Novel therapies for the prevention of atherosclerotic vascular disease

Prof. John KasteleinAcademic Medical Centre

Amsterdam, The Netherlands

2

Novel Approaches to Modify Lipids and Lipoproteins

•Low Density Lipoprotein•High Density Lipoprotein•Triglyceride Rich Lipoproteins•Inflammation•Lipoprotein a

3

Statin Prescription in the UK

0

100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

91/

92

92/

93

93/

94

94/

95

95/

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96/

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99/

00

00/

01

01/

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02/

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03/

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08/0

9

Net

Ingr

edie

nt C

ost (

000s

)

0

10,000

20,000

30,000

40,000

50,000

60,000

Pres

crib

ed It

ems (

000s

)

Statins – Prescribed Statins – Cost ( £ 000s)

4

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

0

10

20

30

40

50

60

70

80

90

100

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 the

Pop

ulati

on

1994

199820032006

Year

1994

1998

2003

2006

5

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

8942

52

32

141

114

115

107

0

50

100

150

200

250

300

350

400

450

P Ave 95-97 P Ave 06-08

Mor

talit

y - D

SR p

er 1

00,0

00 -

All C

ause

s

Other Cancer Other Circulatory CHD

Data

-

1995-1997 2006-2008

397

296

53% reduction

6

New Approaches to LDL Reduction What is in development?

• Cholesterol Absorption Inhibitors• Squalene Synthase (SSI) inhibitors• Thyroxin Receptor Agonists• Apo B mRNA antisense drugs • Microsomal Triglyceride Transfer Protein (MTP) inhibitors• PCSK9 Inhibitors

7

New Approaches to LDL Reduction

•Ezetimibe is and will be the only cholesterol absorption inhibitor in clinical use

•Squalene synthase inhibitor development was discontinued because of liver toxicity

•The thyroxine receptor agonist Eprotirome study in FH (Akka) was halted for toxicity in animals

8

Heterozygous Familial Hypercholesterolemia- Study Design

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

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 patients screened;

124 patientsenrolled

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

9

Mipomersen Significantly Reduced LDL-C

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

–28.0%

5.2%PET

10

Distribution of LDL-C % Change From Baseline

% c

hang

e in

LDL

-C fr

om b

asel

ine

at P

ET

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

1111

MTPIs – Efficacy comes from its dual mechanism of action

Decreasesecretion to bloodstream

Liver source

cholesteroltriglyceride

Apo B-100

MTP

Diet Source

cholesteroltriglyceride

Apo B-48

MTPIntestinal cell

Liver cell

VLDL

ChylomicronX

X

MTP inhibition will limit secretion of cholesterol and triglycerides from the intestine and liver

12

AEGR 733HoFH Phase II Study Design

AEGR 7330.03 mg/kg

AEGR 733 0.3 mg/kg

6 Patients

4 weeks 4 weeks 4 weeks

Patients:- Men/women aged

18-40- HoFH confirmed by

genetic analysis- Mean Baseline LDL

= 614 mg/dl

AEGR 7330.1 mg/kg

AEGR 7331.0 mg/kg

4 weeks

Cuchel, M. et al. NEJM 2007; 356:148-56.

Washout

4 weeks

Open label, ascending dose trial Very low fat diet Visits: Screen, baseline, every 1, 2, and 4 weeks

after each new dose, end of washout period

1313

Change in Lipids Using Lomitapide with no Background Therapy

% C

hang

e fr

om B

asel

ine

Cuchel, M. et al. NEJM 2007; 356:148-56.

-5

-60

-31

-9-10

+10+12 0

-65

-34

-25

+4

-51

-25

-7-4

-70

-60

-50

-40

-30

-20

-10

0

10

20

LDL-C TGs HDL-C nonHDL-C

0.03 mg/kg

0.1 mg/kg

0.3 mg/kg

1.0 mg/kg

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HoFH Phase 3: 6-Month Lipid Efficacy

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LDL Receptor Function and Life Cycle

1515

16

The Role of PCSK9 in the Regulation of LDL Receptor Expression

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Impact of an Anti-PCSK9 mAb on LDL Receptor Expression

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18

Study Design heFH study REGN727

WK -1 LDL-C ≥ 100 mg/dL (2.6 mmol/L) on stable

statin dose ezetimibe for ≥6 wks

Placebo Q2W

N=15

N=16REGN727 200 mg Q4W w/alt PBO

REGN727 300 mg Q4W w/alt PBO

N=15

N=15

N=16

Treatment Period (12 weeks) Follow-up Period (8 weeks)

Run-in/Screening Period (1–7 weeks)

Primary Endpoint% calculated LDL-C

from baseline to week 12

Secondary Endpoints% in other

lipoproteins and apolipoproteins and %

patients reaching prespecified LDL-C

levels

REGN727 150 mg Q4W w/alt PBO

REGN727 150 mg Q2W

Stein EA et al. Lancet on-line May 26, 2012

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InterventionBaseline

LDL-C mg/dL [mmol/L]

% ChangeLDL-C1

Placebo 150.8 [3.9] –10.7 (5.0)

REGN727 150 mg Q4W 166.7 [4.3] –28.9 (5.1)*

REGN727 200 mg Q4W 169.8 [4.4] –31.5 (4.9)*

REGN727 300 mg Q4W 139.6 [3.6] –42.5 (5.1)*

REGN727 150 mg Q2W 147.2 [3.8] –67.9 (4.9)*

Changes in LDL-C from Baseline to Week 12 by Treatment Group (mITT Population)REGN 727

*P<0.0001 for % change REGN727 vs. Placebo.1LS mean (SE), using LOCF method.

Stein EA et al. Lancet on-line May 26, 2012

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Change in Calculated LDL-C at 2 Weekly Intervals From Baseline to Week 20REGN727

Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, 12 , 16 and 20 in the modified intent-to-treat (mITT) population, by treatment group.

Mea

n (

SE) %

Cha

nge

in L

DL-C

from

Bas

elin

e

BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12 WEEK 16 WEEK 20

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

Placebo 150 mg Q4W 200 mg Q4W 300 mg Q4W 150 mg Q2W

Stein EA et al. Lancet on-line May 26, 2012

21

Attainment of Prespecified LDL-C Levelsat Week 12 (mITT Population) - REGN727

% P

atien

ts A

chie

ving

Pre

spec

ified

LDL

-C L

evel

*P=0.006; **P=0.007; †P<0.0001P-values obtained from the exact score test.

*

**

†

†

Stein EA et al. Lancet on-line May 26, 2012

22

Novel Approaches to Modify Lipids and Lipoproteins

•Low Density Lipoprotein•High Density Lipoprotein•Triglyceride Rich Lipoproteins• Inflammation•Lipoprotein a

23

New Approaches for Raising HDL

What is in development?

• Cholesterol Ester Transfer Protein (CETP) inhibitors• ER-Niacin / Laropiprant combination• ApoA1 based strategies• LCAT replacement strategies• ABCA1 agonists / miR-33 inhibition

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The dal-HEART Program tests a novel hypothesis: enhancing HDL efficacy through CETP modulation treats the underlying disease of atherosclerosis and will attenuate CV riskDouble blind, randomized, placebo-controlled studies

dal-OUTCOMES1

15,600 patients recently hospitalizedfor ACS

To evaluate the effect of dalcetrapib on CVoutcomesRECRUITMENT COMPLETE

dal-VESSEL2

450 patients withCHD or CHD riskequivalent

To evaluate the effect of dalcetrapib onendothelial function and blood pressure, measured by FMD and ABPMRECRUITMENT COMPLETE

dal-PLAQUE3

130 patients withCHD

To evaluate the effect of dalcetrapib oninflammation, plaque size and burden, measured by PET/CT and MRIRECRUITMENT COMPLETE

The Dal-HEART Programdalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport

dal-PLAQUE 24

900 patients withCAD

To evaluate the effect of dalcetrapib onatherosclerotic disease progression, assessed by IVUS and carotid B-mode ultrasoundRECRUITING

25

26

Effects on LDL-C and HDL-C

HDL-C

Base-line

6 12 18 24 30 46 62 76

HDL-

C (m

g/dL

) (SE

)

0

20

40

60

80

100

120

AnacetrapibPlacebo

LDL-C

Study weekBase-line

LDL-

C (m

g/dL

) (SE

)

0

20

40

60

80

100

AnacetrapibPlacebo

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

6 12 18 24 30 46 62 76

Study week

27**Post hoc analysis.

Adjudicated CV Events and Death

Anacetrapib N=808n (%)

Placebo N=804n (%)

Hazard ratio (95% CI) P value

Pre-specified adjudicated CV safety endpoint 16 (2.0) 21 (2.6) 0.76 (0.39, 1.45) 0.40

Cardiovascular death4 (0.5) 1 (0.1) - -

Non-fatal MI6 (0.7) 9 (1.1) - -

Unstable Angina1 (0.1) 6 (0.7) - -

Non-fatal Stroke5 (0.6) 5 (0.6) - -

Death from any cause11 (1.4) 8 (1.0) - -

Revascularization 8 (1.0) 28 (3.5) 0.29 (0.13, 0.64) 0.001

Death or major CV event (Death/MI/UA/S/Revasc)** 27 (3.3) 43 (5.3) 0.62 (0.38, 1.01) 0.048

28

Anacetrapib N=808

(%)

Placebo N=804n (%)

Hazard ratio (95% CI) P value

Pre-specified adjudicated CV safety endpoint 16 (2.0) 21 (2.6) 0.76 (0.39, 1.45) 0.40

Cardiovascular death 4 (0.5) 1 (0.1) - -

Non-fatal MI 6 (0.7) 9 (1.1) - -

Unstable Angina 1 (0.1) 6 (0.7) - -

Non-fatal Stroke 5 (0.6) 5 (0.6) - -

Death from any cause 11 (1.4) 8 (1.0) - -

Revascularization 8 (1.0) 28 (3.5) 0.29 (0.13, 0.64) 0.001

Death or major CV event (Death/MI/UA/S/Revasc)** 27 (3.3) 43 (5.3) 0.62 (0.38, 1.01) 0.048

**Post hoc analysis.

Adjudicated CV Events and Death

Primary Bayesian Analysis: Event distribution indicates a 94% predictive

probability of dismissing a 25% increase (Torcetrapib-Type) in CV events

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

• Background LDL-lowering with atorvastatin

• Randomized to anacetrapib 100 mg vs. placebo

• Primary outcome: Coronary death, myocardial infarction or coronary revascularization

www.revealtrial.org.

Future

30

New Approaches for LDL Reduction and HDL Raising

•The real battle in the future will be between PCSK9 Mab’s and CETP inhibitors

* oral versus sc* every day versus bi-weekly or once monthly* atherogenic lipoproteins with or without HDL increase* time to efficacy* cost

31

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.

•ApoA1 Milano, The Medicines Company

•Trimeric ApoA1, Borean Pharma and now Roche

•RVX-208, as developed by Resverlogix

32

New Approaches for Reduction of TG rich Lipoproteins

What is in development?

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors• DiacylGlycerol AcylTransferase (DGAT) inhibitors• Marine Omega 3 Fatty Acids• ApoCIII mRNA antisense drugs• Lipoprotein lipase gene therapy

33

Conclusion

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

than statins is effective and

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