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  1. 1. Innovations – Treatments for Rare Bleeding Disorders Paula Bolton-Maggs Chair, WFH Rare Bleeding Disorders Committee 2007 Global Forum
  2. 2. Innovations? <ul><li>More information about the rare disorders </li></ul><ul><li>Improvements in current products </li></ul><ul><ul><li>Licensing </li></ul></ul><ul><ul><li>Modifications with regard to viral inactivation and half-life </li></ul></ul><ul><li>New products in development </li></ul>
  3. 3. WFH Data on Rare Bleeding Disorders <ul><li>Global surveys begun 1998 </li></ul><ul><li>First report 1999 </li></ul><ul><li>Now annual </li></ul><ul><li>Seeks information on </li></ul><ul><ul><li>Basic demographics </li></ul></ul><ul><ul><li>Resources for care and treatment </li></ul></ul><ul><ul><li>Prevalence of infectious complications (HCV, HIV) </li></ul></ul>
  4. 4. WFH Global Survey Data Each year questionnaires are sent to national haemophilia associations linked with the WFH with the request that they in turn work with physicians or health officials, as necessary, to complete the survey. The WFH reviews the completed questionnaires for inconsistencies, which are clarified where possible by communicating directly with the participating organization. The quality of the data from different countries is variable WFH Data on Rare Bleeding Disorders
  5. 5. <ul><li>“ Enhance Access to Treatment for von Willebrand Disease, Rare Factor Deficiencies, and Inherited Platelet Disorders… </li></ul><ul><li>we will: </li></ul><ul><li>Improve diagnosis and enhance data collection on their prevalence by country; </li></ul><ul><li>Collaborate with regulators and industry to enhance access to safe treatment; </li></ul><ul><li>Expand training, educational materials, and web-based resources; </li></ul><ul><li>WFH Strategic Plan, 2006 - 2010 </li></ul>WFH Data on Rare Bleeding Disorders
  6. 6. New Global Survey questions for 2005 WFH Data on Rare Bleeding Disorders For 2006: split into GT, BSS and other       B14j. Other hereditary bleeding disorders: type unknown       B14i. Other hereditary bleeding disorders: platelet disorders       B14h. Other hereditary bleeding disorders: Factor XIII deficiency       B14g. Other hereditary bleeding disorders: Factor XI deficiency       B14f. Other hereditary bleeding disorders: Factor X deficiency       B14e. Other hereditary bleeding disorders: Factor VII deficiency       B14d. Other hereditary bleeding disorders: Factor V+VIII deficiency       B14c. Other hereditary bleeding disorders: Factor V deficiency       B14b. Other hereditary bleeding disorders: Factor II deficiency       B14a. Other hereditary bleeding disorders: Factor I deficiency       B13. von Willebrand disease       B12. Hemophilia, type unknown       B11. Hemophilia B       B10. Hemophilia A Number of persons Diagnosis
  7. 7. 2006 WFH Global Survey Summary 56 Number of countries using national registries 175,530 Total number of people with bleeding disorders 19,689 Number of people with other bleeding disorders 48,901 Number of people with von Willebrand disease 21,334 Number of people with hemophilia B 104,597 Number of people with hemophilia A 135,475 Number of people identified with hemophilia A and B 87 Percentage of world population covered by survey 99 Number of countries in this survey
  8. 8. Data from successive WFH Global Surveys 56/99 (87%) 49/98 (88%) 40/96 (85%) National registries (% global population) 19,689 16,735 11,384 Other bleeding disorders 48,901 45,001 43,334 Von Willebrand disease 135,475 131,264 120,812 Haemophilia A + B 2006 2005 2004
  9. 10. Some issues <ul><li>Quality of data </li></ul><ul><li>Are countries reporting only cases with severe deficiency? </li></ul><ul><li>Clearly some countries are reporting mild deficiency as well as severe </li></ul>
  10. 11. Source: WFH Global Survey 2004 WFH Data on Rare Bleeding Disorders Countries Reporting >100 Patients Reflects UK register
  11. 12. Rare Bleeding disorders – Global Survey 2006 1 in 500,000 1 in 2 million
  12. 13. Variable distribution in different parts of the world
  13. 15. What products are manufactured? <ul><li>FV deficiency : no concentrate – use virally-treated FFP </li></ul><ul><li>Octaplas – pooled from approx 1500 donations, SD treated, sourced from Austria, Germany and USA </li></ul><ul><li>Methylene-blue treated single donor units UK </li></ul>
  14. 16. Fibrinogen Treatment products <ul><li>Unlicensed virally inactivated concentrates </li></ul><ul><ul><li>CSL Behring </li></ul></ul><ul><ul><li>SNBTS </li></ul></ul><ul><ul><li>LFB </li></ul></ul><ul><li>Half life 3-5 days </li></ul><ul><li>Tranexamic acid </li></ul><ul><li>Cryo is a good source but not virally inactivated </li></ul>
  15. 17. Treatment for FII <ul><li>Beriplex PN (CSL) contains II, VII, IX and X </li></ul><ul><li>DEFIX HT (SNBTS) contains II, IX and X </li></ul><ul><li>Prothromplex T (Baxter) with factor VII </li></ul><ul><li>Kaskadil (LFB) with VII </li></ul><ul><li>Octaplex (Octapharma) with VII </li></ul>
  16. 18. Treatment Products FVII <ul><li>rVIIa is the treatment of choice although little data </li></ul><ul><li>Factor VII concentrates (LFB and Baxter) </li></ul><ul><li>Factor IX concentrates containing FVII </li></ul><ul><li>(FFP) </li></ul><ul><li>A level of 10-15 u/dl is probably sufficient for surgery </li></ul>
  17. 19. Factor X Treatment Products <ul><li>No factor X concentrate </li></ul><ul><li>Intermediate purity Factor IX concentrates </li></ul><ul><ul><li>Increased risk of thrombosis </li></ul></ul><ul><li>(FFP) </li></ul><ul><li>A level of 10-25 u/dl is probably sufficient for surgery </li></ul><ul><li>People with levels >10 u/dl probably require no replacement therapy </li></ul>
  18. 20. Therapeutic options in FXI deficiency <ul><li>Fresh frozen plasma (Virally treated) </li></ul><ul><li>Factor XI concentrates (BPL, LFB) but thrombogenic </li></ul><ul><li>Fibrinolytic inhibitors – very effective for dental extractions </li></ul><ul><li>Fibrin glue – main experience in Israel </li></ul><ul><li>Desmopressin - unconvincing </li></ul><ul><li>rVIIa – risk of thrombosis </li></ul>
  19. 21. Factor XIII deficiency <ul><li>Prophylaxis – long half life 11-14 days </li></ul><ul><li>Pasteurised plasma-derived concentrate available from CSL Behring (Fibrogammin-P) </li></ul><ul><li>Give 1000 units every 5-6 weeks which raises level to 30-35 u/dl (NB assay problems) </li></ul><ul><li>Platelets contain FXIII and in an emergency may be useful. </li></ul>
  20. 22. What innovations? <ul><li>GOOD NEWS! But it is secret </li></ul><ul><li>Several companies are developing new products for rare disorders </li></ul><ul><ul><li>rXIII (NN) </li></ul></ul><ul><ul><li>Pd V (Kedrion) and rV (Crucell) </li></ul></ul><ul><ul><li>Plasminogen concentrate for ligneous conjunctivitis (Kedrion) </li></ul></ul><ul><ul><li>rVWF (Baxter) </li></ul></ul><ul><ul><li>ADAMTS13 (Baxter) </li></ul></ul><ul><li>Companies are seeking further evidence about pharmacokinetics </li></ul><ul><ul><li>Fibrinogen concentrate (CSL Behring) </li></ul></ul><ul><ul><li>FXI concentrate (LFB) </li></ul></ul>
  21. 23. WFH Data on Rare Bleeding Disorders and Patient Registries Thank you
  22. 24. Fibrinogen products France SD Adsorption, UF, ion exchange and affinity chromatography Clottagen (LFB) 1.5g USA, Germany, Austria Pasteurised (60 o , 20h) Multiple pptn Haemocomplettan HS (CSL) (1g, 2g) Plasma source Viral steps Process Product
  23. 25. Products for FVII deficiency France SD + nanofiltration DEAE absorption and ion exchange chromatography Factor VII LFB USA, Germany, Austria, Sweden, Czech Republic Vapour heat 60 o , 10h ,190 mbar + 80 o , 1h, 375mbar New addition of nanofiltration step Ion exchange chromatography Factor VII Baxter Plasma source Viral inactivation Manufacture Product
  24. 26. Products for FX (and FII) deficiency USA, Austria, Germany, Sweden, Switzerland SD + nanofiltration Ion exchange chromatography Octaplex (Octapharma) (+VII) France SD Ion exchange chromatography, UF Kaskadil (LFB) (+VII) USA, Austria, Germany, Sweden, Czech republic Vapour heat 60 o , 10h,190 mbar + 80 o , 1h, 375mbar DEAE sephadex Prothromplex-Total (+VII) USA SD DEAE cellulose Profilnine SD (Alpha) USA, Germany, Austria Pasteurised 60 o , 10h + nanofiltration DEAE sephadex Beriplex PN (CSL) (+VII) Plasma source Viral inactivation Manufacture Product
  25. 27. Products for FXI deficiency France SD + nanofiltration Dialysis + cation-exchange chromatography Hemoleven LFB (1000u) USA Dry heat 80 o , 72h Affinity heparin sepharose chromatography FXI BPL (1000u) Plasma source Viral inactivation Manufacture Product