lp(a) ready for prime time? - cvgk · distribution lipoprotein(a) levels in the normal population...
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Lp(a)Ready for prime time?
E Stroes
AMC
Male, 45 years old
Hypertension: –
DM: –
Smoking: –
Dyslipidemia: –
Fam history: brother MI (55yr)
Case
Lipoprotein(a): 1240 mg/L!!!
Lipoprotein(a) = LDL + apo(a) tail + OxPls
Tail = kringle repeats
Tsimikas S. JACC (2017). 69(6):692-711
Structure of Lp(a) and Sites of OxPL Accumulation
Leibundgut et al JACC 2012 and JLR 2013, Rao ATVB 2015
5
Distribution lipoprotein(a) levels in the normal
population
Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853
Copenhagen General Population Study
Impact of Lp(a) elevation
• Prevalence of Lp(a) elevation
– 75th percentile 470 mg/L
– 90th percentile 900 mg/L
– 99th percentile 1800 mg/L
• Lp(a) 1800mg/L
– risk equivalent of heterozygous FH
– More prevalent than heterozygous FH (1:100 vs 1:250)
Impact of Lp(a) on ‘LDL’-cholesterol
Lp(a) is an indepedent, genetic risk factor for
cardiovascular disease
Erquo et al. (2009) JAMA. 302:412-423 Kamstrup et al. (2009) JAMA. 301:2331-2339 Clarke et al. (2009) NEJM: 361:2518-2528
Torzewski, M. et al. J Am Coll Cardiol Basic Trans Science (2017). 2(3):229-41
Lp(a) is associated with atherosclerosis ánd calcified aortic
valve stenosis
Pathogenic mechanisms of Lp(a)
Tsimikas S. JACC (2017). 69(6):692-711
Pathogenic mechanisms of Lp(a)
Tsimikas S. JACC (2017). 69(6):692-711
1. Lp(a) atherogenic trough it’s LDL moiety→ accumulation in atherosclerotic plaques
Libby. Nature (2002). 420, 868-874 / Van Dijk et al. JLR (2012). 53, 2773-2790.
Contribution of lp(a) to ‘residual risk’ after statin
treatment
Pathogenic mechanisms Lp(a)
Tsimikas S. JACC (2017). 69(6):692-711
2. Lp(a) also atherogenic via apo(a) tail / OxPL
Tsimikas S. JACC (2012).
OxPls on Lp(a) induce a systemic pro-inflammatory response
Bernelot Moens et al, Eur hrt J, 2017 & vd Valk et al, Circulation 2016
Characteristic Healthy
controls
(n=30)
Subjects with
elevated lp(a)
(n=30)
Age, y 53±12 52±11
Gender,
%male
45 (9) 43 (15)
BMI 24±4 24±3
Lp(a), mg/dl 7[2-28] 108[50-195]
Total
cholesterol
5.21±0.83 5.79±1.44
LDL-c 2.91±0.8 2.80±1.16
HDL-c 1.68±0.42 1.60±0.40
Triglycerides 0.8[0.24-2.18] 0.82[0.39-2.16]
Lp(a) patients have increased vessel wall inflammation
measured with 18F-FDG PET/CT-scan
Van Der Valk et al. Circ 2016. 134(8):611-24
18F-FDG PET/CT-scan
Yellow = metabolic activity
*
*
Lp(a) patients have increased influx of monocytes in atherosclerotic plaques
In vivo
Van Der Valk et al. Circ 2016. 134(8):611-24
SPECT/CT-scans met 99mTc-labeled
autologous PBMCs
Green = accumulated monocytes
Therapeutic agents affecting Lp(a) levels
• Increase:
– Statins
– Low fat diets
– Garlic supplements
• ‘small’ decrease:
– Niacin
– LDL-apheresis
– CETP-inhibition
– apoB-antisense
– MTP inhibitors
– Anabolic steroids
– aspirin
Effect of diet, statin therapy and apheresis on Lp(a)
Time
Lp(a)
(mg/dL)
Time Averaged (35%)
Diet
Therapy
(No effect)
Apheresis Treatment
Pre
Post
150
45
102
175 mg/dL
21
45 mg/dL
102 mg/dL
150 mg/dL
Statin
Therapy
15% increase)
22
Mean Annual Rates for MACE, ACVE, MI, PCI, and CABG for 2 Years Before
(y-2, y-1) and After (y+1, y+2) Commencing Chronic lipid Apheresis and
Percentage Changes (Δ) Between Periods Before and During Apheresis
Leebman et al. Circulation 2013;128:2567–2576
ACVE indicates adverse cardiac or vascular events; CABG, coronary artery
bypass graft; LA, lipoprotein apheresis; MACE, major adverse coronary events;
MI, myocardial infarction; and PCI, percutaneous coronary intervention.
Antisense Oligonucleotides Targeting Lp(a)
Tsimikas JACC 2017;69:692-711
Antisense
Oligonucleotide
23
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
Placebo Cohort A (50-175 mg/dL) Cohort B (>175 mg/dL)
Viney et al, Lancet 2016
A B
Transendothelial migration Assay
Lowering Lp(a) Reduces Plasma Monocyte ActivationChanges in Monocyte Transendothelial Migration (TEM)
Changes & correlations of TEM vs. changes in Lp(a) and OxPL-apoB in response to IONIS-APO(a)Rx vs. Placebo Viney et al, Lancet 2016
Hepatocyte Targeting Antisense via Asialoglycoprotein Receptor
(ASGPR) Enhances Drug Delivery to the Liver 10-15xLICA - ligand conjugated antisense
T. P. Prakash et al . Nucleic Acids Res. 2014 Jul;42(13):8796-807
IONIS-APO(a)-LRx Produced Dose-dependent Significant
Reductions in Lp(a)
Up to 97% Reduction in Lp(a),
with Mean Reduction of 85%Up to 99% Reduction in Lp(a),
with Mean Reduction of 92%
Single Ascending Dose Multiple Ascending Dose
▪ Well tolerated with no safety
concerns
Lp
(a)
(nm
ol/
L)
Mean
% C
ha
ng
e f
rom
Baseli
ne
(+
/-S
EM
)
Study Day
20 mgPlacebo 80 mg10 mg 40 mg 120 mg
Lp
(a)
(nm
ol/
L)
Mean
% C
ha
ng
e F
rom
Baseli
ne
(+
/-S
EM
) Study Day
20 mgPlacebo 10 mg 40 mg
Viney et al. Lancet 2016
Mean Lp(a) reductions:
10 mg= ↓ 68%
20 mg= ↓ 80%
40 mg= ↓ 93%27
• No serious AEs
• No AEs leading to treatment discontinuation
• No hepatic or renal signals
• No injection site or flu-like reactions
• No clinically significant findings in routine
hematology or biochemistry
• No platelet reductions
Clinical Safety and Tolerability for Hepatic Targeted Antisense
Prevalence of Lp(a) Levels Globally
--CVD Outcome Trials will be Needed--
Varvel et al. Arterioscler Thromb Vasc Biol 2016
Lp(a) distribution in general population extrapolated from the graph
Lp(a) levels >30 mg/dL >60 mg/dL >90 mg/dL >116 mg/dL >180 mg/dL
Prevalence 35% 20% 10% 5% 1%
Number (US) 112,000,000 64,000,000 32,000,000 16,000,000 3,200,000
Number (EU) 262,500,000 150,000,000 750,000,000 37,500,000 7,500,000
Globally 2,450,000,000 1,400,000,000 700,000,000 350,000,000 70,000,000
Estimated prevalence assumes:
320M in US, 750M in EU and 7B globally
N=~531,000
29
Significant Advances in Medicinal Chemistry of Antisense
Improve Potency and Tolerability
LICALICA
Gen 2.5LICA Gen 2/2+
cEt Gapmer Design GalNac DesignMOE Gapmer Design
LICA 1st Gen
P-S
1X ↑10X ↑10X ↑10X =1000X
Side effect profile
Potency
(600-1200/wk) 100-300/wk 10-40/wk 10-40/wk 1-3/wk
30
“Urgent need for Awareness, Measuring and ACTION!”
Take home message
Lp(a) measurement in:
- Patients above 50yr (both primary as secondary prevention)
- Premature atherosclerosis patients
- ‘Unexplained’ CVD
- Progressive disease dispite CVRM
For questions:
lpa@amc.nl
Acknowledgments
AMC
- Jeffrey Kroon, PhD
- Lotte Stiekema, PhD
- Simone Verweij, MD
- Renate Hoogeveen, MD
- Jan Schnitzler
- Rutger Verbeek, MD
- Fleur van der Valk, MD PhD
UCSD
- Sam Tsimikas
- Joe Witztum
REPROGRAM consortium
- Alberico Catapano
- Borge Nordestgaard
- Mihai Netea
- Menno de Winter
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