1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Expanding Therapeutic Options for Hemophilia A and B: Results of Recent Clinical Trials Holleh D. Husseinzadeh, MD Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 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 Pharmacokinetics and Safety of BAX 855 in Patients with Severe Hemophilia A In this phase I study, the mean half-life of BAX 855, a PEGylated recombinant factor VIII (FVIII) product, was 1.4 to 1.5 times greater than that of octocog alfa. Other pharmacokinetic parameters were similar to, or better than, those of octocog alfa. The mean peak thrombin concentration was elevated above baseline for > 120 hours after a single infusion of 60 IU/kg of BAX 855. No adverse events were recorded, nor did any of the patients develop FVIII inhibitors or experience thrombotic or allergic events or significant changes in their vital signs or lab values. Bevan D et al. NHF 2013, Abstract CR40

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 First Successful Gene-Transfer Therapy for Patients with Severe Hemophilia B Ten adults with severe hemophilia B received F9 gene-transfer therapy, using an adeno-associated virus as a vector, and were followed for 0.5–3 years. Of the four patients given low or intermediate doses, baseline factor IX (FIX) levels remained between 1% and 3%, resulting in prolonged intervals between prophylactic factor infusions in one patient and eliminating the need for prophylaxis in two others. All six patients given high-dose therapy had postinfusion baseline FIX levels > 3% and no longer required factor prophylaxis. Transaminitis was managed with oral prednisolone. Reiss UM et al. NHF 2013, Abstract CR24

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 Extending the Half-life of Recombinant Factor VIII with Fc Fusion Technology In the A-LONG study, 165 previously treated males 12 years and older with severe hemophilia A received prophylactic or on-demand treatment with rFVIIIFc. The annualized rate of bleeding episodes was 1.6 in patients receiving individualized, pharmacokinetically driven prophylaxis; 3.6 in those receiving weekly prophylaxis; and 33.6 in those receiving episodic treatment. Administration of just one injection of rFVIIIFc resolved 87.3% of bleeding episodes. None of the patients developed inhibitors to rFVIIIFc, and no unusual adverse events were observed. Mahlangu J et al. NHF 2013, Abstract CR38

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Extending the Half-life of Recombinant Factor IX with Fc Fusion Technology In the B-LONG study, 123 previously treated males 12 years and older with severe hemophilia B received prophylactic or on-demand treatment with rFIXFc. Over one half the patients on pharmacokinetically adjusted intervals between doses were able to be maintained on a dosing interval of 14 days or longer. The annualized rate of bleeding episodes was 1.4–3.0 in patients receiving prophylaxis, compared with 17.7 episodes in those receiving on-demand therapy. A single dose of rFIXFc was sufficient to control 90.4% of bleeding episodes. No patients developed inhibitors to rFIXFc. Powell J et al. NHF 2013, Abstract CR39

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Prophylactic vs On-demand FEIBA NF Therapy in Patients with Inhibitors Prophylactic, recurrent administration of FEIBA NF appeared to be as safe as on-demand therapy while significantly reducing all types of bleeds by 72.5% in 36 patients with hemophilia A or B who had developed inhibitors to factor replacement concentrates. Antunes SV et al. NHF 2013, Abstract CR41

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Adherence of Patients with Hemophilia A or B to Prophylactic Factor Infusions In adults, lower adherence was associated with an increased number of bleeding episodes requiring infusion of replacement factors, as well as more days of work or school missed due to bleeding episodes. Increased adherence was associated with better physical health in children but not in adults. In pediatric patients, adherence was not significantly associated with the number of bleeding episodes but was significantly associated with infection at the injection site, increased hospital stays for control of bleeding episodes, and missed school or work days due to bleeding. Vietri J et al. NHF 2013, Abstract SPI56

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Obesity Linked to Decreased Adherence to Prophylactic Factor Infusions Data were analyzed from 10,814 males 6–79 years old in the United States with hemophilia A or B. Half the population was overweight or obese. Obese patients were 20% less likely to use home infusion than were those of normal weight. The percentage of obese patients using self-infusion (44%) declined after age 40 years, no matter what the patient's severity of disease or prophylactic regimen. The increased difficulty of performing venipuncture due to excessive adiposity was thought to contribute to the low rate of adherence and decline with age. Ullman M et al. NHF 2013, Abstract OTM47

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Outcomes After Total Joint Replacement Total joint replacement resulted in improvements in range of motion and decreased pain among 28 patients with hemophilia A or B or other bleeding disorders. Goto Y et al. NHF 2013, Abstract OTM51

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Outcomes After Insertion of an Arterio- venous Fistula (AVF) for Venous Access Seventeen patients, including 2 with von Willebrand disease, 12 with hemophilia A, and 3 with hemophilia B, who had an AVF inserted for venous access were followed for 1–15 years (mean, 5 years). No patients had bleeding complications, AVF-related infection, or difficulty achieving venous access for administration of factor replacements. Fifteen patients reported "excellent" results, with continued fistula viability. Four of the 17 patients (24%), however, reported dissatisfaction with the appearance of the AVF. Tapia C et al. NHF 2013, Abstract CR35

11. Food Insecurity in Hemophilia Patients The overall prevalence of food insecurity was 16.7% among 42 children and adolescents with hemophilia, which is similar to that of the national average. Food insecurity was less prevalent among children with mild or moderate disease (5.6%) than among those with severe hemophilia (25.0%). Children who tended to be at increased risk of food insecurity were: » Older, taller, or heavier than the other children; » Had a higher body mass index (BMI); or » Belonged to a minority. © 2014 Direct One Communications, Inc. All rights reserved. 11 Ziha S et al. NHF 2013, Abstract CR25