1. Nathan Visweshwar MD.,FRCP.,FRCPath.,FRCPC Director, Hemophilia/Hematology Program University of South Florida Tampa, FL. USA Joint bleed in hemophilia - impact on resources in developing countries

2. Disclosures Nothing to disclose

3. Outline Incidence & Prevalence Prophylaxis Vs. On-demand Pathogenesis of Arthropathy Subjective Vs. Objective bleed Role of U/S in Hemophilia Utilization of resources What is new in hemophilia?

4. A study of variations in the reported haemophilia A prevalence around the world Haemophilia Volume 16, Issue 1, pages 20-32, 21 OCT 2009 DOI: 10.1111/j.1365-2516.2009.02127.x http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2516.2009.02127.x/full#f2 Volume 16, Issue 1, http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2516.2009.02127.x/full#f2

5. Reported hemophilia A prevalence in the early 1970s for the United Kingdom was approximately 10 per 100 000 males versus 20 per 100 000 males in the United States Thirty years later the reverse is true – the prevalence in 2006 in the United States was reported as 8.0 per 100 000 males versus 20.7 per 100 000 males in the United Kingdom The literature suggests that the hemophilia A and B incidence is the same for all populations and racial groups

6. Hemophilia in developing world About 80% of patients with hemophilia live in developing countries. Only 10% are registered with HTCs Most of the patients in developing countries are receiving on-demand therapy The world Federation of Hemophilia is aiming for “treatment for all” patients with hemophilia

8. Brinkhaus, Davie & Ratnoff

9. Coagulation Cascade

10. Hemophilia time-line 1939 – Brinkhaus identifies anti-hemophilia factor- factor VIII as deficiency in Hemophilia 1952 - factor IX deficiency-Christmas disease identified 1952 - thromboplastin test developed 1958 - Nilsson in Sweden proposes primary prophylaxis 1964- coagulation cascade described

11. Plasma concentrates 1984- CDC tests on heat- treated concentrates (HIV is heat susceptible) 1985- Viral inactivated factor concentrates become available. ELISA/Western blot in use 1989- HCV identified 1991- Testing for HCV introduced 1995- In UK variant Creutzfeldt-Jacob disease 2009- Hemophilia patient with variant CJD

12. Recombinant proteins 1984- factor VIII gene is cloned 1992 - recombinant factor VIII developed 1996 - recombinant VIIa approved 1997 - recombinant factor IX 1998 - gene therapy trials in humans for factor IX deficiency 2014 - extended half-life product approved in USA 2016 – Factor VIII mimetic bispecific Ab.

13. Primary prophylaxis versus On-Demand therapy

14. Manco-Johnson MJ, et al. N Engl J Med. 2007;357:535-5.

15. Average American life span - 76

16. Duration of prophylaxis When the prophylaxis is stopped in the adult age group about one third of the patients maintain healthy joints About one third of the patients develop recurrent spontaneous joint bleeds – need to continue prophylaxis The rest may need – factor VIII concentrate according to the physical activity/ exercise

17. Financial burden to society In developing countries, because of the financial constraints, primary prophylaxis with factor VIII (costing about 300,000 US dollars) is too expensive for an average individual

18. Adherence Concerns in Adolescents for primary prophylaxis Repeated infusaport infection Denial and fear of their Hemophilia Misinformation Distrust of the medical establishment Lack of confidence in the effectiveness of medications Low self-esteem Unstructured and chaotic lifestyles Mood disorders and other mental illness Lack of familial and social support Lack of or inconsistent access to care

20. New Intervention

21. Disparity of Factor VIII level & severity Some patients with trough levels less than 1% do not bleed, whereas others bleed despite trough levels more than 3% Arthropathy develops in patients who have reported few or no joint bleeds - “micro-bleeds” can not be prevented by primary prophylaxis About 10-15% of severe Hemophiliacs are without symptoms Nearly 50% with severe Hemophilia do not have major joint symptoms High incidence of ankle arthropathy in mild and moderate haemophilia A. Ling M, Heysen JP, Duncan EM, Rodgers SE, Lloyd JV Thromb Haemost 2011; 105:261–268.

22. Rationale for individualizing haemophilia care - Sorensen B et al. Blood Coagul Fibrinolysis - 2015 Dec;26(8):849-57

23. On- demand treatment Treatment to be tailored to the individual's clinical, pharmacokinetic and pharmacodynamic characteristics Therapy be individualized and encompass all aspects of patient care that may impact QoL Blood Coagul Fibrinolysis - 2015 Dec;26(8):849-57

24. Joint pain What is perceived as a bleed by the patient on-demand therapy may be pain from other causes including pain secondary to joint complications, including synovitis, hemosiderin deposition, fibrosis of the joint and osteophytes from osteoarthritis.

25. Pain in Knee Joint space Synovium Hoffa’s fat pad Bursae Cartilage/Menisci

26. Hemophilic “Target Joint” 11-19 Yrs. - there is marked villus proliferation 20-29 Yrs. - disappearance of proliferative changes >30 Yrs. - complete atrophy with flat synovium >40yrs. - fibrosis of the subsynovial connective-tissue with penetration of fibrosis to the deeper layers of the articular cartilage occurs (Roosendaal et al., 1999).

27. Diagnostic accuracy of ultrasonography – Doria et al. 2015 Only 40% have US confirmed bleed

29. HTCs role Education of bleed detection Evaluation of early joint changes and appropriate management Preservation of musculoskeletal function Preservation of activities Effective communication between the patient, hematologist, physical therapist and orthopedic surgeon

30. Future Prolonged efficacy Higher potency Resistance to inhibitors Resistance to inactivation New products Different delivery Higher production

31. Extended half-life Fusion Fc fusion molecules Albumin fusion PEGylation (Glyco/Site-directed/Random) Modifying synthesis/delivery Single chain - fusion of heavy/light chains Liposomal delivery Polymer based delivery

32. Potentiation of factor concentrates Mutation IX – arg338ala – 776% potency Activation VIII/HC II Increased binding Mutation of Gla – domain (GGA of IX-VIIa) Post translational Sulfation/phosphorylation/glycosylation

33. Alter Immunogenicity Change protein sequence tyr2105cys/arg593cys –most immunogenic Porcine hybrid Factor VIII human/porcine hybrid

34. Prevent Inactivation Heavy/Light chain stabilization by stabilizing disulfide bonds Hybridization Human/HC II hybrid

35. Higher Production FVIII – A1 domain and B domain mutations FIX- arg338ala - increased production in cell culture

36. Gene therapy Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B Amit C. Nathwani, et al. N Engl J Med 2014; 371:1994-2004 November 20, 2014DOI: 10.1056/NEJMoa1407309November 20, 2014 (UCH/St.Jude’s)

37. Emicizumab in waterfall hypothesis - FVIII mimetic bispecific Ab. Emicizumab

38. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Published by Massachusetts Medical Society. 3 Effect of Emicizumab on Coag. screening Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. Shima, Midori; Hanabusa, Hideji; Taki, Masashi; Matsushita, Tadashi; Sato, Tetsuji; Fukutake, Katsuyuki; Fukazawa, Naoki; Yoneyama, Koichiro; Yoshida, Hiroki; Nogami, Keiji New England Journal of Medicine. 374(21):2044- 2053, May 26, 2016. DOI: 10.1056/NEJMoa1511769

39. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Published by Massachusetts Medical Society. 4 Emicizumab –efficacy 71% reported no bleeding with 1mg/kg. weekly Emicizumab

41. Intervention in hemophilia Optimal utilization of the factor concentrates can only be achieved by: Education Expedited physical therapy Evaluation of the joint for secondary complications Early intervention and prenatal diagnosis Expectant mothers (5Es).