new targets in lipid management · new targets in lipid management john j.p. kastelein, md phd...

New Targets in Lipid Management

John J.P. Kastelein, MD PhD

Academic Medical Center / University of Amsterdam

The Netherlands

Novel Approaches to Modify Lipids and Lipoproteins

� Low Density Lipoprotein

� High Density Lipoprotein

� Triglyceride Rich Lipoproteins

2

� Triglyceride Rich Lipoproteins

� Inflammation

� Lipoprotein a

Statin Prescription in the UK

500,000

600,000

700,000

800,000

Net

Ingr

edie

nt C

ost (

000s

)

40,000

50,000

60,000

Pre

scrib

ed It

ems

(000

s)

3

0

100,000

200,000

300,000

400,000

500,000

91/9

2

92/9

3

93/9

4

94/9

5

95/9

6

96/9

7

97/9

8

98/9

9

99/0

0

00/0

1

01/0

2

02/0

3

03/0

4

04/0

5

05/0

6

06/0

7

07/0

8

08/0

9

Net

Ingr

edie

nt C

ost (

000s

)

0

10,000

20,000

30,000

Pre

scrib

ed It

ems

(000

s)

Statins – Prescribed Statins – Cost (£000s)

Percentage of the UK-population with TC > 5 mmol/l

70

80

90

100

% o

f th

e P

op

ula

tio

n

1994

1998

2003

4

0

10

20

30

40

50

60

16–24 25–34 35–44 45–54 55–64 65–74 75+ 16–24 25–34 35–44 45–54 55–64 65–74 75+

Men Women

% o

f th

e P

op

ula

tio

n

1994

1998

2003

2006

Year2006

All-Cause Mortality in the UK in those < 75 Years

115350

400

450

All

Cau

ses

-

397

296

5

8942

52

32

141

114

115

107

0

50

100

150

200

250

300

P Ave 95-97 P Ave 06-08

Mor

talit

y -

DS

R p

er 1

00,0

00 -

Other Cancer Other Circulatory CHD

Data

1995-1997 2006-2008

296

53% reduction

New Approaches to LDL Reduction

What is in development?

• Cholesterol Absorption Inhibitors

• Squalene Synthase (SSI) inhibitors

• Apo B mRNA antisense drugs

6

• Apo B mRNA antisense drugs

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors

• Thyroxin Receptor Agonists

• PCSK9 Inhibitors

New Approaches to LDL Reduction

What is in development?

• Cholesterol Absorption Inhibitors

• Squalene Synthase (SSI) inhibitors

• Apo B mRNA antisense drugs

7

• Apo B mRNA antisense drugs

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors

• Thyroxin Receptor Agonists

• PCSK9 Inhibitors

New Approaches to LDL Reduction

What is in development?

• Cholesterol Absorption Inhibitors

• Squalene Synthase (SSI) inhibitors

• Apo B mRNA antisense drugs

8

• Apo B mRNA antisense drugs

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors

• Thyroxin Receptor Agonists

• PCSK9 Inhibitors

Mipomersen: Apo B-100 as a Target

Cholesterol

Apo B Triglyceride

VLDL� Apo B-100 is an important structural

and functional component of lipoproteins

� Blocking Apo B-100 production blocks VLDL and LDL production

Mipomersen

9

Apo B Triglyceride

VLDL IDL

LDL1LDL2 LDL3

Lp(a)

Apo A

� A 20-mer phosphorothioate antisense oligonucleotide that is complementary in sequence to a segment of the human Apo B mRNA

Overview of Mipomersen

10Kastelein JJ, et al. Circulation. 2006;114(16):1729-1735.

G C C T C A G T C T G C T T C G C A C C

PhosphorothioateBackbone

2′ MOE2′ MOE2′ Deoxy

(Supports RNase H Activity)

OB

O

O

B

O

O

OP

O

S

OP

O OCH3

O OCH3

5'

Antisense: A Novel Approach to Drug Discovery by Inhibition of Translation of a Specific Targeted Pr otein

Antisense Strand

Cell Membrane

2nd Generation Antisense Drugs

� ~20X more potent

� 1X/week to 1X/quarter dosing

� Better tolerated

RNase H Dependent Mechanism of Action

11

O

O

B

O

O

BO

OP

S

O

OP

S

OP

S

3'

Sense-Antisense Duplex

RNase H

DNA

mRNA

Nucleus Cytoplasm

Membrane

� Lower cost of therapy

Heterozygous Familial HypercholesterolemiaStudy Design

� Patients were randomized 2:1 to receive weekly subcutaneous injections of mipomersen 200 mg or placebo for 26 weeks

Active treatment

12

Active treatment

Placebo

R 2:1 active:placebo

Screening

≤4 weeks

Treatment period

26 weeks

Safety follow-up

24 weeks

Safety follow-up(for patients not entering OLE study)

225 patientsscreened;

124 patientsenrolled

Cromwell W, et all, [poster]. American Heart Association Scientific Sessions; Nov 14-18; Orlando, FL; 2009

Mipomersen Significantly Reduced LDL-C

Reduction in LDL-C over 28 weeks(full analysis set)

5.2%PET

13

–28.0%

Distribution of LDL-C % Change From BaselineC

fro

m b

asel

ine

at P

ET

14

% c

han

ge

in L

DL

-C f

rom

bas

elin

e at

PE

T

PET, primary efficacy time point, 2 weeks after final dose. Data on file.

New Approaches to LDL Reduction

What is in development?

• Cholesterol Absorption Inhibitors

• Squalene Synthase (SSI) inhibitors

• Apo B mRNA antisense drugs

15

• Apo B mRNA antisense drugs

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors

• Thyroxin Receptor Agonists

• PCSK9 Inhibitors

1616

The Rationale

� Thyroid hormone receptors modulate lipid metabolism and energy expenditure through transcriptional effects

� The liver is the target organ for thyroid hormone-mediated regulation of lipid metabolism

16

of lipid metabolism

� Association between thyroid status and atherosclerosis clearly demonstrated

� The thyroid hormone receptor is a well known target

1717

Selective Thyroid Receptor Agonist Provides New Treatment Opportunities

Selective thyroid agonist

17

� Heart

� Bone

� Skeletal muscle

� Cholesterol

� Triglycerides

� Lipoprotein(a)

� Reverse cholesterol transport

� Metabolic rate

Side effects Metabolic effects

1818

Eprotirome is…

� a small molecule

� a thyroid receptor agonist

� acting in the liver

18

� as potent as T3

� for once daily oral administration

1919

Eprotirome Monotherapy Efficiently Lowers LDL-C

Placebo25 µg50 µg100 µg

LDL cholesterol

125

150

mg/

dL

LDL-cholesterolBaseline to week 12

-6

-10

0

% c

hang

e

19

100

125

750 4 8 12 16

Time (weeks)p <0.0001Mean ± 95% CI

-21-26

-32

-40

-30

-20

% c

hang

e

New Approaches to LDL Reduction

What is in development?

• Cholesterol Absorption Inhibitors

• Squalene Synthase (SSI) inhibitors

• Apo B mRNA antisense drugs

20

• Apo B mRNA antisense drugs

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors

• Thyroxin Receptor Agonists

• PCSK9 Inhibitors

23

24

LDL-C Mean % Change from Baseline in Subjects Treated with IV REGN727/SAR236553

or PlaceboLS

ME

AN

S P

erce

nt C

hang

e (%

)

2727

Swergold G. J Clin Lipidol 2011;5(3):219. Study R727-CL-0902

LSM

EA

NS

Per

cent

Cha

nge

(%)

27

Novel Approaches to Modify Lipids and Lipoproteins

� Low Density Lipoprotein

� High Density Lipoprotein

� Triglyceride Rich Lipoproteins

28

� Triglyceride Rich Lipoproteins

� Inflammation

� Lipoprotein a

New Approaches for Raising HDL

What is in development?

• Cholesterol Ester Transfer Protein (CETP) inhibitors

• ER-Niacin / Laropiprant combination

• ApoA1 based strategies

29

• ApoA1 based strategies

• LCAT replacement strategies

• ABCA1 agonists

Future DirectionsPost-Torcetrapib Era

30Newsweek, March 26th, 2007

Odds ratio for future CAD

2

3

4

CETP Levels and CAD risk:CETP Levels and CAD risk:The EPIC The EPIC –– Norfolk studyNorfolk study

31

CETP quintile 1 2 3 4 5

Odds ratio for future CAD

0

1

2Trig>1.7 mmol/L

Boekholdt et al. Circulation 2004

Trig<1.7 mmol/L

Range, mg/L <2.4 2.4–2.9 3.0–3.7 3.8–4.9 >4.9

LDL-C

60

80

100

120

140

160

Per

cent

Cha

nge

from

Bas

elin

ein

HD

L-C

HDL-C

Per

cent

Cha

nge

from

Bas

elin

ein

LD

L-C

-40

-20

0

20

Anacetrapib Dose Ranging Study

32Bloomfield et al. Am Heart J 2009;157:352-60

PlaceboAnacetrapib 10 mgAnacetrapib 40 mgAnacetrapib 150 mgAnacetrapib 300 mg

Weeks on Treatment

-20

0

20

40

60

0 2 4 8

Per

cent

Cha

nge

from

Bas

elin

ein

HD

L

Per

cent

Cha

nge

from

Bas

elin

ein

LD

L

Weeks on Treatment0 2 4 8

-80

-60

-40

FutureFuture

33

�� 30,000 patients with occlusive arterial disease in North America, 30,000 patients with occlusive arterial disease in North America, Europe and AsiaEurope and Asia

�� Background LDLBackground LDL--lowering with atorvastatinlowering with atorvastatin

�� Randomized to anacetrapib 100 mg vs. placeboRandomized to anacetrapib 100 mg vs. placebo

�� Primary outcome: Coronary death, myocardial infarction or Primary outcome: Coronary death, myocardial infarction or coronary revascularizationcoronary revascularization

www.revealtrial.org. www.revealtrial.org.

The Verdict is Still Out on CETP Inhibition as a Mechanism

34

New Approaches for Raising HDL

What is in development?

• Cholesterol Ester Transfer Protein (CETP) inhibitors

• ER-Niacin / Laropiprant combination

• ApoA1 based strategies

35

• ApoA1 based strategies

• LCAT replacement strategies

• ABCA1 agonists

Niacin-Induced Flushing Limits Niacin Utilization

36

Niacin Flushing Pathway: Two Separate Steps and Sites of Action

1. Epidermal Langerhans Cells

• Niacin binds

• PGD2 is produced and released

37

Illustrations are artistic renditions.PGD2=prostaglandin D2; PLA2=phospholipase A2; DP1=prostaglandin D2 receptor 1.Benyó Z et al. Mol Pharmacol. 2006;70:1844–1849; Morrow JD et al. J Invest Dermatol. 1992;98:812–815; Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687.

2. Dermal Blood Vessels

• PGD2 binds to DP1

• Vasodilation results

An Overview of the Niacin-Induced Flushing Pathway

Niacin

NiacinReceptor

(+)

Phospholipids

PLA

Arachidonic Acid Pathway

Epidermal Langerhans Cells Dermal Blood Vessel

PGD2

Prostaglandin D2 Receptor 1 (DP1) Pathway

38

Arachidonic Acid

PGG2

PGH2

PGF2α

PGI2PGE2

TXA2

PLA2

PGD Synthase

DP1

PG=prostaglandin; PLA2=phospholipase A2; TXA2=thromboxane A2.Dashed arrows are normal parts of the arachidonic acid pathway that may or may not occur in Langerhans cells. Maciejewski-Lenoir D et al. J Invest Dermatol. 2006;126:2637–2646; Narumiya S et al. Physiol Rev. 1999;79:1193–1226;Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687; Morrow JD et al. Prostaglandins. 1989;38:263–274.

PGD2

Vasodilationand Flushing

Factorial Study: Lipid Efficacy

Primary end point

HDL-C27.5

23.4

0 4 8 12

% C

hang

e

0

10

20

30

6.0-17.0

% C

hang

e

-30

-20

-10

0

39

� ER niacin/laropiprant (n = 160)

� Simvastatin (all doses pooled; n = 565)

� ER niacin/laropiprant + simvastatin (all doses pooled; n = 520)

TG-33.3

-21.6

-14.7

0 4 8 12

% C

hang

e-40

-30

-20

-10

0

Weeks on Treatment

Weeks on Treatment

LDL-C

-37.0

-47.9

0 4 8 12

% C

hang

e

-60

-50

-40

-30

Weeks on Treatment

ER niacin/laropiprant 2 g/40mg

Placebo

All patients receive either simvastatin 40mg or ezetimibe/simvastatin 10/40 mg

HPS2-THRIVE (Heart Protection Study 2 – Treating HDL to Reduce V ascular Events)

40

Patient Population Subjects Primary End Point

�Age 50-80

• History of MI or cerebrovascular atherosclerotic disease or PAD or diabetes mellitus with any of the above or with other evidence of symptomatic CHD

�25,000 �UK

(n=8500), Scandinavia (n=6000) and China (n=10500)

�Major vascular events (non-fatal MI or coronary death, non-fatal or fatal stroke or revascularisation)

New Approaches for Raising HDL

What is in development?

• Cholesterol Ester Transfer Protein (CETP) inhibitors

• ER-Niacin / Laropiprant combination

• ApoA1 based strategies

41

• ApoA1 based strategies

• LCAT replacement strategies

• ABCA1 agonists

ApoA1 Based Therapies

� ApoA1 Mimetics, such as APL-180 Novartis

� Full-length ApoA1, such as ApoA1 Cerenis Therapeutics

� Pre-Beta HDL, as generated by delipidation, HDL Therapeutics Inc.

� Reconstituted HDL, CSL Ltd.

42

� Reconstituted HDL, CSL Ltd.

� ApoA1 Milano, The Medicines Company

� Trimeric ApoA1, Borean Pharma and now Roche

� RVX-208, as developed by Resverlogix

CERCER--001001

43

Cerenis HDL (CER-001)Homogeneous Drug Product

Traditional rHDL complexes

HDL

44

Proprietary charged CerenisrHDL complexes

Validated, scaleable GMP process for producing proprietary charged lipoprotein complexes

HDL

GMP run

CER-001 Mobilizes Cholesterol in Rabbits: Comparison with ETC-216

Total Cholesterol1.0

0 mg/kg2.5 mg/kg5 mg/kg10 mg/kg20 mg/kgETC-216 (100 mg/kg) *

CER-001 is at least 10 to 20 time more potent to mobilize cholesterol than ETC-216

45

2 4 6 80.0

0.5

Time (h)

Co

nce

ntr

atio

n (

g/L

)

* ETC-216 data were extracted from Marchesi M. et al (2004) J Pharmacol Exp Ther, 311(3): p. 1023-31

CHI SQUARE Study Design

�4 Treatment Groups

�Placebo

� Low dose CER-001

�Mid dose CER-001

46

�Mid dose CER-001

�High dose CER-001

�6 doses per subject

�125 subjects enrolled per group

�Estimated 75 - 80% completion rate

==> ~98 subjects w/ follow-up IVUS per group

N = 126 Placebo

N = 126 Low dose

N = 126 Mid dose504

Su

bje

cts

Ran

do

miz

ed

50 SitesCanada, US, France,

Netherlands

Core IVUS LabMontreal Heart

Up to 1000 SubjectsScreened w/

Baseline IVUS

CHI-SQUARE Study Design

47

N = 126 High dose

Observation Period2 to 5 weeks

Baseline IVUS following

Acute ACS Event

Screen Period2 weeks

IVUS VisitScreening

Follow-Up IVUS Visit

Infusion Visits InterimVisit

Therapy Period5 weeks

Long Term Follow-up6 months

Follow-UpVisit

DelipidationDelipidation

48

Step 1Step 1Collected~1 litreCollected~1 litre

of plasmaof plasma

Step 2Step 2Plasma enrichedPlasma enrichedthrough processthrough process

Step 3Step 3ReRe--infused preinfused preββenriched plasmaenriched plasma

IVUS clinical trial using selective delipidated HDL

49

•• Used patients own HDLUsed patients own HDL•• Cholesterol removed fromCholesterol removed fromαHDLαHDL to yield to yield preβpreβ--HDLHDL

•• PreβPreβ enriched plasma isenriched plasma isrere--infused into patientinfused into patient

WalksmanWalksman R, R, et al. J Am et al. J Am CollColl CardiolCardiol 2010; 55 : 27272010; 55 : 2727--35.35.

Treatment arm (N=14)Treatment arm (N=14)

Control arm (N=Control arm (N=1414))

1:1 randomization1:1 randomization

(N=28)(N=28)

IVUS Clinical Trial Using Selective Delipidated HDL

50

Day 0Day 0 11 22 33 44 55 66 77 88

WeekWeek

IVUSIVUS IVUSIVUS

Treatment or control plasma infusionTreatment or control plasma infusion

WalksmanWalksman R, R, et al. J Am et al. J Am CollColl CardiolCardiol 2010; 55 : 27272010; 55 : 2727--35.35.

44

22

00

--22--1.731.73

2.82.8

volu

me

(mm

volu

me

(mm

33 ))

Results of the IVUS Clinical Trial Using Selective Delipidated HDL

51

--1414

Change in totalChange in totalatheromaatheroma volumevolume

Change in 10mm most Change in 10mm most diseased segmentdiseased segment

--44

--66

--88

--1010

--1212--12.1812.18

--6.246.24

Cha

nge

in

Cha

nge

in a

ther

oma

athe

rom

avo

lum

e (m

mvo

lum

e (m

m

PrePreββ--HDL infusionHDL infusion

ControlControl infusioninfusion

Waksman R, Waksman R, et al. J Am Coll Cardiolet al. J Am Coll Cardiol 2010; 55 : 27272010; 55 : 2727--35.35.

Conclusion

In the next five years, we will prove or disprove that additional LDL lowering with other agents than statins is

effective

and

52

we will show or not show that the HDL hypothesis is true

and

that lowering of triglycerides in patients on statins and inhibiting inflammation leads to a reduction of CVD events

Novel Approaches to Modify Lipids and Lipoproteins

� Low Density Lipoprotein

� High Density Lipoprotein

� Triglyceride Rich Lipoproteins

53

� Triglyceride Rich Lipoproteins

� Inflammation

� Lipoprotein a

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