1

European Haemophilia Consortium Round Table of Stakeholders

Orthopaedic Aspects in Haemophilia Care

What are the goals of

treatment?

A Haematologist’s perspective

Professor Cedric HERMANS

MD PhD FRCP (Edin, Lon)

Haemostasis and Thrombosis Unit

Haemophilia Clinic

Division of Haematology

Cliniques Universitaires Saint-Luc

Catholic University of Louvain

1200 Brussels, Belgium

cedric.hermans@uclouvain.be

Speaker disclosures

Shareholder No relevant conflicts of interest to declare

Grant / Research Support

No relevant conflicts of interest to declare

ConsultantPfizer, Bayer, Shire, Novo Nordisk, CSL Behring, Octapharma, Sobi, LFB, CAF-CDF, OctaPharma

Employee No relevant conflicts of interest to declare

Paid Instructor No relevant conflicts of interest to declare

Speaker bureau No relevant conflicts of interest to declare

Other

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THE MOST FAMOUS HAEMOPHILIA PATIENT

TSARÉVITCH ALEXIS (1904-1918)

4 year-old

8 year-old

10 year-old

4

HAEMOPHILIA TODAY : NOT LONGER A ROYAL

DISEASE BUT A DISEASE THAT CAN BE

TREATED

This young boy with severe

haemophilia can now be

treated safely and have a

normal life.

HAEMOPHILIA

Blood Coagulation Defect Debilitating Arthropathy

6

Bleeding complications in patients with

haemophilia

Intra-Cranial

Hip

Ilio-psoas Muscle

7

Factor Level(%)

PhenotypeAnnual bleeding rate (ABR)

without Replacement

Moderate

Severe<1%

1–5%

6–24%

25–49%

50–150%

>150%

Mild

52

1–5

0–1

0

0

0

The Most Affected Joints in Haemophilia

• 90% of bleeding episodes affect MSK system

• Up to 80% in ankles, knees and elbows

• 10% of hematomas

• Begin by age 2

• Nonvital tissues express low levels of TF.

• These tissues appear to rely more on the intrinsic pathway of coagulation to maintain hemostasis.

• This may explain why hemophilia A and B patients exhibit spontaneous hemorrhages into skeletal muscle and joints.

Mackman N. Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1015-22.

Why do patients with haemophilia bleed in

their joints ? Haemotological reason

Elbows, knees and ankles are the

most susceptibe to acute

haemarthrosis

« hinge joint » synovium gets stuck

in the joint

Shoulders and hips are less

susceptible to acute

haemarthrosis

Why do patients with haemophilia bleed in

their joints ? Anatomical reason

Interleukin-1Interleukin-6

TNF-alpha

Consequence of hemarthrosis: Inflammation and hypertrophy of the Synovium

Source: S. Lobet

Source: Novo Nordisk

Musculoskeletal bleeding episodes in patients with haemophilia

Features

Location Joint Muscle

Reason Spontaneous Induced (trauma, physical activity)

Presentation Clinically patent Suclinical

Symptomatic

Asymptomatic

Clinical haemarthrosisLarge amount of blood

Clinically patent

Subclinical haemarthrosisSmall amount of blood

Clinically silent

Treatment of haemophilia

Replacement or substitutive

therapy by regular intravenous

infusions of exogenous clotting

F8 or F9 to correct clotting

factor deficiency in order to

treat or prevent bleeding

episodes

Injection of missing

Factor VIII or IX

Treatment of haemarthrosis

should not be delayed

WITH A JOINT BLEED, TIME LOST IS JOINT

AND CARTILAGE LOST

Visit our Website: http://www.hemophilie-ucl.be and discover our

computer-generated movie on blood coagulation and haemophilia

The benefits of early treatment : a well-known

concept in various therapeutic areas

CARDIOLOGY

Acute myocardial infarction

Saves cardiac

muscle

NEUROLOGY

Acute ischemic stroke

Saves

neurones

HAEMOPHILIA

Acute haemarthrosis

Saves

cartilage

PATIENT

Education

Good understanding

Rapid recognition

Good venous access

HEALTH CARE

SYSTEM

Home-treatment

Education

TREATMENTReplacement or

Bypassing

Haemostatic efficacy

Convenience of use

Requirements for early treatment of bleeding

episodes in patients with haemophilia

Better than early treatment,

PREVENTION of haemarthrosis is

the optimal option

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Ideal treatment of Severe Haemophilia :

Prevention 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%

F8 correction by regular infusion

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The Concept of Prophylaxis

<1%

1–5%

6–24%

25–49%

50–150%

>150%

• Patients with moderate hemophilia

(FVIII / FIX 2–5%) have much less

frequent haemarthrosis than

patients with severe disease (<1%)

• The rationale for prophylaxis is to

maintain FVIII / FIX >1% in order to

prevent spontaneous bleeding

episodes, especially haemarthrosis

• Regular infusions of FVIII

concentrates aim to convert

severe into moderate

• No consensus on optimal

prophylaxis regimen

• Considering a recovery of 2, and

a half-life of 9-13 hours for

currently available FVIII

concentrates, 2-3 infusions per

week are needed

10 %

20 %

30 %

40 %

50 %

60 %

Monday Tuesday Wednesday Thursday Friday Saturday Sunday

Fact

or

VII

I m

easu

red

in

blo

od

1 %

Infusions of concentrate

Prophylactic Treatment of Haemophilia A:

Basic Principles

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Choices of Treatment Regimens and Different Ages at

Which They Are Implemented

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)

• To all boys with severe haemophilia A/B

• Around the age of one year

• At a low dose, i.e. usually 25 U/kg

• Frequency of every 2nd day/trough guided

• Avoiding “immunological danger signals” first 20 ED

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

How should prohylaxis be started in 2017 ?

DATA SUPPORTING PROPHYLAXIS: RETROSPECTIVE AND PROSPECTIVE STUDIES

Author Outcome Prophylaxis On-Demand

Liesner et al. 19961 All bleeds/year (median) 1.5 14.7

Szucs et al. 19982 Joint bleeds/6 mos(mean)

3.1 8.8

Yee et al. 20023 Joint bleeds/year (median)

0.5 3.5

Panicker et al. 20034 Major bleeds/year (mean) 1.9 15.5

Feldman et al. 20065

(Interim results: prophylaxis only)

Joint bleeds/year (mean) 1.2 N/A

N/A = not available.

1. Liesner et al. Br J Haematol. 1996;92(4):973-978 2. Szucs et al. Haemophilia. 1998;4(4):498-501 3. Yee et al. Haemophilia. 2002;8(2):76-82.

4. Panicker et al. Haemophilia. 2003;9(3):272-278 5. Feldman et al. J Thromb Haemost. 2006;4(6):1228-1236.

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Prophylaxis Reduces the Occurrence of

Bleedings

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)

PK of FVIII and the risk of haemarthrosis

Peak

Trough

Monday FridayWednesday

Reduced bleeding risk zone

Collins PW: Plenary lecture „Personalized Prophylaxis“ WFH congress July, 10 2012

FVII

I lev

el (

%)

time

Peak / time spent in reduced bleeding risk zone:

Important to prevent activity related and traumatic bleeds

Trough Important to prevent spontaneous break through bleeds

AUC Important to prevent subclinical bleeds, maximizing the window of protection

RISKS OF STOPPING PROPHYLAXIS IN ADULTS

• Haemophiliacs do not lose the risk of joint bleeding at the age of 18

• Switching to “on-demand” will lead to haemarthroses –how many before haemophilic arthropathy develops ?

• Risk of losing the benefits of the financial and human resource invested in childhood

SECONDARY PROPHYLAXIS

• Introducing prophylaxis in adulthood is effective in reducing joint bleeding and improving joint function

Median (interquartile

range) number of bleeds per

patient

On-demand treatment*

Prophylactic treatment†

P value‡

Months 1–6 (n = 20)

Months 7–13 (n = 19)

Joint bleeds 15.0 (11–26) 0 (0–3) < 0.001

All bleeds 20.5 (14–37) 0 (0–3) < 0.001

Spontaneous bleeds

13.5 (7–29) 0 (0–1) < 0.001

Trauma bleeds 2.5 (0–9) 0 (0) < 0.001

NUMBER OF BLEEDS ON SECONDARY PROPHYLAXIS

Median observation period was 192 days. †Median observation period was 177 days. ‡Wilcoxon test.

Collins et al JTH 2009 8, 83-89

Patients receiving prophylaxis had 15.2 times fewer bleeds

Note: Median treatment duration at time of data analysis was 1.4 years; data shown are for all nondiscontinued patients who completed at least

1 study year.

*On demand vs prophylaxis; adjusted for stratification variables (presence/absence of target joints and number of previous BEs).

References: 1. Kempton C, et al. Presented at: XXXth International Congress of the World Federation of Hemophilia; July 8-12, 2012; Paris, France.

2. 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.

40.7

29.2

1.93.5

52.7

36.9

2.0*4.2*

P<0.001, on demand vsprophylaxis*

Mea

n B

Es, n

Total BEs per yearTotal BEs

Mea

n B

Es, n

10

20

30

40

50

60

0 0

10

15

25

30

40

45

20

35

5

Joint BEs per yearJoint BEs

On demand (n=42)Prophylaxis (n=42)

31G.SM.HEM.03.2014.0146

SPINART (Secondary Prophylaxis in Adults, Randomized Trial)

One year mean efficacy results1,2

Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens.

• Current prophylactic regimens, although very effective, do not completely prevent joint disease in a long-term perspective.

• Joint arthropathy in primary prophylaxis develops over many years, sometimes over a decade or even longer time periods.

• The ankle joints are the first and most severely affected joints in those patients and thus may serve in outcome assessment as an indicator of early joint arthropathy when followed by ultrasound or magnetic resonance imaging.

J. Oldenburg Blood. 2015 Mar 26;125(13):2038-44.

Patients with Different Lifestyle and Activity Level may need Different FVIII Trough Levels

>3% ?

10% ?

33

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• Based on FVIII PK parameters

• Based on bleed pattern

• (presence of target joints/joint damage)

• Tailored to activity level (sports)

• Tailored to personal circumstances

• Based on all available information

• Efficient

Hemostasis

Joint Status

Activity Level

Valentino LA. Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia 2014 Sep; 20(5): 607-15.

Individualized prophylaxis should be

Standard prophylaxis not optimal for everybody

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Patient with an average half-life (25 IU/kg every other

day)

Patient with a short half-life (25 IU/kg every other

day) Time spent with FVIII plasma

levels <1%

Increased risk for

break through bleeds

1%

1%

FV

III

leve

l (%

)F

VII

I le

ve

l (%

)

PHARMACOKINETIC DOSINGFV

III:

C (

U/d

L)

6,000 IU/week

1,575 IU/week

770 IU/week

100

10

1

0.1

100

10

1

0.1100

10

1

0.1

0 3 6 9 12 15 18

Time (days)

2000 IU, 3 times a week

450 IU, every 2 days

110 IU, daily

Carlsson et al. Eur J Haematol 1993;51:247–52. JA

« ZERO » bleed world

A new ambition in haemophilia therapy

Not only an issue of treatment availability and intensity

Only achievable with major collaboration of the patient and his family

Aiming for zero bleeds

Lifetime joint bleeds

Joint scores

Normal joints

Moderate damage

Substantial damage

Joint health

Patient impact

Patient–doctor relationship

Funk M et al. Haemophilia 2002; 8:98–103.

4 or more 3 0–2

Physical examination 3–7 0–2 0

X-ray 7–12 0–3 0

MRI 3–8 2 0

Which FVIII Trough Levels are needed for Zero Joint Bleeds?

Den Uijl et al. Haemophilia 2011; 6: 849-53

3%

12%

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Correlation of endogenous FVIII level and annual

number of joint bleeds

INTEGRATION OF REAL WORLD-DATA COLLECTION, TAILORED CARE AND PATIENT EMPOWERMENT

Personalized Medicine

1. PK profiling

2. Bleeding risk profiling

1. Bleeding phenotype

2. Target joints

3. Joint status

4. Work and sport activity

5. Lifestyle

6. Compliance

3. Bleeding recognition

Patient Empowerment

1. Disease and treatmentunderstanding (adherence) / psychological support

2. Shared treatment and goals decision making (GAS)

3. Life-style and activity adjustment

4. Promotion of self-management

Real-World Data Collection

Treatment tracking

(recording of bleedingepisodes and factor

consumption)

Outcome tracking

Patient-centricprophylaxis

Adapted from Gringeri A, Doralt J, Valentino LA, Crea R, Reininger AJ. Expert Rev Pharmacoecon Outcomes Res. 2016 Jun;16(3):337-45.

Haematological treatment of hemophilia

TODAY TOMORROW

Compensation of defectiveproduction of FVIII or FIX

"Cure"

Factor replacement therapy withplasma-derived or recombinant concentrates

Gene therapy

Non-factor replacement / Disruptive therapy

Endogenous production of natural/unmodified FVIII or FIX

Could IL-1 blockers prevent

blood-induced joint damage in

hemophilia ?

• It would be ideal if there were oral

drugs which could be taken soon

after a joint bleed for a short period

of time during the period

associated with damaging

inflammatory responses along with

CFC replacement to prevent

further bleeding.

• This could be particularly

significant for the vast majority of

patients in the world who do not

have access to prophylaxis with

CFC.

Srivastava A. Blood. 2015 Nov 5;126(19):2175-6.

Antibodies to block TNF-a / IL-1

antiangiogenesisdrugs

Impact of innovation on haemophilia care

More efficient treatments

Persistent control of FVIII or FIX deficiency

Cure of the disease

No BLEEDS

More time and resources for assessing and following non-

bleeding consequences of haemophilia

CONCLUSION

• The goal / ambition of the haematological treatment of haemophilia should be a complete abolition of all bleeding episodes and a full preservation of the musculo-skeletal system

• This is now achievable with current treatment options in a large proportion but not all patients with severe haemophilia

• The focus should be on patients with an Annual Bleeding Rate (ABR) > 0 . In these patients, different strategies should be implemented to better control their disease.

Thank you for your attention