Research in bleeding disorders: the importance of access to a choice of treatment for patients with Haemophilia

1. Research in bleeding disorders: the importance of access to a choice of treatment for patients with Haemophilia Flora Peyvandi Haemophilia and Thrombosis Centre, University of Milan European Haemophilia Consortium Roundtable of Stakeholders Brusseles, 7 December 2011

2. Coagulationdisorders • Rare diseaseaffects 1 out of 2.000 citizens: 230.000 individualsfor eachrare disease in Europe • 30 millionpeoplehave a rare disease in Europe • Inherited coagulation deficiencies affect 65,000 people in Europe • The most common congenital deficiency of clotting factors are: • Hemophilia A and B (the frequency is approximately 1:5.000 and 1:30.000 respectively) • von Willebrand disease (VWD) (the frequency is 1:100) • Rare coagulation Disorders (RBDS): • - the frequency is approximately 1:500,000 to 1:2,000,000 (3-5% of all the inherited coagulation deficiencies)

3. Whatisneeded Patients associations TRAINING and SUPPORT to RESEARCH EXPERTS ASSISTANCE HOSPITAL EXPERTS ASSISTANCE HOSPITAL Early diagnosis Assays development Data collection Clinical trials Guide lines Governments Companies FUNDS and COORDINATION NEW PRODUCTS

4. Research in Rare diseases: • Basic research • Novel Therapies • Genetic analysis: next generation sequencing • gene therapy • Clinical experimentation • clinical trials • Novel techniques to evaluate the efficacy of novel drugs • Development of registries • Patient registries • Drug registries

5. INNOVATIVE RESEARCH • Next-generation DNA sequencing • Gene therapy

6. Next-generation DNA sequencing New generation of DNA sequencing methods allows to sequence parts of the genome or even the entire genome at unprecedented speed and per-base costs

7. Next-gen sequencing is becoming the gold standard for the identification of causal genes for monogenic, Mendelian diseases

8. Basic Research Novel therapies

9. rFVIII PEGylated liposomes PEGylated rFVIII Progress in haemophiliatreatment Clonaggio FVIII Recombinant Era Clonaggio FIX Gene Therapy 1965 1984 1936 1968-69 1992 2005 2000/1 High-purity concentrates Plasma Recombinant 1st generation Recombinant 4th generation Cryoprecipitates Plasma-derived FVIII e FIX Recombinant 2nd e 3rd generation HIV/HCV screening Asn322 Asn 145

10. Recombinant CoagulationFactors • The most significant improvements have been the availability of recombinant forms of factors VIII and IX. • These highly purified recombinant molecules have proved to have a safety and efficacy profile that has made them the primary form of replacement factors used in the treatment of hemophilia in the developed world.

11. Safety and limitations Manufacturing processes of recombinant and plasma derived coagulation factors have dramatically decreased the risk of viral transmission in hemophilia Nevertheless, past and recent experience teaches us that pathogens will continue to emerge and reemerge Safety surveillance should not diminish • Limitations • Available only to ~30% of all hemophiliacs worldwide • Costly • Immunogenic: development of antibody 25-30% inhibitor incidence in hemophilia A • Short half-life: require frequent intravenous infusion (half-life of FVIII is 12-14 hours and FIX is ~18 hours)

12. Gene therapy Gene therapy is a technique that allows the introduction of specific genes in the cells of an individual with therapeutic intent, in order to prevent, treat or cure a disease

13. Noveltreatment options • The major aim in the development of new concentrates is the prolongation of the half-life of the clotting factors • The goal is the acquisition of concentrates once weekly at a standard dose to maintain a trough factor level above 1% Development of modified FVIII and FIX molecules with improved potency, stability and half-life • “Slow-release” delivery vehicle (eg liposomal factor) • Hydrophilic Polymer Conjugation (eg PEGylation) • Variant Protein Generation (eg Fc-fusion factors) • Inactivation-resistant variants (eg APC resistant FVIII/TFPI Inhibition)

14. Treatment Haemophilia A - Next Generation

15. Treatment Haemophilia B - Next Generation

16. GREATER AND WIDER PRODUCTS AVAILABILITY: no available treatment for at least 80% of persons with hemophilia in the world!

18. Registries and Clinicaltrials

19. ClinicalTrial Development ‘Challengesin rare diseases’ • Small populations • Diseases are chronic, progressive, serious, life-limiting and life-threatening with unmet medical needs • Highly diverse group of disorders • Natural history not well understood • No SPECIAL methods for designing clinical trials in small population, BUT less conventional approaches may be acceptable if they help to improve the interpretability of the study results

20. Many rare diseases affect only a few thousand or even fewer than one hundred patients • Under such circumstances, a trial enrolling several hundred patients may not be practical or possible • Accordingly, conduct, analysis, and interpretation of studies in rare conditions may be limited by the prevalence of the disease • Similarly, in paediatric trials it may be difficult to recruit large numbers of patients

21. Importance of Registries in Rare Diseases • Knowing the natural history of disease • Data on incidence • Collection of patients suitable for clinical trial inclusion • Effectiveness and adverse events evaluation of therapies • Treatment patterns needed for clinical trials of new tests and treatments

22. Diseases/Conditions Targeted by Designated Orphan Drugs Cote, T. Presentation to FDA Rare Disease Review Ctte. March 11, 2010 (data 2000-2006)

23. Available products for bleeding disorders WFH Registry of Clotting Factor Concentrates *phase III clinical trial 2008

24. Clinical trials in coagulation disorders

25. Orphan designations and approvals 1983-2009

26. Designating an OrphanProduct • The FDA Orphan Drug Act provides for granting special status to a product to treat a rare disease or condition upon request • The approval of an orphan designation request does not alter the standard regulatory requirements • Safety and efficacy of a compound must be established through adequate and well-controlled studies • Orphan drug designation could be asked for a previously unapproved drug or a new orphan indication for an already marketed drug • A common application for orphan designation of the same medicinal product for the same use could be apply in Europe and USA by using

27. EudraCT is a database of all clinical trials commencing from 1 May 2004. It has been established in accordance with Directive 2001/20/EC • Trialists and sponsors will have access, but only to their own entry (Tonk, BMJ 2002) Databases on clinicaltrials • This database currently contains 104,178 trials (sponsored by the NIH, other federal agencies, and private industry) • Studies listed are conducted in USA and other 174 countries

28. What needs to be done: Pharmaco-vigilance registry to evaluate long term safety of new generation products Improve the quality of products (less immunogenicity/prolongation of activity) Collaboration with regulatory agencies (novel statistical/epidemiological studies to design models for the rare diseases)

29. Europeancommissionactions Decision No 1295/1999/EC (29 April 1999) adopting a programme of Community action on rare diseases Funds: • development of databases and surveillance networks • new therapies • supportpatientsassociations Task force in 2004 (RDTF) • to assist the Commission in the prevention, diagnosis and treatment of rare diseases • provide a forum for discussion and exchange of experiences between experts Reccomendation to members (June 2009) Help to develop and implement strategies involving expertise centres at national level and consulting patients associations

30. European Commission (Health Directorate, DG Research and Innovation) and U.S. NIH to maximize scarce resources, coordinate research and avoid duplication of efforts and economic loss and time International Rare Disease Research Consortium (IRDiRC) • MEETING: • Ottobre 2010, a Reykjavik, Iceland • Aprile 2011, Washington DC, USA Seek collaboration between agencies in the world to have diagnostic tests for rare diseases and 200 new therapies by 2020 http://www.geneticalliance.org/irdirc

31. Established collaborations International Rare Disease Research Consortium (IRDiRC) Establish between European Commission and the National Institute of Health (USA) to: maximize scarce resources, coordinate research and avoid duplication of efforts and economic losses EURORDIS/NORD Partnership (associations) Founded in 2009 with the aim of: promote rare diseases as a public international health priority set key initiatives for greater cooperation joint transatlantic

32. Conclusive remarks - basic research - next generation sequencing - gene therapy new products development of modified molecules to improve potency /stability and reduce the immunogenicity to increase the safety and efficacy profile development of novel techniques to estimate the efficacy and safety of the next generation products (es. global assay to evaluate the global hemostasis) improvement and enlargement of international database - lower costs of the products, more availability