1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Meeting the Challenges of Managing Hemophilia: Prophylactic vs Episodic Therapy Duc Q. Tran, MD Winship Cancer Institute, Emory University, Atlanta, Georgia 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 Disease Characteristics Hemophilia is an X-linked recessive bleeding disorder caused by a deficiency of: » Hemophilia A: coagulation factor VIII » Hemophilia B: coagulation factor IX Severity depends on coagulation factor activity levels: » Mild disease: greater than 5 IU/dL but less than 40 IU/dL » Moderate disease: between 1 and 5 IU/dL » Severe disease: less than 1 IU/dL Prevalence: » Hemophilia A: 1 in 5,000 male live births » Hemophilia B: 1 in 30,000 male live births Tuddenham EGD, Cooper DN. The Molecular Genetics of Haemostasis and Its Inherited Disorders; 1994

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Disease Characteristics The most common morbidity of patients with severe hemophilia A or B is spontaneous joint bleeding (hemarthrosis), which primarily affects the ankles, knees, and elbows. Patients also are at risk for spontaneous soft-tissue, gastrointestinal, and central nervous system (CNS) bleeding. Recurrent hemarthroses can lead to debilitating joint disease (hemophilic arthropathy). Treatment revolves around coagulation factor replacement Srivastava A et al. Hemophilia. 2013;19: e1

4. Prophylaxis in Children © 2014 Direct One Communications, Inc. All rights reserved. 4

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Prophylaxis in Children Current treatment goal is to prevent bleeds to allow patients to have more active and fuller lifestyles. Prophylactic factor replacement therapy was first pioneered in Sweden in 1958, when patients with moderate hemophilia were found to be less likely to have chronic debilitating joint disease than those with severe hemophilia. The Joint Outcome Study in the United States and the Evaluation Study on Prophylaxis: a Randomized Italian Trial (ESPRIT), which compared prophylactic therapy with episodic treatment, showed definitive benefits with early prophylaxis. Nillson IM et al. J Intern Med. 1992;232:25

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Prophylaxis in Children Both the Joint Outcome Study and ESPRIT evaluated the use of prophylactic factor replacement in young boys who had either no or few joint bleeds. Manco-Johnson MJ et al. N Engl J Med. 2007;357:535; Gringeri A et al. J Thromb Haemost. 2011;9:700

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Prophylaxis in Children: Joint Outcome Study Results Bleeding was significantly less with prophylactic therapy compared to episodic treatment, even as the children grew older and became more active. Manco-Johnson MJ et al. N Engl J Med. 2007;357:535

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Prophylaxis in Children: Joint Outcome Study Results Final evaluation of 56 patients at 6 years old by MRI showed that 93% of patients on the prophylactic treatment arm did not have joint damage, compared to 55% of patients on the episodic treatment arm. Manco-Johnson MJ et al. N Engl J Med. 2007;357:535

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Prophylaxis in Children: ESPRIT Results Fewer bleeding episodes with less radiographic evidence of arthropathy were observed among patients on the prophylactic treatment arm, compared with those on the episodic treatment arm. Gringeri A et al. J Thromb Haemost. 2011;9:700

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Prophylaxis in Children: Joint Outcome Study and ESPRIT Data Both the Joint Outcome Study and ESPRIT showed significantly more use of coagulation replacement factor on the prophylactic treatment arm than on the episodic treatment arm. In addition to greater cost due to higher factor consumption, complications related to the placement of indwelling catheters to maintain the prescribed prophylactic regimen were more frequent on the prophylactic therapy arm in both studies. Manco-Johnson MJ et al. N Engl J Med. 2007;357:535; Gringeri A et al. J Thromb Haemost. 2011;9:700

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 Prophylaxis in Children: Canadian Tailored Prophylaxis Study Altogether, 25 boys began primary prophylaxis with 50 IU/kg of recombinant factor VIII (rFVIII) once weekly, followed by stepwise increases to 30 IU/kg twice weekly and then 25 IU/kg every other day, depending on the frequency of bleeding episodes. After 5 years, 10 of the 25 children were receiving weekly infusions, 8 were being treated twice weekly, and 7 were being treated every other day. At the end of the study, all of the children had normal joints by physical examination and minimal radiographic changes. Feldman BM et al. J Thromb Haemost. 2006;4:1228

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 Prophylaxis in Children: Canadian Tailored Prophylaxis Study Only 10 of the 25 children (40%) required indwelling IV catheters, compared with 29 of the 32 children (91%) who were on the prophylactic treatment arm of the Joint Outcome Study. All of the children in the Canadian study had follow- up MRI examinations at age 9 years, and about 50% of them showed evidence of changes in target joints. This approach resulted in a cost reduction of about 20%–25% over the first 5 years, as compared with the cost of a standard high-dose prophylactic regimen over the same 5-year period. Feldman BM et al. J Thromb Haemost. 2006;4:1228

13. © 2014 Direct One Communications, Inc. All rights reserved. 13 Prophylaxis in Children: Netherlands Intermediate-Dose Study In the Netherlands, children who started prophylaxis at the onset of joint bleeding with intermediate doses (15–25 IU/kg given 2–3 times/wk) of factor VIII used less than 0.5 units/patient per year. Outcomes were good but somewhat inferior to high- dose prophylaxis, with some increase in bleeding and greater clinical evidence of arthropathy. Fischer et al. Haemophilia. 2002;8:753

14. Prophylaxis in Adults © 2014 Direct One Communications, Inc. All rights reserved. 14

15. © 2014 Direct One Communications, Inc. All rights reserved. 15 Prophylaxis in Adults About one third of patients on primary prophylaxis choose to switch to episodic treatment as young adults. An analysis of a self-reported cohort of Danish and Dutch men with severe hemophilia A compared outcomes of those who continued on prophylaxis with those of men who switched to episodic treatment (median follow-up, 3.6 years). Although men who chose to switch to episodic treatment experienced more joint bleeding, the incidence was still less than that reported in other cohorts of adults with severe hemophilia who received episodic treatment their entire lives. Makris M. Blood Transfus. 2012;10:165; van Dijk et al. Br J Haematol. 2005;130:107

16. © 2014 Direct One Communications, Inc. All rights reserved. 16 Prophylaxis in Adults Three recent studies in adults evaluated the efficacy of prophylaxis versus episodic treatment: Those on episodic treatment who had a history of very significant joint bleeding experienced no bleeding episodes once switched to prophylaxis. Annualized bleeding rates were reduced by 99% in a second study after switching to prophylaxis, with improvements in pain and physical function. The third study (SPINART) showed a 93% decrease in bleeding rate and less severe bleeding episodes in patients on prophylaxis versus episodic therapy. Collins P et al. J Thromb Haemost. 2010;8:83; Valentino LA et al. J Thromb Haemost. 2012;10:359; Manco-Johnson MJ et al. J Thromb Haemost. 2013;11:1119.

17. © 2014 Direct One Communications, Inc. All rights reserved. 17 Prophylaxis in Adults Based on pediatric evidence and the results of pharmacokinetic studies, many adult patients with hemophilia A can probably achieve bleeding control with less than the standard 20–40 IU/kg rFVIII three times per week, since the 48-hour trough levels with this prophylactic dosing regimen are 3–6 IU/dL in recent studies. Individualizing dosing strategies will optimize the costs of factor replacement to obtain the best outcomes for these patients. Collins P et al. J Thromb Haemost. 2010;8:83; Valentino LA et al. J Thromb Haemost. 2012;10:359

18. Alloimmune Inhibitory Antibodies and Current Management Options © 2014 Direct One Communications, Inc. All rights reserved. 18

19. © 2014 Direct One Communications, Inc. All rights reserved. 19 Alloimmune Inhibitory Antibodies Alloimmune inhibitory antibodies (inhibitors) are serious complications of treatment with factor VIII concentrates and develop in about 25%–30% of patients with severe hemophilia A after a median of 14–16 days of treatment. The most significant risk factor are F8 gene mutations, especially those with large multiexon gene deletions. Black patients are more susceptible than white patients. Other risk factors include early intensive exposure to factors, polymorphisms in immune regulatory genes, and association with specific HLA class II alleles. Gouw SC et al. Blood. 2012;119:2922; Miller CH et al. Haemophilia. 2012;18:375; Gouw SC et al. Blood. 2013;121:4046; Gouw SC at al. J Thromb Haemost. 2007;5:1383; Astermark J et al. Haemophilia. 2010;16:747

20. © 2014 Direct One Communications, Inc. All rights reserved. 20 Alloimmune Inhibitory Antibodies Prophylactic therapy may afford some protection from inhibitor formation. The prospective Research of Determinants of Inhibitor Development (RODIN) study among 574 previously untreated patients with haemophilia: » Found no immunogenic difference among patients treated with plasma-derived coagulation factor products and those treated with recombinant factors. » A subgroup analysis suggested a second-generation full- length recombinant factor might have a slight increase relative risk for inhibitor formation, but there were no definitive conclusions. Gouw SC et al. Blood. 2012;119:2922; Miller CH et al. Haemophilia. 2012;18:375; Gouw SC et al. Blood. 2013;121:4046; Gouw SC at al. J Thromb Haemost. 2007;5:1383; Astermark J et al. Haemophilia. 2010;16:747

21. © 2014 Direct One Communications, Inc. All rights reserved. 21 Current Management Options Eradicating inhibitors utilizing immune tolerance induction (ITI) works in about 60%–80% of patients. Median time to tolerance is about 9–12 months. The International ITI Study randomized good-risk patients to 50 or 200 IU/kg of rFVIII 3 times/wk: » No difference between low- and high-dose regimen in time to tolerance induction or the rate of tolerance induction. » Time to negative inhibitor titer and time to normal recovery were slower in the low-dose arm. » Trial stopped early due to significantly more bleeds in the low-dose arm and futility, since the enrollment was not robust enough to determine equivalence between the arms. Hay CR, DiMechele DM. Blood. 2012;119:1335

22. © 2014 Direct One Communications, Inc. All rights reserved. 22 Current Management Options Patients who cannot have their inhibitor eradicated and have a high inhibitor titer (> 5 BU/mL) are treated with bypassing agents: » Activated prothrombin complex concentrate (FEIBA) » Recombinant factor VIIa Prophylactic treatment with either bypassing agent resulted in improved bleeding control when compared with episodic treatment. Konkle BA et al. J Thromb Haemost. 2007;5:1904; Leissinger C et al. N Engl J Med. 2011;365:1684