2008© COPYRIGHT

Rare Coagulation Disorders: The Way Forward ATHN Data Summit 2008July 31, 2008Presenters: Donna DiMichele, M.D. and

Amy Shapiro, M.D.

2008© COPYRIGHT

2

The Need

• Patients with rare coagulation disorders (RCDs) need safe and effective therapies and deserve excellent long term health outcomes

– Many RCD patients still have no treatment options other than non-virally attenuated plasma products or non-specific PCC’s

– RCD patients may not have access to new product trials

• Industry sponsors and investigators need special incentives to develop products for and conduct trials on rare disease populations

2008© COPYRIGHT

3

Objectives

• Prioritize rare coagulation disorder-related initiatives for ATHN

• Explore the clinical need and current evidence base of support for RCD product development

• Begin to formulate a work plan for RCD data collection that ensures coordination among national and international efforts with the 3 primary goals of:

– Developing an evidence base for the clinical care of RCD patients

– Promoting and supporting RCD product development

– Stimulate clinical and basic research in this filed

2008© COPYRIGHT

4

ATHN’s Strategic Direction

Network Network InfrastructureInfrastructure

Data Data ManagementManagement

Public Health Public Health and Safetyand Safety

Outcomes Outcomes ImprovementImprovement

Data Analysis Data Analysis and Researchand Research

Data safety, back-up, and portability

Support surveillance and patient safety

Use data to drive quality, service, and patient centered care

Facilitate knowledge creation and advocacy

Develop electronic database capacity

2008© COPYRIGHT

5

ATHN’s Strategic Opportunities

Network Infrastructure

Develop electronic database capacity

• Gain and engage ATHN Affiliates re: database

• Build community trust

• Expand local capacity by funding and training data managers

• Establish regional data management structure

• Define and establish the core dataset: rare coagulation disorders

2008© COPYRIGHT

The Current State of Understanding :

RCD Epidemiology, Pathophysiology and Treatment Options

2008© COPYRIGHT

7

Rare Bleeding Disorders

Clotting Protein Disorders Platelet Defects

Fibrinogen

Prothrombin

Glanzmann Thrombasthenia

Factor V

Factor VII

Bernard Soulier Syndrome

Factor X Storage Pool Disease

Factor XI

Factor XIII

Combined Factors V & VIII

Combined Factors II, VII, IX, X

Connective Tissue Diseases

PAI – 1 Deficiency Collagen Defects

2008© COPYRIGHT

8

Rare Clotting Protein Disorders Prevalence

Rare Bleeding Disorders (Deficiencies of Factors II, VII, X, V, XIII, Fibrinogen & Dysfibrinogenemia)

Prevalence – 1 in 500,000 to 1 in 1,000,000 ( 0.0002%)

Iranian Registry

(RIBD)

UK Registry (HCDO)

Italian Registry

(AICE)

0.3 – 6.6% 0.02 – 3.3% 0.2 – 1.3%

Source: D DiMichele

2008© COPYRIGHT

9

N° affected patients

RBDD survey(66 Centres)

WFH survey (98 countries)

AFIBRINO 241 644

FII 55 167

FV 232 769

FV+FVIII 494 188

FVII 904 1689

FX 338 597

FXI 757 2446

FXIII 209 434

TOT 3230 6934

Prevalence of Patients Affected by RBDs

WFH survey

RBDD survey

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

7

2

7

15

28

10

23

6

0

10

20

30

40

FIBRINOGEN FI I FV FV+FVI I I FVI I FX FXI FXI I I

9

2

11

3

24

9

35

6

0

10

20

30

40

FIBRINOGEN FI I FV FV+FVI I I FVI I FX FXI FXI I I

Data derived from RBDD are concordant with those of the WFH survey (2006)

RBDD survey (www.rbdd.org)

2008© COPYRIGHT

10

RBD distribution from National Registry data

reported during the SSC 2006-2007

F. Peyvandi

I ran

FII2% FV

10%

FV+FVIII15%

FVII31%

FX10%

FXI9%

FXIII13%

Fibrinogen10%

EMRO e Africa

FII1%

FV30%

FV+FVIII2%

FVII18%

FX13%

FXI19%

FXIII9%

Fibrinogen8%

Central and South America

FV7%

FV+FVIII4%

FVII23%

FX13%

FXI29%

FXIII3% FII

11%

Fibrinogen10%

France

FII0%

FV14%

FV+FVIII0%

FVII29%

FX5%

FXI25%

FXIII12%

Fibrinogen15%

UK

FVII19%

FX7%

FXI61%

FV4%

FII0%

Fibrinogen7%

FXIII2%

FV+FVIII0%

India

FV11%

FV+FVIII12%

FVII13%

FX10%

FXI2%

FXIII31%

FII4%

Fibrinogen37%Egypt

Fibrinogen23%

FII0%

FV29%

FVII12%

FX14%

FXI19%

FXIII2%

FV+FVIII1%

2008© COPYRIGHT

11

N° affected patients

RBDD survey(66 Centres)

WFH survey (98 countries)

AFIBRINO 241 644

FII 55 167

FV 232 769

FV+FVIII 494 188

FVII 904 1689

FX 338 597

FXI 757 2446

FXIII 209 434

TOT 3230 6934

Prevalence of Patients Affected by RBDs

WFH survey

RBDD survey

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

7

2

7

15

28

10

23

6

0

10

20

30

40

FIBRINOGEN FI I FV FV+FVI I I FVI I FX FXI FXI I I

9

2

11

3

24

9

35

6

0

10

20

30

40

FIBRINOGEN FI I FV FV+FVI I I FVI I FX FXI FXI I I

Data derived from RBDD are concordant with those of the WFH survey (2006)

RBDD survey (www.rbdd.org)

2008© COPYRIGHT

12

Distribution Results (Families)

Fibrinogen17%

FI I5%

FV12%

FV+FVI I I13%

FVI I25%

FX16%

FXI11%

FXI I I1%

82%77%

55%

75%

7%

82%

73%

14%

3%

16%

5%

22%

6%

13%

5%

20%

29%

20%

71%

12% 13%

0

10

20

30

40

50

60

70

80

90

FII FV FV+FVIII FVII FX FXI FXIII

severe

moderate

mild

DEFICIENCYN° OF

PROBANDSN° OF

FAMILIES

FIBRINOGEN 55 50

FII 16 15

FV 39 36

FV+FVIII 42 34

FVII 81 69

FX 52 43

FXI 35 32

FXII 2 1

FXIII 35 34

TOTAL 357 314

2008© COPYRIGHT

13

Clinical Manifestations

FVIII Fibrinogen FII FV FVII FV+FVIII FX FXIIIFXI

Nose bleeding

Uterine bleeding

Haematuria

GI bleeding

Joint bleeding

Muscle bleeding

CNS bleeding

Cord bleeding

Post-partum, -operation bleeding

Oral cavity bleeding

15%

25%

13%

75%

81%

16%

75%

90%

0%

0%

60%70% 64% 72%57% 77%

75% 50%

60% 50% 35% 50% 58%

7% 10% 25% 6%

15% 14% 38% 10% 6% 7%

38% 50%

21% 69% 55%26% 25%

38% 12% 66% 58%29%

7%5% 17% 9% 25% 6%

15%75% 28% 73% 3% 22%

23% 40% 55% 84%43%

46%70% 66%57% 51%

48%

32%

10%

7%

4%

0%

0%

0%

0%

0%

20%

8%

0%

29%

32%

0%

63%

55%

34%

3%

2008© COPYRIGHT

14

North American Rare Bleeding Disorder Registry ( NARBDR)

• HTC’s U.S. and Canada (26% RR)

• 94 / 3809 – (2.4%) adults

• 200 / 4583 - (4.4%) children

• Age: 0-73 yrs (median – 7 yrs)

• Family history - 50%

• Gene studies - 5.4%

0

20

40

60

80

100

120

II

VII X V

XII

I

FB

N

Dys

FB

N

To

tal

Pe

rce

nta

ge

of

Pa

tie

nts

Hetero

Homo

(135)

(4

II(16)

XIII(32)

FBN(16)

DysF(13)

VII

X (37)

V(35)

Source: Acharya et al. J. Thromb Haemost 2000;2:248

2008© COPYRIGHT

15

N.A. Rare Bleeding Disorders Registry Ethnicity and Rare Factor Deficiencies

Caucasian

(%)

AA

(%)

Latino

(%)

Asian

(%)

Others

(%)

% US Dem 76 12 8.2* 3 0.8

% RBD 61 13 19* 2 5

*p < 0.00001

Source: D DiMichele

2008© COPYRIGHT

16

N.A. Rare Bleeding Disorders RegistryDisease Related Complications*

Anemia MS CNS Other None

Factor II (Homo)

49 17 11 0 23

Factor VII (Homo)

19 18 2 0 61

Factor X(Homo)

34 7 22 0 37

Factor V(Homo)

36 23 9 0 32

Factor XIII 24 15 15 2 44

Afibrin 0 23 22 0 56

DysFBN 0 10 0 0 60

Source: D DiMichele *Numbers refer to % of each group with the symptoms

2008© COPYRIGHT

17

• For the rare factor deficiencies fresh frozen plasma and cryoprecipitate infusions have been the primary therapeutic strategy for the treatment or prevention of bleeding episodes.

• This treatment modality has disadvantages– potential viral contamination – volume overload – allergic reactions

Rare Bleeding Disorders: General Treatment Principles

(Source: D DiMichele)

2008© COPYRIGHT

18

NA Rare Bleeding Disorder RegistryTreatment Related Complications

• Allergic reactions 26%

• CVAD – related 14%

• Inhibitor development 3%

• Viral seropositivity

– Hepatitis A 15%

– Hepatitis C 25%

– HIV 1%

2008© COPYRIGHT

19

Summary of Factor Replacement

Factor

Deficiency

FFP Platelets Cryo Plasma Concen-

trate

Prothrom-bin

Complex

Recom-binant Factor

Fibrinogen X X X X (study only)

Prothrombin X X

Factor V X X

Factor VII X X (not US) X

Factor X X X

Factor XI X X (not US)

Factor XIII X X X (study only)

X (study only)

Source: D DiMichele

2008© COPYRIGHT

20

New Product Development: Underway but Challenging

• Fibrinogen concentrate (Haemocomplettan; CSL- Behring)

• FXIII concentrate (Fibrogammin ( CSL- B); rFXIII (NovoNordisk)

• FXI concentrate (HemEleven; LFB)

• FX concentrate (BPL)

• FV concentrate (Kedrion)

• Possibly, plasminogen

Source: D. DiMichele

2008© COPYRIGHT

21

Rare Platelet Disorders

2008© COPYRIGHT

22

Collagen Defects

2008© COPYRIGHT

23

Need for Standardized Data

• Demonstrate service delivery.

• Better understand the epidemiology, clinical presentation, genetics and natural history of the disorders;

• Facilitate the development of standards of care;

• Support advocacy for drug development;

• Identify population subsets for special study;

• Identify subjects eligible for clinical trials of new products;

• Aid in post-marketing surveillance;

• Analyze clinical outcomes;

• Identify care providers with patients to facilitate communication & networking;

2008© COPYRIGHT

24

Proportion of Patients in UDC

Factor Deficiency

In HTCs In UDC Percent

Factor I 89 29 33%

Factor II 49 16 33%

Factor V 148 62 42%

Factor VII 615 218 35%

Factor X 94 39 41%

Factor XI 520 144 28%

Factor XIII 97 64 66%

Source: CDC Division of Blood Disorders, Updated July, 2008

2008© COPYRIGHT

25

RBD UDC Working Group

• Collaboration of the Lab Tracker (web) development to ultimately capture and report data to RDB UDC working group

– Formed July 2007; Multi-disciplinary

– Work on data collection forms started in August 2007 (demographics; diagnosis; bleeding manifestations; treatment; complications)

– Coordination with the CC and CDC grant research priorities (Diane Nugent, Chair)

2008© COPYRIGHT

ATHN Initiatives :

Present and Future

2008© COPYRIGHT

27

ATHN Roles and Activities:Stewardship of A Secure National Database

• Present platform: Lab Tracker

• Conversion to web based system

• Server housed at CDC

02040

6080

100

Hemophili

aVW

D

Other

Ble

edin

g

Throm

botic

Plate

let D

isord

ers

Carrie

rs

Other

% of HTC Lab Tracker Users

(Based on 61 users of the 78 responding HTCs)

85% 64%

Patient Types Entered into Lab Tracker

2008© COPYRIGHT

28

ATHN Roles and Activities:Coagulation Disorder Resource Room

• Planned link from ATHN to NHF, WFH and NATT web sites to help disseminate peer-reviewed information to providers, researchers and patients

– Spearheaded by Amy Shapiro MD

– 17 manuscripts (e.g., clinical manifestations, treatments, diagnostic testing, etc.)

– Publication date Sept. – Nov. 2008

– All manuscripts in final stages of review & revisions

2008© COPYRIGHT

29

ATHN Role and Activities:Rare Disorders Projects

• Plasminogen registry– In process

• International harmonization– Exploring data sharing/interface with EN-RBD

• Development of a data collection module & training more specific to rare disorders for national database

– Just starting

2008© COPYRIGHT

30

U.S. Rare Bleeding and Clotting Disorder Database Pilot Project

• ATHN funded by Baxter for next 2 years

• Uses the infrastructure funded by Novo Nordisk

• The purpose is to support the development and testing of standardized data collection and supporting components for rare coagulation factor deficiencies that is compatible with the ATHN infrastructure.

• Conference call held May 08 to discuss plans

• Members of MASAC RDB subcommittee included

2008© COPYRIGHT

31

Three Components to the Grant

• Rare coagulation deficiency standardized data collection

– Review existing data collection efforts;

– Identify data elements for rare disorders;

– Validate applicability of existing data fields in Lab Tracker (web)

– Integrate changes to Lab Tracker (web) data dictionary and data collection templates

• National system for patient identifier

• Portal for development of data collection forms

2008© COPYRIGHT

32

Desire to Collaborate and Harmonize

• HDS Reporting

• UDC Women Study, Rare Bleeding Disorder Group

• Rare Bleeding Disorder Resource Room

• EN-RBD approach

• ISTH RBD Working Group

• World Federation of Hemophilia efforts

• Others

2008© COPYRIGHT

33

Example Disease Specific TemplatePlasminogen Activator Inhibitor 1 (PAI-1) DeficiencyRegistration Form - Draft

• Demographics• Diagnosis (phenotypic and genotypic)

• Birth history (gestation, method of delivery, therapy, complications)

• Bleeding history (symptoms, provider intervention)

• Reproductive/gynecologic history (gynecologic abnormalities, menses, pregnancy)

• Other health impairments• Treatment history (product, dose, frequency, regimen, first

exposure, home infusion)

• Complications (anemia, infection, musculoskeletal, allergies, death)

Source: A. Shapiro

2008© COPYRIGHT

34

European Network on Rare Bleeding Disorders (EN-RBD)

• Type and severity of deficiency• Demographics• Family• Bleeding manifestation and treatment (frequency,

localization, duration, trigger, treatment, outcome, prophylaxis, complications)

• Surgery management (major/minor/delivery type, age, bleeding type, duration, treatment, outcome, prophylaxis, complications)

• Other associated diseases• Phenotype studies• Molecular defect / Polymorphisms

Source: F. Peyvandi

2008© COPYRIGHT

Beginnings of a Work Plan:

Journey Initiated

2008© COPYRIGHT

36

Advance The Web-Based Infrastructure

• ATHN should enable centers to collect the full spectrum of historical and cross sectional data needed to:

– Care for patients and anticipate their issues– Design studies– Enroll patients in studies– Complete study requirements– Track impact of interventions on care

• To get started, ATHN can provide guidance to centers to maximize the benefit

2008© COPYRIGHT

37

Staging Rare Disorder Data Collection

Stage Goal

1. How many patients?

Identify patients with rare disorders

2. Who’s served?

Gather what’s needed for HDS report

3. What if disaster strikes?

Other info for the emergency preparedness flash drive

4. Where is public health at risk?

(UDC specific measures in development)

5. What outcomes?

Specific disease management templates and research

2008© COPYRIGHT

38

Staging Rare Disorder Data Collection

Stage Data Types

1. How many patients?

Demographics; diagnosis; deaths

2. Who’s served?

Clinical presentation; factor level; visit date, type and disposition; co-morbidities; presence of inhibitor; genetic or acquired

3. What if disaster strikes?

Contacts, treatment type, dose and instructions; allergies; warnings; insurance

4. Where is public health at risk?

(UDC specific measures in development)

5. What outcomes?

Cause of death; lab tests; outcome measures; pregnancies/fertility; genetic mutations; risk factors; adverse events; surgeries, infusions, new product trials and long term surveillance, etc.

2008© COPYRIGHT

39

Synchronize with CDC

• Enter data into Lab Tracker today

• Encourage sites to start enrolling rare coagulation disorder patients in UDC

• Encourage CDC Coordinating Committee to include in the Data Sharing Agreement under development, the ability to share data with ATHN to facilitate study coordination and site recruitment through ATHN

2008© COPYRIGHT

40

Aid Implementation by Study Sites

• ATHN should aid HTCs and other potential study sites with implementation of studies

– Communications network to share knowledge of studies

– Database to identify subjects for study– Access to central IRB– Standardized templates for consent/data capture– Patients flags in Lab Tracker for easy reference – Ability to re-use data once captured– Funding to help cover costs

2008© COPYRIGHT

41

Help Companies Coordinate Studies

• ATHN should begin to build capacity to help companies coordinate studies in the U.S.

– Refer to experts to frame studies

– Identification of study sites

– Active tracking of site interest

– Data to help define data points

– Outcomes data to determine that the product is working

– Aid in post-marketing surveillance