EVACETRAPIB

A hope in order to treat cardiovascular disease…

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Laurent MAGNIESClaire JAGODZINSKI

INTRODUCTION

CV disease = 1st cause of death

Statins: Introduction in 1987 Revolution in CV disease prevention

People with high HDL-C level: reduced incidence of coronary heart disease Elevation of 1mg/dL HDL-C results in 2-3% reduction in CV risk=> Rational: Increase HDL-C levels would yield substantial clinical benefit

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Lipid Exchange

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HDL-C protection:- Reverse cholesterol transport- Anti-inflammatory- Anti-oxidative- Anti-thrombotic processes- Vessel relaxation

Journal of Lipid Research – Vol 52 – Sept 25, 2011

CETP Activity

CETP: Cholesteryl Ester Transport Protein

Synthetised by liver and adipose tissues

Secreted into the circulation Catalyzes lipid exchange

(CETG) Plasma HDL-C is reduced

Evacetrapib: Inhibition of CETP

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Journal of Lipid Research – Vol 52 – Sept 25, 2011

Preclinical Studies (1)

In vitro pharmacology: Buffer CETP assay with human recombinant CETPHuman plasma CETP assay

⇒ Selectivity of Evacetrapib

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Journal of Lipid Research – Vol 52 – Sept 25, 2011

Preclinical Studies (2)

In vivo pharmacology Human CETP transgenic mice⇒ Effect of human CETP activity on mice HDL-C level:

not as significant as expected

Human CETP and human Apo A1 double transgenic mice

⇒ Generation of human like HDL-C

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Journal of Lipid Research – Vol 52 – Sept 25, 2011

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Journal of Lipid Research – Vol 52 – Sept 25, 2011

Preclinical Studies (2)

In vivo pharmacology Human CETP transgenic mice⇒ The effect of human CETP activity on mouse HDL-C

level: not as significant as expected

Human CETP and human Apo A1 double transgenic mice⇒ Human Apo A1 transgenic mice generate human like

HDL particule

Evacetrapib = Potent, Selective CETP inhibitor

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Clinical Trial: April 2010 to Jan 2011

Phase II randomised, multicenter, double blind

Characterization of efficacy, safety and tolerability

12 weeks

Endpoint: Percentage changes in HDL-C or LDL-C levels

Inclusion criteria: HDL-C level: less than

45-50mg/dL LDL-C level: between

100-190mg/dL

Exclusion criteria: Atherosclerotic disease HT Hyperaldosteronism …

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Torcetrapib (Pfizer)

Studied in a phase III Prematurely discontinued in 2006 because :

increase of CV events and total mortality

Off-targets effects: Increase blood pressure Increase plasma aldosterone levels Alter electrolyte concentrations

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Study Design

N = 398

RANDOMIZATION

Monotherapy

Combination with statins

PLACEBO n = 38

EVACETRAPIB-30mg n = 40-100mg n = 38- 500mg n = 40

ATORVASTATIN-Placebo n = 41

- Evacetrapib n = 35

SIMVASTATIN-Placebo n = 41

- Evacetrapib n = 40

ROSUVASTATIN

-Placebo n = 39- Evacetrapib n = 41

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Evacetrapib 100mg

Clinic Visits and Laboratory Tests

Visits at 2, 4, 8, 12 weeks Follow up visits 4 to 6 weeks after

Laboratory tests Blood pressure Quantification of LDL-C, HDL-C, and TG levels CRP: Early marker of atherosclerosis CETP activity

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Average lipid levels at the beginning: LDL-C: 144.3mg/dL HDL-C: 55.1 mg/dL TG : 121.3 mg/dL

Monotherapy

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Combination with statin therapy14

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Results

Combination with statins => Similar increase of HDL-C than monotherapy Greater decrease of LDL-C than monotherapy

HDL-C changes: greater among patients with: lower level of HDL-C at baseline higher TG levels at baseline

Increase of ApoA-I and ApoA-II => accumulation of CE in HDL-C => larger

Increase of circulating ApoE => increase of chol efflux capacity

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Safety Data16

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Adverse Events

Well tolerated

Discontinuation and treatment due to AEs: low

No increase in blood pressure

No effects on aldosterone synthesis

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CONCLUSION (1)

Real need of antiatherosclerotic therapy

Evacetrapib : good profile AEs of Torcetrapib aren’t seen, or are less important Full safety and efficacy assessment is needed, with

exposition of more patients Need a large phase III trial

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CONCLUSION (2)

Good rational but the effects of CETP inhibitor On prevention of CV disease On regression of plaques

=>No demonstrated yet in clinical

2 others products are developed: Dalcetrapib (Roche; 5 phase II in 2010) Anacetrapib (Merck; phase III; results : Dec 2012)

Big economical stakes

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