Camille . S -Cécile .T – Maëlle . D - Marion. R

12 février 2010

LES ENJEUX STRATÉGIQUES DANS LE SECTEUR

DE LA THROMBOSE

Le dernier congrès de l’ESC à Barcelone a permis la

présentation de très nombreux résultats positifs sur de

nouveaux antithrombotiques ou antiagrégants

plaquettaires: le dabigatran avec l’étude RELY, le

prasugrel avec l’étude TRITON TIMI 38, le ticagrelor

avec l’étude PLATO

INTRODUCTION

Reminder of thrombosis

THROMBOSIS, BASIC POINTS

o Thrombosis = formation of a blood clot(thrombus) inside a blood

vessel, obstructing the flow of blood through the circulatory system.

o Virchow's triad :

o 2 subtypes :

- Veinous thrombosis

- Arterial thrombosis

Venous thrombosis

o Blood clot within a vein

o Deep or superficial vein

o Mainly composed of fibrin

Drugs Anticoagulants

Arterial thrombosis

o Thrombus in an artery

o follows a rupture of atheroma

o Mainly composed of platelets

Drugs Antiplatelets

ANTITHROMBOTIC AGENTS

Thrombolytic agents

AnticoagulantsAntiplatelet

drugs

1ST PART

Antiplatelets in Acute Coronary

Syndrom (ACS)

ACUTE CORONARY SYNDROM (ACS)

Set of symptoms linked to erosion or rupture of the

atheromatous plaque

Consequences : myocardial infarction (MI) and

unstable angina (UA)

2 forms of MI: - non-ST segment elevation MI

- ST segment elevation MI

PREVALENCE OF ACUTE CORONARY

SYNDROME

THERAPEUTIC STRATEGIE IN SCA

Beta-blokers

Antiplatelets (Aspirine-Clopidogrel / Lovenox)

Statins

Inhibitors of ACE

Control of CV risks

B

C

A

I

S

CURE

trial

ANTIPLATELETS MARKET IN 2006

Plavix

84,1%

dipyridamole

0,8%

Aggrastat

0,3%

Reopro

3,1%

Integrilline

7,8%

Ticlopidine

0,3% agrrenox

3,6%

Frost & Sullivan 2006

• CURE

• AMM: 1998 end of patent: 2009

• Sanofi Aventis

Clopidrogrel: PLAVIX®

• TRITON TIMI 38

• AMM: 2010

• Eli Lilly

Prasugrel: EFFIENT®

• PLATO

• AMM: 2010

• Astra Zeneca

Ticagrelor: BRILINTA®

ONGOING CLINICAL TRIAL

CLOPIDOGREL

Clopidogrel: PLAVIX ® (Sanofi

Aventis)

-Thienopyridine

-Inhibitor of P2Y12 ADP receptor

-300mg bolus / 75mg oral tablets

combined with aspirin

-Prodrug

-Irreversible link (covalent)

P2Y12

ADP receptor

S

N

Cl

H COOCH3

S

N

Cl

H COOCH3

O

N

Cl

H COOCH3

SH

HOOC

2-oxo clopidogrel

(thioester)

Reactive thiol

Active metabolite

(2%)

Clopidogrel

Catalytic

oxydation

CYP 450 (2C19 ( 45%))

CYP 450 (2C19 (21%))

15 to 30%

Individual variability

CYP2C19 POLYMORPHISMS AND BENEFIT OF CLOPIDOGREL

Problems with this drug:- non-reponder = inhibition level < to 20 % in respons of 20 µM of ADP

- CYP2C19*2 allelic variant = reduced platelet response

- gene dose-effect

http://www.theheart.org/article/1042749.do ; http://timi.org/services.htm

PLAVIX® FUTURE…

Source: Thomson 2008

Interpretation : M.

Maffrand

Clopidogrellimitations

Slow onset

Low level of inhibition

Much variability

Real resistance

PRASUGREL

Prasugrel: EFFIENT® (Eli

Lilly)

-thienopyridine

-Inhibitor of P2Y12 ADP receptor

-60mg oral loading dose/ 10 mg oral tablets

combined with aspirin

-Irreversible link (covalent)

-Prodrug

P2Y12

ADP receptor

S

N

F

O

CH3

O

O

S

N

F

O

O

SH

N

F

O

O

OH

Prasugrel EFIENT®

Esterases

CYP450 (few 2C19 metabolisation)

2-oxoprasugrel

few

Individual variability

Reactive thiol

TRITON TRIAL

ACS (STEMI or UA/NSTEMI)

& Planned PCI

Randomize

PRASUGREL 60 mg LD / 10mg MD

CLOPIDOGREL300 mg LD / 75 mg MD

N= 13,608ASA

Median duration of therapy- 12 month

1° endpoint: CV death, MI and stroke

Safety endpoints: TIMI major bleeds

STUDY DESIGN

http://timi.org/services.htm

http://timi.org/services.ht

m

RESULTS OF TRITON TIMI 38 TRIAL.

Taux de non-

répondeurs (%)

P value par rapport

au clopidogrel

Prasugrel 60 mg (dose de charge) 3 0,00002

Clopidogrel 300 mg (dose de charge) 52 -

Prasugrel 10 mg 0 0,0007

Clopidogrel 75 mg 45 -

http://timi.org/services.htm

DIABETIC PATIENTS AND ENHANCED

BENEFIT OF ANTIPLATELET DRUGS

http://timi.org/services.htm

PRASUGREL REDUCES THE RISK OF

STENT THROMBOSIS

PRASUGREL PROFILE

Prasugrel advantages

- A significant reduction in CV death, MI and

stroke (19%)

- An earlier and sustained benefits

- Less non reponders

- good response of diabetes patients

Prasugrel Inconvenients

- Not a reversible drug

- Significant increase in serious bleeding (32% increase)

- Doses adjustement for < 60kg and > 75 years (5mg?)

- Contre-indication in stroke.

TICAGRELOR

Ticagrelor: BRILINTA® (Astra

Zeneca)

-cyclopentyl-triazolo-pyrimidines

-Direct-acting inhibitor

-Reversible + short half life

-Bolus 180 mg

-90 mg twice daily

combined with aspirine

P2Y12

ADP receptor

PLATO TRIAL

PLATO STUDY DESIGN

ACS (STEMI or UA/NSTEMI)

& Planned PCI

Randomized

TICAGRELOR 180mg LD/ 90 mg 2/j MD

CLOPIDOGREL300 mg LD / 75 mg MD

N=18,624ASA

Median duration of therapy- 6 to 12 month

1° endpoint: CV death, MI and stroke

Safety endpoints: total major bleeds,

PRIMARY EFFICACY ENDPOINT

CV DEATH, MI AND STROKE

Astra

zen

eca

pre

sen

tatio

nn

ovem

ber

20

09

SECONDARY EFFICACY ENDPOINTA

strazen

eca

pre

sen

tatio

n n

ovem

ber 2

00

9

PRIMARY SAFETY ENDPOINT

MAJOR BLEEDING

Astra

zen

eca

pre

sen

tatio

n n

ovem

ber 2

00

9

NEW SIDE EFFECTS

•dyspnea

•(13,8 vs 5,8 % ; p < 0,001)

•bradyarrhythmia

•(2,0 vs 1,2%)

•increased uric acid and creatinine levels

TICAGRELOR PROFIL

-reduction of total mortality

-no significant increase of major bleeding

- Reversible

-½ life short

-not a prodrug

Inconveniences of ticagrelor

-compliance

-exclusion of patients

•higher risk of bleeding,

•BPCO (chronic obstructive pulmonary disease)

•Bradyarrhythmias

•Moderate or severe renal failure

•Hyperuricemia

•History of stroke

-evaluation of complication in a long term more bleedings in the real

world ?

Advantages of ticagrelor

Dr Albert Schömig (Munich,

Germany)

“now we have a new and better

alternative to standard treatment

to prevent patients with myocardial

infarction from new myocardial

infarction, and also to improve their

chances of survival “

UCLA cardiologist Dr. Gregg C.

Fonarow

"Ticagrelor represents an

important new treatment advance

for the management of patients

with acute coronary syndromes."

Dr. Byron Lee, a

cardiologist from the

University of California at

San Francisco

“ I expect this new drug to

get FDA approval very

soon.”

Steen D. Kristensen, MD, of

Aarhus University, Skejby,

Denmark

“a promising drug “

Med 2009;361. DOI 10.1056/NEJMe0906549

European Soiety of Cardiology Congress 2009; Aug.

29-Sept. 2, 2009; Barcelona

Schomig said. "We have now the opportunity to choose between three drugs, clopidogrel, prasugrel [Effient] and ticagrelor, in patients with acute coronary syndromes, taking into account the advantages and disadvantages of each one"

2ND PARTAnticoagulants in Atrial Fibrillation (AF)

ATRIAL FIBRILLATION (AF)

The most common cardiac arythmia

Fibrillating of the muscles of the atria

blood stagnancy Thrombus

Complication:

Increases risk of arterialthromboembolism speciallystroke

Treatments for the consequences of AF (Thrombus)

AF EPIDEMIOLOGY

750 000 patients withAF in France

5 million in USA

( x2 to 3 between 2000 and 2050)

2 of 3 cases in patients between 60 and 80

years old

1 of 6 stroke with AF

Patient with AF annual cost:

2 500 to 3 500 €

(in Europe, including drugsbut also hospitalizations)

AF

Cardiologie-cardinale;Janvier 2010; vol 4 numero 25

THERAPEUTIC STRATEGIE IN AF

Treat the rhythm trouble

-Betablokers, calcic inhibitors, digoxine

- Cardioversion

Keep a basal rythm

antiarythmics

Prevent blood clots and strokes

Heparin or AVK or Aspirin

Ablation and pace maker

Treat the cause

GLOBAL ANTICOAGULANTS MARKET IN 2008

LMWH

72%

Heparin

5%

Warfarin

5%

Direct

thrombin

inhibitors

8%

Factor Xa

inhibitors

5%

Others

5%

NATURE REVIEWS; DRUG DISCOVERY; VOLUME 8; MAY 2009;

“THE ANTICOAGULANTS MARKET” IRENA MELNIKOVA

WARFARIN

WARFARIN KEY DATA

Coumadin/ warfarin sodium

Bristol-Myers Squibb Pharma

oral anticoagulant

Vitamin K antagonist

inhibits the synthesis of

clotting factors II, VII, IX, X

Approved in EU and by FDA

COAGULATION PATHWAY

• Suitable for long use

• Provide predictable and reliable protection

• Without coagulation monitoring

• Low risk of bleeding and toxicity

• Ease of administration

• Minimal interactions with food and drugs

MEDICAL NEED FOR A NEW ANTICOAGULANT

DABIGATRAN ETEXYLATE

Drug (brand/generic) Pradaxa/dabigatran

Company Boehringer Ingelheim

Therapy class Anticoagulant

Product description direct thrombin

inhibitor(DTI)

Current indication Primary prevention and

treatment of VTE following

orthopaedic surgery

In need indication Prevention of stroke in FA

SCA

Market sector Cardiovascular ,veinous

thrombosis

Development status Approved Europe in VTE,

not approved by FDA

KEY DATA

HOW DOES DABIGATRAN ETEXILATE WORK?

specifically and selectively binds to thrombin's active site,

thereby blocking its activity

blocks both free and clot-bound thrombin effective

thrombin inhibition ( # heparins)

interferes with thrombin's effects on the coagulation cascade, e.g.:

conversion of fibrinogen to fibrin

platelet aggregation (thrombin is the most potent stimulus for

platelet aggregation)

activation of clotting Factors V, VIII and XI (thrombin can initiate

the up-regulation)

Pharmacokinetic

Oral administration, once or twice

daily

Bioavailability:6,5%

Rapid onset: 2 - 4 hrs

Half life :14 - 17 hrs

Reversibility : Yes

Elimination

Renal : 85%

Fecal : 6 %

Pharmacodynamic

not metabolized by cytochrome

P450 isoenzyme

Low potential for drug –drug

interaction

Contraindication if severe renal

impairement (<29ml/min)

Contraindication if hepatic

impairement or life threatening

hepatic diseases.

dose dependent Effects

RELY TRIAL

RELY RANDOMIZED EVALUATION OF LONG-TERM ANTICOAGULANT

THERAPY, WARFARIN, COMPARED WITH DABIGATRAN

Non-valvular atrial fibrillation at moderate

to high risk of stroke or systemic embolism

(at least one high risk factor)

R

Dabigatran

etexilate 110mg

bid

N=6000

Dabigatran

etexilate 150mg

bid

N=6000

Warfarin

1mg,3mg,5mg

(INR 2.0-3.0)

N=6000

Primary objective : Noninferiority to warfarinMinimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up.

Primary efficacy endpoint : stoke and systemic embolism

Safety criteria : bleeding events, hepatic dysfunction

N= 18,113pts

EFFICACY RESULTS

CUMULATIVE HAZARD RATE FOR PRIMARY OUTCOME OF STROKE OR

SYSTEMIC EMBOLISM ACCORDING TO TREATMENT GROUP

SAFETY ENDPOINT: MAJOR OR MINOR BLEEDINGS

Compared with Warfarin:

D 110:RR 0.78 (IC 95% 0.74-0.83;p<0.001)

D150:RR 0.91 (IC 95% 0.86-0.97;p<0.001)

14,6

16,4

18,2

0

4

8

12

16

20

Dabigatran 110 mgDabigatran 150 mg Warfarin

An

nu

alra

te (

%)

D 110mg D 150mg Warfarin D 110 mg vs Warfarin D 150 mg vs Warfarin

TTR Annual

rate

Annual

rate

Annual

rate

RR

IC 95% p

RR

IC 95% p

All

patients

0.23% 0 .30% 0.740.31

0.20-0.74 0.001

0.40

0.27-0.60 <0.001

SAFETY ENDPOINT: INTRACRANIAL

HAEMORRHAGE AND INTESTINAL BLEEDINGS

Intracranial haemorrhage

D 110mg D 150mg Warfarin D 110 mg vs Warfarin D 150 mg vs Warfarin

Annual

rate

Annual

rate

Annual

rate

RR

IC 95% p

RR

IC 95% p

Major gastro

intestinal

bleedings1.1% 1.5% 1.0%

1.10

0.86-1.41 0.43

1.50

1.19-1.89 0.001

Most common side effect

observed

On dabigatran

(P<0.001)

D 110mg D 150mg Warfarin

dyspeptia 11.8% 11.3% 5.8%

688 patients 707 patients 348 patients

SIDE EFFECTS

Also observed myocardial infarction

DABIGATRAN PROFILE

Dabigatran advantages

-Oral therapy ,fixed dose

-Rapid onset of action

-No food and drug interactions

-Wide therapeutic window

-No coagulation monitoring

Dabigatran Inconvenients

-No antidote (half-life 17 hrs)

-C.I if severe renal impairement

-dyspectic symptoms

-risk of major gastrointestinal bleeding

Warfarin is a tough comparator,but the challenge for competitor products is now even tougher

Waiting for the NDA in the indication (FA)

Other trials are ongoing

A real revolution for the practicians

Dabigatran Market

2/3 of patients with AF important market

Untreated Patients with medium or high risk of AF

Patients taking aspirin instead of warfarin

Patients unstable with Warfarin

Maybe patients well balanced on Warfarin

Doses adaptation with Dabigatran according to safety profile

DISCUSSION

DISCUSSION

Anticoagulants

GLOBAL ANTICOAGULANTS MARKET IN 2008

LMWH

72%

Heparin

5%

Warfarin

5%

Direct

thrombin

inhibitors

8%

Factor Xa

inhibitors

5%

Others

5%

NATURE REVIEWS; DRUG DISCOVERY; VOLUME 8; MAY 2009; “THE

ANTICOAGULANTS MARKET” IRENA MELNIKOVA

• Rely COMPLETED Boerhinger IngelheimDabigatran: PRADAXA®

• Rocket AF end in 2012 BSP/J and JRivaroxaban:

XARELTO®

• Averroes end in 2011 Pfizer/BMS

• Aristole end in 2013 Apixaban

• 2Phases II ongoing Astrazeneca AZD 0837

• Engage AFTimi48 end in 2014 D SankyoEdoxaban

ONGOING CLINICAL TRIAL ON STROKE

PREVENTION IN ATRIAL FIBRILLATION

GLOBAL ANTICOAGULANT MARKET

FOR THE FUTURE (2014)

LMWH

31,5%

Heparin

1,7%

Warfarin

1,1%

Direct

thrombin

inhibitor

s

26,5%

Factor

Xa

inhibitor

s

32,0%

Others

7,2%

RIVAROXABAN

LOVENOX

DABIGATRAN

NATURE REVIEWS; DRUG DISCOVERY; VOLUME 8; MAY 2009; “THE

ANTICOAGULANTS MARKET” IRENA MELNIKOVA

DISCUSSION

Antiplatelets

ANTIPLATELETS MARKET IN 2006

Plavix

84,1%

dipyridamole

0,8%

Aggrastat

0,3%

Reopro

3,1%

Integrilline

7,8%

Ticlopidine

0,3% agrrenox

3,6%

Frost & Sullivan 2006

ONGOING CLINICAL TRIAL ON ACS

• Eli lilly; Triton timi 38 COMPLETED• => Inhibitor of P2Y12 ADP receptorPrasugrel

• Astrazeneca; Plato COMPLETED• => Inhibitor of P2Y12 ADP receptorTicagrelor

• Champion Platform ongoingAstraZeneca

•=> Inhibitor of P2Y12 ADP receptor

Cangrelor

• Novartis; Erase MI ongoing•=> Inhibitor of P2Y12 ADP receptor

Elinogrel

• Servier; Perform ongoing•=> TP receptor antagonistTerutroban

ANTIPLATELETS MARKET IN 2016

Ticagrelor

Others

Clopidogrel

New drug arrival

Market fragmentation

Low cost of clopidogrel

New drugs: large clinicaltrial

Future:

Individualize treatement

Prasugrel

Student hypothesis

DISCUSSION

Global market

ANTITHROMBOTIC SALES IN THE 7

MAJOR MARKETS IN 2007

Plavix

38%

Lovenox

23%

All other

products

39%

SANOFI

AVENTIS

ANTITHROMBOTIC SALES IN THE 7

MAJOR MARKETS IN 2017

Lovenox

12%

Ticagrelor

7%

Clopidogrel

14%

Prasugrel

7%

Dabigatran

14%

Rivaroxaban

14%

AUTRES

32%

Student hypothesis

Venous thrombosis and

arterial thrombosis not so

segmented

Short term: choice

between clopidogrel,

prasugrel and ticagrelor

Long term: addition of

warfarine, dabigatran,

rivaroxaban

THANK YOU FOR YOUR ATTENTION

IS THERE ANY QUESTION?