1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Hemophilia A and B: Disease Differences and the Use of Prophylactic Therapy Anna Chalmers, MD Rush University Medical Center, Chicago, Illinois A REPORT FROM THE 65 TH ANNUAL MEETING OF THE NATIONAL HEMOPHILIA FOUNDATION (NHF 2013) AND THE 55 TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY (ASH 2013)

2. © 2014 Direct One Communications, Inc. All rights reserved. 2 Similarities and Differences Hemophilia A and B are X-linked, recessive disorders caused by a deficiency or absence of coagulation factors VIII (FVIII) and IX (FIX), respectively. They are clinically indistinguishable. Not until 1952 was hemophilia B recognized as a separate disease entity. Hemophilia A and B have different causal mutations; as a result, 35% of patients with hemophilia B have severe disease, compared with 45% of patients with hemophilia A. Soucie JM et al. Blood. 2000;96:437

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Similarities and Differences Hemophilia A and B have different pharmacokinetics. The half-life of FIX if 18 hours, compared with 11 hours for FVIII. As a result, post-infusion levels of FIX are sustained longer than FVIII levels, thereby reducing the risk of recurrent bleeding. This difference in pharmacokinetics may explain why patients with hemophilia B need joint arthroplasty at one third the rate of those with hemophilia A. Nevertheless, the treatment approach to hemophilia A and B is similar. Collins PW et al. Haemophilia. 2011;17:2; Björkman S. Haemophilia. 2003;9:101; Tagariello G et al. Blood. 2009;114:779

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 Evolution of Current Treatment Multiple factor replacements are available in the United States to treat hemophilia B. Prophylaxis with factor infusions two to three times a week is the standard of care for children with hemophilia B. In March 2014, a new recombinant FIX product (Alprolix) was approved that may be infused as infrequently as once a week or every 10 days. Shapiro A. Treatment update on hemophilia B. NHF 2013; Iorio A et al. Cochrane Database Syst Rev. 2011;(9):CD003429

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 When to Start Prophylactic Therapy Starting prophylaxis at an early age is important for both hemophilia A and B, as it can lessen the risk of degenerative joint disease. The exact age to start is debated. There are multiple treatment approaches: Astermark J et al. Br J Haematol. 1999;105:1109; Donadel-Claeyssens S. Haemophilia. 2006;12:124

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 When to Start Prophylactic Therapy The approach to primary prophylaxis of hemophilia B used at Malmö Hemophilia Center in Sweden Berntorp E. Prophylaxis for hemophilia B: best practices. NHF 2013

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Optimal Dosing The optimal dosing strategy for long-term prophylaxis is hotly debated. Various prophylactic treatment strategies are used throughout the world: Berntorp E, Shapiro AD. Lancet. 2012;379:1447

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Optimal Dosing A retrospective analysis of Dutch intermediate dosing versus Swedish high-dosing found minimal added benefit, with a large increase in cost. More study is needed to compare these two options. There is interest in the feasibility of low-dose regimens, especially in resource-poor settings. In China, using low-dose prophylaxis (10 IU/kg of FVIII twice weekly for hemophilia A or 20 IU/kg of FIX once weekly for hemophilia B) reduced the number of bleeding episodes and improved joint function over a 12-week period; however, patients still experienced some joint bleeds on these doses. Fischer K et al. Blood. 2013;122:1129; Wu R et al. Haemophilia. 2011;17:70

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Continue Prophylaxis Indefinitely? Prophylaxis has dramatically improved the quality of life and reduced the risk of arthropathy in children with hemophilia; however, it is unknown if it should be continued into adulthood. At one hemophilia treatment center in the United States, two thirds of the children and one half of the adults with hemophilia B are on prophylaxis. Early retrospective data have not shown a significant difference in arthropathy scores when on-demand and prophylactic treatment are compared in adults. Prospective, randomized clinical trials are needed. Koerper M. Burden of illness and quality of life in hemophilia B: HUGS VB study. NHF 2013; van Dijk K et al. Br J Haematol. 2005;130:107

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Challenges in Implementing Prophylaxis Cost of regular replacement factor infusions. Poor adherence: patients with hemophilia B receiving standard factor replacement products require prophylaxis two to three times a week. Only 60% of hemophilia patients report infusing three fourths or more of the recommended factor. Missed doses: reasons include the complexity and time commitment of treatment. Prophylaxis also eliminates symptoms, paradoxically decreasing adherence. Patients who have little understanding of the importance of prophylactic treatment are less likely to adhere to it. Hacker MR et al. Haemophilia. 2001;7:392; De Moerloose P et al. Haemophilia. 2008;14:931; Tang L et al. Haemophilia. 2013;19:27

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 Improving Adherence Patients who are treated at dedicated hemophilia centers adhere better to their prophylcatic replacement factor regimen than those who are treated at home or an outpatient clinic. Healthcare providers can improve patient adherence to prophylactic therapy by: » Maintaining a good relationship with their patients » Reinforcing their patients’ positive belief in the importance of prophylactic treatment » Expanding their patients’ access to continuing health education about hemophilia and its treatment Hacker MR et al. Haemophilia. 2001;7:392; De Moerloose P et al. Haemophilia. 2008;14:931; Tang L et al. Haemophilia. 2013;19:27; Schrijvers LH et al. Haemophilia. 2013;19:355

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 Therapies on the Horizon New replacement factors with longer half-lives may: » Reduce the cost and inconvenience of frequent infusions » Improve adherence to prophylactic therapy by allowing significantly longer intervals between infusions » Decrease complications related to frequent venous access Gene therapy has the potential to cure hemophilia B, as a small increase in factor level can drastically improve bleeding rates. » Six patients with severe hemophilia B were treated with a virus vector that expressed factor IX; all of the patients had a decrease in their need for factor replacement, with four patients stopping prophylaxis completely. Nathwani AC et al. N Engl J Med. 2011;365:2357