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In a randomized, multicenter trial involving boys with severe hemophilia A, the incidence of neutralizing antibodies to factor VIII was 87% higher with recombinant factor VIII products than with plasma-derived factor VIII products. Hemophilia A is an inherited bleeding disorder characterized by plasma deficiency of coagulation factor VIII. 1 , 2 A major complication in 30% of patients is the occurrence of alloantibodies (inhibitors) that inactivate factor VIII activity and may nullify replacement therapy. 3 – 6 Risk factors include unmodifiable patient-related factors such as residual plasma factor VIII concentration and gene mutation. 7 – 9 Putative treatment-related risk factors are early replacement therapy and the source of factor VIII (i.e., human plasma or recombinant DNA technology). 3 , 8 , 10 – 13 Experimental studies have shown that plasma-derived factor VIII in complex with the chaperone protein von Willebrand factor, which masks . . .

Emicizumab is a humanized bispecific antibody that mimics the cofactor function of factor VIII. In a dose-escalation study in Japanese persons with hemophilia A, including those with factor VIII inhibitors, emicizumab markedly reduced the number of bleeding episodes. Hemophilia A is a serious bleeding disorder caused by a deficiency of clotting factor VIII. Approximately 50% of patients have severe hemophilia A, 1 defined as less than 1% residual factor VIII activity (<1 IU per deciliter). 2 Such patients have severe bleeding from early childhood, and without appropriate treatment, recurrent bleeding into joints can lead to irreversible hemoarthropathy. 3 , 4 Standard treatment for hemophilia A includes regular prophylaxis and episodic treatment with recombinant or plasma-derived factor VIII. The goals of prophylaxis with factor VIII are to increase factor VIII activity to at least a moderate level (1 to 5 IU per deciliter) . . .

In patients with hemophilia A in whom inhibitors of factor VIII develop, the prophylactic use of a factor VIII bypassing agent (anti-inhibitor coagulant complex) three times a week significantly reduced the risk of bleeding. After exposure to factor VIII, alloantibodies (inhibitors) that neutralize factor VIII clotting function develop in approximately 30% of patients with severe hemophilia A. 1 The development of high-titer factor VIII inhibitors (>5 Bethesda units [BU]) complicates treatment because bleeding no longer responds to standard factor VIII replacement. 2 , 3 Alternative forms of clotting-factor concentrates, known as bypassing agents, are used to treat bleeding in these patients. 3 Two bypassing agents are currently available: anti-inhibitor coagulant complex (AICC) and recombinant activated factor VII (rFVIIa). Both agents control approximately 80% of bleeding episodes in patients with hemophilia and inhibitors. 4 Nonetheless, their hemostatic efficacy is difficult . . .

Background: TB-402, a human monoclonal antibody that partially inhibits Factor VIII activity (FVIII:C), is being developed as a long-acting antithrombotic agent. Objectives: The primary goal of this study was to investigate the tolerability of TB-402 in healthy male volunteers. Secondary objectives were to determine the pharmacokinetics and pharmacodynamics of TB-402. Methods: In this ascending-dose study, healthy subjects aged 18 to 45 years were randomly assigned in a 2:1 ratio to receive TB-402 administered as a single intravenous bolus at 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620, or 1860 μg/kg or matching inactive vehicle (placebo). An older group (55–75 years) was also administered the highest dose that was well tolerated in the younger group (1860 μg/kg). Adverse events (AEs) were obtained from spontaneous reporting and from answers to nonleading questions asked by the principal investigator and study staff during follow-up visits on days 4, 7 (±1 day), 14 (±1 day), 21 (±2 days), 28 (±3 days), 42 (±3 days), and 56 (±3 days) after TB-402 administration. AEs were monitored up to the last study visit on day 56 after the administration of TB-402 or placebo, with special attention to bleeding events. The pharma-codynamic assessment of TB-402 included changes in FVIII:C, activated partial thromboplastin time (APTT), and prothrombin time (PT). Results: The study enrolled 56 subjects (mean ages: younger group, 28 years [range, 20–45 years]; older group, 65 years [range, 58–76 years]; weight, 79 kg [range, 60–104 kg] and 81 kg [range, 64–94 kg], re-spectively). Thirty-one of the 38 subjects who received TB-402 (82%) experienced a total of 85 treatmentemergent AEs (TEAEs), and 14 of 18 subjects who received placebo (78%) experienced 35 TEAEs. A total of 34 bleeding events were reported in 13 of 38 subjects (34%) who received TB-402 and 7 of 18 subjects (39%) who received placebo. Most common AEs reported in subjects who received TB-402 were headache (11 [29%]), vessel puncture-site hematoma (7 [18%]), and traumatic hematoma (5 [13%]); with placebo, these AEs were vessel puncture-site hematoma (4 [22%]), headache (3 [17%]), vasovagal reaction (3 [17%]), and hematuria (3 [17%]). No serious AEs considered to be related to TB-402 were reported, and no dose-dependent increases in bleeding events were observed. On pharmacokinetic analysis of TB-402, the t 1/2 values across doses were 22.9 days (age 18–45 years) and 19.5 days (age 55–75 years). TB-402 was associated with a reduction in FVIII:C over a period of ~48 hours in the d37.5-μg/kg dose groups. TB-402 was associated with a prolonged APTT at doses ≥2.5 μg/kg ~1.1–1.2-fold predose APTT). Administration of a higher dose of TB-402 was associated with an extended duration of APTT prolongation. No significant effect on PT was found. Conclusions: In this study in healthy male volunteers, TB-402 was well tolerated in the population studied. Based on the findings from this study, the long t 1/2 of TB-402 may allow a pharmacodynamic effect over a prolonged period after single-dose administration. Further trials are needed to address the tolerability and efficacy of this agent in preventing thromboembolism. Clinicaltrials.gov identifier: NCT00612196.

Background Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I–I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Methods Using the phase I–I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. Results The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. Conclusions A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were \"high risk\" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

Genome editing using transcription-activator like effector nucleases or RNA guided nucleases allows one to precisely engineer desired changes within a given target sequence. The genome editing reagents introduce double stranded breaks (DSBs) at the target site which can then undergo DNA repair by non-homologous end joining (NHEJ) or homology directed recombination (HDR) when a template DNA molecule is available. NHEJ repair results in indel mutations at the target site. As PCR amplified products from mutant target regions are likely to exhibit different melting profiles than PCR products amplified from wild type target region, we designed a high resolution melting analysis (HRMA) for rapid identification of efficient genome editing reagents. We also designed TaqMan assays using probes situated across the cut site to discriminate wild type from mutant sequences present after genome editing. The experiments revealed that the sensitivity of the assays to detect NHEJ-mediated DNA repair could be enhanced by selection of transfected cells to reduce the contribution of unmodified genomic DNA from untransfected cells to the DNA melting profile. The presence of donor template DNA lacking the target sequence at the time of genome editing further enhanced the sensitivity of the assays for detection of mutant DNA molecules by excluding the wild-type sequences modified by HDR. A second TaqMan probe that bound to an adjacent site, outside of the primary target cut site, was used to directly determine the contribution of HDR to DNA repair in the presence of the donor template sequence. The TaqMan qPCR assay, designed to measure the contribution of NHEJ and HDR in DNA repair, corroborated the results from HRMA. The data indicated that genome editing reagents can produce DSBs at high efficiency in HEK293T cells but a significant proportion of these are likely masked by reversion to wild type as a result of HDR. Supplying a donor plasmid to provide a template for HDR (that eliminates a PCR amplifiable target) revealed these cryptic DSBs and facilitated the determination of the true efficacy of genome editing reagents. The results indicated that in HEK293T cells, approximately 40% of the DSBs introduced by genome editing, were available for participation in HDR.

Background Acquired hemophilia A (AHA) is a rare hemorrhagic disease characterized by isolated prolongation of activated partial thromboplastin time (aPTT) and existence of autoantibodies against factor VIII (FVIII). Methods Here, we present a patient with subcutaneous hemorrhage and remarkable prolongation of irreversible aPTT. Results Further laboratory testing revealed reduced activity of multiple coagulation factors; this finding was subsequently identified as an artifact caused by the high‐titer FVIII inhibitor, confirmed through dilution studies. Despite the high inhibitor titer and the presence of bleeding manifestations, specific anti‐hemorrhagic therapy was not required for this patient. Following 6 months of immunosuppressive treatment, the patient achieved resolution of ecchymosis and maintained normal coagulation factor activity. Throughout the 12‐month follow‐up period, the patient ultimately died from disease progression under palliative support. Conclusion In all, this study demonstrated atypical characteristics of an AHA patient and emphasized that the treatment strategy should be guided by clinical manifestation rather than testing results solely. Patient with a bladder cancer history presented was diagnosed with Acquired hemophilia A (AHA) according to imaging findings and laboratory tests. The parameters returned to normal after treatment of methylprednisolone and cyclophosphamide. With the recurrence of AHA, the patient was finally confirmed to have liver metastases.

Hemophilia A is a genetic disorder that results in the deficiency of functional factor VIII protein, which plays a key role in blood coagulation. Currently, the majority of hemophilia A patients are treated with repeated infusions of factor VIII protein. Approximately 30% of severe hemophilia A patients develop neutralizing antibodies to factor VIII (known as factor VIII inhibitors) due to treatment, rendering factor VIII protein infusions ineffective. Previously, mice receiving murine IL-2 complexed with α-murine IL-2 mAbs (JES6-1A12) showed a lack of factor VIII inhibitor formation after factor VIII treatment, which was associated with the proliferation and the activation of factor VIII-specific regulatory T cells (Tregs). In this paper, we evaluated if an Fc-fused mutated protein analog of mouse IL-2, named Fc.Mut24, engineered to selectively promote the expansion of Tregs can modulate factor VIII-specific immune responses. The mice received one intraperitoneal injection of Fc.Mut24. When the regulatory T cell population reached its highest frequency and peak activation, the mice received a hydrodynamic injection of factor VIII plasmid (day 4) followed by a second Fc.Mut24 dose (day 7). Peripheral blood was collected weekly. Flow cytometry was used to characterize the peripheral blood cell populations, while ELISA and Bethesda assays were used to assess the inhibitor concentrations and the functional titers in plasma. The activated partial thromboplastin time assay was used to assess the functional activities of factor VIII in blood. The mice receiving Fc.Mut24 showed a dramatic and transient increase in the population of activated Tregs after Fc.Mut24 injection. Factor VIII gene therapy hydrodynamic injection resulted in high anti-factor VIII inhibitor concentrations in control PBS-injected mice, whereas the mice treated with Fc.Mut24 produced no inhibitors. Most significantly, there were no inhibitors generated after a second hydrodynamic injection of factor VIII plasmid administered at 19 weeks after the first injection in Fc.Mut24-treated mice. The mice receiving Fc.Mut24 maintained high levels of factor VIII activity throughout the experiment, while the control mice had the factor VIII activity dropped to undetectable levels a few weeks after the first factor VIII plasmid injection. Our data show that human therapies analogous to Fc.Mut24 could potentially provide a method to prevent inhibitor formation and induce long-term immune tolerance to factor VIII in hemophilia patients.

Emicizumab-kxwh (Hemlibra ® ) is a bispecific humanized monoclonal antibody that restores the function of missing activated FVIII by bridging activated FIX and FX to facilitate effective haemostasis in patients with haemophilia A. Subcutaneous emicizumab-kxwh is approved in the USA for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and paediatric patients with haemophilia A (congenital FVIII deficiency) with FVIII inhibitors. Subcutaneous emicizumab-kxwh is awaiting approval in several countries worldwide, including in the EU and Japan, and is undergoing phase 3 development in haemophilia A without FVIII inhibitors. This article summarizes the milestones in the development of emicizumab-kxwh leading to its first global approval for use as prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with haemophilia A.