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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
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Page 1: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Lp(a)Ready for prime time?

E Stroes

AMC

Page 2: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Male, 45 years old

Hypertension: –

DM: –

Smoking: –

Dyslipidemia: –

Fam history: brother MI (55yr)

Case

Lipoprotein(a): 1240 mg/L!!!

Page 3: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Lipoprotein(a) = LDL + apo(a) tail + OxPls

Page 4: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Tail = kringle repeats

Tsimikas S. JACC (2017). 69(6):692-711

Page 5: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Structure of Lp(a) and Sites of OxPL Accumulation

Leibundgut et al JACC 2012 and JLR 2013, Rao ATVB 2015

5

Page 6: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Distribution lipoprotein(a) levels in the normal

population

Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853

Copenhagen General Population Study

Page 7: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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)

Page 8: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Impact of Lp(a) on ‘LDL’-cholesterol

Page 9: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 10: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 11: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Pathogenic mechanisms of Lp(a)

Tsimikas S. JACC (2017). 69(6):692-711

Page 12: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Pathogenic mechanisms of Lp(a)

Tsimikas S. JACC (2017). 69(6):692-711

Page 13: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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.

Page 14: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Contribution of lp(a) to ‘residual risk’ after statin

treatment

Page 15: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Pathogenic mechanisms Lp(a)

Tsimikas S. JACC (2017). 69(6):692-711

Page 16: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

2. Lp(a) also atherogenic via apo(a) tail / OxPL

Tsimikas S. JACC (2012).

Page 17: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

OxPls on Lp(a) induce a systemic pro-inflammatory response

Bernelot Moens et al, Eur hrt J, 2017 & vd Valk et al, Circulation 2016

Page 18: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 19: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

*

*

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

Page 20: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 21: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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)

Page 22: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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.

Page 23: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

Antisense Oligonucleotides Targeting Lp(a)

Tsimikas JACC 2017;69:692-711

Antisense

Oligonucleotide

23

Page 24: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 25: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 26: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 27: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 28: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

• 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

Page 29: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 30: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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

Page 31: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

“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:

[email protected]

Page 32: Lp(a) Ready for prime time? - CVGK · Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population

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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