ALBERT

Description: Key Points Previously untreated patients with severe hemophilia A caused by F8 null mutations show a more severe phenotype than previously untreated patients with non-null mutations. The phenotypic differences are modest, and as such not likely to affect decisions regarding when and how to start prophylaxis.

Description: Introduction Clearance of infused factor VIII (FVIII) varies approximately 2-fold between persons with severe hemophilia A. This results in significant interpatient differences in factor levels following an infusion of FVIII and contributes to potentially significant differences in protection against spontaneous musculoskeletal bleeding in patients on fixed dose prophylaxis regimens. Aim The aim of this study is to compare two PK protocols: 1) a 6-point PK protocol with a 72 hour washout; and 2) a 2-point, one clinic visit PK protocol with no washout using the following pharmacokinetic (PK) parameters: clearance (Cl) and time to FVIII:C of 1% above baseline (tt1%) in persons with severe hemophilia A. Methods Inhibitor negative males with severe hemophilia A (FVIII

Description: Introduction Three trials, F13CD-1725, F13CD-3760 and F13CD-3720 have investigated the pharmacokinetics (PK) of recombinant FXIII (rFXIII), given at a dose of 35 IU/kg once monthly, in a total of 54 patients with FXIII congenital deficiency (Inbal A et al Blood 2012;119(22):5111-5117; Williams M et al Haemophilia 2013;DOI:10.1111/hae.12224; Kerlin B et al JTH 2013;11(Suppl 2):235-236). The aim of the current analysis was to assess and compare the PK characteristics of rFXIII among trials and 3 different age groups of patients (1-

Description: Background: Although Factor VIII (FVIII) concentrates are now routinely used for the prophylactic treatment of hemophilia A (HA), the optimal doses and intervals between administrations are difficult to predict because of variable pharmacokinetics of FVIII (FVIII-PK) between patients. Previous studies in HA have revealed a close relationship between FVIII-PK and the FVIII carrier protein, von Willebrand factor (VWF). A large genome-wide association study from the CHARGE consortium highlighted several novel loci associated with plasma levels of VWF and FVIII in normal subjects, and the five genetic loci associated with FVIII levels coincided with those influencing VWF levels (Smith, 2010). Objective: To investigate the effects of VWF synthesis, clearance and genetic variability on FVIII-PK in young HA patients. We hypothesized that 1) plasma VWF:Ag levels (VWF secretion and clearance), 2) polymorphic variants within the FVIII binding region of VWF, and 3) the glycosylation pattern of VWF (N-linked and ABO blood group antigen) would influence FVIII-PK. Methods: HA males recruited at two large academic pediatric hemophilia centers (The Hospital for Sick Children in Toronto and the Medical University of Vienna) were enrolled. Blood was collected at 5 time points (pre, post FVIII-infusion: 1, 9, 24, and 48 h), and FVIII-PK parameters, clearance (CL), volume of distribution (VD) and half-life (HL), were calculated based on a Bayesian model. Plasma levels of VWF (VWF:Ag), VWF propeptide (VWFpp) and FVIII binding ability of VWF (VWF:FVIIIB) were also evaluated. Genetic analysis of the FVIII-binding region and glycosylation sites of VWF was performed. Results: Samples from 33 boys [median age 10.9 years (range 6.5-17.9)] with severe HA were evaluated. Median values of FVIII-CL, VD and HL were 0.032 dl/h/kg (range 0.018-0.062), 0.47 dl/kg (0.29-0.78), and 10.2 h (6.7-16.8), respectively. VWF:Ag, VWFpp, VWFpp/VWF:Ag ratio and VWF:FVIIIB were 86.6 IU/dl (39.9-141.6), 88.2 U/dl (43.5-156.6), 1.09 (0.33-1.71) and 70.3% (41.2-101.9), respectively. FVIII-CL (r=-0.41, p

Description: Background: Primary prophylaxis in severe hemophilia patients has been shown to improve patient outcomes and quality of life by decreasing the number of joint bleeds, lowering the subsequent risk of developing hemophilic arthropathy (Blanchette et al.Haemophilia 2010 (Suppl. 5); Ljung R. Blood Rev 2009) and by reducing the incidence of other bleeds including intracranial hemorrhages. Currently licensed factor concentrates have a relatively short half-life, and require frequent infusions for effectiveness. The intensity of this prophylaxis is difficult for most patients (particularly young children) and contributes to reduced compliance and quality of life. Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) with a prolonged half-life (up to 111 h in adolescent and adult patients) as compared to currently available standard plasma-derived and rFIX products (18-19 h). N9-GP is therefore expected to be effective in preventing bleeds when given less frequently than currently available FIX products. It is hoped that this will improve patient compliance, clinical outcomes and quality of life. Until now only adolescents and adults have received N9-GP. Given this experience a trial (paradigm™5) was undertaken to evaluate the safety and effectiveness of N9-GP in children ≤12 years of age. Aims: The primary objective of this trial was to evaluate immunogenicity of N9-GP in previously treated pediatric (≤12 years of age) hemophilia B patients (FIX≤2%) with no history of inhibitors and at least 50 exposures days (ED) to other FIX products. Key secondary objectives were to evaluate efficacy, pharmacokinetic (PK) properties and general safety of N9-GP in this group of patients. Methods: paradigm™5 was a multicenter, single arm, open label trial investigating the safety, efficacy and PK of N9-GP in this group of patients. A total of 20 children allocated to two age cohorts ≤6 years and 7-12 years (minimum 10 patients per age cohort) were required to be dosed with a prophylactic regimen of 40 U/kg N9-GP once weekly for at least 50 exposures (as per EMA guidelines), with treatment of breakthrough bleeds with 40 U/kg N9-GP (80 U/kg N9-GP for severe bleeding episodes). Results: 25 patients were enrolled and treated in the trial: 12 in the younger (0-6 years) and 13 in the older (7-12 years) age group. No patients developed inhibitors during the trial, and no safety concerns were observed in standard safety parameters and clinical evaluation. Among patients on prophylaxis prior to inclusion (N=22), the median (range) number of bleeds in the 12 months prior to inclusion was 2.0 (0–9). The median (range) annualized bleeding rate during the trial was 1.0 (0.0–6.5); 5 of the 12 younger patients (41.7%) and 10 of the 13 older patients (76.9%) reported bleeds. 72.7% of these bleeds in the younger cohort were reported as traumatic vs. 54.8% in the older age cohort. All bleeding episodes were treated with 40 U/kg N9-GP: 92.9% were successfully treated; 85.7% were treated with a single injection. PK analysis showed 1) an incremental recovery (IR) of N9-GP of 0.016 (U/mL)/(U/kg) with no difference between the 2 age groups; 2) a geometric mean single-dose half-life of 69.6 (0-6 years) and 76.3 hours (7-12 years) and 3) a faster clearance in the younger vs. older age group (0.758 and 0.650 mL/h/kg, respectively). Geometric mean FIX trough levels after the first dose of N9-GP was 0.084 U/ml in the 0-6 year age group and 0.109 U/ml in the 7-12 year age group. Estimated mean steady state trough levels (95% CI) for the younger age group was 0.154 U/ml (0.127; 0.186), as compared to 0.190 U/ml (0.159; 0.228) in the older age group. Steady state trough levels were reached after approximately 4 weeks of treatment. Conclusion: In this trial, N9-GP appeared to have a safe and well-tolerated profile. Prophylactic protection and treatment of bleeds with N9-GP in previously treated pediatric hemophilia B patients was confirmed. The PK profile of N9-GP confirmed an extended half-life and high trough levels with 40 U/kg once weekly injections in the pediatric population. As with other FIX products younger patients show lower IR, shorter half-lives and higher clearance than what is observed in adolescents and adults. Disclosures Carcao: Baxter, Bayer, Biogen, Novo Nordisk, Pfizer, CSL Behring, Octapharma: Honoraria, Research Funding, Speakers Bureau. Off Label Use: N9-GP is not yet FDA approved. Information provided will discuss phase 3 pediatric clinical trial data.. Zak:Novo Nordisk A/S: Employment. Hanabusa:Baxter Healthcare, Novo Nordisk, Bayer, Pfizer, Biogen Idec and KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Persson:Novo Nordisk A/S: Employment. Rangarajan:Baxter, Biotest, Grifols, Pfizer: Honoraria, Research Funding, Speakers Bureau. Santagostino:Pfizer, Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, Biotest: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background: Long-term prophylaxis is standard of care in children with severe hemophilia A (SHA) and B (SHB) without inhibitors. Studies have shown benefit from long-term prophylaxis in adults with SH and in both adults and children with SH and inhibitors. Yet there is little data on the prevalence of prophylaxis in these groups. Aim/Methods: To understand the current use of long-term prophylaxis in these groups of patients in countries capable of underwriting the high cost of prophylaxis we surveyed (2013) hemophilia treatment centers (HTCs) in countries where long-term prophylaxis in children is routinely used. Results: 134 HTC from 14 countries in North America, Australasia, and Western Europe reported on 4,763 adults with SH (4,011 SHA; 752 SHB) and on 751 children and adults with inhibitors. Prophylaxis use in these groups is shown in table 1: Table 1. Prophylaxis use in adults with SH (without inhibitors). Adults without inhibitors Children and adults with inhibitors HA HB In ITI setting In non-ITI setting % on Prophylaxis 59 49 29 28 Most common regimen EOD 2 d/wk FEIBA EOD or 3 d/wk FEIBA EOD or 3 d/wk EOD, every other day Adults without inhibitors: A higher proportion of SHA (59%) vs SHB adults (49%) were on prophylaxis (Χ2 p70 y (29%). There was little drop in the proportion of SHB adults on prophylaxis with increasing age. 67% of SHA adults on prophylaxis were receiving ≥3 infusions/wk while 80% of SHB adults on prophylaxis were receiving ≥2 infusions/wk. Once/wk prophylaxis was reported in 3% of SHA and by 19% of SHB patients on prophylaxis. Daily prophylaxis was rarely reported in both groups. Children and adults with inhibitors: Data was available on 407 children and 344 adults with SH and inhibitors. Table 2 shows the proportion of children and adults on/not on Immune tolerance induction (ITI) and on/not on bypassing agent prophylaxis (BA-P). Most children (78%) were on either ITI (with or without BA-P) or on BA-P alone and as such were having some bleed protection. In contrast only 28% of adults were on either ITI (with or without BA-P) or on BA-P and as such most adults with inhibitors are not on any bleed protection. Table 2. Use of ITI and of BA-P in children and adults with SH (+ inhibitors). 403 children 344 adults On ITI. Not on BA-P 43% 8% On ITI. On BA-P 17% 4% Not on ITI. Not on BA-P 23% 71% Not on ITI. On BA-P 18% 16% In total, 185 patients had received FEIBA prophylaxis while 70 had received rFVIIa prophylaxis. FEIBA prophylaxis was particularly more common (vs. rFVIIa prophylaxis) in the non-ITI setting [FEIBA (n=107 pts) vs rFVIIa (n=33 pts)]. The most common prophylactic FEIBA regimen was EOD or 3/wk while the most common rFVIIa prophylaxis regimen was daily. Conclusions: This survey captured data on 4,763 adults with SHA/SHB and on 751 adults and children with SH and inhibitors. This is the largest survey of prophylaxis in these 2 groups of patients. Given the benefits of prophylaxis in children it is reassuring to observe that prophylaxis in adults (without inhibitors) is more prevalent than previously reported. Use of BA-P in patients with inhibitors still however lags far behind the use of prophylaxis in non-inhibitor patients - particularly in adults. FEIBA is more commonly used for prophylaxis than rFVIIa. Our survey did not capture longterm patient outcome data; this needs evaluation. Note: This abstract includes data presented as separate abstracts at the ISTH 2015 meeting. The data has been combined and analyzed in this abstract to show the increasing use of prophylaxis outside of children without inhibitors. Disclosures Blanchette: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data Safety Monitoring Board; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding. Santagostino:CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Biogen/Sobi: Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Kedrion: Speakers Bureau; Biotest: Speakers Bureau; Octapharma: Speakers Bureau; Roche: Speakers Bureau. Leissinger:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Aledort:Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: DSMB Participation; Kedrion BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Hereditary spherocytosis (HS) is the most common congenital hemolytic anemia in Caucasians. Patients with HS show a high degree of phenotypic variability from asymptomatic to transfusion dependence. Much of this variability stems from HS not being a single uniform disorder but instead being a collection of disorders involving mutations in 5 different genes (ANK1, SPTB, SPTA1, SLC4A1, and EPB42 ) encoding for the 5 major cytoskeletal proteins in red blood cells (ankyrin, β and α spectrin, band 3, and protein 4.2 respectively). These proteins are responsible for maintaining the biconcave disk morphology of red blood cells. Traditionally the diagnosis of HS has been made without genetic testing. We believe that knowledge of the HS subtype may impact future clinical management decisions, e.g. what type of splenectomy to perform-partial vs total and impact on genetic counseling needs. As a result we are now pursuing genetic testing on all our patients with HS. Over the past 16 years at Sick Kids Hospital (Toronto, Canada), we have followed 257 children with HS. In the past year we have also been offering genetic testing (following informed consent) to all children (T in SPTA1 (referred to as the αLEPRA mutation) in 4 children/2 families with an α spectrin form of HS, and in another 2 children (1 family) with an ankyrin form of HS; 2) an ANK1 c.5097-33G〉A (8 children/6 families); 3) an ANK1 c.1405-9G〉A (4 children/3 families); 4) SPTB c.6037C〉T (3 children/2 families); and 5) SPTB c.5266C〉T (3 children/2 families). The ANK1 c.5097-33G〉A mutation had not been previously identified and yet was the most frequently detected mutation in our HS population. Most children (68/103) were found to have autosomal dominant (AD) HS: 33 children with the ankyrin subtype, 26 with the β spectrin subtype, 4 with the band 3 subtype and 5 in whom no mutation could be found but where there was a clear history of AD inheritance. Autosomal recessive (AR) inheritance was confirmed in 7 children - all 6 with α spectrin form of HS and 1 with a β spectrin form of HS. Twenty-eight children were spontaneous new mutations for HS: ANK (n=17), β spectrin (n=5), band 3 (n=3) and 3 in whom no mutation could be found. In all AR forms of HS, the index case had initially been thought to be a spontaneous new mutation for an AD form of HS; genetic testing resolved the inheritance pattern. Patients were categorized according to disease severity, primarily on the basis of their need for transfusions (a reflection of baseline hemoglobin) and splenectomy. The proportion of children that have required transfusions and needed splenectomies was: 83%/83% (α spectrin); 48%/18% (ankyrin), 23%/10% (β spectrin) and 29%/0% (band 3). Most children in our center undergoing splenectomy have undergone partial splenectomy; few have required subsequent total splenectomy. However, of the 5/6 children with α spectrin form of HS that underwent partial splenectomy 3 have subsequently needed, or are being considered for, total splenectomy. This suggests that due to the extreme severity of the α spectrin subtype of HS, children with this form of HS may not do well long-term with partial splenectomy and are likely to eventually require a total splenectomy. Our study to date represents one of the largest and most comprehensive genetic analyses of a cohort of HS patients. Our findings will add to the growing understanding of the disease, and will be important to provide comprehensive genetic counseling and possibly in the future to guide management of selected cases. Disclosures Drury: Prevention Genetics: Employment.

Description: Introduction Rare bleeding disorders (RBDs) may lead to life-threatening hemorrhages that occur spontaneously, or that are related to trauma or surgery. A common issue for women with RBDs is obstetric/gynecological (OB/GYN) bleeding, and there is a growing interest in understanding the unmet needs and treatment of women with RBDs, such as Glanzmann thrombasthenia (GT) and congenital FVII deficiency (FVII-CD). Recombinant FVIIa (rFVIIa; NovoSevenRT®) is available for the management of these two RBDs. This report addresses bleeding episodes and surgeries in women with GT or FVII-CD identified from updated analyses of clinical trials and registries utilizing rFVIIa, and provides an overview of the outcomes and safety of rFVIIa use in women with GT or FVII-CD. Methods Clinical trial and registry databases were explored for female participants with reported bleeds/surgeries, including OB/GYN bleeds/procedures. For female patients with GT, we report unblinded independent adjudicator assessment of bleeding events and surgeries treated with rFVIIa from the Glanzmann Thrombasthenia Registry (GTR), and a post-hoc analysis of the female population in the Hemostasis and Thrombosis Research Society (HTRS) Registry. For patients with FVII-CD, we present a pooled analysis of female patients in three compassionate use programs (CUPs) for rFVIIa completed by Novo Nordisk (between 1988 and 1999). Results The GTR included 112 females (mean age 24 years, range 1-80). There were 160 bleeding events managed with rFVIIa-based regimens (with and without other concomitant hemostatic agents), including 36 OB/GYN bleeds, all of which were menorrhagia (Table 1). In addition, 92 surgeries were performed under cover of rFVIIa-based treatment, including 3 OB/GYN surgeries, all of which were curettages (Table 1). Table 1 provides further details on the events disposition and dosing regimens for bleeds and surgeries. Adjudicator-assessed effectiveness of rFVIIa-based treatment was rated as successful in 96.3% of all bleeds, 97.2% of OB/GYN bleeds, and 100% of surgical interventions. No differences by age group, platelet refractoriness or antibody status were observed in the effectiveness of treatment in bleeds or surgeries. Few AEs were reported in the GTR, which reflects the known safety profile of rFVIIa. The HTRS Registry included 6 rFVIIa-treated females with GT (mean age 5.6 years, range 0-13). There were 22 bleeds treated with rFVIIa (median dose per infusion 122.5 μg/kg, range 30-315; median number of doses 4.5, range 1-129), including 1 OB/GYN bleed. rFVIIa was effective in achieving hemostasis in 90.9%. No SAEs or thrombotic complications were reported. The CUPs included 10 female patients with FVII-CD (mean age 25 years, range 0-81). rFVIIa (median dose per infusion 26 μg/kg, range 6-98; median number of doses 22, range 1-112) was used for 13 non-OB/GYN surgeries and 7 non-OB/GYN bleeds, and was effective in 92% and 86% of cases, respectively. No SAEs were considered related to treatment by the investigator. FVII-neutralizing antibodies were reported in 1 patient, who had unintentionally received 40 times more than the recommended dose of rFVIIa. The same patient also received other plasma-derived factors and the cause of antibody development was therefore unclear. A few months after stopping rFVIIa treatment, the same patient died following intracranial hemorrhage, which was judged as not related to the use of rFVIIa by the investigator. Conclusion Without therapy, patients with RBDs may have high rates of bleeding with considerable risk of morbidity and mortality. Data presented here indicate that rFVIIa-based treatment regimens have an acceptable safety profile and are effective in the management of bleeds and surgeries in women with GT or FVII-CD. Disclosures Chitlur: Bioveritiv/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Carcao:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. Cooper:Novo Nordisk Inc.: Employment. Jain:Novo Nordisk Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; BPL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kavakli:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Kerlin:CSL Behring: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding. Peltier:Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees. Poon:Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; World Federation of Hemophilia: Other: Not-for-profit organization affiliation: volunteer ; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation in sponsored research; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding. Saad:Novo Nordisk Inc: Employment. Shapiro:Kedrion Biopharma: Other: Clinical Research Protocol with the company; Shire/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company, Research Funding; Bayer: Other: Clinical Research Protocol with the company; OPKO: Other: Clinical Research Protocol with the company; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; Novo Nordisk Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; Prometic Life Sciences: Consultancy; Sangamo Biosciences Inc: Consultancy, Other: Clinical Research Protocol with the company; Agios: Other: Clinical Research Protocol with the company; BioMarin: Other: Clinical Research Protocol with the company; Daiichi Sankyo: Other: Clinical Research Protocol with the company; Glover Blood Therapeutics: Other: Clinical Research Protocol with the company; Novartis: Other: Clinical Research Protocol with the company; Pfizer: Other: Clinical Research Protocol with the company; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Clinical Research Protocol with the company; Prometic Bio Therapeutics: Other: Clinical Research Protocol with the company.

Description: Abstract 20 Congenital Factor XIII (FXIII) deficiency is a rare autosomal recessive disorder affecting approximately 1 in 2–5 million individuals without gender or ethnic predilection. The plasma form of FXIII is a heterotetramer [A2B2] comprising two FXIII-A subunits and two FXIII-B subunits. A-subunit deficiency predominates (95%). FXIII deficient patients have a high risk of life-threatening bleeds, notably spontaneous intracranial haemorrhage. They experience impaired wound healing, and recurrent first trimester spontaneous abortions. Given the severity of the disorder there is a clinical need for providing effective haemostatic replacement therapy. Currently, only plasma derived products are approved for use in the United States. These may carry a risk of blood borne infection, sensitization and allergic reactions. A multi-center, multi-national, open-label, single-arm, multiple dosing phase 3 (prophylaxis) trial was undertaken to evaluate the efficacy and safety of a novel recombinant FXIII (rFXIII) in the prevention of bleeds in congenital FXIII-A subunit deficiency. This rFXIII-A2 dimer is expressed in Saccharomyces Cerevisiae and is an exact copy of the human A-subunit, which is the active cross-linking enzyme. When rFXIII is administered, it immediately binds to the B subunit that is present in the bloodstream. Forty-one patients aged ≥7 years [mean: 26.4 (range: 7–60); 23 males; 18 females] with a diagnosis of severe congenital FXIII-A subunit deficiency were enrolled. Patients entered a 4-week run-in period followed by monthly treatment with 35 IU/kg of rFXIII for 52 weeks. Informed consent was obtained prior to any trial-related activities. Bleeding episodes and adverse events were recorded. Testing was conducted monthly to measure pre- and post-dose FXIII activity and concentration, 5M urea clot solubility and anti-FXIII antibodies. Where antibodies were found, detailed testing for neutralizing potential was performed. Data were compared with bleeding rates based on historical data. During the treatment period with rFXIII (466 patient months) five bleeding episodes treated with FXIII-containing products were observed in four patients. All five were associated with trauma. No spontaneous bleeds that require treatment or intracranial haemorrhage occurred during rFXIII treatment period in any of the patients. The annual rate of bleeds requiring treatment was estimated via a Poisson model to be 0.048 bleeds/patient/year (95% CI: [0.0094; 0.2501] - significantly lower than the historic bleeding rate of 2.91 (p