SUBSTITUTE OR TARGET THE COAGULATION CASCADE : FROM A RARE COAGULATION DISEASE TO COMMON THROMBOTIC DISORDERS SUCCESS STORY OF KOGENATE AND XARELTO

(1)

SUBSTITUTE OR TARGET

THE COAGULATION CASCADE :

FROM A RARE COAGULATION DISEASE TO

COMMON THROMBOTIC DISORDERS

SUCCESS STORY OF KOGENATE®

AND XARELTO®

Professeur Cedric HERMANS, MD, PhD, MRCP (Lon), FRCP (Lon, Edin)

Haemostasis and Thrombosis Unit

Haemophilia Clinic

Division of Haematology

Cliniques Universitaires Saint-‐Luc

Catholic University of Louvain

1200 Brussels, Belgium

(2)

D

ISCLOSURE

FOR

C

EDRIC

HERMANS

Shareholder

No relevant conflicts of interest to declare

Grant / Research Support

Bayer, Baxter, Pfizer

Consultant

Bayer, Baxter, Pfizer, Sobi Biogen, CSL Behring, LFB,

_{Octapharma, Novo Nordisk, CAF-DCF}

Employee

No

Paid Instructor

No

Speaker bureau

Bayer, Baxter, Pfizer, Sobi Biogen, CSL Behring, LFB,

_{Octapharma, Novo Nordisk}

(3)

D

IFFERENT

COAGULATION

DISEASES

WITH

TARGETED

TREATMENT

OPTIONS

CARDIOLOGY

AF and stroke

VTE DISEASE

DVT and PE

HAEMOPHILIA

Acute haemarthrosis

Prevention of stroke

Prevention of venous clot

formation

Resolution of the clot

Prevention of intra-articular

bleeding episodes

Reduction of thrombin generation

Restoration of thrombin

generation

Efficient, safe and convenient to use

anticoagulant

Efficient, safe, convenient to use

anticoagulant

Safe and efficient replacement

of FVIII or FIX deficiency

(4)

A

NTI

-FX

A

AND

R

EC

-FVIII

A

VTE DISEASE

DVT and PE

XARELTO®

CARDIOLOGY

AF and stroke

XARELTO®

HAEMOPHILIA

(5)

5 I

DEAL

TREATMENT

OF

S

EVERE

H

AEMOPHILIA

:

P

REVENTION

OF

BLEEDING

EPISODES

BY

REGULAR

INFUSIONS

Regular self-administration of

F8 or F9 concentrate in order to

prevent bleeding episodes

(20-40 units/kg – 3x/week or

1x/2days)

Time

FVIII

1%

(6)

6 I

DEAL

TREATMENT

OF

ATRIAL

FIBRILLATION

:

P

REVENTION

OF

STROKE

BY

DAILY

TREATMENT

WITH

A

DIRECT

ORAL

ANTICOAGULANT

Once daily administration of

Xarelto 15 to 20 mg

20 mg or 15 mg once a day

Time

Anti-Xa

FXa inhibition by daily intake of

Xarelto

(7)

7 R

ANDOMIZED

C

LINICAL

T

RIAL

OF

P

ROPHYLAXIS

US J

OINT

O

UTCOME

S

TUDY

(2007)

R

IVAROXABAN

O

NCE

D

AILY

O

RAL

D

IRECT

F

ACTOR

X

A

I

NHIBITION

C

OMPARED

WITH

V

ITAMIN

K A

NTAGONISM

FOR

P

REVENTION

OF

S

TROKE

AND

E

MBOLISM

T

RIAL

IN

A

TRIAL

F

IBRILLATION

(ROCKET AF)

(8)

ESC

UPDATE

ON

ANTITHROMBOTIC

THERAPY

IN

AF

*Includes rheumatic valvular disease and prosthetic valves; ESC = European Society of Cardiology;

NOAC = novel oral anticoagulant; VKA = vitamin K antagonist

Camm AJ et al. Eur Heart J 2012;33:2719–47

8

Yes

Atrial fibrillation

Valvular AF*

<65 years and lone AF (including females)

Assess risk of stroke

CHA

₂

DS

₂

-VASc score

Assess bleeding risk

(HAS-BLED score)

Consider patient values and

preferences

No antithrombotic

therapy

Oral anticoagulant therapy

NOAC

VKA

0

1 No (i.e. nonvalvular)

Yes

No

≥

2 = CHA

₂

DS

₂

-VASc 0

= Best option

= CHA

2

DS

2

-VASc 1

= CHA

₂

DS

₂

-VASc ≥2

= Alternative option

Disclaimer: Dabigatran etexilate, rivaroxaban, and apixaban are approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Edoxaban is not approved for stroke prevention. Please check local prescribing information for further details

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9 P

ROPHYLAXIS

R

ECOMMENDATIONS

IN

PATIENTS

WITH

SEVERE

HAEMOPHILIA

• Prophylaxis considered optimal

therapy for individuals with

severe haemophilia A or B

– 

World Health Organization

(WHO)

– 

World Federation of

Haemophilia (WFH)

– 

National Haemophilia

Foundation (NHF) Medical an

Scientific Advisory Council

National Haemophilia Foundation, MASAC, recommendation 179, Nov 2007 Srivastava et al. WFH guidelines for the management of haemophilia Berntorp et al. Bull World Health Org. 1995; 73: 691-701.

(10)

10 Vitamin K

Antagonists

Heparins

Anti-Xa

Anti-IIa

Mode of

action

Interference with vit K

recycling

Potentiation of

antithrombin

Direct inhibition of

FXa or FIIa

Targets

FII, FVII, FIX, FX

Reduced synthesis

Indirect inhibition of

FXa and FIIa

Selective inhibition

of FXa or FIIa

Indications

Universal anticoagulants

including

mechanical cardiac

valve

Universal

anticoagulants

Acute phase of PE

Prevention and

treatment of VTE

(DVT/PE)

Prevention of

stroke in AF

I

NDIRECT

AND

D

IRECT

A

NTICOAGULANTS

:

M

ULTIPLE

-

VERSUS

S

INGLE

-F

ACTOR

(11)

D

EVELOPMENT

AND

VALIDATION

OF

NOAC

S

DVT/VTE

Prophylaxis

Orthopaedic

Surgery

DVT/VTE

Treatment

AF/Stroke

Prevention

DVT/VTE

Prophylaxis

Medical

patients

Acute Coronary

Syndrome

(12)

Registries

N=~97,000

NIS

N=~47,000

Phase IV

N=~3,900

Phase II/III

N=~51,000

Completed

Phase I, II & III

N=~86,000

Over 275,000 patients expected

(13)

H

AEMOPHILIA

(14)

14 C

ORRECTION

OF

F8

OR

F9

DEFICIENCY

1 FFP (200 ml) = 200 units of F8

1 ml FFP = 1 unit of F8

Fresh Frozen Plasma

Cryoprecipitate

Concentrates of F8 or F9

Plasma-derived

Biotechnology

(15)

15 W

HY

ARE

R

EC

-F8

CONCENTRATES

DIFFERENT

?

1. Transfected cells (CHO (Advate/Refacto), BHK (Kogenate), HEK)

2. Transfected sequence

- Full length (Kogenate)

- B-domain deleted – truncated

- Co-expression of VWF

- Haplotype (H1)

3. Cell culture

- Addition of human or animal proteins

- Continuous versus intermittent process

4. Purification processes

- Immunoaffinity (synthetic ligands versus Monoclonal Abs (specificity

and Affinity))

- Number of steps involved (nanofiltration)

(16)

16 KOGENATE

®

_B

_AYER

KOGENATE

®

Bayer

Expression cell line

Baby hamster kidney

1

Culture medium additives

Human albumin, recombinant

_insulin

2

Fermentation system

2

_{Continuous perfusion}

Specific virus inactivation

S/D treatment

1

Overall virus removal

11 –

17 log

₁₀2

Prion removal

>9 log

₁₀3

Final formulation stabilizer

Sucrose

1

Storage

RT (up to 25°C) or refrigeration

3

(RT for ≤12 months)

Reconstituted volume (mL)

2.5, 5.0

3

Half-life (hr)

3

_{13.74 ± 1.82}

Inhibitor incidence

PUPs/MTPs

PTPs

1

15%

1

_-35%

2,3

0%

1.  Suiter TM. Semin Thromb Hemost 2002; 28(3): 277–284. 2. Boedeker BG. Semin Thromb Hemost 2001; 27(4): 385–394. 3. Bayer Pharma AG. KOGENATE® Bayer summary of product characteristics. Bayer Pharma AG; Berlin, August 2010. Available at: http://www.kogenate.co.uk/patient-info.asp. Accessed August 2011. 4. Drugs.com. Antihemophilic Factor (Systemic). Available at: http://www.drugs.com/mmx/kogenate.html. Accessed May 2010. 5. Lusher JM et al. J Thromb Haemost 2004; 2: 574–583.

2.  Calvez et al. Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood. September 24, 2014; DOI 10.1182/blood-2014-07-586347

3.  Collins et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe haemophilia A, 2000-2011. Blood. October 22, 2014; DOI 10.1182/blood-2014-07-580498

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17 P

ROPHYLAXIS

R

EDUCES

THE

O

CCURRENCE

OF

B

LEEDINGS

Manco-Johnson M. et al, NEJM, 2007; 357:535-44.

On-demand

(n=33)

Prophylaxis

(n=32)

Total Bleeds/year

18

1.9 Joint Bleeds/year

5

0.5 (90% less)

(90% less)

(18)

Reference: 1.

Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, Rusen L, Ghinea M, Uscatescu V,

Rescia V, Hong W. Randomized, controlled, parallel-group trial of routine prophylaxis versus on-demand treatment with rFVIII-FS in adults

with severe hemophilia A (SPINART) [published correction appears in

J Thromb Haemost

. 2014;12:119–122.]

J Thromb Haemost.

2013;11:1119-1127.

₁₈

Study overview

1 An ongoing, 3-‐year, mul3center, open-‐label, parallel-‐group, prospec3ve,

randomized controlled clinical study of the eﬀect of rou3ne prophylaxis with

rFVIII-‐FS

vs on-‐demand use on bleeding frequency in adults and adolescents

with severe hemophilia A

Primary endpoint

Evaluate the eﬀect of rou3ne prophylaxis on bleeding frequency (number of

all bleeds per year) compared to on-‐demand (episodic) treatment:

• Evaluated aFer the last subject entered had completed at least 1 year of

study treatment

• If primary eﬃcacy variable was sta3s3cally signiﬁcant, then secondary

eﬃcacy variables are to be analyzed at 3 years

SPINART

(Secondary Prophylaxis in Adults, Randomized Trial)

(19)

SPINART data prove KOGENATE® Bayer is eﬀec]ve for adult prophylaxis

In adults, Kogenate prophylaxis compared to on-‐demand use leads to improved joint outcomes.

• A large, sustained reduc3on of joint bleeding

– 

Median annualized total bleed rate with prophylaxis was 0

• 52% of pa3ents experienced 0 bleeds

à

94% reduc3on in mean total bleeds per

year

– 

Median annualized joint bleed rate with prophylaxis was 0

• Improved joint func3on

• BeUer quality of life

Reference: 1. Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, Rusen L, Ghinea M, Uscatescu V, Rescia V, Hong W. Randomized, controlled, parallel-group trial of routine prophylaxis versus on-demand treatment with rFVIII-FS in adults with severe hemophilia A (SPINART) [published correction appears in

J Thromb Haemost. 2014;12:119–122.] J Thromb Haemost. 2013;11:1119-1127.

SPINART: key outcomes

(20)

20 Plasma-Derived

Clotting

Factors

(1969)

Therapeutic

Value

Evolution of Products

Prolonged

Half-Life

Potential Outcomes

Ø 

Extended protection

when used on-demand

Ø 

Provide prolonged

protection with fewer

infusions for prophylaxis

Ø 

Decreased burden for

patients and caregivers

Ø 

Increased use of

prophylaxis and better

compliance

Recombinant Long-Lasting Factors in

Development

Removal of

Human-Derived

Material

Improved Safety

Ø 

Eliminated potential

for transmission of

blood borne

pathogens

Currently Approved Recombinant

Clotting Factors

(1990s – present)

E

VOLUTION

OF

H

AEMOPHILIA

T

REATMENT

(21)

L

ONG

-‐

ACTING

FVIII

COMPOUNDS

PRESENTED

AT

MEETINGS

AND

DESCRIBED

IN

THE

PATENT

LITERATURE

A1

A2

A3

C1

C2

PEGylated mutant

FVIII

B

c

Directed

Pegylation

Fusion

Proteins

A1

A2

A3

C1

C2

FVIII

:Fc hybrid protein

Fc

B

Random

Pegylation

PEGylated

FVIII

A1

A2

A3

C1

C2

B

Glyco-

Pegylation

FVIII Glyco

Pegylated

A1

A2

A3

C1

C2

B

Turecek PL et al. Blood 2007;110:3147; Murphy JE et al. J Thromb Haemost 2007;5(2):P-T-022;

Dumont JA et al. Blood 2009;114:545; Stennicke HR et al. Haemophilia 2010;16(4):08P37

(22)

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P

ONTENTIAL

APPLICATIONS

OF

LONG

-‐

ACTING

CONCENTRATES

• Reduced frequency of injec3ons

• May be par3cularly beneﬁcial in some circumstances

o 

Very young (?reduced need for portacath)

o 

BeUer adherence and easier ini3a3ons

o 

Immune tolerance induc3on

• S

ame number of injec3ons -‐

Higher trough levels

• BeUer protec3on from arthropathy for all

• Less subclinical and breakthrough bleeds

• More con3nuous protec3on – especially highly ac3ve

games etc.

• May aid target joint resolu3on

(24)

F

UTURE

INNOVATIVE

TREATMENTS

:

(25)

C

ONCLUSIONS

• With Kogenate

®

, Xarelto

®

and Cardioaspirin

®

, Bayer has provided the

medical community and the rare pa3ents with haemophilia (1.000 in

Belgium), the numerous candidates for prolonged oral an3coagula3on (>

100.000) and the even larger group requiring an3platelet therapy

(1.000.000) with an armementorium of innova3ve, safe and eﬃcient

haemosta3c and an3thrombo3c agents.

• These agents are constantly being further validated and improved to

correct eﬃciently and safely the defec3ve cloeng system typical of rare or

common diseases.

SUBSTITUTE OR TARGET THE COAGULATION CASCADE : FROM A RARE COAGULATION DISEASE TO COMMON THROMBOTIC DISORDERS SUCCESS STORY OF KOGENATE AND XARELTO