ALBERT

Description: Background: Intracranial hemorrhage (ICH) is a serious complication for patients with Hemophilia. In the Universal Data Collection (UDC) program (Witmer C et al., 2011), the rate of ICH in patients with hemophilia (PWH) was 3.9 per 1000 patient-years, with the majority of events (74.4%) taking place in patients with severe hemophilia. The incidence of mortality for hemophilia patients experiencing ICH approaches 20%. Prophylaxis with replacement factor remains the standard of care for PWH and is efficacious in reducing the incidence of ICH by 48% in HIV-negative, severe hemophilia patients and by 50% in severe hemophilia patients with inhibitors. Multiple investigational non-factor products are currently undergoing clinical evaluation for the treatment of Hemophilia. Given their different mechanisms of action, it is unknown if they will provide the same level of protection from ICH as the current standard of care. Aims: We aimed to estimate the sample size needed to power a clinical study adequately to detect a reduction in the risk of ICH in PWH using a hypothetical investigational agent compared to the rates of ICH observed in the UDC Hemophilia cohort. Methods: We conducted a simulated power analysis to quantify the number of patients needed to detect a reduction in risk of ICH in PWH exposed to a hypothetical investigational agent compared to the risk of ICH observed in the UDC cohort. Based on published data, we assumed an overall ICH risk of 1.9% over a 10-year follow-up (average follow-up 5 years). We assumed a risk of ICH of 1.7% over an average of 5 years in patients prescribed prophylaxis with replacement factor and a risk of mortality due to ICH within patients with hemophilia of 0.4%. We used a two-sided Z test with pooled variance and targeted the significance level of the test at 0.05 and the power at 0.8. Results: A sample size of 11,595 patients per group followed for 1 year is required to achieve 80% power to detect a 2-fold reduction in ICH risk for patients receiving investigational treatment compared to the overall observed risk in PWH receiving treatment at federally funded HTCs. Sample sizes of 13,650 would be required per group, to demonstrate a 2-fold reduction in ICH risk for patients receiving investigational treatment vs. patients prescribed prophylaxis with replacement factor. Additionally, sample sizes of 11,737 per group, would be required to achieve 80% power to detect a 2-fold reduction in the risk of ICH mortality in a population of patients treated with an investigational agent vs. patients with hemophilia under the current standard of care. Conclusions: The relatively high mortality associated with incidence of ICH, highlights a need to determine how efficacious investigational agents are in protecting from these events. However, the relatively infrequent incidence of ICH represents an obstacle for current clinical studies to adequately evaluate protection against these types of events. These analyses demonstrate that clinical trials of investigational non-factor products would require extremely large samples sizes in order to demonstrate a level of protection that is comparable or superior to that observed with the current standard of care. Additional clinical and scientific strategies will be required in order to thoroughly assess the efficacy of non-factor agents in protecting from ICH. Disclosures Gallo: Shire: Employment. Chiuve:Shire: Employment. Rowan:Baxalta: Consultancy. Valentino:Shire: Employment.

Description: Hemophilia is a rare congenital bleeding disorder that is due to the deficiency of blood coagulation factor VIII or IX. Recurrent musculoskeletal bleeding is common and bleeding into joints results in a chronic inflammatory condition termed hemophilic synovitis. This destructive process is characterized by hemosiderin deposition in the superficial and deeper layers of the synovial membrane as well as a proliferation of synovial fibroblasts and vascular cells. The hyperplastic synovium and neovascular changes are reminiscent of the histopathologic appearance observed in malignant tissues. Indeed, the benign hyperplastic synovium in patients with hemophilia displays similar invasive and destructive behaviors suggesting the possibility of analogous disturbances in growth control and locally invasive mechanisms. Iron plays a role in malignant cell growth, local invasion, and tumor progression, possibly due to changes in the expression of the proto-oncogene, c-myc. We hypothesized that iron plays a similar role in hemophilic synovitis. To explore this hypothesis, we investigated the in vitro effects of iron on the proliferation of a primary, human synovial fibroblast cell (HSFC) line and the involvement of c-myc in this process. We also examined the role of ceramide, a sphingolipid capable of inducing apoptosis in this model system. HSFC proliferation was increased in a dose-dependent fashion and c-myc expression was enhanced by ferric citrate compared to sodium citrate control. Ceramide prevented both the iron-induced increases in HSFC proliferation andc-myc expression. These results indicate that iron probably plays a role in the proliferative changes observed in hemophilic joint disease and that aberrant expression of c-myc may underlie the iron effects. Furthermore, these results suggest that there may be a therapeutic role for ceramide in reversing these changes.

Description: Hemophilia is a genetic disease due to the deficiency of blood coagulation factor VIII or IX. Bleeding is common, especially into joints where a proliferative synovitis develops resulting in a debilitating arthritis, hemophilic arthropathy. The pathogenesis of blood-induced hemophilic synovitis (HS) is poorly understood. Repeated episodes of bleeding induce synoviocyte hypertrophy and hyperplasia, an intense neovascular response and inflammation of the synovial membrane. The component(s) in blood that initiates these changes is (are) not known, although iron is often proposed as one possibility. Previously, we reported that iron promotes the proliferation of human synovial fibroblasts and increases c-myc expression in vitro (Blood2002; 100(3)912–6). Here, we describe the proliferative effects of joint bleeding following traumatic hemarthrosis in a murine model of severe, human hemophilia A. Controlled, blunt trauma to the right knee joint consistently resulted in joint swelling due to a combination of bleeding and inflammation. The left, control knee was sham injured and remained normal for the duration of the experiment. Hemarthrosis resulted in acute morbidity evidenced by inactivity, weight loss and immobility. Hemosiderin was found in the synovial membrane of the right knees only. The numbers of synovial cell layers present in the membrane of the right (injured) knee increased during the experiment (figure). Expression of Ki67 in the nucleus, a marker of cell proliferation, confirmed the increase in synovial cell proliferation in membranes from the right (injured) knees. Taken together these data support the notion that iron causes aberrant gene expression and is, at least in part, responsible for the pathological findings observed in the joints of patients following bleeding and contributes to the development of hemophilic synovits. Figure Figure

Description: Background Several predisposing risk factors exist for decreased bone mineral density in patients with hemophilia increasing the likelihood of osteopenia and osteoporosis in this population. We report the findings of a study evaluating the association of vitamin D deficiency, osteoporosis and hemophilia. Objective Describe the findings of a prospective study evaluating vitamin D levels and bone mineral density in patients with hemophilia. We hypothesize that males with hemophilia have decreased vitamin D levels increasing their risk of osteoporosis along with arthropathy and periods of immobility resulting in reduced bone loading. Design/Method Males with hemophilia, age 1-66 years, were eligible for a 3 part study including: 1) data collection on basic health; 2) laboratory measurement of 25-OH Vitamin D, liver enzymes, ionized calcium, magnesium, phosphorus, parathyroid hormone (PTH), and thyroid function tests; and 3) DEXA scan. Results 86 male subjects, age 2-64 years (mean: 19.9, median: 15.0) including 69 (80%) with hemophilia A and 17 (20%) with hemophilia B were enrolled along with 9 (10%) with history of an inhibitor. Vitamin D levels were reduced in 51 (65%) subjects, including 23 (30%) who were vitamin D insufficient (20-29 ng/mL) and 28 (36%) who were vitamin D deficient (

Description: Introduction Prophylactic factor VIII (FVIII) administration is the standard of care for patients with severe hemophilia A; however, frequent injections are required to maintain protective factor levels. To reduce injection frequency, we developed a long-lasting recombinant FVIII Fc fusion protein (rFVIIIFc) consisting of one rFVIII molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1). rFVIIIFc had a 1.53-fold higher half-life and a 36% reduction in clearance (CL) versus FVIII (Advate®) in a phase 3 study of adults and adolescents (J Thromb Haemost. 2013;11[2]:169). The Kids A-LONG study (NCT01458106) was designed to investigate the pharmacokinetics (PK), safety, and efficacy of rFVIIIFc in pediatric subjects with hemophilia A who were previously treated with FVIII products. The objective of this planned interim analysis was to determine the PK parameters of rFVIIIFc in pediatric subjects and compare these parameters to those of the subjects' prescribed FVIII products. Methods This multi-center, open-label, phase 3 study is currently enrolling previously-treated subjects aged

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: Background: The aim of FVIII prophylaxis in Hemophilia A management is the reduction of risk for any bleed events (BE) in order to preserve long-term joint health and QOL. One proposed measure of the ideal prophylactic outcome is the virtual elimination of all BE not associated with trauma and/or of spontaneous etiology. Given the wide inter-patient variance in PK parameters, long-term prophylaxis outcomes and costs of therapy, PK-guided dosing has become an attractive approach to add more precision to dosing decisions and improve outcomes. Knowledge of the appropriate FVIII trough target for each individual patient to achieve a bleed-free outcome is needed however to design the ideal personalized PK-guided regimen. Objective: Model individual FVIII trough targets for achieving ideal outcomes in hemophilia A patients prescribed PK-guided prophylaxis every third day. Methods: FVIII infusion and BE records, and PK parameters from each subject participating in the 12-month PK-guided dosing arm of the randomized rAHF-PFM prophylaxis study (Valentino et al, 2012) were used to determine the predicted FVIII level at time of each BE. Median and maximum predicted FVIII values at time of spontaneous/non-trauma BE for all sites, and for joint and non-joint sites were estimated per subject. Number (%) of subjects with any spontaneous/non-trauma BE that occurred at predicted FVIII levels (maximum value and/or median value for those with more than one bleed) above and below specific theoretical FVIII trough values was modeled. Results: Of 34 subjects on PK-guided prophylaxis with rAHF-PFM targeting 1% trough every third day, 19 (56%) had no spontaneous BE during one year observation at FVIII levels (median) above the theoretical trough value of 1%. The number (%) of subjects with no spontaneous/non-trauma BE at FVIII levels (median) above the theoretical trough value of 3%, 5%, 10%, 15% and 20% levels increased to 71%, 79%, 31 91%, 97%, and 100%, respectively (Figure 1). All 57 spontaneous/non-trauma BE occurred at predicted FVIII levels ≤30%. Figure 1 Figure 1. Conclusions: Evaluation of individual bleeding events and treatment records for this prophylaxis study population, most of which had pre-established hemophilic arthropathy, suggests that some patients may require higher trough targets to achieve an ideal outcome. Targeting a 1% trough FVIII level every 72 hrs was effective with 56% of subjects achieving a full year with no spontaneous BE. Modeling showed that targeting a 3 - 5% FVIII trough level would have led to more than 75% overall achieving zero spontaneous annual bleed rate (ABR), and that others may have benefitted from trough targets even as high as ≥15%. While this study could not necessarily account for or examine the role of differing levels of physical activity and/or arthropathy on levels of bleeding risk, modeling of FVIII levels post-infusion using individual PK parameters and infusion records along with the contemporaneous overlay of BE should provide valuable insight when designing the optimal, personalized prophylaxis regimen for patients. Valentino LA, Mamonov V, Hellmann A, et al. J Thromb Haemost 2012 Mar; 10(3): 359-67. Disclosures Spotts: Baxter Healthcare Corporation: Employment, Equity Ownership. Pipe:Baxter: Consultancy, Honoraria. Berntorp:Baxter: Honoraria. Collins:Baxter: Consultancy, Honoraria. Oh:Baxter: Employment. Valentino:Baxter: Consultancy, Employment, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; GTC Biotherapeutics: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Inspiration Bioscience: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.