 4. Mean percentage change from baseline in LDL-C. Change over time is shown for the (A) Q14 days and (B) Q28 days placebo and bococizumab dose groups.

Ballantyne CM. The American Journal of Cardiology, 2015;115:1212–1221

Bococizumab

Bococizumab: AE

FDA approves Praluent to treat certain patients with high cholesterol

PCSK9 mAb

Praluent is approved for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol.

PCSK9 mAb (US)

Repatha is approved for use in addition to diet and maximally-tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, such as heart attacks or strokes, who require additional lowering of LDL cholesterol.

PCSK9 Outcome Trials Alirocumab Evolocumab Bococizumab

Trial ODYSSEY Outcomes (secondary prevention)

FOURIER (secondary prevention)

SPIRE1 (secondary prevention)

SPIRE2 (primary prevention)

No of patients 18,600 27,500 17,000 10,600 Dosage s/c, Q2W s/c, Q2W or Q4W s/c, Q2W s/c, Q2W

Start date Oct 2012 Jan 2013 Oct 2013 Oct 2013

Expected End date Mar 2018 Feb 2018 Aug 2017 Aug 2017Primary endpoint

• CHD death • non-fatal MI • fatal and non-fatal ischemic stroke • high risk UA

requiring hospitalization

• CV death • MI • Stroke • hospitalization for

UA • coronary

revascularization

• CV death • non-fatal MI • non-fatal stroke • hospitalization for

UA needing urgent revascularization

• CV death • non-fatal MI • non fatal stroke • hospitalization for

UA needing urgent revascularization

Duration Up to Month 64 Up to 5 years Up to Month 60 Up to Month 60

Population Patients 4 to 52 wks post ACS • LDL-C ≥70 (1.8)

History of clinically evident CVD: MI, stroke or symptomatic PAD and ≥1 major RF or ≥ 2 minor RFs • LDL-C ≥70 (1.8) or

High risk patients • LDL-C ≥70 (1.8) and

<100 (2.6) or

High risk subjects • LDL-C ≥100 (2.6) or

73,700 patients

Q1 2017?

Anti-drug Antibodies (ADA)

Anti-drug antibodies (ADA): the challenge

Immunogenicity:▪ The potential for an antigen to

induce an immune response ▪ Immunogenicity against

therapeutic proteins that are not in the normal human repertoire is a normal immune response.

▪ Reaction to neo-antigens ▪ Proteins are non-human ▪ Fusion proteins create new

epitopes ▪ Unusual glycosylation

Anti-drug antibody formation

Anti-PSCK9

Antibody Fc

Antibody Fab (Neutralizing)

Lancet 383;9911, 60–68

PCSK9 RNAi

PCSK9 and Diabetes

41

Background: Statin Treatment and Increased Risk of T2DM

CI, confidence interval; OR, odds ratio; T2DM, type 2 diabetes mellitus. Case = developed T2DM. Non-case = did not develop T2DM. Swerdlow DI, et al. Lancet. 2015;385:351–361.

Henry N Ginsberg1

, Michel Farnier2

, Jennifer G Robinson3

, Christopher P Cannon

4

, Naveed Sattar5

, Marie T Baccara-Dinet6

, Christelle Lorenzato

7

, Maja Bujas-Bobanovic8

, Michael J Louie9

, Helen M Colhoun

10

Efficacy and Safety of Alirocumab: Pooled Analyses of 1051 Individuals with Diabetes Mellitus from

Five Placebo-Controlled Phase 3 Studies of at least 52 weeks’ duration

This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.

Mean Fasting Plasma Glucose Over Time (Safety Population)

43

†75 mg Q2W increased to 150 mg Q2W at W12 if LDL-C levels at Week 8 were ≥70 mg/dL (1.81 mmol/L). FPG, fasting plasma glucose.

5

6

7

8

9

10Alirocumab 75/150 mg Q2W †

5

6

7

8

9

10Alirocumab 150 mg Q2W

Placebo with DMAlirocumab with DM

Placebo without DMAlirocumab without DM

Mea

n (S

E) F

PG, m

mol

/L

12 24 36 520 241236 52 0Week Week

Mean HbA1c Over Time (Safety Population)

44

†75 mg Q2W increased to 150 mg Q2W at Week 12 if LDL-C levels at Week 8 were ≥70 mg/dL (1.81 mmol/L). HbA1c, glycated hemoglobin.

Mea

n (S

E) H

bA1c

, %

Placebo with DMAlirocumab with DM

Placebo without DMAlirocumab without DM

55.5

66.5

7

7.58

8.59

9.510 Alirocumab 75/150 mg Q2W †

55.5

66.5

77.5

88.5

99.510 Alirocumab 150 mg Q2W

12 24 520 0 12 24 52Week Week

Evaluation of the One-Year Efficacy, Safety and Glycaemic Effects of Evolocumab

(AMG 145) in 4,802 Subjects With, at High Risk for, or at Low Risk for, Diabetes Mellitus

Naveed Sattar,1 David Preiss,1 Dirk Blom,2 C. Stephen Djedjos,3 Mary Elliott,4

Andrea Pellacani,3 Scott M Wasserman,3 Michael Koren,5 Rury Holman6

 1BHF Cardiovascular Research Centre, University of Glasgow, UK; 2Division of Lipidology, Department of Medicine, University of Cape Town, South Africa; 3Amgen Inc., Thousand Oaks, CA, USA; 4Amgen Limited, Cambridge, UK; 5Jacksonville Center for

Clinical Research, Jacksonville, FL, USA; 6Diabetes Trials Unit, OCDEM, University of Oxford, UK

European Association for the Study of DiabetesStockholm, Sweden

17 September, 2015 – Session OP 27

Results: Median Fasting Plasma Glucose Over One Year*

*48 weeks of open-label treatmentError bars represent SE of the medianSoC, standard of care; T2DM, type 2 diabetes mellitus

46

Med

ian

Glu

cose

, mm

ol/L

Results: Median HbA1c Over One Year*

*48 weeks of open-label treatmentError bars represent SE of the medianHbA1c, glycated haemoglobin; SoC, standard of care; T2DM, type 2 diabetes mellitus

47

Med

ian

HbA

1c, %

Conclusion • In patients with T2DM, or people at high or low

risk of T2DM, one year of treatment with evolocumab or alirocumab: – markedly reduced LDL-C in all groups – showed encouraging safety – showed no measurable effect on glycaemic

parameters including new-onset T2DM vs SoC alone

• Clinical trials are ongoing to examine the effects of evolocumab on patients with T2DM, and on the incidence of new-onset T2DM

48

PCSK9inh au Canada

• PCSK9 inhibitors (evolocumab, alirocumab*) to lower LDL-C for patients with heterozygous FH whose LDL-C remains above target despite maximally tolerated statin therapy

(Conditional recommendation, moderate quality evidence). • We suggest that PCSK9 inhibitors be considered

to lower LDL-C for patients with atherosclerotic cardiovascular disease in those not at LDL-C goal despite maximally tolerated statin +/- ezetimibe therapy.

(Conditional recommendation, moderate quality evidence).

PCSK9 mAb Clinical Indications

Familial Hypercholesterolemia

ASCVD (Atherosclerotic Cardiovascular Disease) not at goal despite maximally tolerated lipid-lowering therapy

Statin intolerant

CETPinh

Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

Schawartz GG. N Engl J Med. 2012 Nov 5. [Epub ahead of print]

53

DALcetrapib Outcomes

54

Anacetrapib: Effects on LDL-C and HDL-C

HDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(mg/

dL) (

SE

)

0

20

40

60

80

100

120

AnacetrapibPlacebo

Anacetrapib n = 776 757 718 687 647 607 572 543Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

LDL-

C (m

g/dL

) (S

E)

0

20

40

60

80

100

AnacetrapibPlacebo

Anacetrapib n = 804 771 716 687 646 604 568 540Placebo n = 803 759 741 743 735 711 691 666

-39.8% (p<0.001) +138.1% (p<0.001)

Figure 3. Changes in anacetrapib concentrations during the treatment and reversal phases: anacetrapib concentrations during the treatment phase (weeks 12, 24, and 76), at the week 12 reversal visit, and at the reversal visit 2.4 to 4 years after stopping anace...

Gotto AM. Am J Cardiol 2014; 113:76

Evaluation of Lipids, Drug Concentration, and Safety Parameters Following Cessation of Treatment With the CETPinh Anacetrapib in Patients With or at High Risk for CHD

CETPinh

• Torcetrapib: off-target effects (?) increase MACE • Dalcetrapib: HDL elevation but no LDL-C lowering: no

effect on MACE • Anacetrapib: Decrease in LDL-C overestimated by

Friedewald formula; effect size smaller. Concerns with prolonged terminal half-life

• Evacetrapib. Decrease in LDL-C overestimated by Friedewald formula; effect size smaller. Shorter terminal T1/2 but still prolonged

• Orocetrapib (TA-8995) TULIP trial reported 2015

Augmenter le HDL-C Pharmacologiquement

▪ Ne réduit pas les MCAS ▪ Niacine, Fibrates, CETPi

▪ HDL-C: mauvais biomarqueur de risque? ▪ Fonction des HDL plus importante que le HDL-C ▪ Protéoliposomes (rHDL) ne sont pas de HDL

➔ La mesure des HDL plasmatiques ne reflète probablement pas la fonction sub-intimale des HDL

HDL: Localisation Sub-Intimale

Apo A-I

Choi H, Genest J. Can J Cardiol

Medications for Hypercholesterolemia

StatinsEzetimib

eFibratesNiacinBAR

PCSK9 mAbCETP inh

MTP inhApoB iRNABempedoic Acid

Bempedoic acid inhibits ATP-citrate lyase (ACL)

Bempedoic Acid Esperion ETC 1002

Bempedoic Acid Esperion ETC 1002

Hypercholesterolemie Familiale

Medicaments pour Maladies Orphelines

Franz Hals (1683)

Portrait d’une femme de 60 ans avec un livre

HeFH clinical features (stigmata)Xanthelasmas

Xanthomas

Xanthomas

Arcus Corneus

LDL accumulates to cause CHD early in life in FH

Normal

Female

Male HypertensionDiabetesSmoking

HeFHHoFH

Threshold for CHD

0

5

10

1 20 40 60 80

Cum

ulat

ive

LD

L-C

(g

/dL-

year

s)

■ Threshold for CHD reached by: – Age 15 y in HoFH patients – Age 40 y in HeFH patients – Age >60 y in healthy individuals

Age Patients Meet CHD Threshold

Age (years)

Adapted from Horton JD, et al. J Lipid Res. 2009;50(Suppl):S172-S177.

LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy.

Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273

© The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.

L’HF est l’un des désordres génétiques les plus communs

Fréquence par 1000 naissances

HF hétérozygote

Hémophilie

Ostéosclérose dominantePolykystose rénale

Chorée de HuntingtonFibrose kystique

Dystrophie musculaire de Duchenne

Anémie falciformePhénylcétonurie

0 1 2 3 4 5

Syndrome de Marfan

Prévalence au Canada = plus de 140.000 pts

Hypercholestérolémie Familiale (HF)

Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490

LDL-C 95% PourcentileComparison in 95th percentile of LDL between males and females cohort: GDML

lab data95

th p

erce

ntile

of L

DL

(mm

ol/L

)

0.00

1.50

3.00

4.50

6.00

Age Group in 5-year segment0- 5 11-15 21-25 31-35 41-45 51-55 61-65 71-75 81-85 91plus

FemaleMale

N=3,336,000 patients

1st degree relative with ↑ LDL-Cor

1st degree relative with early onset ACVD

Definite FH

Probable FH(Consider DNA

testing)

*LDL-C ≥ 5.0 mmol/L (>40 yo)

DNA MutationXanthomas

LDL >8.5 mmol/l

+

Yes No

Yes No

Hypercholesterolemia

(Consider DNA testing)

Confirmation du défaut génétique

Séquençage de LDLR, ApoB et

PCSK9(M iSeq)

Oui

Non Oui

Non

Requête de laboratoire

Rapport

Défaut génétique connu?

Positive?

Analyse Del/dup de LDLR (MLPA)

Dépistage Génétique pour l’HF au Québec*

* Proposition a l’INESSS

Mutations du gène LDL-R au Québec

Clin Genet 19V7: 52: 1-6

The Founder Effect in Genetics

The Founder Effect in Genetics

The founder effect occurs when the following conditions are met: ▪ Small number of migrants ▪ Evolutionary bottleneck (war, pestilence, natural catastrophe) ▪ High birth rate and increase in inbreeding (co-sanguinous

marriages), ▪ Low genetic variation (lack of genetic mixing)

▪ This can be observed in Iceland, Faroe Islands, Easter Islanders ,Pitcairn Island, Tangier Island.

▪ Also in French Canadians, Ashkenazi Jews, South Afrikaners, Mormons, etc…

Canadian Familial Hypercholesterolemia Registry Régistre Canadien d’hypercholestérolémie familiale

McPhersonOoi

Frohlich

HegeleFiller

Gaudet

McCrindleGenestBrophyRuel

BergeronCouture

CarpentierPerron

St-Pierre

EngertBaassDufourDavignon

GuptaLeiterNgCheung

HendersonLeberge

JunaidKatzMyminNguyenMillerWoo

ManciniSaeediFrancis

MorrisonPare

RaggiRomneyPearson

Hoag Ransom

SussexChandurkar

Bose

BewickLauMaWong

www.FHCanada.net

www.FHCanada.net or www.HFcanada.net

PCSK9 in heterozygous FH(HeFH)

PCSK9-inhibition safe and effective in heterozygous and homozygous familial hypercholesterolaemiaRaal et al., The Lancet 2014Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial.Lancet. 2014 Raal FJ, Honarpour N, Blom DJ et al.PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.Raal FJ, Stein EA, Dufour R et al. Lancet. 2014 Oct 1.

Evolocumab: Add-on to Statins – Significant LDL-C Lowering with Monthly or Bi-weekly Dosing

† Reflexive LDL-C measurements; Co-primary Endpoints: Mean % change from baseline in LDL at week 10/12 Adapted from Robinson JG, et al. JAMA. 2014;311(18):1870-1882 (LAPLACE-2); Raal F, et al. Lancet. 2014. Published Online October 2, 2014. http://dx.doi.org/10.1016/S0140-6736(14)61399-4.(RUTHERFORD-2).

-60-50-40-30-20-10

010

% C

hang

e fr

om B

asel

ine

in L

DL-

C†

–1%

+2%

–61% –64%

HeFH: Heterozygous Familial Hypercholesterolemia

RUTHERFORD-2

QMQ2W

HeFH Study (n = 331)

• HeFH patients unable to achieve LDL-C < 2.6 mmol/L despite statin ± EZE

• ~ 60% LDL lowering in this difficult patient group

LDL-C Reduction with Alirocumab in Both Pooled Study Groups

81

LS m

ean

(SE)

% c

hang

e fro

m

base

line

to W

eek

12/W

eek

24 in

LD

L-C

-60

-43

-25

-8

10 7.11.3

-48.8-55.0

5.4

-43.6

Alirocumab 75/150 mg Q2W †Alirocumab, n=488; placebo, n=244

Alirocumab 150 mg Q2W Alirocumab, n=346; placebo, n=174

41.8% had dose increase

at Week 12

Week 12 Week 24 Week 24

All % changes P<0.0001 versus placebo

Baseline‡ 3.66 mmol/L

Week 12 change‡

-1.62 mmol/L

Week 24 change‡

-1.84 mmol/L

Baseline‡ 4.36 mmol/L

Week 24 change‡

-2.32 mmol/L

Alirocumab

Placebo

Medications for Hypercholesterolemia

StatinsEzetimib

eFibratesNiacinBAR

PCSK9 mAbCETP inh

MTP inhApoB iRNABempedoic Acid

VLDL Assembly and secretion

Mipomersen

Lomatipibe

83

(Juxtapid®)

84

Lomatipide and Homozygous FH

(Kynamro®)

86

Extracorporeal LDL Filtration

Liposorber(Kaneka)

HELP(Braun)

Le filtre avant et après un traitement: diminution du cholestérol-LDL~60% + Lp(a) et fibrinogène

Courtoisie Dr Jean Bergeron

0.00

3.25

6.50

9.75

13.00

91.01.2392.08.19 93.02.0293.05.26 93.08.3194.01.04 94.04.1894.09.14 95.12.0196.04.1796.08.21 97.01.1097.05.02 97.09.1898.01.22 98.06.09

Mea

n LD

L-C

(mm

ol/L

)

Time (years)

+ Atorvastatin

Apheresis19

92

1993

1994

1995

1996

1997

1998

400

300

200

100

Mea

n LD

L-C

(mg/

dL)500

1999

Extracorporeal LDL Filtration (HELP)

Genest J. NEJM 1999;341:490

A

C D

B

1989 1999

Conclusions

• Le lien de causalité entre le cholesterol (LDL-C) et la MCAS est sans équivoque.

• La diminution du LDL-C représente le meilleur moyen, après l’arrêt du tabagisme et un bon style de vie, de diminuer le risque de MCAS

Cholesterol et MCAS

▪ Liens avec l’inflammation

Dr. Goran HANSSON Dr. Peter LIBBY Dr. Paul RIDKER

Immunity, Inflammation and CVD

Inflammation and Atherosclerosis

Gout: Uric acid crystalopathy

Atherosclerosis: Cholesterol Crystalopathy?

European Heart Journaldoi:10.1093/eurheartj/ehv653

Proposed mechanism of cholesterol crystal (CHC)-induced inflammasome activation

Rajamäki K. PLoS One. 2010; 5(7): e11765

Duewell, P, et al, Nature 2010; 464:1357-1362

Rajamaki K et al, PLoS One 2010;5:e11765

Cholesterol crystals activate the caspase-1-activating NLRP3 inflammasome to generate IL-1β and initiate atherosclerosis

Cholesterol Crystals;

Modified LDL Pro-caspase-1

ASC Cardinal

NLRP3

Cathepsin B

Caspase-1Pro-IL-1βIL-1β

IL-1βVascular inflammation hsCRP

IL-1B mab or IL-1rA

IL-1β

IL-1β

Phagosome

Lysosome

Phagolysosome

NLRP3 Inflammasome

Innate immune cell

Liver

IL-6

Duewell et al, Nature (2010) 464:1357-62

Endogenous Danger Signal

Libby P. Inflammation and atherosclerosis. Nature 2002;420:868Arnaud C et al. Statins reduce IL6 induced CRP secretion in human hepatocytes ATVB 2005;25;1231

Cholesterol and Inflammation

IL-6

CRP

IL-1

Lowering Cholesterol Modulating Inflammation