“Management of Hemophilia : Where are we now and what

does the future hold?”

Prasad Mathew, MD

Professor of Pediatrics, UNM

GMA – Hematology, Bayer

Hemophilia

Blood coagulation defect

(Factor VIII or IX < 1 %)

Spontanenous bleeding complications

Debilitating arthropathy 2

Circumcision: The first hemostatic challenge!

“For it was taught: if she

circumcised her first child

and he died, and a

second one also died,

she must not circumcise

her third child..”

Talmud, Yevamoth, 64b Tzipori, Israel fourth century

Thrombogram™ measurement in platelet-rich plasma: effect of FVIII infusion in hemophilia

0

50

100

150

0 5 10 15 20 25 Time (min)

Thro

mb

in (

nM

)

Normal control

Hemophiliac before Rx

FVIII – 32.0%

FVIII – 45.0%

FVIII – 7.0%

Evolution of FVIII / FIX concentrates

6 Key NS, Negrier C. Lancet 2007;370:439–48

rFVIII: Recombinant FVIII; rFIX: Recombinant FIX; pdFVIII: Plasma derived FVIII; HBV: Hepatitis B virus; HCV: Hepatitis C virus; S / D: Solvent detergent; NAT: Nucleic acid testing

Cryo-

precipitates

Low purity pdFVIII

concentrates

Donor / plasma

screening for HBV

Heat treatment

of pdFVIII

Heat-treated

concentrates

widely available

HIV / HCV

screening

Immunoaffinity,

S / D, ion exchange

Qualification of donors,

inventory hold, NAT,

nanofiltration

rFVIII

rFIX High purity

concentrates

Intermediate

purity concentrates

Early

1970s

Late

1970s

Early

1980s

Mid

1980s

Late

1950s

Early

1990s

Late

1990s

Early

2000s

Late

1980s

Mid

1960s

Subfraction I-O

Plasma

fractionation

Modified rFIX and rFVIII

Life expectancy of patients with hemophilia

Larsson. Br J Haematol 1985;59:593-602

0

10

20

30

40

50

60

70

1831-1920 1921-1960 1961-1980

Life

expectancy

(years)

7

Hemophilia treatment goals

8

• To treat/avoid/abolish bleeding

complications

• To avoid joint disease

• To avoid side effects

• Inhibitors

• Infection

• To achieve the life the patient chooses

Ideal treatment of severe hemophilia:

Prevention of bleeding episodes by regular infusions

9

Regular self-administration

of FVIII or FIX concentrate

in order to prevent

bleeding episodes

(20-40 units/kg – 3x/week

or 1x/2days)

Time

FVIII

1%

FVIII correction by regular infusion

<1%

1–5%

6–24%

25–49%

50–150%

>150%

• Patients with moderate hemophilia

(FVIII / FIX 2–5%) have much less

frequent hemarthrosis than patients

with severe disease (<1%)

• The rationale for prophylaxis is to

maintain FVIII / FIX >1% in order

to prevent spontaneous bleeding

episodes, especially hemarthrosis

The concept of prophylaxis

10

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

Prophylaxis reduces but does not abolish

the occurrence of bleedings

11

On-demand

(n=33)

Prophylaxis

(n=32)

Total Bleeds/year 18 1.9

Joint Bleeds/year 5 0.5

(90% less)

(90% less)

Choices of treatment regimens and different ages

at which they are implemented

12

A. Coppola. Blood transfusion, 2008

0 5 10 15 20 25 30 35 40

Prevention of Life-

threatening

Bleeding

Reduction of

Progression of

Arthropathy and

Disability

Enable Normal

Activities of Daily

Life and Physical

Exercise

Enable Practically

Normal

Psychosocial

Development

without

Overprotection

Primary Prophylaxis

Early Secondary Prophylaxis

Late Secondary Prophylaxis

Secondary Prophylaxis in

Adolescents and Adults

Short-term Prophylaxis

On-demand Treatment

Age (years)

Challenges of replacement therapy in

different age categories

13

Children

• Venous access

• Inhibitors

• Parents

Adolescents

• Compliance

• Adherence

• Self-management

Adults

• Joint disease

• Infection

• Comorbidities

How should prohylaxis be started in 2016?

14

• To all boys with severe hemophilia A/B

• Around the age of one year

• At a low dose

• Avoiding “immunological danger signals” first 20 ED

• As “prophylaxis” during first 20 ED instead of “on demand”

0-2 3 4 or More Lifetime

Joint Bleeds

Joint

Scores

Normal

Joints

Moderate

Damage

Substantial

Damage Joint

Health

Patient

Impact

Aiming for zero bleeds enables patients

to live normal lives

15 Sources: Funk M et al. Haemophilia 2002; 8:98-103

PhEx 3-7 0-2 0

X-ray 7-12 0-3 0

MRI 3-8 2 0

Standard of care 2015

• Prophylaxis is the gold standard of care for children with severe hemophilia

• Increasing numbers of adults are taking advantage of prophylaxis as well

• On-demand treatment with pdF/rF is used for those who are not on prophylaxis

• Uniform, weight based dosing is most often used

• A “one size/dose fits all” policy has dominated hemophilia treatment for decades

• And has helped to significantly improve the care

1

6

Does “one size fits all” work?

… perhaps, it is time to shift our paradigm …

1

7

Environmental

factors

HEMOPHILIA

PHENOTYPE

Genetic factors

BMI Treatment

First joint

bleed

Physical

activity

FVIII:C lab

assays

Factor 8/9

genotype Co-inherited

genetic variables

Modifiers of severe

hemophilia phenotype

Inherited FVIII:C

assay discrepancy

Missence mutations with

discrepancy between FVIII:C

assays

Small del/ins in

a stretch

Nonconserved

splice-site mutations

Missense

mutations

FV Leiden/

prothrombin 20210

AT, PROT C, PROT S

deficiencies

Polymorphisms in F7

Platelets function

Polymorphisms in inflammatory,

immunoregulatory genes

Hemophilia is characterized by phenotypic variability

18

Patient’s hemophilia severity

19 Their prophylaxis needs may be very different

Patients are different

(even those with severe hemophilia)

Severe hemophilia A:

A heterogenous disease with phenotypic variation

20

• 10 to 15% of patients with

phenotypically severe hemophilia

(<1% clotting factor activity) have

relatively mild disease clinically with

less frequent spontaneous bleeding

• Among patients who bleed, the

extent of joint damage tends to

vary considerably

Inter-individual variability

21

Needs of hemophilia patients do differ!

22 Should the treatment be the same for these patients ?

FVIII half-life vs. time-to-trough

23 Adapted from Collins PW et al. Haemophilia 2011;17:2-10

Factor VIII / IX levels and bleeding rates

24

• Some patients have normal joints despite factor levels below 1%

• Orthopaedic Outcome Study (1994): approx. 10% of severe patients (FVIII

<1%) entered with all six joints normal

• Some patients bleed with factor levels >1%

• Ahlberg (1965) suggested a 3% threshold level to prevent arthropathy

0

2

4

6

An

nu

al

no

. J

oin

t

Ble

ed

s

FVIII Activity (IU dL-1) 0 1 5 10 15 20

Joint bleeds versus FVIII level in 377 patients

3 Aledort 1994; den Uijl et al. 2011,

Ahnström et al. Haemophilia. 2004;10:689–97

When should a trough level >3 % be targeted?

25

• For prolonged periods, in patients with

• Target joint

• Repeated breakthrough bleeding episodes

• Concomitant treatment with antithrombotic agents

• Punctually, in patients

• Before active physical activities

Collins PW. Haemophilia. 2012;18 Suppl 4: 131-5. Mannucci PM, Schutgens RE, Santagostino E, Mauser-Bunschoten EP. Blood. 2009 Dec 17;114(26):5256-63

26

Tailoring treatment

• Age of start may be a more important independent

predictor of arthropathy regardless of dosing regimen

• Personalized approach should be applied as individual PK

response is variable

• Any form of tailoring of prophylaxis needs to take into

consideration the economic resources of the country; for

many countries very intense prophylaxis regimens are just

not possible

What have we learned about prophylaxis? A patient tailored approach

Astermark J et al , Br J Hematol 1999; Ljung R et al, Hemophilia 2013

Carcao MD, Iorio A. Individualizing Factor Replacement Therapy in Severe Hemophilia. Semin Thromb Hemost. 2015

Strategies to optimize hemophilia therapy by

individualizing the prophylactic regimen

28

Clinical approach

• Clinical bleeding patterns may be significantly different in patients having similar

coagulation factor activity

• Base dosing on observed bleeding pattern and clinical response to treatment

Pharmacokinetic approach

• Standard number of 2 to 3 infusions per week to maintain residual plasma FVIII/FIX

activity >1 IU/dL

• Dosing and frequency of infusions according to individual PK data

Laboratory markers such as global hemostasis assays

• Significant correlation between the thrombin-generating capacity of patients and their

bleeding symptoms

• Thrombin generation measurement may be useful for determining individually tailored

prophylactic regimens Salvagno et al. Haemophilia 2009;15: 290–6

Two ways to use PK

• Tailor your dosing to your life-style

• Tailor your life-style (daily activities) to your dosing (PK profile)

2

9

Pharmacokinetics – is it difficult?

• Hemophilia A

• < 30 min prior FVIII infusion

• 7 time-points post infusion in older kids

• 30min, 1, 3, 6, 12, 24, 48 hours

• At least 5 time-points in patients ≤ 6 years old

• Hemophilia B

• 7 samples over a period of 72 hours

Lee et al. Haemophilia; 12 (Supplement s3): 1–7 (2006)

30

A Bayesian approach takes into

account the individual value and

the population profile to predict an

individual half-life

0 6 12 18 24 30 36 42 48 Time (hours)

20

80

60

40

100

0

1

... Do you know the average curve of your population!

FV

III le

vel (%

)

Bayesian pharmacokinetic evaluation

31

Join the WAPPS network at:

www.wapps-hemo.org

Age Bleeding phenotype

Joint status Venous Access

Availability of replacement therapy

(qualitative and quantitative)

Goals of treatment (prevention - abolition

of bleeds, even subclinical)

Response to replacement therapy

(measured or predicted)

Family support – understanding

(partner, parents)

Life-style

Physical activities

Expected quality of life

Adherence and compliance to

treatment

Availability of tailoring approaches

Optimal target level …

Parameters to be taken into account when deciding

how to treat a patient with hemophilia

32

The 10 European Principles of Hemophilia Care

33 Colvin BT, Astermark J, Fischer K, et al. Haemophilia 2008; 14: 361-374

1. A central hemophilia organisation with supporting local groups

2. National hemophilia patient registries

3. Comprehensive care centres and hemophilia treatment centres

4. Partnership in the delivery of hemophilia care

5. Safe and effective concentrates at optimum treatment levels

6. Home treatment and delivery

7. Prophylaxis treatment

8. Specialist services and emergency care

9. Management of inhibitors

10. Education and research

34

Ideally, hemophilia management in 2016 should

conciliate evidenced-based individualization of treatment

and care, and integration of individual data in

multicenter and international prospective databases.

A memorable past: Now it’s time to look to the future

Recombinant era

1900 1993 2000/1 2014 1950s 1965 1969 2009 2012 1985

Pla

sm

a-d

eri

ve

d c

on

ce

ntr

ate

s

Wh

ole

blo

od

tr

an

sfu

sio

n

Pla

sm

a

Cry

op

rec

ipit

ate

Vir

al in

ac

tiva

tio

n

KO

GE

NA

TE

KO

GE

NA

TE

FS

/Ba

ye

r

Lip

os

om

al

F8

Sit

e-s

pe

cif

ic P

EG

yla

tio

n

Prophylaxis

becomes

standard of care

Prophylaxis becomes possible

Challenge:

taking treatment to the next level

Anti-TFPI and gene therapy

BAY 81-8973

BAY 94-9027

Kovaltry: Bayer’s new standard-acting rFVIII

• A new, full-length, unmodified rFVIII product with the same amino acid sequence as Kogenate FS/Bayer, but is produced with enhanced manufacturing technologies

• Manufactured using an improved cell bank compared with Kogenate FS/Bayer; the inclusion of the gene for HSP70, which inhibits apoptosis, may increase proper folding of the FVIII protein and expression

• No human- or animal-derived materials are added to the cell culture, purification, or formulation processes

• A new viral filtration step has been added, which uses 20 nm pore-size viral filter capsules capable of removing even small non-enveloped viruses and potential protein aggregates

• Has consistent glycosylation and increased sialylation relative to Kogenate FS/Bayer

• Offers advanced protection with proven efficacy and dosing as few as 2x weekly

PK, pharmacokinetic.

Kovaltry:

Manufacturing technique advancements

Improved consistency in glycosylation and expression

compared with rFVIII-FS

Co-expression of human HSP70

Nanofiltration step

No human or animal raw materials added to cell culture, purification, or formulation processes

Additional level

of virus removal Enhances viability of

expression cell line

• Inhibits apoptosis

• May enhance proper

folding of the FVIII protein

1. Kavakli K et al. J Thromb Haemost 2015; 13 (3): 360–369.

2. Vogel JH, et al. Haemophilia. 2010;16 (suppl 4):40.

HSP70=70 kilodalton heat shock protein

Consistent Gylcosylation

Kovaltry: Glycan structure

Consistent glycosylation2

High level of branched glycans2

Highly sialylated galactose branches2

Potential reason for decreased FVIII clearance3

Mono Di Tetra

Asialo

FVIII=factor VIII

1. Image Adapted from Preston RJ et al. Blood. 2013;121(19):3801-3810.. 2. Data on file. Bayer HealthCare.. 3. Zhong X, Wright JF. Int J Cell Biol. 2013:273086.

Asialo

Kovaltry: Improved protein translates into excellent efficacy at

high and low dose regimens

LEOPOLD Kids (PTP, ≤12 years old):

Mean ABR per Treatment Arm

40

0.5

1.0

2.5

0.9

0.0

1.0

1.6

0.3

0

1

2

3

4

2x/week 3-4x/week 2x/week 3-4x/week

0 to <6 years 6 to 12 years

Joint bleeds / year

Spontaneous bleeds / yearN=13

N=9 N=16 N=13

AB

R

The median number of bleeds is 0 for any bleeds in both age groups and all

treatment regimens

No inhibitors were reported in PTPs

Treatment regimens children included 2x/week (39%), 3x/week (43%) and every other day (16%)

41

Novel treatment regimens with longer-acting FVIII

Novel treatment regimens with longer-acting FVIII

42

Fewer injections

Higher troughs

Reduction of bleeds

Physical activity

Higher consumption and cost?

…

Reduced burden for families

Reduced need for CVLs

More acceptable regimens

Less importance of morning injections

Higher FVIII doses might be needed

Longer periods with low level FVIII

Higher adherence?

… Astermark et al. Br J Haematol. 1999; 105(4): 1109-13. 1999, Petrini et al. Haemophilia. 2001; 7(1): 99-102.

Carcao et al. Semin Thromb Hemost. 2015 Aug 13. [Epub ahead of print]

Advantages of long-acting products • Potential to dramatically improve treatment and overall quality of life of

patients: • Maintain higher trough levels than 1% level usually aimed for nowadays, offering

greater protection against bleeds

• Less frequent venipuncture and reduced need for venous access devices

• Facilitate early prophylaxis in children

• Fewer doses for bleeds in “on demand” patients

• Facilitate management of surgical patients

• More obvious advantage for long-acting IX: • Five fold prolongation of half-life of FIX, by contrast with factor VIII where not even

twofold prolongation has been achieved

Technology Description Mechanism of prolonged half-life Examples

Fc fusion1 Fusion of the Fc domain of

human immuno-globulin G

(IgG) to rFVIII

Binding of Fc to FcRn delays lysosomal

degradation of the fusion protein and

recycles it back into the circulation1

Efraloctocog alfa

(Biogen Idec)

Single-chain2 Single-chain rFVIII Improves FVIII stability by increasing the

interaction between the heavy and light

chains, and increasing affinity for vWF2

CSL-627

(CSL Behring)

Polysialylation3 Conjugation of linear polymers

of

N-acetylneuraminic

acid (sialic acid) to rFVIII

Improves enzymatic stability and

decreases renal excretion by increasing

molecular mass3

BAX 826

(Baxter)

PEGylation4 Covalent attachment of long-

chained PEG molecules to

rFVIII

Improves stability and reduces clearance of

rFVIII4

Damoctocog alfa pegol (BAY

94-9027; Bayer);

N8-GP (Novo Nordisk);

BAX 855 (Baxter)

1. Dumont. Blood. 2012;119:3024-3030; 2. Schulte. Thromb Res. 2013;131(suppl 2):S2-6

3. Rottensteiner, et al. ASH Annual Meeting Abstracts. 2007;110:3150; 4. Mei, et al. Blood. 2010;116(2):270-279

Longer-Acting FVIII Technologies

44

PEGylated FVIII Products in Development

Product

Recombinant

protein Modification Cell line Manufacturer

Damoctocog alfa pegol (BAY

94-9027)

BDD-rFVIII

(Ser743-Gln1638)

Site-specific PEGylation1 (PEG

60 kDa branched) BHK Bayer

N8-GP BDD-rFVIII

(Ser750-Gln1638)

Site-specific glycoPEGylation2

(PEG 40 kDa branched) CHO Novo Nordisk

BAX 855 FL-rFVIII Random PEGylation3

(PEG 20 kDa) CHO Baxter

BDD=B-domain–deleted; BHK=baby hamster kidney; CHO=Chinese hamster ovary; FL=full length

1. Coyle, et al. J Thromb Haemost. 2014;12:488-496

2. Stennicke, et al. Blood. 2013;121:2108-2116

3. Turecek, et al. Hämostaseologie. 2012; 32 (Suppl 1):S29–S38 45

Half-life of PEGylated factor IX (N9-GP)

Two weeks after dosing, four patients had received FIX treatment as on-demand or prophylaxis. Four weeks after dosing, nine patients had received FIX treatment. FIX activity values from these patients were excluded from the pharmacokinetic evaluation after two or four weeks depending on the time when they received their FIX treatment.

10.000

1.000

0.100

0.010

0.001

FIX

(U

/mL)

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700

Time (hours)

0.01 U/mL

0.03 U/mL

Treatment

25 U/kg

50 U/kg

100 U/kg

1 week 2 weeks 4 weeks

Negrier C et al. Blood 118: 2695-2701 (2011)

What is our goal?

• FVIII level of 1% “wholly insufficient”

• Trough level of 15% “ideal” but “unattainable in short term due to cost”

• “Improving patient quality of life should drive treatment decisions, not economics”

• “Moving forward incrementally to higher baseline levels of 3 or 5% would be a step in the right direction”

• Longer-acting products will certainly help achieve this goal but: • Will they be affordable?

• Should we use long-acting products for prophylaxis but use cheaper current products for breakthrough bleeds?

Skinner M. Haemophilia 18 (Suppl. 4): 1-12 (2012)

BAY 94-9027 is a site-specific PEGylated B-domain-deleted recombinant FVIII

• BAY 94-9027 has undergone

site-specific PEGylation

(60 kDa PEG) to increase

half-life

• Half-life of BAY 94-9027 is

~19 hours, as demonstrated

in a Phase I study1

A3 C1 C2

Me

A1 A2

Single branched 60 kDa PEG molecule anchored to cysteine point mutation in A3 domain

Site-specific

PEGylation

to extend

FVIII half-life

B-domain

deletion

Coyle TE et al. J Thromb Haemost 2014; 12 (4): 488–496.

2x/wk, low bleeders 30–40 IU/kg n=11

PROTECT VIII Study Design

• 134 patients were treated (prophylaxis, n=114; on demand, n=20)

• 4 prophylaxis patients discontinued during the run-in phase

2x/wk, high bleeders 30–40 IU/kg n=13

Every 7 days 60 IU/kg n=43

6

Randomization

0 10 14 20 28 36

2 or more breakthrough bleeds (joint or muscle, no identified trauma)

No or 1 breakthrough bleeds

Screening

Screening

2

On-demand treatment Individual dosage n=20

Every 5 days 45–60 IU/kg n=43

Weeks

Boggio et al. Presented at: European Association for Haemophilia and Allied Disorders; February 11–13, 2015; Helsinki, Finland

2x/wk 25 IU/kg n=114

BAY 94-9027 Prevented Bleeding at Dose Intervals Up to

Every 7 Days

ABR in 2x/wk low bleeder group was comparable to every-5-days group

All patients randomized to every 5 days (n=43) remained in the treatment arm

Med

ian

AB

R

23.4

4.1 1.9 1.9

3.9 0

5

10

15

20

25

On-demand(n=20)

2x/wk, highbleeders (n=13)

2x/wk, lowbleeders (n=11)

Every 5 days(n=43)

Every 7 days† (n=43)

17.8; 37.3 2.0; 10.6 0.0; 5.2 0.0; 4.2 0.0; 6.5

– 17.4 0 0 0

– 4497.8 3341.1 3671.8 3466.7

– 38.9 31.5 45.3 56.8

Q1; Q3*

Run-in ABR

Mean total dose, IU/kg/y

Mean IU/kg/infusion

*Weeks 0–36 for on-demand arm, weeks 10–36 for other treatment arms †Includes all bleeds for the entire time patient was in the treatment arm

Reding et al. Presented at: Congress on Controversies in Thrombosis and Hemostasis; October 30–November 1, 2014; Berlin, Germany

Excellent bleeding control continues in long-term extension

32.96

2.21 1.17 0.54 3.94

On-demand(N=14)

2x/wk(N=24)

E5D(N=37)

E7D(N=29)

Var Freq(N=17)

Median ABR for all prophylaxis

groups:1.87

Improved bleeding control in extension likely reflects a learning curve and

increased comfort in making treatment and dose decisions

ABR in once weekly arm continues to improve from 0.96 to 0.54

Data on file, BHC (Global Clinical Development)

Hemophilia gene therapy

• Can we ultimately achieve a bona fide cure by gene therapy in patients

suffering from hemophilia ‘A’ or ‘B’? YES

52

Hemophilia gene therapy:

Adeno-associated virus (AAV) & lentiviral vectors (LV)

• Mainly episomal

• Anti-AAV T cells

• Limited innate immune response

VandenDriessche et al., Blood. 2002; 100: 813. VandenDriessche et al. J. Thromb. Hemostasis. 2007; 5: 16-24 53

• Genomic integration

• No anti-LV T cells

• Innate immune response

LV AAV

Clinical gene therapy for hemophilia B

54 Nathwani AC et al. N Engl J Med. 2014; 371(21): 1994-2004

2-6% FIX activity 6/6 high dose subjects

How to further improve efficacy and safety?

55 1. Nair N et al. Blood. 2014; 123(20): 3195-3199. 2. Markusic DM et al. Blood. 2014; 123(20): 3068-3069. 3. Chuah MK et al. Mol Ther. 2014; 22(9): 1605-1613

Anti-TFPI antibody for prophylactic hemophilia therapy

for inhibitor-/ non inhibitor patients (Hem A/B)

High unmet medical need:

• Current prophylactic treatment for hemophilia:

• Frequent intravenous infusion

• Low compliance

• FVIII resulting in 15–30% inhibitor formation

Goal:

• To develop improved prophylactic treatment to reduce frequency of intravenous injections

• Potential for subcutaneous administration

Approach:

• BAY 1093884, human monoclonal antibody blocking the function of TFPI

• High affinity (KD <50 pM) to compete with TFPI/Xa binding

• Sequence optimized framework for potential low immunogenicity TFPI, tissue factor pathway inhibitor.

Bayer and FVIII gene therapy program

In 2014, Bayer entered into a

collaboration agreement with

Dimension Therapeutics

Efforts will be focused on

developing and making available a

novel gene therapy for the

treatment of hemophilia A

Fully synergistic collaboration that

combines Bayer’s strength in

hemophilia with Dimension’s

strength in novel AAV gene therapy

treatments AAV, adeno-associated virus.

Alternative MoA to FVIII replacement

Aiming to reduce treatment burden

Alternative prophylactic

option for inhibitor patients

PROTECT VIII

study ongoing

Partnered with industry experts in AAV-based gene

therapy

First clinical trials expected within

2 years

Bayer – continuing to drive innovation

Extended-

acting FVIII

therapy

Anti-TFPI

therapy Gene therapy

AAV, adeno-associated virus; MoA, mechanism of action; TFPI, tissue factor pathway inhibitor.

Thank you!

59