ALBERT

Description: AMG 531 is a novel platelet-stimulating peptibody that stimulates the thrombopoietin (TPO) receptor, and is being studied for its ability to increase production of platelets. Here we report efficacy data in nonsplenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-two nonsplenectomized patients were enrolled (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 18.3x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50-200x109/L. One patient randomized to placebo received 3 doses of AMG 531 in error and was included in the efficacy analysis as a placebo. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24-week treatment period in the absence of rescue medications. Starting at a low dose of AMG 531 and gradually increasing it, as well as reducing the dose of steroids in certain patients, contributed to lower platelet counts early in the study. Twenty-five of the 41 patients (61.0%) receiving AMG 531 achieved a durable platelet response compared to 1/21 (4.8%) receiving placebo (p

Description: Background: The patients with multiple myeloma (MM) have an increased risk of venous thromboembolism (VTE), particularly during the induction phase of therapy. Low molecular weight heparins (LMWH) seem to be useful for thromboprophylaxis in these patients. We analyzed prophylactic efficiency of LMWH based on dose either lower or higher than 70 IU/kg of body weight. Patients and Methods: 223 patients with newly diagnosed MM were treated with induction chemotherapy consisting of vincristine, doxorubicin and dexamethasone (VAD) or vincristine, idarubicin and dexamethasone (VID) as a part of multicenter CMG 2002 trial. The first cohort of 137 patients received no systematic thromboprophylaxis. After a high incidence of thrombotic complications has been reported, the thromboprophylaxis with different doses of LMWHs was used in 86 consecutive patients for 4 months of induction therapy. Finally, 101 patients enrolled to the CMG 2002 trial in single centre were analyzed retrospectively, based on dose either lower or higher than 70 IU/kg of body weight. From this 101 patients 34% (34/101) received no systematic thromboprophylaxis, 38% (39/101) received LMWH (dalteparin) daily dose lower than 70 IU/kg, and 28% (28/101) received LMWHs daily dose higher than 70 IU/kg. The efficacy and safety of this treatment were analyzed. The chi-square test was used for statistical analysis. Results: Incidence of VTE was significantly reduced in the group of 86 patients receiving the recommended thromboprophylaxis, as compared to 137 patients without prophylaxis (1.2% vs. 12.4%, p=0.003, risk reduction 11.25%). Single centre analysis showed that no VTE was developed in the group of 28 patients receiving more than 70 IU/kg of LMWH daily. It was significantly different from the 34 patients without prophylaxis (0% vs. 15%, p=0.002). The incidence of VTE in 39 patients with LMWHs daily dose lower than 70 IU/kg was reduced to 7.6%, which is still clinicaly significant as compared to cohort of 28 patients receiving more than 70 IU/kg of LMWH daily (0% vs. 7.6%, p=0.05). No case of major bleeding was developed in any group. Conclusions: Thromboprophylaxis with LMWHs is effective in patients with newly diagnosed multiple myeloma during the induction chemotherapy only if the LMWH dose is sufficient. Our date shown that minimal sufficient dose seems to be more than 70 IU/kg of LMWH daily, as in this cohort of patients no case of VTE was developed.

Description: AMG 531 is a novel thrombopoiesis-stimulating peptibody that acts by stimulating the thrombopoietin (TPO) receptor. We report efficacy data in splenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-three splenectomized patients were enrolled (placebo, 21; AMG 531, 42), with a median age of 52 years (range 26 to 88) and a mean baseline platelet count 14.7x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50–200x109/L. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24 week treatment period in the absence of rescue medications. Sixteen of the 42 splenectomized patients (38.1%) receiving AMG 531 achieved a durable platelet response compared to 0/21 (0.0%) receiving placebo (p=0.0013). Overall response, defined as either durable or transient platelet response (≥4 weekly platelet responses), was observed in 33/42 (78.6%) patients receiving AMG 531, compared to 0/21 (0%) placebo patients. The mean number of weekly platelet responses (platelet count ≥50x109/L) was significantly greater in patients receiving AMG 531 (12.3/24 weeks, 51%) compared to placebo (0.2/24 weeks, 1%) (p25% their concurrent ITP medications. AMG 531 was well-tolerated. There were 2 treatment-related serious adverse events; 1 patient with elevated bone marrow reticulin that returned to baseline 3 months after withdrawal of AMG 531, and 1 patient experienced thrombosis that was successfully treated allowing study continuation. No patient developed neutralizing antibodies against either AMG 531 or endogenous TPO. In summary, AMG 531 was well-tolerated, and effectively increased and sustained platelet counts in splenectomized patients with ITP. AMG 531-treated patients required less frequent rescue medications in comparison to those receiving placebo, and were able to reduce their use of concurrent therapies.

Description: Introduction: The PK profile of VWF/FVIII concentrate is very important in the treatment of individuals with VWD since this coagulopathy is a combined deficiency of qualitative and/or quantitative VWF functions specifically and of FVIII activity indirectly. A prospective randomized, crossover study was performed to investigate the PK properties of two VWF/FVIII concentrates (Wilate® and Humate-P®) in subjects with inherited VWD. This is the first head-to-head PK study performed within the same subject, comparing two plasma derived concentrates, one a new high purity VWF/FVIII product (Wilate) and an existing first generation intermediate purity concentrate (Humate-P). Methods: This prospective, randomized, controlled, open-labeled, 2-arm crossover, multi-center study included subjects with inherited and defined VWD, who underwent PK assessments after random allocation in Period 1 to a single 40 IU VWF:RCo /kg bolus dose of either Wilate or with Humate-P. After a washout period of at least 7 days, subjects received the other study VWD replacement concentrate for Period 2. During both study periods, plasma samples were tested at multiple time points for coagulation factor activities. The objective of the study was to evaluate the PK profiles of both, including the in-vivo terminal half-life (t1/2) of FVIII:C, VWF:RCo, VWF:Ag, and VWF:CB. Results: A total of 22 subjects with inherited VWD (Type 1, n=6; Type 2, n=9 [6 Type 2A, 1 Type 2B, and 2 Type 2M]; and Type 3, n=7) were randomized in the study. The VWF PK profiles for VWF after Wilate or Humate-P were similar with no appreciable difference in the mean t1/2 for VWF activities in Type 3 and Type 1 subjects (10 hrs for Humate-P and 12.6 hrs for Wilate using the VWF:RCo assay). For VWD Type 2 subjects the mean t1/2 was longer, but with no consistent differences between the concentrates. There were no significant differences in recovery, and consequently Cmax and AUC between Wilate and Humate-P. In patients receiving Wilate, there were almost parallel decay curves and t1/2 between VWF (RCo-12.6hr) and FVIII (FVIIIC -13hr) activity. In the analysis of FVIII:C PK profiles, Humate- P showed an unusually sustained FVIII:C decay curve plateau, which may represent the net combined effects of decreasing exogenous and increasing endogenous FVIII activities in the patient and the increased FVIII:C binding capacity of the excessive quantity of non-functional VWF:Ag present in this product. There was a significant discrepancy in the mean t1/2 for FVIII:C measured in VWD Type 3 subjects (35.7 hrs for Humate-P and 13 hrs for Wilate), using either one stage or chromogenic FVIII:C assays. Conclusions: This study confirms the similarity of the VWF PK properties of Wilate and Humate-P. However, this was not the case for FVIII activity, which revealed a significantly prolonged t1/2 versus the t1/2 of VWF:RCo for Humate-P measured in type 3 VWD patients after infusion. In contrast, following infusion of Wilate there was the initial expected FVIII:C peak followed by a parallel decay curves for both VWF:RCo and FVIII:C activities. This favorable PK profile for the new high purity VWF/FVIII concentrate, Wilate, should facilitate the dosing and laboratory monitoring of VWF replacement in VWD and should improve safety and efficacy by avoiding over or under dosing of each of the two critical coagulation parameters, especially in the situation of repeated dosing of the concentrates.

Description: Abstract 3484 Poster Board III-421 Introduction Treatment of bleeding episodes in patients with congenital hemophilia (CH) can be complicated by the development of alloantibodies (inhibitors). This results in “difficult to control” bleeding episodes, which could lead to significant joint disease and decreased quality of life (QoL). As the site of treatment has moved from the hemophilia treatment center (HTC) and hospital to the home setting, the correlation between prescribed care and the way patients and their families manage their disease at home and the effects on daily life deserves attention. This analysis reports the overall results of the recently completed DOSE study. Methods Patients with congenital hemophilia with inhibitors (CHwI) with 4+ bleeding episodes in the prior 3 months who were prescribed rFVIIa (NovoSeven, Bagsvaerd, Denmark) as their first line or recommended therapy for bleeding episodes including breakthrough bleeds on prophylaxis were eligible for the study. The patients or their caregivers captured all bleed treatments, daily activities, QoL [EQ-5D, health and pain visual analog scales (VAS)], family anxiety/stress, and activity changes over a period of at least 90 days or until they captured 4 bleeds. Patients or caregivers recorded data in primary paper diaries with optional internet-based data entry. Participating sites completed registration forms with demographics, hemophilia history, and descriptions of currently prescribed care. Results There were 51 patients enrolled in this study from 18 participating sites. Mean age was 22.6 years (median 16.1), with 27.5% less than age 11, 19.6% ages 11-18, and 39.2% over age 18. The majority were white (70.6%). Mean (SD) weight was 72.4 (43.8) kg (median 61.0 kg). Nearly half (49%) had a central venous access device. The patients were diagnosed with hemophilia A (84.3%) or hemophilia B (15.7%) with inhibitors, with current severity of illnesses described as severe (76.5%) or moderate/severe (19.6%) in most patients. Mean (SD) age at diagnosis was 0.5 (0.7) years (range 0-4 years). Mean (SD) age at first bleed was 0.6 (0.9) years (range 0-6 years). Most subjects had a history of joint bleeds, with muscle, mucosal, and head bleeds also reported. Mean (SD) number of bleeds in the past year was 17.6 (15.4) with mean number of severe bleeds reported as 5.9 (9.2). There were 45.1% reported to have ever had immune tolerance. First line therapy for joint bleeds was rFVIIa in 94.1% with a mean (median) initial dose of 152.2 mcg/kg (120.0), with 33% prescribed 250-270 mcg/kg. Initial dosing for muscle and other bleeds was similar. From the enrolled population, at least 38 patients have completed paper or electronic diaries of 22-180 days duration (median 96 days). There were over 3705 total diary days captured, including 174 bleeding events and 421 bleed treatment days. On average, bleed days accounted for 7.6% of diary days (range 0-68.6%). Of the 174 bleeds, 100 were joint bleeds including 37 target joint bleeds, 19 were muscle bleeds, 4 were mouth/gum bleeds, 2 were in the brain, 1 was in the nose and 1 was in/on the skin, 31 were other. There were instances of two types of bleeds reported during the same episode. Bleed duration was reported as 2.6 (3.0) days (range 1-26). Conclusions DOSE represents the first large-scale diary study in the small population of patients with congenital hemophilia with high responding inhibitors. In this preliminary analysis of the data, there are several unexpected and previously unpublished results: 1) there is a surprisingly large number of patients with central venous access particularly when considering the mean age of the group, 2) less than half of the patients have undergone immune tolerance despite the fact that the participating centers are all established Hemophilia Treatment Centers, 3) a significant proportion of patients use doses of 250-270 mcg/kg. We expect further detailed analysis to provide valuable data and insight from which hypotheses can be generated for future studies of this rare patient population. Disclosures: Young: Novo Nordisk Inc.: Consultancy, Speakers Bureau. Off Label Use: This abstract describes dosing of rFVIIa that is higher than that in the package insert. Shapiro:Novo Nordisk Inc.: Consultancy, Speakers Bureau. Valentino:Novo Nordisk Inc.: Consultancy, Research Funding. Kessler:Novo Nordisk Inc.: Consultancy. Cooper:Novo Nordisk Inc.: Employment.

Description: Abstract 3538 Poster Board III-475 Introduction Recently, Yttrium-90 labeled anti-CD20 (90Y-ibritumomab tiuxetan, Zevalin®) has been introduced as a new therapeutic option in relapsed malignant B cell lymphoma. The results of adding 90Y-ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation(auSCT) are promising. However, the toxic impact of radioimmunotherapy to the haematopoietic microenvironment, and its effects on stem cell homing and engraftment are largely unknown. Stromal Derived Factor-1 (SDF-1α) is a key regulator of stem cell engraftment. SDF-1α has been found to co-localize with hyaluronan (HA) on human bone marrow sinusoidal endothelium and endosteum, supporting transendothelial migration of human progenitor cells and their final anchorage within specific niches of the BM. External irradiation influences levels of SDF-1α and HA. Therefore, we studied the effect of 90Y-ibritumomab tiuxetan on in vivo SDF-1α and HA levels. Patients and methods Patients with relapsed B cell NHL, treated with Zevalin-BEAM and autologous stem cell transplantation were included after obtaining their informed consent. At 3 different time points, bone marrow aspirates and peripheral blood samples of 9 consecutive patients were analysed: day -22 (before Z-BEAM), day -8 (7 days after Zevalin (0.4 mCi/kg, max. 32 mCi (n=8) or 64 mCi (n=1) (before BEAM)) and day 0 (after BEAM and before auSCT). SDF-1α and HA protein levels were determined in bone marrow and peripheral blood plasma using ELISA. Also, SDF-1α mRNA expression was quantified by real time PCR. Quality of bone marrow stroma was determined by investigating CFU-F after 1 and 2 weeks and the percentage of confluency in cultures after 1, 2 and 3 weeks. Also, in 5 patients dosimetry of Zevalin was performed. Results In 5 patients dosimetry of Zevalin was performed, by using Zirconium-89 labelled Zevalin as surrogate for PET scanning at day 0, +3 and +6 after injection. Patients received 3.4.10 * 6/kg(mean, range 1,9-8,3) CD34+ cells, and all but one showed engraftment. ANC〉0.5 10*9/l was reached at 12,8 days (range 11-15, n=9), platelets〉50 10*9/l at 18 days (range 11-38, n=8) ), being comparable with retrospective data on BEAM transplantation. In the one patient not recovering, a second transplant did not result in platelet recovery. Zevalin alone did not affect bone marrow MNC count (23,3 vs 17,4 10*6/ml, p=0.40), CFU-F capacity (colonies 〉 50 cells: 2,4 vs 8,3, p=0.35) and stromal confluency (41,9 vs 62,1%, p=0.31). In addition, the levels of SDF-1α (4584 vs 5305 pg/ml, p=0.11) and HA (227 vs 247 mcg/ml, p=0.86) were not influenced. Following BEAM, production of SDF-1α (4584 vs 6166 pg/ml, p=0.01) and HA levels (227 vs 356 mcg/ml, p=0.03), significantly increased. A corresponding increase in SDF-1α mRNA copies was observed (0.16 vs 17.2 cps % GAPDH, p=0.02), indicating that induction of SDF-1α gene expression was involved. There was a trend in decreased quality of bone marrow stroma, as determined by MNC count, CFU-F capacity and confluency. Whereas Fibroblast Growth Factor increased the confluence of stromal culture before and after Zevalin, it didn't overcome the harmful effect of the BEAM chemotherapy. Conclusion 90Y-ibritumomab tiuxetan alone did not effect the bone marrow environment as measured by SDF-1α and HA. As expected, significant changes were found after high dose chemotherapy. Engraftment and repopulation after Z-BEAM and auSCT was similar to standard BEAM followed by auSCT. Disclosures: No relevant conflicts of interest to declare.

Description: Angiopoietin-1 (Ang-1) and its natural antagonist Angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie2, are known to play an essential role in normal and pathological angiogenesis. However, the importance of angiopoietin signaling in the pathophysiology of hematologic neoplasias such as acute myeloid leukemia (AML) remains to be elucidated. We investigated the expression of Ang-1, Ang-2 and Tie2 by immunohistochemical analyses in bone marrow biopsies of 64 adult patients with newly diagnosed AML and correlated angiogenic factor expression with clinicopathological variables and long-term survival. Expression of Ang-2 was significantly increased in the bone marrow of AML patients (median [interquartile ranges]: 4.7 [3.3 – 5.7] AU [arbitrary units]) as compared with 16 control patients (1.5 [1.5 – 1.8] AU; P 〈 0.0001). In contrast, Ang-1 expression levels in AML patients did not differ from those found in controls. Thus, we observed a reversal of the Ang-1 and Ang-2 expression balance in the neoplastic bone marrow (Ang-2:Ang-1 ratio: 1.73) as compared with normal bone marrow (0.51; P 〈 0.0001). Furthermore, the angiopoietin receptor Tie2 was significantly overexpressed in leukemic blasts (3.8 [2.8 – 4.9] AU vs. 1.8 [1.6 – 2.3] AU; P 〈 0.0001). Patients expressing high levels of Ang-2 showed significantly longer overall survival (OS) than those with low Ang-2 levels (52.7 vs. 14.7 months; P = 0.039). The impact of Ang-2 expression on OS was especially evident in AML patients simultaneously expressing low levels of Ang-1 (P = 0.0298). Multivariate Cox regression analysis revealed karyotype and Ang-2 expression as independent prognostic factors for OS (hazard ratio [CI]: 3.06 [1.39 – 6.70] and 0.31 [0.14 – 0.69], respectively; P 〈 0.01). In conclusion, these data provide evidence that the alteration of angiopoietin balance in favor of Ang-2 may play a critical role in the pathophysiology of AML. Furthermore, high pre-therapeutic bone marrow Ang-2 levels indicate a favorable prognosis in polychemotherapy treated AML by a yet unknown mechanism.

Description: To define conditions for improved efficiency of retroviral-mediated gene transfer and expression in primate progenitor cells, four rhesus monkeys were treated with a 200 mg/kg intravenous bolus of 5- fluorouracil (5-FU). The kinetics of hematopoietic suppression and recovery were assessed in peripheral blood, bone marrow mononuclear cells, and bone marrow cells fractionated in an albumin density gradient. Bone marrow mononuclear cells were transduced with N2, a retroviral vector carrying the bacterial neomycin phosphotransferase gene (NPT), which confers resistance to the otherwise toxic neomycin analogue, G418. Circulating colony-forming units-granulocyte-macrophage (CFU-GM) disappeared at 2 days. CFU-GM, transducible CFU-GM, CD34+ cells, and the percent of cells in cycle decreased at 3 days in unfractionated bone marrow cells and in a light density population known to be enriched for these progenitors and for stem cells. NPT activity in the light-density fraction, marginally detectable before treatment, disappeared at 3 days as well. At day 7 the CFU-GM plating efficiency, the CD34+ cell content, and the percentage of cells in cell cycle began to increase in the light-density fraction. The NPT assay became faintly positive again but the CFU-GM were not yet transducible, implying that it was an earlier progenitor population that was dividing and differentiating. By day 15, there was a marked rebound in all of the progenitors measured, and transduction efficiency assessed by G418R CFU-GM and NPT assay rebounded to several times pretreatment levels. The data suggest that CFU-GM are optimally transduced at 15 days but that earlier progenitors are more likely cycling and transducible before 5 days, a time when a gene transfer experiment would probably have the best chance to succeed.

Description: In 1999, recombinant factor VIIa (rFVIIa, NovoSeven®) received FDA approval with recommended dosing of 90 mcg/kg every 2 hours. Individual case reports and small series have described the use of rFVIIa at doses ≥ 270 mcg/kg and 3 randomized trials have suggested that one bolus dose of rFVIIa at 270 mcg/kg provides equivalent efficacy and safety when compared to the conventional regimen of three doses of 90 mcg/kg over 6 hrs. The extent to which higher doses of rFVIIa have been used in clinical practice in the US is unknown. The HTRS registry records data regarding the treatment of acute bleeding episodes in those with hemophilia A or B and related hemorrhagic disorders with special emphasis on outcomes in individuals with congenital hemophilia complicated by alloantibody inhibitors; From over 5,000 evaluable bleeding episodes reported between January 2004 and March 2008, all episodes treated with at least one dose of ≥ 250 mcg/kg rFVIIa were examined for their initial and total dose, number of doses, and number of days on rFVIIa therapy. The efficacy of two treatment regimens was assessed: an initial high dose ≥250 mcg/kg followed by “as needed” lower doses; some of these only required a single high dose; and initial smaller doses of rFVIIa or aPCC followed by a≥250 mcg/kg dose for salvage. Of 2,532 bleeds treated with rFVIIa, 153 bleeds treated with at least one dose ≥ 250 mcg/kg were reported in 21 individuals with either congenital hemophilia A (n=17) or B (n=4) with alloantibody inhibitors. These 153 bleeding episodes required 1642 doses of rFVIIa of which 358 doses were ≥ 250 mcg/kg. The mean patient age was 12.6 years (0.9– 41.7 years). Mean titers of anti-FVIII and anti-FIX alloantibodies were 104.6 BU (0–683) and 0.9 BU (0–5.6), respectively. Bleed sites were in joints (102 bleeds, 67%), muscles (31 bleeds, 20%), mucosal surfaces (7 bleeds, 5%), and subcutaneous areas (6 bleeds, 4%). Bleeds were treated mainly in the home (78%). Of 153 bleeding episodes treated with at least one dose ≥ 250 mcg/kg rFVIIa, 80 had at least one dose ≥ 270 mcg/kg, and 49 had at least one dose ≥ 300 mcg/kg. For the whole group, mean (median, range) total dose was 1835 (867, 250–27323) mcg/kg with 10.4 (4, 1–201) doses over 3.8 (2.0, 1–79) days. Half of the doses received for these bleeds were ≥ 250 mcg/kg, and 79.1% had an initial dose of ≥ 250 mcg/kg. For those receiving a dose of ≥250 mcg/kg, there were 14.5 (4, 1–157) doses prior to the dose of ≥ 250 mcg/kg. Efficacy was 90% in 147 bleeds where rFVIIa was used as primary treatment and 100% in 6 bleeds where rFVIIa was used after a mean 154 U/kg (2.0 doses) of aPCC. Efficacy was 90% for joint bleeds and 94% for muscle bleeds. There were 15 episodes of presumed efficacy where documentation did not indicate bleeding stopped, but no other medications were recorded, resulting in adjusted overall efficacy of 100%. There were 9 patients with 23 bleeding episodes treated with a single dose of ≥ 250 mcg/kg, including mostly joint bleeds (10 spontaneous, 7 traumatic), and mostly home treatment (21). Dosing was 307 ± 62.1 (300, 250–500) mcg/kg and in 91% physicians reported “bleeding stopped” (remaining 2 had no other doses or medications). Cumulative exposure in this group was 157 doses of 250–269 mcg/kg, 70 doses of 270–299 mcg/kg, and 131 of 300–500 mcg/kg. There were no serious adverse drug related events or thrombotic complications reported after treatment of these bleeding episodes. The 2004–2008 data from HTRS provides the largest single source of data on the safety and efficacy of higher doses of rFVIIa administered to reverse moderate to severe bleeds in a broad cohort of inhibitor patients with hemophilia. Efficacy was consistent for both intra-articular or muscle bleeds in a home setting and rFVIIa was an effective single hemostatic agent in this context so the administration of additional replacement products was unnecessary. Importantly, rFVIIa ≥250 mcg/kg was not associated with any serious adverse drug reactions or thrombogenicity. These data support the feasibility of an initial high dose of rFVIIa for treatment of bleeds in inhibitor patients and justifies the conduct of a prospective, randomized clinical trial to confirm these observations.

Description: Development of inhibitors to human FVIII (hFVIII) is a significant complication in the reversal and prevention of bleeding events in hemophilia A patients. Porcine FVIII (pFVIII) possesses low cross reactivity to anti-hFVIII antibodies. OBI-1, a recombinant B-domain deleted pFVIII, has recently been tested in a Phase II trial in patients with congenital hemophilia A and inhibitors experiencing a non-life/non-limb threatening bleed. In patients with a measurable anti-pFVIII antibody titer, dosing was initiated with a loading dose (LD) followed by up to 8 doses of 50 to 150 U/kg of OBI-1 administered at 6 hour intervals until the bleed was controlled. The PK profile of OBI-1 was assessed for the first OBI-1 infusion of each patient. FVIII levels were measured 30 minutes after each infusion. Inhibitor titers were evaluated for a minimum of 6 months after the first OBI-1 infusion. A total of 25 bleeding episodes in 9 patients were treated successfully with OBI-1. The median time from bleeding onset to treatment was 7 hours (range: 3 20 hr). OBI-1 showed a cumulative efficacy of 72% after 1 injection, 84% after 2 injections or less, 92% after 3 injections or less, and 100% after 8 or less injections. In over 40 infusions, OBI-1 was well tolerated and no drug related SAEs were observed. One case of pruritus rated as mild was easily controlled with diphenhydramine. FVIII levels measured 30 minutes after each OBI-1 infusion ranged from 〈 0.5% to 226%. They were generally lower with higher anti-pFVIII titers although all bleeds were successfully controlled. Follow up inhibitor titers are still being monitored and final results will be presented and discussed. Other investigative parameters, including vital signs and laboratory variables did not show treatment related abnormalities. OBI-1 can be given as a short infusion. It was effective in controlling all bleeds which occurred in this study and was well tolerated. The results suggest that a LD is not needed with OBI-1 treatment, and in some instances patients may have been over treated. Given the promising results in this study, additional studies are planned to optimize dose range for OBI-1 and to confirm the long term safety and efficacy of OBI-1 in the treatment of bleeds in a larger cohort of individuals with hemophilia A complicated by the presence of hFVIII inhibitors.