1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Recent Advances in Preventing Bleeding, Reducing Inhibitors, and Managing Acute Bleeding Noa Biran, MD Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York 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 Introduction Hemophilia is caused by a functional or quantitative deficiency of one of the coagulation proteins: » Factor VIII in hemophilia A » Factor IX in hemophilia B Sequelae: » Musculoskeletal complications caused by uncontrolled or unrecognized bleeding into joints and muscles » Development of inhibitory antibodies in approximately 25%–30% of patients with severe hemophilia A and 3%–13% of those with moderate or mild disease » Transmission of viral bloodborne infections due to use of plasma-derived coagulation factor concentrates Srivastava A et al. Haemophilia. 2013;19:e1

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Current Standard Prophylactic Regimens First recombinant factor VIII (rFVIII) was approved in the US for patients with hemophilia A in 1992: » Improved the supply of factor VIII » Decreased the incidence of viral bloodborne infections » Advanced the adoption of prophylactic treatment regimens Based upon nadir factor levels accomplished with regularly scheduled infusions. Specific prophylactic regimens to achieve optimal bleed suppression and prevention vary. Poor adherence with demanding regimens, especially in adolescent patients, is frequent. Schrijvers LH et al. Haemophilia. 2013;19:355

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 A-LONG Study: Bleeding Tendency Relates to FVIII Activity In this prospective clinical trial, 180 patients with severe hemophilia A were treated with a recombinant FVIII crystallizable fragment (Fc) fusion protein. Multivariate regression analysis showed that the more time the patients had a FVIII activity level < 1 IU/dL, the fewer overall bleeding episodes they experienced. A significant association also was found between the length of time in which patients had a FVIII activity level < 1 IU/dL and the type of bleeding they had. The results reinforced the importance of a therapeutic threshold of 1 IU/dL of FVIII activity. Pasi J et al. ASH 2013, Abstract 3590

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Long-Lasting rFIXFc Is Safe and Effective in Adolescents with Hemophilia B This planned subgroup analysis examined whether patient age affects the pharmacokinetics, safety, and efficacy of a recombinant FIX crystallizable fragment (Fc) fusion protein (rFIXFc). In all, 123 patients were enrolled in the B-LONG study at 50 study centers. Median duration of treatment was 51.4 weeks. Pharmacokinetic parameters, safety profiles, and annualized bleeding rate were similar in adolescents and adults. Shapiro A et al. ASH 2013, Abstract 2350

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Joint Outcome Study: Delayed Prophylaxis Has Long-Term Effects Included boys with severe FVIII deficiency Compared prophylaxis with an enhanced episodic treatment regimen given only in response to bleeding At age 6, patients were discontinued from the study, and joint outcome was assessed by sensitive MRI and physical examination of six index joints. Following delayed initiation of prophylaxis, adolescents manifested increased numbers of hemarthroses and increased MRI damage. MRI was more sensitive than joint physical examination in determining joint outcomes. Manco-Johnson MJ et al. ASH 2013, Abstract 210

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Sensitivity of MRI for Detecting Hemophiliac Joint Disease Data from 275 patients with severe hemophilia A who received on-demand therapy in three studies (Joint Outcome Study, SPINART, and Cross- Sectional MRI Study) were aggregated into a single database. MRI data for knees and ankles were analyzed. MRI scores—in contrast to bleeding rates and Gilbert scores—showed continued age-related deterioration. Joint bone and cartilage abnormalities increased continuously across the age span despite an early leveling in bleeding rate and joint physical function. Glorioso TJ et al. ASH 2013, Abstract 209

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Reducing the Incidence of Inhibitors: Early Low-Dose Prophylaxis The EPIC Study aimed to assess prospectively if a prophylactic regimen started before 1 year and before the onset of a joint bleed, together with minimization of immunologic danger signals, could reduce the incidence of inhibitor formation. In all, 22 patients with severe hemophilia A enrolled. The study was terminated based on a futility analysis: » A total of 67 major protocol deviations were reported in 15 patients. » These deviations contrasted with the intention of the study protocol, which was to minimize immunologic danger signals using an early low-dose prophylactic regimen. Auerswald G et al. ASH 2013, Abstract 576

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Prompt Immune Tolerance Induction at Inhibitor Diagnosis Affects Outcome Data were collected retrospectively from two hemophilia centers in the United States on 58 male patients with severe/moderate deficiency of factor VIII undergoing immune tolerance induction (ITI). Success rate depended on the time interval from inhibitor detection to the start of ITI: » Of the 23 patients who started ITI within 1 month of detection, 91% achieved success. » All 13 patients starting ITI with a pre-ITI inhibitor titer ≥ 10 BU achieved success. » Of the 11 patients who started ITI 6 months after detection of inhibitor, only 64% achieved success and 36% failed. Nakar C et al. ASH 2013, Abstract 575

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Management of Acute Bleeding with Four-Factor Prothrombin Complex The efficacy and safety of a single dose of four-factor prothrombin complex (4F-PCC) was compared with plasma in patients requiring vitamin K antagonist reversal prior to an urgent surgical procedure. Effective hemostasis was achieved in 89.7% of patients in the 4F-PCC group versus 75.3% in the plasma group, demonstrating both noninferiority and superiority of 4F-PCC over plasma (14.3% difference; 95% confidence interval, 2.8–25.8) The frequency of death, serious adverse events, and thromboembolic events was similar in both groups. Refaai MA et al. ASH 2013, Abstract 3888

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 Conclusion Advances in hemophilia are the result of parallel advances in the development of replacement therapies and use of MRI, as well as the use of prophylactic regimens. Prompt immune tolerance induction may increase success rate of prophylactic therapy in patients with hemophilia A who develop inhibitors. In settings where rapid correction of coagulopathy is required, PCCs may offer some advantages over plasma. Ongoing studies are crucial for continued improvement in the quality of life and decreased cost of care for patients with hemophilia.