Haemophilia:millenium goalsAngelika Batorova

National Haemophilia Center, EHCCC

Dept. of Hematology and Transfusion Medicine,

Faculty of Medicine of Comenius University,

University Hospital, Bratislava,

Slovak Republic

Conflicts of interest to disclose

Shareholder No

Grant / Research Support Shire, Grifols, Octapharma, Pfizer

Consultant Shire

Employee No

Paid Instructor No

Speaker bureau Shire, Grifols, Roche, Pfizer, Octapharma

Travel support Shire, SOBI, Grifols, Pfizer, Roche

2-19th CenturyInherited disorder

transmitted by women

Fatal bleeding

Joints damage

20 th Century-Transfusion medicine

Blood coagulation defined

Plasma fractionation

F9 and F8 genes cloned

F8/F9 gene transfer

Trauma avoidance

▪ On demand

▪ Home therapy

▪ Comprehensive

care

▪ Prophylaxis

▪ ITI

Time Knowledge Therapy Treatment options

period

No treatment–FATAL DISEASE

• Blood, FFP, cryoprecipitate

• pd Factor VIII/IX concentrates

• Recombinant products

Blood FFP Cryo pd-FVIII/IXr-FVIII/IX

Start of replacement therapy

First attempts of gene therapy

HISTORY OF HAEMOPHILIA TREATMENT BEFORE THE 3RD MILLENIUM

Safe pdFVIII/FIX rFVIII/rFIX Wide use of prophylaxis Patients with inhibitors- PCR testing new generation - 1st prospective study - ITI for all new inhibitors

- Quarantine in children - Prophylaxis FVIIa/aPCCof source plasma - Prophylaxis in adults

PK-guided EHL rFVIII Non-factor Promisingprophylaxis EHL rFIX therapy results of

for inhibitor pt. gene therapyPatient tailored Human rFVII

prophylaxis Porcine rFVIII ITI protocols

New Non-factor Gene coagulation therapy therapy

products for affordability (?)immunogenicity non-inhibitor pt.

TREMENDOUS PROGRESS IN THE FIRST TWO DECADESOF THE 21ST CENTURY AND FUTURE PROSPECTS

Cure of haemophilia

Mannucci. Haemophilia 2008;14(Suppl. 3);10-8

Vision for 2020´s

2010´s

2000´s

However, most of theseadvances will be availableonly in resources richcountries

?

Haemophilia

treatment

Haemophilia treatersSupply &

safe treatment products

Compliant patients

Zero bleedsNo inhibitors

Pharma industry

New products development

Increasing market

Patients/familiesSafe & convenient therapy

Life style tailored prophylaxis

No bleeds

Independence & normal life

Patients organizations

Adequate access to therapy

&

good quality of life

FOR ALL

Government/payers

Reduction of

economic burden

of haemophilia care

EXPECTATIONS AND AIMS FOR HEMOPHILATHERAPY IN THE 3RD MILLENIUM

Cureof haemophilia

RECENT GUIDELINES FOR HAEMOPHILIA MANAGEMENT

Accomplishment depends on availability of treatment products and factor supply

10 principles

WFH Initiatives

▪ Minimum FVIII supply 1 IU/cap/yr

to save the life of PWH´s

▪ Humanitarian Aid

AIM:

ADEQUATE TREATMENT

FOR ALL PWH´s

OVER THE WORLD

2009 Kreuth II: min. FVIII level in Europe 2 IU/cap/yr

2013 Kreuth III: min. F VIII supply 3 IU/cap/yr

2017 Kreuth IV: F VIII supply 4 IU/cap/yr

2010´s

2000´s

M.Skinner

Berger K. Biologicals 2011;39:189-93; Giangrande et al.Haemophilia 2014;20:322-5;

Giangrande et al. Haemophilia 2017;23:370-5; Skinner. Haemophilia 2012;18(Suppl 4):1-12

WFH-GAP: Global Alliance for Progress Program

for underserved countries and regions

• WFH, EHC

• Haemophilia specialists

ACTIVITIES AIMED TO INCREASE THE ACCESS TO HAEMOPHILIA THERAPY IN 2000´S

Joint damage curve

Mortality curve

Imp

rove

d o

utc

om

es

Factor consumption (IU/cap/yr)

Replacement therapy

PROPHYLAXIS

<1 1 2 3 4 5 6

Personalised PROPHYLAXIS

RELATIONSHIP BETWEEN OUTCOME AND FACTOR CONSUMPTION

Great disparities over the world

▪ Adequate factor supply

▪ Equal access to replacement therapy

▪ Home therapy

▪ Prohylaxis

▪ Treatment of inhibitors/ITI

▪ Comprehensive haemophilia care

▪ Diagnostics

▪ Patients registries

▪ Joints health status

▪ Quality of life

Regular WFH and EHC Surveys on haemophilia care

World haemophilia population: 400,000

Still no/very limited therapy: 70-80%

UNMET NEEDS IN HAEMOPHILIA THERAPY AT THE BEGINNING OF THE 21ST CENTURY

Global F VIII use per capita in 2016

GNI Value (US $)

Low income $ 905

Lower-middle income $ 906-3,595

Upper-middle income $ 3,596-11,115

High income $ >11,116

WFH comprises 134 National Member

Organizations (NMO)

Annual Survey: reports of 113 NMO´s

Classification of countries according to

Gross National Income (GNI)

6.2

1.8

0.3 0.04

6.3

1.4

0.1 0.03

0

2

4

6

8

High UpperMiddle

LowerMiddle

Low

Mean/capita

Median/capita

110,000

41,000

10,500 7,500

85,000

34,000

8,000 7,000

0

20000

40000

60000

80000

100000

120000

High UpperMiddle

LowerMiddle

Low

Mean/patient

Median/patient

Global F VIII use per 1 patient in 2016F

VII

I (U

/ca

p/y

r)F

VII

I (U

/pa

tie

nt/

yr)

WFH ANNUAL GLOBAL SURVEY 2016

0,1

1,3

1,6

1,8

2,0

3,0

3,3

3,6

4,2

4,8

5,7

5,9

6,3

6,4

7,1

7,1

7,3

8,2

8,6

8,7

10,5

10,9

0 1 2 3 4 5 6 7 8 9 10 11

Uzbekistan

Romania

Albania

Azerbaijan

Georgia

Serbia

Latvia

Denmark

Greece

Russia

Czech Rep

Lithuania

Spain

Poland

Germany

Slovakia

France

Slovenia

Finland

UK

Hungary

Ireland

FVIII SUPPLY IN EUROPE: MEDIAN 5.8 IU/CAP/YRProphy ≤18 yrs

86-100%

55%

90-100%

10%

55%

0%

90%

0%

WFH Survey 2016

North America

1,425 9.532

Country IU/cap/yr Prophy

US 9.532 n.r.

Canada 8.036 n.r.

Mexico 1,425 n.r.

FVIII SUPPLY IN AMERICA (WFH SURVEY 2016)

0.02 5,08

n.r.= not reported in Survey

0,02

0,19

0,24

0,53

0,57

0,83

1,05

1,07

1,43

2,49

3,24

3,56

4,39

5,08

0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 5,5

Bolivia

Ecuador

Nicaragua

Dominican Rep

Cuba

Panama

Honduras

Belize

Mexico

Venezuela

Costa Rica

Brazil

Argentina

Colombia

Prophyl

86%

75%

77%

20%

20%

n.r.

0%

0%

100% (?)

15%

12%

0%

n.r.

0%

0%

Latin America

Western Pacific

0,01 0,5

Country IU/cap. Prophy

Cambodia 0.046 50%

Philippines 0.063 1%

Vietnam 0.226 30%

Malaysia 0.272 60%

Mongolia 0.592 0%

S. Korea 4.673 n.r.

N. Zealand 5.408 100%

Japan 5.766 90%

Australia 6.689 90%

FVIII SUPPLY (IU/CAP/YR) IN SOUTH EAST ASIAAND WESTERN PACIFIC (WFH SURVEY 2016)

0.046 6.689

n.r.= not reported in Survey

0,01

0,15

0,12

0,15

0,28

0 0,25 0,5

Bangladesh

India

Indonesia

Sri Lanka

Thailand

Prophyl

20%

24%

0%

n.r.

n.r.

South East Asia

0,00

0,01

0,01

0,01

0,02

0,02

0,03

0,04

0,04

0,05

0,06

0,12

0,14

1,05

1,75

0 0,5 1 1,5 2

Tanzania

Burkina Faso

Ethiopia

Zambia

Nigeria

Uganda

Ivory Coast

Madagascar

Ghana

Cameroon

Mali

Senegal

Kenia

South Africa

Mauritius

0,02

0,17

0,17

0,26

0,52

0,88

1,21

1,89

2,24

2.87

0 1 2 3

Pakistan

Sudan

Jordan

Egypt

Marocco

Tunisia

Iraq

Algeria

Iran

Saudi Arabia

Africa Eastern Mediterranean

0.004 1.75 0.021 2,87

Prophy

100%

35%

15%

18%

6%

28%

10%

Prophy

nr

20%

90%

80%

50%

20%

1%

nr

nr

1%

FVIII SUPPLY IN AFRICA AND EASTERN MEDITERRANEAN

Haemophilia 2018; First published: 24 September 2018 |https://doi.org/10.1111/hae.13610

Impact of intermediate‐dose prophylaxis on progression

of haemarthropathy in patients with severe haemophilia A:

a 10‐year, single‐centre experience in KoreaKim JY, Lee DJ, Chun TJ, You CW.

J.Thromb Haemost. 2015;114(1):35‐45.

Benefits of prophylaxis versus on-demand treatment

in adolescents and adults with severe haemophilia A:

the POTTER study.Tagliaferri A, Feola G, Molinari A, et al.

Manco-Johnson M, Thomas MD, Abshire C, et al.

Effects of secondary prophylaxis started in adolescent

and adult haemophiliacs.Tagliaferri A, Coppola A, Franchini M, et al.

Haemophilia 2008; 14,5: 945-951

PROPHYLAXIS: A GOLD STANDARD OF HAEMOPHILIA CARE

A randomized study of very low‐dose factor VIII prophylaxis in severe

haemophilia – A success story from a resource limited countryS. P. Verma, T. K. Dutta, S. Mahadevan

Haemophilia 2016;22(3):342-8

FVIII dose 10 IU/kg twice a week

vs 25 IU/kg on demand

0

5

10

15

20

25

Wrist Knees Elbows Ankles

Prophylaxis On demand

Prophylaxis 1000 IU / kg / yr in children

prevents >80% of all bleeds1,2

Episodic treatment can not

prevent joint disease2,3

Low dose prophylaxis:

accepted policy of WFH

What FVIII supply is needed?

1. Verma et al. Haemophilia 2016;22(3):342-8

2. Wu et al. Haemophilia 2017;23(3):430-6

3. Manco-Johnson et al. N Engl J Med 2007;357:535-44

Annual number of joint bleeds on prophylaxis

and episodic therapy

PROPHYLAXIS IN COUNTRIES WITH LIMITED RESOURCES

Severe

Moderate

Mild

Unknown

Population

severe

≤18 yrs 20-30% 30-40% 25-60%

0.8%26.9%

9.9%45.6%

47.6% 36.7%

12.4%High income Upper middle income Lower middle income

n=27 =24 n=33

38.7%18.7%

WFH survey 2016

14.8%23.9%

23.0%12,4%

Haemophilia A

USEFUL DATA TO ESTIMATE THE NEED FOR FVIII SUPPLY

SEVERITY & PROPORTION OF PWH´S ≤18 YRS ACCORDING TO GNI /CAP.

0

1

2

3

4

10 IU/kg2/w

20 IU/kg2/w

20 IU/kg3/w

20 IU/kgeod

30 IU/kg3/w

0,5

1

1,6 1,8

2,3

Total dose 1040 2080 3120 3720 4680 IU/kg/yr/pt

Supply IU/cap/year

Country population: 10 mio inhab.; HA all/severe/severe 1-18 yrs = 1000/460/138

Starting point: prophylaxis 90% children 1-18 yrs (n=124), mean BW: 40 kg

regimen

ESTIMATED FVIII SUPPLY REQUIREDFOR DIFFERENT PROPHYLAXIS REGIMENS

Prophy 90%

children; 1,6

Prophy 50%

adults; 3,6

On demand;

1,8

ITI; 1,5

Prophy 90% children Prophy 50% adults

On demand ITI

Prophy 75%

children; 0,4

On demand;

1,6

ITI; 0

Prophy 75% children On demand ITI

Prophylaxis: 20 IU/kg 3x/wk 10 IU/kg 2x/wk

FVIII supply: 8.5 IU/cap/yr FVIII supply: 2.0 IU/cap/yr

GNI high GNI low

H A prevalence: 100/1 mio 50/1 mio

Severe 46% 37%

Children ≤18 yrs: 30% 40-45%

ESTIMATED PROPORTION OF FVIII SUPPLY FOR PARTICULAR TREATMENTS IN COUNTRIES WITH THE SAME POPULATION BUT DIFFERENT ECONOMY CONDITIONS

Pearce GF, Haffar A, Ampartzidis G et al.

PWH on prophylaxis 2014 2016

Reasons for donations

Improvement of prophylaxis

Total amount donated and No of countries 2002-2016

Countries reached and % of PWH from those

countries receiving humanitarian aid in 2016

Haemophilia 2018;24:119-235

144 000 000 IU

Acute bleeds

Prophylaxis

Surgery

Other (+ITI)

WFH: HUMANITARIAN AID

Characteristic Median IQR Range

Prevalence of haemophilia A (n/1 mio) 81 73; 95 40-120

Number of inhibitors 49 14; 119 3-811

Proportion of inhibitors (%/severe) 6.3% 3.6%; 9.6% 0.9% - 20.2%

FVIII supply (IU/cap/yr) 7.6 6.0; 9.0 4.2-10.4

FVIII consumption (IU/pat/yr) 98,000 78,000; 120,000 63,000-315,000

Use of rFVIII (%) 77% 53%; 86% 3%-100%

Data from WFH

Survey 2016

* ≥ $12,235: Europe, North America, Western Pacific

110.000

160.000

83.000

87.000

315.000

113.000

114.000

0 50.000 100.000 150.000 200.000 250.000 300.000 350.000

Russia (4.8)

Germany (7.1)

France (7.3)

UK (8.7)

Finland (8.6)

Sweden (10.0)

Hungary (10.4)

FVIII supply (IU/cap) vs consumption per patient in Europe

IU/patient/yr

A HIGH GNI*:DISPARITIES IN TREATMENT CHARACTERISTICS

ADHERENCE TO EU PRINCIPLES:2015 SURVEY OF 38 COUNTRIES

Country No of

Centres

Principle 1

Central

organization

Principle 2

Pats.

registry

Principle 3

All pats

treated in

HCCC/HTC

No of

HCCC/

1 mio

inhab.

Principle 7

Children on

prophy (%)

Principle 7

Adults on

prophy (%)

Belgium 1 NO NO NO 0,83 75-100 50-75

France 1 Yes Yes NO 0.71 75-100 1-25

Germany 2 Yes Yes Yes 0.89 75-100 50-75

Greece 1 Yes Yes Yes 0.37 75-100 1-25

Italy 3 Yes Yes Yes 0.81 75-100 1-25

Netherlands 2 Yes NO Yes 0.78 75-100 50-75

Norway 1 Yes NO Yes 0.40 75-100 50-75

Poland 1 Yes NO Yes 0.84 75-100 1-25

Portugal 1 NO NO NO 3.77 75-100 1-25

Slovakia 1 Yes Yes 7.8 8.7 75-100 1-25

Spain 3 NO Yes Yes 0.9 75-100 1-25

Sweden 1 Yes NO Yes 0.32 75-100 50-100

Switzerland 1 Yes Yes NO 1.27 75-100 1-25

UK 2 Yes Yes Yes 1.1 75-100 50-75

Hemans C. Tenders and Procurement of Coagulation Factor Concentrates: Brussels June 15th, 2015

BO Mahony. EHC 2015, Brussels

DISPARITIES IN ACCESS TO INHIBITOR THERAPY IN EUROPE IN 2015

✓Comprehensive haemophilia care

✓Wider use of recombinant products,

keeping the level of supply achieved

▪ Economical limitations even at high GNI

▪ Products quantity vs price

EHL products▪ Individualized approach

▪ New concept of care: higher

trough levels

▪ Patient´s preference

▪ Skillness with clinical management

surgery (?)

▪ Laboratory monitoring

▪ Pharmacovigilance

Individualised prophylaxis

▪ Trough levels vs bleeding phenotype (?)

▪ Patient and family life style (?)

▪ Joint health (?)

▪ Compliance

Full implementation of current

advanced therapeutical approcahes

Introduction of novel therapies

PK guided prophylaxis

▪ Different PK programs

▪ Aim: zero bleeds

▪ Affordability: impact on factor supply (?)

Gene therapy

Progress

Affordability

PERSISTING CHALLENGES IN THE 3RD DECADE/21ST CENT. NON INHIBITOR PATIENTS

Minimize modifiable risk factors

▪ Products with lower immunogenicity

▪ Safe treatment regimens

▪ Prophylaxis: low dose w/o danger

signalsBispecific antibody (emicizumab-

kxwh)

▪ Clinical management

▪ Laboratory monitoring

▪ Pharmacovigilance!

Anti-TFPI, iRNA-AT

▪ Efficacy and safety

▪ Pharmacovigilance!

Identification of risk factors for inhibitor

development

Introduction of novel non-factor

therapies

Improved ITI for inhibitor patients

Better treatment of bleedings

New generation bypassing agents

in development

Access to ITI for all

Identification of prognostic factors

Evidence-based ITI regimens

CHALLENGES IN THE 3RD DECADE / 21ST CENT. PWH WITH INHIBITORS

Ultimate aim in the 21st Century:

access to adequate treatment for all PWH in each country

Need to define health care prioritiesPreference

Adequate treatment policy for limited treatment regimens

Sufficient supply

Low price

Safe products

Insufficient supply

Expensive products

COUNTRIES WITH LIMITED RESOURCES

FVIII SUPPLY

Mahony et al. Haemophilia 2015;1-8

Conclusion

▪ More appropriate selection criteria

▪ More open and transparent process

▪ Patients and clinicians involvement: best outcomes

▪ Knowledge and involvement: not just focus on price

▪ Lower prices

▪ Guarantee of sufficient supply

▪ Equality in access to therapy nationwide

rVIII pdFVIII rFIX pd FIX rVIII pdFVIII rFIX pd FIX

CLINICIAN AND PATIENT ORGANIZATION INVOLVEMENT IN THE TENDER PROCESS

Twelve Kreuth IV: Recommendations

Developed in 2016 by participants from 36 European countries address all

current challenges and nearest goals to be ultimately achieved

▪ to standardize the level of care for haemophilia persons within Europe

▪ to ensure equitable access to comprehensive care and replacement

therapy within each particular country in Europe

1 Designation of haemophilia centres as EHTC/EHCCC. The EUHANET project

2 National guidelines on management of the ageing patient with haemophilia

3 The minimum FVIII 4 IU/cap/yr in any country

4 The minimum FIX 0.5 IU/cap/yr in any country

5 Hepatitis C therapy with direct-acting antiviral agents available in all PWH

6 Genotype analysis and genetic counselling available

7 Access to ITI for people with inhibitors

8 Access to elective surgery for inhibitor patients at a specialist centre

9National or regional tenders for factor concentrates: participation of haemophilia clinicians and

national haemophilia patient representatives

10 Outcome data collection: HRQoL, ABR, mortality, HJHS, time off from school/work

11 EHL concentrates: treatment individualized, increased troughs, protection against bleeding

12 Inhibitors in PUP: incidence varies between products. Better understand and minimize risk

Giangrande et al. Haemophilia 2017;23:370-5

KREUTH IV MEETING 2017 – RECOMMENDATIONS

Vision for the millenium

must be optimistic

despite current challenges