Evolving New Therapies for the Prevention of Atherosclerosis:

A Glimpse of the Near Future

John J.P. Kastelein, MD PhD FESCAcademic Medical Center / University of Amsterdam

Dept. Vascular MedicineAmsterdam, The Netherlands

Ho Chi Minh City, VietnamAugust 7, 2014

2

Novel Approaches to Modify

Lipids and Lipoproteins

Low Density Lipoprotein

High Density Lipoprotein

Triglyceride Rich Lipoproteins

Inflammation

Lipoprotein a

3

New Approaches to LDL Reduction

What is in development?

• Cholesterol Absorption Inhibitors

• Squalene Synthase (SSI) inhibitors

• Apo B mRNA antisense drugs

• Microsomal Triglyceride Transfer Protein (MTP) inhibitors

• Thyroxin Receptor Agonists

• PCSK9 Inhibitors

4

LDL-Receptor Function and Life Cycle

5

The Role of PCSK9 in the Regulation

of LDL Receptor Expression

6

PCSK9 LOF Mutations

Adapted from Cohen JC. N Engl J Med 2006;354:1264-72; ARIC=Atherosclerosis Risk in the Community

30

20

10

0

PCSK9142x or PCSK9679X

No Yes

12

8

4

0

0 50 100 150 200 250 300

30

20

10

0

0 50 100 150 200 250 300

No Nonsense Mutation

(N=3278)50th Percentile

Plasma LDL Cholesterol in Black Subjects (mg/dL)

Fre

qu

en

cy (

%)

PCSK9142x or PCSK9679X

(N=85)

Coro

na

ry H

ea

rt D

ise

ase

(%

)

88 percent reduction in the risk of CHD

28 percent reduction in frequency

7

Loss of Function PCSK9 Mutations

Only a small number of patients who are homozygous (or compound heterozygotes) for PCSK9 have been discovered and studied.

These patients appear to have:

Very low LDL-C levels (~10-20 mg/dL)

Relatively low TG levels

Normal HDL-C levels

These patients have no other health problems

8

Familial Hypercholesterolemia

9

FH Patients at LDL Goal

10

Impact of a SAR236553/REGN727

on LDL Receptor Expression

11

The Use of a PCSK9 Monoclonal AB

in heFH Patients

A Randomized, Double-Blind, Placebo-Controlled Trial

of the Safety and Efficacy of a Monoclonal Antibody

to PCSK9, REGN727/SAR236553, in Patients with Heterozygous

Familial Hypercholesterolemia

on Stable Statin Dose With or Without Ezetimibe Therapy

Evan A. Stein, Dan Gipe, Jean Bergeron, Daniel Gaudet, Robert

Weiss, Robert Dufour, Richard Wu, Robert Pordy. Lancet, May 2012

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The Use of a PCSK9 Monoclonal AB

in heFH Patients

13

The Use of a PCSK9 Monoclonal AB

in heFH Patients: Results

14

The Use of a PCSK9 Monoclonal AB

in heFH Patients: Results

15

The Use of a PCSK9 Monoclonal AB

in heFH Patients: Goal Attainment

16

The Use of a PCSK9 Monoclonal AB

in heFH Patients: Secondary Results

17

The Use of a PCSK9 Monoclonal AB

in heFH Patients: Safety

18

From Stable Coronary Disease

To Acute Coronary Syndromes

19

Novel Approaches to Modify

Lipids and Lipoproteins

Low Density Lipoprotein

High Density Lipoprotein

Triglyceride Rich Lipoproteins

Inflammation

Lipoprotein a

20

New Approaches for Reduction of Inflammation

What is in development?

• Interleukin 1-beta antagonists

• Interleukin 12-antagonists

• Phosphodiesterase E4 inhibition

• Lipoprotein Associated Phospholipase A2 inhibition

• CRP mRNA antisense drugs

• Anti-ox-LDL antibodies and vaccinations

• P38 MAPK inhibitors (Losmapimod)

• JAK 1-3 inhibitors

• Anti-ox40 and CTLA4 monoclonal antibodies

• Oxidized phospholipids (VBL)

21

The Balance of IL-1 and IL-1Ra :

Contribution to Human Disease

IL-1R

Pro-Inflammatory Anti-Inflammatory

Severe Imbalance (Inflammasome mutations) CAPS, MWS, NOMID

Moderate Imbalance Psoriasis, contact hypersensitivity syndromes

Gout, inflammatory arthritis,

Crohn’s, Ulcerative colitis

Autoimmune Disorders, thyroiditis

Mild Imbalance Atherosclerosis, Diabetes

NLRP3

cryopyrin

Inflammasome

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

• LCAT agonists

• Bile-acid based strategies

24

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

• LCAT agonists

• Bile-acid based strategies

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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 MDCO216, The Medicines Company

Trimeric ApoA1, Borean Pharma and now Roche

RVX-208, as developed by Resverlogix

Fx-5A, as developed by Kinemed Inc.

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Novel Strategies for the Management of Acute

Coronary Syndromes

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ApoA1-Milano

28

Percent Change in Atheroma Volume with IVUS LDL-C Reduction vs. HDL-C Increasing Therapy

Nissen SE et al. JAMA. 2003 and 2004

2.7*

Prava 40 mg18 months

-0.3†

Atorva 80 mg18 months

-4

-2

0

2

4

P=0.02

4

Media

n c

hange in T

AV (

%)

Progression From no change to regression

ApoA-1 Milano5 weeks

-4.2-0.8

Rosuva 40 mg24 months

REVERSAL

ASTEROID

APOA-1 Milano

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ApoA1 Milano

Manufacturing changes require a full re-start of the development of MDCO-216 (= ApoA1 Milano)

Toxicology programme has been completed

Discussion with regulatory agencies on the clinical development are ongoing

Clinical development of MDCO-216 is expected to be initiated in the second half of 2012.

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Delipidation

31

Step 1

Collected~1 litreof plasma

Step 2

Plasma enrichedthrough process

Step 3

Re-infused preβenriched plasma

• Used patients own HDL

• Cholesterol removed from

αHDL to yield preβ-HDL

• Preβ enriched plasma is

re-infused into patient

IVUS clinical trial using

selective delipidated HDL

Walksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.

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Treatment arm (N=14)

Control arm (N=14)

1:1 randomization

(N=28)

Day 0 1 2 3 4 5 6 7 8

Week

IVUS IVUS

Treatment or control plasma infusion

IVUS Clinical Trial Using

Selective Delipidated HDL

Walksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.

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-14

Change in totalatheroma volume

Change in 10mm most diseased segment

4

2

0

-2

-4

-6

-8

-10

-12-12.18

-6.24

-1.73

2.8C

hange in a

thero

ma

volu

me (

mm

3)

Preβ-HDL infusion

Control infusion

Results of the IVUS Clinical Trial

Using Selective Delipidated HDL

Waksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.

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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.