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Background:Due to challenges of factor (F)VIII administration, many infants with severe hemophilia A (HA) do not receive prophylaxis until ≥1 year of age. Emicizumab can be administered subcutaneously from HA diagnosis, which may reduce risk of spontaneous and traumatic bleeds, including intracranial hemorrhage. This primary analysis of HAVEN 7 (NCT04431726) evaluates the efficacy, safety, and pharmacokinetics (PK) of emicizumab in infants ≤12 months of age with severe HA without FVIII inhibitors.

Background:Fidanacogene elaparvovec (PF-06838435, formerly SPK-9001) is an adeno-associated virus (AAV)-based gene therapy designed to deliver a high-activity human factor IX (FIX) variant transgene, FIX-R338L, resulting in endogenous FIX production in people with hemophilia B. To date, 45 participants with moderately severe to severe (FIX:C ≤2%) hemophilia B have received fidanacogene elaparvovec as part of the ongoing phase 3 study, BENEGENE-2 (NCT03861273). Of these 45 participants, 6 returned to prophylaxis (RTP) of FIX after initially responding to treatment. We describe the characteristics of the RTP participants.

Background

The HLA class I/II alleles and the tumor necrosis factor α (TNFA)locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (–827C>T, –308G>A, –238A>G, and 670A>G) in the TNFAgene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malmö International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA –308 A/A genotype within this haplotype compared with 39.7% for TNFA –308 G/G patients and 46.9% for TNFA –308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P= .008). The association between the –308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P< .001) and with inversions (n = 75; OR, 11.8; 95% CI, 1.3-105.1; P= .013). Associations were found for the HLA A26 and B44 alleles, but these were not consistent in the subgroup analysis. Our data imply that the TNFA –308G>A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.

The HLA class I/II alleles and the tumor necrosis factor α (TNFA) locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (–827C>T, –308G>A, –238A>G, and 670A>G) in the TNFA gene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malmö International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA –308 A/A genotype within this haplotype compared with 39.7% for TNFA –308 G/G patients and 46.9% for TNFA –308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P = .008). The association between the –308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P < .001) and with inversions (n = 75; OR, 11.8; 95% CI, 1.3-105.1; P = .013). Associations were found for the HLA A26 and B44 alleles, but these were not consistent in the subgroup analysis. Our data imply that the TNFA –308G>A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.

Introduction: Congenital factor X (FX) deficiency (FXD) is a rare bleeding disorder characterized by spontaneous joint and mucocutaneous bleeding and gastrointestinal or intracranial hemorrhage. A high-purity plasma-derived FX concentrate (pdFX; Coagadex®, Bio Products Laboratory, Elstree, UK) is licensed in the United States (US) and European Union to treat congenital FXD. This open-label, multicenter, international study collected retrospective data on compassionate use of pdFX in subjects with hereditary FXD.

Introduction:Concizumab is a humanized monoclonal antibody (mAb) that enhances thrombin generation (TG) potential by inhibiting tissue factor pathway inhibitor (TFPI). explorer™3 (NCT02490787) was a phase 1b, double-blind, multiple-dose escalation trial of subcutaneously administered concizumab in patients with severe hemophilia A without inhibitors in which the safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of concizumab were assessed. Three dose cohorts (0.25, 0.5, 0.8 mg/kg every fourth day) of eight participants were included. The primary analysis of explorer™3 raised no safety concerns and a PK/PD relationship among concizumab dose, unbound TFPI and TG was confirmed. Here, we present results from exploratory PK/PD analyses that aimed to determine the association between concizumab exposure and PD markers (unbound TFPI, reported bleeding episodes and peak TG).

Current treatment options for the management of bleeds in hemophilia patients with inhibitors are primarily with bypassing agents, either recombinant activated factor VII (rFVIIa, NovoSeven®) or plasma-derived activated prothrombin complex concentrates. Whilst these products are efficacious, an improvement in the time to hemostasis could lead to better efficacy and improved quality of life. NN1731 was developed with the aim to provide a safe, rapid and sustained resolution of bleeds in patients with hemophilia and inhibitors. NN1731 is a recombinant factor VIIa analog with three point mutations in the protease domain at amino acid positions 158, 296 and 298, thereby stabilizing the active conformation of the molecule (Persson et al. PNAS 2001). It is produced without any human- or animal-derived raw materials. The aim of this phase 2 dose-escalation trial was to evaluate the safety and preliminary efficacy of NN1731 for the treatment of acute joint bleeds in subjects with congenital hemophilia A or B with inhibitors.This was a prospective, multi-center, randomized, double-blinded, active-controlled, dose-escalation trial evaluating 1–3 doses of NN1731 at 5, 10, 20, 40, and 80 mcg/kg bw vs. 1–3 doses of rFVIIa at 90 mcg/kg bw with a randomization ratio of 4:1 NN1731:rFVIIa for all dose tiers. Enrolled male patients ≥12 years of age experiencing a joint bleed were asked to report to the hemophilia center and were randomized to treatment within 3 hours of onset if the bleed met entry criteria. After first trial product administration (TPA), subjects were assessed at 3-hourly intervals and up to two additional doses of trial product could be given 3 and 6 hours later. Other hemostatic agents could be given as per local standard of care if, according to the investigator, the bleed was not controlled after three doses of trial product. The primary endpoint was number of adverse events, including non-serious adverse events (AEs) occurring within seven days of first TPA, and serious adverse events (SAEs) from first TPA to the end of subjects' participation in the trial. Secondary safety endpoints included evaluation of immunogenicity, biochemistry, hematology, and coagulation parameters. Efficacy endpoints included the number of doses needed to control bleeding, need for additional hemostatic medication, and improvement of symptoms (pain, swelling and range of motion). Furthermore, pharmacokinetic (PK) parameters were evaluated based on FVIIa activity. An independent Data Monitoring Committee (DMC) reviewed all data throughout the trial period, and made assessments after the first 10 bleeding episodes in each dose tier before allowing escalation to the next dose tier.96 bleeding episodes in 50 patients from 18 countries were dosed. Baseline demographic characteristics of the patients were comparable between NN1731 and the active control group. There were more target joints (defined as three bleeding episodes or more in the same joint in the past six months) treated in the NN1731 groups combined vs. rFVIIa (49% vs. 32%, respectively). Fewer AEs, including SAEs, were reported in the NN1731 groups vs. rFVIIa. AE rates, including SAEs rates, were similar for all dose levels of NN1731 studied, with no safety concerns. No antibody formation was detected in any patient treated with trial product. The PK profile of NN1731 observed in these actively bleeding hemophilia patients confirmed the PK seen in healthy subjects (Moss et al. J Thromb Haemost 2009). Initial analysis of the efficacy results show that 98% of the joint bleeds were controlled with NN1731 in a combined evaluation of 20 to 80 mcg/kg dose groups. The efficacy of rFVIIa was similar to that observed and reported in clinical studies and practice. Remaining data analyses are ongoing at the time of submission but will be completed for presentation at the meeting.In this largest prospective, randomized, controlled clinical trial of recombinant bypassing agents ever conducted in actively bleeding hemophilia patients with inhibitors, NN1731 was well tolerated, with no safety concerns observed at any dose levels. In particular, no antibodies were detected in any exposed patient. Preliminary results confirm the fast acting pharmacokinetic profile of NN1731 and show a high efficacy rate of NN1731 in controlling acute joint bleeds.de Paula: Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau, Traveling cost to scientific events; Bayer: Honoraria, Speakers Bureau, Traveling cost to scientific events; Baxter: Traveling cost to scientific events; Octapharma: Traveling cost to scientific events. Kavakli:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahlangu:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Maxygen: Membership on an entity's Board of Directors or advisory committees. Ayob:Novo Nordisk: Research Funding. Lentz:Novo Nordisk: Consultancy, Research Funding; Celgene: Equity Ownership; Schering-Bayer: Research Funding. Morfini:Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Baxter: Honoraria, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Wyeth: Membership on an entity's Board of Directors or advisory committees. Nemes:Novo Nordisk: Research Funding. Zupancic Salek:Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Baxter: Consultancy, Speakers Bureau. Shima:Novo Nordisk: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Windyga:Novo Nordisk: Honoraria, Research Funding, Speakers Bureau, Travel to attend scientific meetings. Ehrenforth:Novo Nordisk: Employment. Andersen:Novo Nordisk: Employment. Chuansumrit:Novo Nordisk: Honoraria, Research Funding. behalf of 1804 (ADEPT-1) Investigators:Novo Nordisk: Research Funding.

Radioisotope Synovectomy (RS) is defined as the intra-articular injection of radioisotopic agents with the aim of fibrosis on hypertrophic synovium in the target joint for hemophilia. Yttrium90(Y90) and Rhenium186(Re186) are approved isotopes in Europe. The only radioisotope which approved in the USA for RS is Phosphorus 32 (P32). We have successfully used Y90and Re186for 8 years in target joints of hemophiliac patients. For the last 30 years, no malignant transformation has been reported in hemophilia with RS. However, recently, development of acute lymphoblastic leukemia in two hemophiliac children after RS has been reported in the USA. Even though P32was the responsible radioisotopic agent, safety concerns have arisen due to exposure to all type of radioisotopic agents which may cause chromosomal breakages (CBs) and oncological transformation. The aim of this prospective and Ethics commitee-approved study was to investigate the early genotoxic effect on peripheral blood lymphocytes induced by Y90and Re186in children who underwent RS for chronical synovitis. All patients and parents were informed according to Helsinki Decleration. Thirty-three patients with persistent synovitis (23 hemophilia-A, 9 hemophilia-B,1 FVII deficiency) were enrolled to the study. All patients were male except one case. The mean age was 16.4 ±6.2 years (range:8–40). RS was performed as an outpatient procedure by using Y90for knees (n=9)(5 mCi) and Re186for elbows and ankles (n=14)(2 mCi)(CIS Bio International/Gif-sur-Yvett Cedex-France). In 6 patients, both agents were used simultaneously in one session. No radioisotope leakage away from the injection site was observed during and after procedure. Heparinised peripheral blood samples were obtained for lymphocyte cultures from all patients at three different time points (prior to RS, after 3 days and after 90 days). Diepoxybutane (DEB) test was used for the evaluation of chromosomal breakages in patients by culturing their blood along with blood from a sex-matched control with a working solution of 11 ug/ml. Five μl pure DEB was added to 5 ml of sterile dH2O. Afterwards, 10 μl of the first solution was added to 1 ml of sterile dH2O. This is the working solution at 11 ug/ml. A total of 50 metaphases from each culture were examined and scored according to the procedure. All cytogenetic analysis were performed in the Medical Genetics Laboratory of Ege University Hospital. Due to technical problems, parameters of 29 patients were evaluated. Chromosomal breakages (CB) were found in 20 patients prior to treatment. We have found CBs in 4 additional patients after 3 days of RS. However, all these CBs were disappeared 90 days after. CBs were found to be persisted in 17 patients. Mean frequency of CBs was (0.0707±0.0829/1000 cells) and was not significantly increased after 3 days (0.0828±0.0747) but significantly decreased at 90 days (0.0379±0.0456). The difference of the results of two radioisotopes were not significant. In conclusion, although RS with Y90and Re186does not seem to induce the genotoxic effects significantly on peripheral blood lymphocytes in hemophilic children, the significant decrease in the number of CBs between the 3rd and 90th days may be accepted as a warning for the requirement of risk/benefit ratios which should be taken into account for any individual patient. Therefore medical treatment in hemophilia for synovitis should be suggested before RS and families should be informed properly.