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Abstract 3371 Background: Acquired hemophilia (AH) is a rare (1 per 1.5 million), life-threatening autoimmune disorder characterized by autoantibodies to coagulation factor VIII (FVIII). It is associated with life-threatening bleeding and ≈20% mortality. Following approval of recombinant factor VIIa (rFVIIa) by the FDA in 2006 for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in patients with AH, Novo Nordisk agreed to monitor treatment through the IRB-approved Hemostasis and Thrombosis Research Society (HTRS) research registry, although this proved impractical outside of existing registry sites and hemophilia treatment centers (HTCs). Therefore, the Acquired Hemophilia Surveillance (AHS) Project was developed as a web-based, IRB-exempt method to collect additional rFVIIa safety data, and particularly assess for thromboembolic events (TEs) in these generally older patients. Methods: The AHS project was launched in April 2008 as a one page fax-in reporting system and in June 2008 converted to a web-based platform located at novosevensurveillance.com. AHS takes advantage of the HIPAA exclusion for collection of safety information (45 CFR μ164.512(b)(iii)(D)). Reporting HCPs were provided fair market compensation per case entry. Information on demographics, rFVIIa dosing (entered via an optional free text field) and incidence of thrombotic events was collected and reported using descriptive statistics through project completion in 2011. Results: From April 2008 through November 2011, 38 individual health care professionals submitted 99 case reports (including 65 treated with rFVIIa) via facsimile or electronic data capture interface. The reports were from both HTCs (44) and non-HTCs (48), and more commonly from centers that did not participate in HTRS (84) than did participate (8). Of the 99 patients, 41 (41%) were male and 58 (59%) were female. The mean age was 66.6 years (range 16.4 to 97.3 years). The most common underlying conditions were autoimmune (34 patients), malignancy (12 patients), and post-partum (5 patients). The mean (SD) anti-VIII titer was 154.5 (453.7) Bethesda units (BU) and the median (range) anti-VIII titer was 35(1–3789) BU. Factor VIII levels were reported for 93 of the 99 patients. Fifty-eight percent (57/99) of the subjects had reported factor VIII levels ≤ 1%. The mean (median) factor VIII level in 36 remaining patients (>1% FVIII levels) was 8.1% (4.0%) with a range of 1.8–50%. There were reported to be a mean (median) of 4.3 (2.0) discrete bleeding episodes per patient (range 0–100 episodes). Most of these episodes were spontaneous (84 patients), surgical (14 patients), or related to a procedure (12 patients). Details on specific bleeding episodes were not captured in this brief report format. No bypassing agent was indicated to have been used in 21 case reports. The use of rFVIIa was indicated in 65 case reports (83%), including 50 first-line treated cases (77%), 14 second-line treated cases (22%), and 1 with unspecified line of treatment. A bypassing agent other than rFVIIa was indicated to have been used in 13 case reports (17%). AH was reported to have been resolved in 51 cases (52%) and not resolved in 30 cases (30%). The mean (median) time to AH resolution was 7.5 (2.0) months with a range of 1–52 months. There were 5 reported deaths. The reporters affirmed that none of the 99 cases suffered an adverse event that was considered possibly/probably related to rFVIIa. Conclusion: For rare disorders or rare complications of common disorders, the standard post-marketing surveillance approach of an IRB-approved observational or product registry may have significant limitations and barriers at the site implementation level. AHS provides an innovative approach for HTCs, hematology/oncology practices, and even critical care physicians/pharmacists to capture basic surveillance data for AH patients exposed to rFVIIa. The AHS project reaffirms the safety of rFVIIa and the low rate of thrombotic complications. However, AHS lacks the detailed information available through traditional research registries at large centers, such as data on individual bleeds, treatment of individual bleeding episodes, rFVIIa dosing, time to hemostasis, and the relationship of immunosuppressive treatments to AH resolution. Disclosures: Lentz: Novo Nordisk A/S: Consultancy, Investigator Other. Tandra:Novo Nordisk Inc.: Investigator Other. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

4624 Introduction: Acquired hemophilia (AH) is a rare disorder marked by the development of autoantibodies to factor VIII. Patients typically present with bleeding and a prolonged aPTT that does not correct with mixing with normal plasma. Recombinant factor VIIa (rFVIIa) is the only FDA approved bypassing agent for treatment of bleeding in AH. The Hemostasis and Thrombosis Research Society Registry was established as an IRB-monitored web-based platform with informed consent in 1999 to support the society's research needs and monitor rFVIIa use after its FDA approval. AH surveillance was initiated in October 2006. Methods: Data on bleeding episodes entered between January 2004-November 2011 were analyzed. For each rFVIIa-treated bleed, the initial dose, total dose, mean dose per infusion, number of doses, and treatment duration were calculated. Results: Of 166 registered AH patients, 110 had bleeding episodes reported. Of 237 bleeds, 17 (7%) occurred in patients aged ≤40, 54 (23%) in ages 41–60, and 166 (70%) with age >60. The most common sites were subcutaneous (40%), mucosal (32%), muscle (20%) and joint (11%). Subcutaneous bleeds were more commonly reported in females (55% vs. 40% males) and white patients (44% vs. 27% black). Mucosal bleeds were more common in black patients (49% vs. 25%) and muscle bleeds more common in white patients (14% vs. 23%). There were 139 (59%) rFVIIa-treated bleeds (89 rFVIIa alone, 50 rFVIIa plus other agents/blood components); 127 were treated with rFVIIa first-line. There were 75 episodes (43 patients) treated with other hemostatic agents or blood components only, 21 episodes (18 patients) recorded with no treatment for the episode, and 2 episodes (2 patients) with no treatment data recorded. For rFVIIa-treated episodes, 71 were in males and 68 females; 101 were Caucasian and 30 were black. Mean (median) age at bleeding was 67 (69) years. rFVIIa-treated bleeds were spontaneous (95), traumatic (30), surgical/procedure-related (7), dental (2) or other (4). Median (IQR) initial rFVIIa dose was 90 (88–100) mcg/kg, and average dose per injection was 90 (88–99). The total dose per episode was 334 (166–1383) mcg/kg administered as 3 (2–14) injections over 1 (0–2.75) day. Median (IQR) data for rFVIIa dosing by treatment sequence, bleed location and type is described below: | | First line n=127 | Second line n=12 | Subcutaneous n=52 | Mucosa n=45 | |:--------------------- | ---------------- | ---------------- | ----------------- | -------------- | | Initial dose (mcg/kg) | 90 (87–100) | 90 (87–100) | 90 (90–97) | 90 (87–100) | | Mean dose (mcg/kg) | 90 (88–99) | 90 (90–97) | 90 (90–97) | 90 (88–99) | | Total dose (mcg/kg) | 300 (119–1345) | 577 (275–3430) | 577 (275–3430) | 300 (119–1345) | | # doses | 3 (1–13.5) | 7 (3.5–25) | 7 (3.5–25) | 3 (1–13.5) | | Duration (days) | 1 (0–4) | 7.5 (0.8–13.5) | 1.5 (0.8–4.1) | 1 (0–2.5) | | | Spontaneous n=95 | Traumatic n=30 | Other Medical Procedures n=5 | Surgery n=3 | |:--------------------- | ---------------- | -------------- | ---------------------------- | ---------------- | | Initial dose (mcg/kg) | 90 (83–93) | 93.5 (90–101) | 96 (78–100) | 90 (90–105) | | Mean dose (mcg/kg) | 90 (85–92) | 91.4 (90–100) | 96 (78–100) | 109 (100–115) | | Total dose (mcg/kg) | 290 (110–1132) | 314 (180–1430) | 900 (810–1152) | 9600 (5520–9885) | | # doses | 3 (1–12) | 3.5 (2.0–14.8) | 9 (6–12) | 88 (50–101) | | Duration (days) | 1 (0–2.5) | 1 (0.2–2.0) | 2.3 (0–3) | 10 (6–10.5) | Efficacy of rFVIIa, physician-rated for each regimen, was reported as “bleeding stopped” in 117 (85%) episodes; “bleeding slowed” in 15 (11%) episodes (stopped with other agents in 3 episodes); “no improvement” in 5 (4%) episodes (no bleed stop date identified in 4, stopped with other agent in 1), and was not documented in 1. Considering only the 4 rFVIIa treatment failures where bleeding stopped after switching to another agent, overall rFVIIa efficacy was 97%. The only thromboembolic event was transient neurologic symptoms in a 31-year-old post-partum patient after 110 doses of 90 mcg/kg every 2 hours. The neurologist reported it most likely related to eclampsia and vasculitis. Conclusions: The HTRS registry final analysis represents the 2nd largest data set in AH. While subcutaneous bleeding as a first bleed location was uncommon outside of Caucasians, it represents the most common bleed location of recorded bleeds in all race/ethnicity groups. As this registry was originally intended in part to track the safety of rFVIIa, the proportion of bleeds treated with rFVIIa (59%) and associated data derived from those bleeds may be somewhat biased and selective. Nevertheless, they are certainly indicative that rapid and safe hemostasis can be achieved with rFVIIa in an aging population with AH where thrombogenicity is of concern. Disclosures: Ma: Novo Nordisk Inc.: Consultancy, Speakers Bureau. Kessler: Novo Nordisk: Consultancy, Research Funding. Fisher: Novo Nordisk Inc.: Employment. Gut: Novo Nordisk Inc.: Employment. Cooper: Novo Nordisk Inc.: Employment.

Abstract 3372 Background: AH is a rare disorder caused by autoantibodies against factor VIII (FVIII). Patients can present with peri-operative bleeding, and a prolonged aPTT that doesn't correct with 1:1 mixing after 2 hours (37°C). The Hemostasis and Thrombosis Research Society (HTRS) Registry was established to support the society's research needs and monitor the safety of recombinant activated factor VII (rFVIIa). In October 2006, the FDA approved rFVIIa for the treatment of bleeding and prevention of bleeding during surgery in AH at 70–90 mcg/kg every 2–3 hours. In 2007, a new case report form (CRF) for capturing information about surgeries was added. Methods: Data on treatment during surgical procedures was collected from the HTRS registry surgical CRF. For each rFVIIa-treated surgery, the initial dose, total dose per procedure (prior to and post surgery), average infused dose, number of doses, and treatment duration were calculated. Queries were issued to verify any procedures lacking treatment data or where treatment was listed as “none”. Efficacy was assessed on a 4 point scale and an investigator assessed adequacy of hemostasis on the “planned regimen” immediately and at 24 and 72 hours. Results: Of 166 registered AH patients, 36 patients underwent 58 surgeries. There were 24 (43%) rFVIIa-treated procedures (17 rFVIIa only). The mean (range) age of all patients undergoing surgery was 69 (14–89), and for rFVIIa-treated patients was 77.8 (28–89). rFVIIa-treated patients were mostly female (71%) and Caucasian (59%). Approximately 33% (19/58) of all surgeries were elective, including 54% (13/24) of rFVIIa-treated surgeries. The most common procedures overall were central line placement (12), endoscopy (12) and orthopedic (5). rFVIIa-treated surgeries included: central venous access (6), endoscopy (5), incision, drainage and grafting of hand hematomas (3), AVM embolization (2), orthopedic procedures (2) cholecystectomy (1), colon biopsy (1), catheter removal (1), exchange of prostate brachytherapy implant (1), venipuncture (1) and IVC filter placement (1). rFVIIa was used pre-op in 19 procedures and post-surgery in 15. In 9/24 procedures (8/24 pre-op), a single rFVIIa dose was used. Median (range) for rFVIIa treatment is described in the table below: rFVIIa efficacy was rated as excellent/good in 17 (77.3%), fair/partially effective in 2 (9.1%), and poor/ineffective in 3 (13.6%). For those rated fair/partially effective, one received only one pre-op rFVIIa dose of 75 mcg/kg with antifibrinolytics (no post-surgery treatment) and the other received 1 pre-op and 2 post-op rFVIIa 106 mcg/kg doses at 2 hour intervals with no other treatments. For those rated poor/ineffective, one received rFVIIa and PRBCs only, one received rFVIIa 81 mcg/kg initially every 4–6 hrs then plasma-derived activated prothrombin complex concentrate (pd-aPCC) then rFVIIa, and one had resolution of a neck hematoma with rFVIIa (subsequently switched to pd-aPCC) but could not maintain an airway and was transferred to hospice. No thromboembolic events were reported in rFVIIa-treated patients. Two patients underwent 6 follow-up procedures during ongoing post-op rFVIIa-treatment. Eleven patients used hemostatic agents other than rFVIIa in 12 surgical procedures. These included use of pd- aPCC in 5 cases (3 pre-op; 2 pre-op and post-op) and use of desmopressin in 2 cases, and recombinant FVIII in 3 cases. Blood products (FFP, PRBCs) were used post-op in 2 cases. Thirteen patients underwent 16 surgeries with no reported treatment. Conclusions: rFVIIa provided adequate hemostasis for almost all rFVIIa-treated AH surgeries at doses largely conforming to the package insert. There were no safety concerns and no thromboembolic complications reported in this population of older patients. Lack of hemostatic therapy reported for some procedures may reflect surgery as a presenting AH symptom, surgery during ongoing treatment not requiring additional treatment, or surgery performed following immune suppression/tolerization. Disclosures: Ma: Novo Nordisk Inc.: Consultancy, Speakers Bureau. Kessler:Novo Nordisk: Consultancy, Research Funding. Fisher:Novo Nordisk Inc.: Employment. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Abstract 3316 Objective: Recombinant FVIIa (rFVIIa) is indicated for the treatment of bleeding episodes in hemophilia patients with inhibitors at a dose of 90 mcg/kg every 2–3 hours, or as a single 270 mcg/kg rFVIIa dose (outside US). As patient response and bleeds are variable, treatment is often individualized by the center and by the patient/caregiver administering rFVIIa. With home treatment, it is difficult to ascertain how often patients use higher doses (>90 mcg/kg), and whether these doses are associated with increased risk of thromboembolic events (TEs). The aim of this analysis was to understand the safety of higher rFVIIa doses and the intervals to subsequent doses. Methods: Data for rFVIIa on-demand (OD) bleed treatment in inhibitor patients were obtained from 6 sources: 2 prospective randomized studies; 1 prospective observational US diary study (DOSE); the US-based Hemostasis and Thrombosis Research Society (HTRS) Registry; the international ONE Registry; and the HemoRec registry (Czech data only). Data on prophylactic (PPX) rFVIIa use was obtained from 3 sources: 1 prospective randomized trial; 1 retrospective chart review study (PRO-PACT); and the HemoRec registry (Czech data). Data on intervals between high initial/subsequent doses and any further bypassing agent dose in OD treatment were analyzed from 3 sources that reported time of administration (DOSE, ONE and HemoRec). All studies had data safety monitoring in the form of explicit surveillance, positive affirmations of lack of adverse events, or chart reviews. Overlap in patient participation in studies could not be ruled out; however, all data are believed to be non-overlapping due to study timelines. Demographics, rFVIIa dosing, and frequency of TEs were analyzed and reported using descriptive statistics. Results: A total of 481 inhibitor patients reported using 61,734 rFVIIa doses either for OD treatment or PPX. Most patients had hemophilia A (87%) and were Caucasian (79%). Age ranged from 18y). All data sources included the use of rFVIIa doses higher than current US-recommendations. Overall, 52.2% of doses (45.9% in adults) were >120 mcg/kg, the highest dose referenced from previous clinical trials in the US package insert. For the152 patients from DOSE, ONE and HemoRec included in the dosing interval analyses, age ranged from 18y). Patients received 3,042 rFVIIa doses for 1,017 bleeds. These included 361 initial rFVIIa doses (36%) >240 mcg/kg, including 136 followed by a second dose of bypassing agent (130 with rFVIIa; 15 with pd-aPCC). There were 670 doses >240 mcg/kg used throughout treatments (22%), including 327 followed by a subsequent dose (311 with rFVIIa; 23 with pd-aPCC). Most subsequent doses (79%) occurred after >8 hrs. Conclusions: A review of 61,734 cumulative rFVIIa doses in studies with explicit safety monitoring demonstrates the use and safety of rFVIIa doses >90 mcg/kg in inhibitor patients. When doses >240 mcg/kg were followed by other bypassing agent doses, the dosing interval was >8 hrs after 79% of doses and >24 hrs after 53% of doses. Unlike MedWatch and passive surveillance where underreporting is common, we expect that the explicit surveillance in these studies would adequately identify TE events. Thus, the lack of TEs supports the overall low TE occurrence (0.28%) reported in the original registration trials in inhibitor patients using ≤90 mcg/kg. These data reinforce that the arterial thrombosis risk identified in meta-analyses outside of licensed indications (critical bleeds) are unique to those populations and do not apply to inhibitor patients. Furthermore, higher doses may provide an opportunity to improve bleed treatment with less frequent injections and decreased follow-up infusions. Disclosures: Shapiro: Novo Nordisk inc.: Consultancy, Research Funding, Speakers Bureau. Off Label Use: rFVIIa use in indicated population of congential hemophilia with inhibitors at doses that differ from those in the prescribing information. Neufeld:Novo Nordisk Inc.: Consultancy, Research Funding. Blanchette:Novo Nordisk: Consultancy. Chambost:Novo Nordisk: Consultancy. Salaj:Novo Nordisk: Consultancy. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Abstract 3374 Background: Acquired hemophilia (AH) is a rare disorder marked by the development of autoantibodies to factor VIII, with associated mortality of 8–22%. Patients present with bleeding episodes or unexpected bleeding at surgery, and a prolonged aPTT that does not correct with 1:1 mixing (2 hrs, 37°C). While the antibody often resolves with immunosuppression, most patients will need hemostatic treatment with bypassing agents including rFVIIa (NovoSeven RT) to resolve bleeding episodes or prevent bleeding during surgery. Methods: Data were analyzed from the HTRS registry (January 2004 – July 2011), supporting rFVIIa post-marketing surveillance, including data entered during the past 2 years on acute bleed and new surgical case report forms. Results: Of 154 identified AH patients, 99 had 217 reported bleeds and 35 underwent 56 surgical procedures. There were 125 (58%) rFVIIa-treated bleeds: 82 rFVIIa alone, 43 rFVIIa plus other agents/blood products, and 107 (86%) first-line rFVIIa therapy. For rFVIIa-treated bleeding episodes, 65 (52%) were in males and 60 (48%) in females; 85 were in white-non Hispanics and 24 (19%) in black non-Hispanics. Mean (median) age at bleeding was 66 (68) years. Median (range) of recent inhibitor titer was 16 (0–620) BU. Bleeds were spontaneous (85), traumatic (27), surgical/procedure-related (7), dental (2) or other (3). rFVIIa bleed treatment over a median 1 (range 1–60) day(s) are shown below: Efficacy of rFVIIa (physician-rated for each regimen), was reported as “bleeding stopped” in 105 (84%) episodes; “bleeding slowed” in 14 (11%) episodes (stopped with other agents in 3 episodes); “no improvement” in 5 (4%) episodes (no bleed stop date identified in 4, stopped with other agent in 1), and was not documented in 1. Excluding the 4 rFVIIa treatment failures where bleeding stopped after switching to another agent, overall rFVIIa efficacy was 97%. The only thromboembolic event was in a post-partum patient with transient neurologic symptoms. Of 56 surgical procedures ranging from minor procedures to major surgeries, 24 (43%) were rFVIIa-treated procedures (17 rFVIIa only). The 17 rFVIIa-treated patients had a mean (range) age of 72.4 (28–89) years, and were mostly in female and white non-Hispanic patients. Surgeries included central venous access (6), endoscopy (5), incision, drainage and grafting of hand hematomas (3), embolization of AVM (2), orthopedic procedures (2), cholecystectomy (1), colon biopsy (1), catheter removal (1), exchange of prostate treatment implant (1), venipuncture (1) and IVC placement (1). rFVIIa was used prior to surgery in 19 procedures and post-operatively in 15. rFVIIa treatment parameters are shown below: A single dose was used in 8/24 surgeries; maximum treatment was 19 days. Efficacy of any bypassing agents was rated as excellent/good or fair/partially effective in 20/24 (83%) procedures. Adequate hemostasis was achieved with planned regimens (all agents) in 16 procedures, with minor rFVIIa dose increases in 3, with additional agents in 2 (1 each PRBCs and Helixate), and “other” reported for 1. There were no thromboembolic events (TEs) reported. Conclusions: The HTRS registry now represents the 2nd largest data set reporting rFVIIa use in AH with 75% increase in rFVIIa-treated bleeds in the past 2 years, and is the only one to report data gathered on minor and major surgical procedures in AH. For acute bleeds and surgeries, median rFVIIa dosing was similar to doses recommended for routine treatment of bleeding episodes in patients with autoantibody inhibitors based on published studies. As AH surgeries are uncommon, we believe the surgeries reported relate to bleeding sites or venous access. No safety concerns were reported in this older population. As this registry was originally intended in part to track the safety of rFVIIa, these derived data may be somewhat biased and selective. Nevertheless, the data certainly indicate that rapid and safe hemostasis can be achieved for acute bleeding episodes and prevention of excessive bleeding during surgery with rFVIIa in an aging population where thrombogenicity is of concern. Disclosures: Ma: Novo Nordisk Inc.: Consultancy. Kessler:Novo Nordisk Inc.: Consultancy. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Objective To identify factors associated with growth in children on growth hormone (GH) therapy using data from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® registry. Methods GH-naïve children with GH deficiency, multiple pituitary hormone deficiency, idiopathic short stature, Turner syndrome, or a history of small for gestational age were eligible (N = 1,002). Using a longitudinal statistical approach, predictive factors were identified in patients with GHD for change from baseline in height standard deviation score (ΔHSDS) following 2 years of treatment. Results Gradual increases in ΔHSDS over time were observed for all diagnostic categories. Significant predictive factors of ΔHSDS, ranked by significance were: height velocity (HV) at 4 months > baseline age > baseline HSDS > baseline body mass index (BMI) SDS > baseline insulin-like growth factor I (IGF-I) SDS; gender was not significant. HV at 4 months and baseline BMI SDS were positively correlated, whereas baseline age, HSDS, and IGF-I SDS were negatively correlated with ΔHSDS. Conclusions These results may help guide GH therapy based on pretreatment characteristics and early growth response.

Background A primary goal of recombinant human growth hormone therapy (GHT) in children is attaining normal adult height. In this study, children with growth hormone deficiency (GHD) (including isolated idiopathic growth hormone deficiency [IGHD] and multiple pituitary hormone deficiency [MPHD]), idiopathic short stature (ISS), and Turner syndrome (TS) were evaluated for near-adult height (NAH) and percent achieving NAH within the normal range after approximately 4 years of GHT. Methods Data from the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program were analyzed for NAH from age at treatment start (ATS) (i.e., referral age as defined by age at enrollment in the study) to last clinic visit using one of the following two criteria: 1) age ≥18 years, or 2) if male: ≥16 years and height velocity (HV) -2 were GHD: 87.6%; ISS: 78.9%; TS: 65.8%. Significant negative correlations were found between ATS and NAH HSDS when analyzed by sex. Conclusions Despite a relatively advanced childhood age, the majority of GH-treated patients attained mean near-adult HSDS within the normal range (HSDS > -2). Negative correlations of ATS with near-adult HSDS indicate that an earlier age at treatment start would likely have resulted in greater adult height achieved in both male and female patients.