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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