Explore the vast range of titles available.

This clinical study evaluates the bioequivalence of recombinant factor VIII with Fc fusion protein (rFVIII-Fc) developed by AryoGen Pharmed Company compared to the reference product, Elocta ® by Sobi Co., in severe haemophilia A patients. Fc-fused recombinant factor VIII represents a significant advancement in haemophilia A treatment, offering extended half-life and reduced infusion frequency, thus improving patients’ adherence to treatment and quality of life. In a randomized, double-blind, single-dose crossover trial, 50 Iranian patients were assigned to treatment groups in a 1:1 ratio. Subjects received both the test and the reference product with a 7-day washout period between treatments. Pharmacokinetic assessments were conducted over five days post-administration to evaluate the primary outcome, the dose-normalized area under the curve (DNAUC). The results established bioequivalence between rFVIII-Fc (AryoGen Pharmed Company) and Elocta ® , based on the DNAUC as the primary outcome, in which the ratio of test and reference products was calculated to be 108.56 (90% confidence interval 104.88 to 112.37), falling within the pre-defined equivalence margin of 80–125%. Secondary outcomes, including area under the curve (AUC inf ), maximum concentration (C max ), and half-life, further supported bioequivalence. Safety profiles were comparable, with adverse events mainly related to haemophilia A rather than the intervention. In conclusion, the rFVIII-Fc product is bioequivalent to Elocta ® with a similar safety profile, offering an effective alternative for severe haemophilia A patients. This trial was registered in ClinicalTrials.gov (NCT06137092).

BAY 81-8973 (Kovaltry) is an unmodified full-length recombinant factor VIII (rFVIII) for treatment of hemophilia A. The BAY 81-8973 manufacturing process results in a product of enhanced purity with a consistently high degree of branching and sialylation of N-linked glycans. This study evaluated whether a relationship exists between N-linked glycosylation patterns of BAY 81-8973 and two other rFVIII (sucrose-formulated rFVIII [rFVIII-FS; Kogenate FS]) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM; Advate) and their pharmacokinetic (PK) characteristics. N-linked glycans or terminal carbohydrates were enzymatically removed from immobilized BAY 81-8973, rFVIII-FS, and rAHF-PFM proteins and analyzed using high-performance liquid chromatography to determine the percentage of individual N-linked glycan structures and degree of sialylation of each structure. PK data were available from two separate phase 1 crossover studies in which the PK profile of BAY 81-8973 was compared with that of rFVIII-FS (n=26) and rAHF-PFM (n=18) in patients with severe hemophilia A who received a single 50 IU/kg dose of each product. BAY 81-8973 and rFVIII-FS had increased N-linked glycan branching with higher levels of sialylation compared with rAHF-PFM. Levels of trisialylated glycans were 29.0% for BAY 81-8973 vs 11.5% for rFVIII-FS and 4.8%-5.5% for rAHF-PFM; tetrasialylated glycans were 12.0% vs 2.8% and 0.6%, respectively. Degree of sialylation was 96% for BAY 81-8973, 94% for rFVIII-FS, and 78%-81% for rAHF-PFM. Based on chromogenic assay results from the single-dose phase 1 PK studies, BAY 81-8973 half-life was 15% longer than that for rFVIII-FS and 16% longer than rAHF-PFM. Increased N-glycan branching and sialylation were seen for BAY 81-8973 vs rFVIII-FS and rAHF-PFM. Improved PK for BAY 81-8973 relative to rFVIII-FS and rAHF-PFM as seen in single-dose crossover PK studies might be related to this greater level of branching and sialylation, which can prolong the time BAY 81-8973 remains in the circulation.

Rurioctocog alfa pegol (BAX 855) is a novel third-generation recombinant factor VIII whose active ingredient is chemically modified with polyethylene glycol. A global multicenter phase 2/3 study of the product in 137 patients (including 11 patients from Japan) with severe hemophilia A aged 12–65 years, reported an extended half-life and a good tolerability profile, as well as a significantly lower annualized bleeding rate in the prophylactic treatment arm than in the on-demand treatment arm. Using descriptive statistics, a post hoc analysis was performed to compare the pharmacokinetics, safety, and efficacy profiles of the product in the Japanese subpopulation and the overall population. Extended half-life was demonstrated in the Japanese subpopulation. The mean [standard deviation (SD)] annualized bleeding rates in the prophylactic treatment arm were 3.7 (4.7) for the overall population ( n  = 120) and 4.0 (3.4) for the Japanese subpopulation ( n  = 11). The proportion of bleeds reported as excellent or good was 94.9% (149/157) in the overall population, whereas that in the Japanese subpopulation was 92.3% (12/13). No FVIII inhibition or anaphylactic reaction was reported in the Japanese subpopulation. The post hoc comparisons demonstrated similar pharmacokinetic, safety, and efficacy profiles between the overall population and the Japanese subpopulation.

BAY 81-8973, a new full length recombinant FVIII product, has been developed for prophylaxis and on-demand therapy in patients with hemophilia A. LEOPOLD II was a phase 2/3 study comparing prophylaxis versus on-demand treatment with BAY 81-8973. The analysis herein evaluated the clinical profile in Japanese subjects enrolled in LEOPOLD II. The LEOPOLD II was an open-label randomized crossover study. Our analysis evaluated the efficacy using the annualized bleeding rate, safety, and pharmacokinetics in Japanese subjects with severe hemophilia A enrolled in LEOPOLD II. The median annualized bleeding rate was 59.9/year in the on-demand group and 1.9/year in the prophylaxis group for Japanese subjects. There were no study drug-related adverse events in the Japanese subjects. None of the subjects developed FVIII inhibitors. There were no apparent clinical differences in efficacy, safety, and pharmacokinetics between the Japanese and the non-Japanese subjects. Data for the Japanese subjects showed annualized bleeding rates to be remarkably lower in the prophylaxis group compared to the on-demand group and that BAY 81-8973 exhibited a good safety profile and tolerability. These results were similar for the non-Japanese subjects. The results support adoption of BAY 81-8973 for treatment of Japanese subjects with severe hemophilia A.

Background: Although much attention has been paid to the pharmacokinetics (PKs) of different factor VIII (FVIII) concentrates in persons with hemophilia A (HA), limited information is available in young boys with severe HA. In this study, we aimed to assess the PK parameters of FVIII products in boys with severe HA in China. Methods: A total of 36 boys (plasma-derived [pd]-FVIII, n = 15; recombinant [r] FVIII, n = 21) were enrolled between January 2015 and May 2016 in Beijing Children's Hospital. PK characteristics of FVIII products were studied according to a reduced 4-sampling time point design (1 h, 9 h, 24 h, and 48 h postinfusion). Results: The mean FVIII half-life (t1/2) was 10.99 ± 3.45 h (range 5.52-20.02 h), the mean in vivo recovery (IVR) was 2.01 ± 0.42 IU/dl per IU/kg (range 1.24-3.02 IU/dl per IU/kg) and mean clearance (CL) of FVIII is 4.34 ± 1.58 ml·kg−1·h−1 (range 2.29-7.90 ml·kg−1·h−1). We also analyzed the influence of several parameters that potentially modulate FVIII PK. The age was closely associated with FVIII half-life (R2 = 0.32, P < 0.01). The t1/2of FVIII increased by 0.59 h per year. Besides age, von Willebrand factor antigen (VWF:Ag) also was associated with FVIII half-life (R2 = 0.52, P < 0.01). Patients with blood Group O had a shorter FVIII half-life than patients with non-O blood group (9.40 ± 0.68 h vs. 12.3 ± 0.79 h, t = 2.70, P = 0.01). The FVIII IVR correlated with age (R2 = 0.21, P < 0.01) and VWF:Ag level (R2 = 0.28, P < 0.01). CL rates were faster in young patients and in those with low-VWF:Ag levels. CL rates of FVIII are higher in blood Group O versus non-blood Group O persons (5.02 ± 0.38 vs. 4.00 ± 0.32 ml·kg−1·h−1, t = 2.53, P = 0.02). Conclusions: Chinese boys with severe HA have similar PK values to other ethnic groups and large differences in FVIII PK between individual patients. Age, blood group, and VWF:Ag levels are important determining factors for FVIII CL.

In hemophilia A, routine prophylaxis with exogenous factor VIII (FVIII) requires frequent intravenous injections and can lead to the development of anti-FVIII alloantibodies (FVIII inhibitors). To overcome these drawbacks, we screened asymmetric bispecific IgG antibodies to factor IXa (FIXa) and factor X (FX), mimicking the FVIII cofactor function. Since the therapeutic potential of the lead bispecific antibody was marginal, FVIII-mimetic activity was improved by modifying its binding properties to FIXa and FX, and the pharmacokinetics was improved by engineering the charge properties of the variable region. Difficulties in manufacturing the bispecific antibody were overcome by identifying a common light chain for the anti-FIXa and anti-FX heavy chains through framework/complementarity determining region shuffling, and by pI engineering of the two heavy chains to facilitate ion exchange chromatographic purification of the bispecific antibody from the mixture of byproducts. Engineering to overcome low solubility and deamidation was also performed. The multidimensionally optimized bispecific antibody hBS910 exhibited potent FVIII-mimetic activity in human FVIII-deficient plasma, and had a half-life of 3 weeks and high subcutaneous bioavailability in cynomolgus monkeys. Importantly, the activity of hBS910 was not affected by FVIII inhibitors, while anti-hBS910 antibodies did not inhibit FVIII activity, allowing the use of hBS910 without considering the development or presence of FVIII inhibitors. Furthermore, hBS910 could be purified on a large manufacturing scale and formulated into a subcutaneously injectable liquid formulation for clinical use. These features of hBS910 enable routine prophylaxis by subcutaneous delivery at a long dosing interval without considering the development or presence of FVIII inhibitors. We expect that hBS910 (investigational drug name: ACE910) will provide significant benefit for severe hemophilia A patients.

Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.

Efmoroctocog alfa (Elocta ® , Eloctate ® , Eloctate™), an extended half-life (EHL) recombinant factor VIII (rFVIII)-Fc fusion protein, is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A. The efficacy of efmoroctocog alfa in the prevention and treatment of bleeding in previously treated patients (PTPs) and previously untreated patients (PUPs) with severe haemophilia A has been demonstrated in phase III studies; this includes its use in the perioperative setting (in PTPs). Furthermore, the effectiveness of efmoroctocog alfa in clinical practice has been confirmed in numerous real-world studies; compared with conventional, standard half-life (SHL) FVIII products, prophylaxis with this EHL FVIII product achieved similar or reduced bleeding rates with fewer injections. Efmoroctocog alfa was generally well tolerated; inhibitors occurred in approximately one-third of PUPs in a phase III study. Efmoroctocog alfa is an established and effective EHL FVIII replacement therapy for the management of haemophilia A. Compared with SHL FVIII products, EHL FVIII products such as efmoroctocog alfa have the potential to optimise prophylactic outcomes by decreasing the burden of treatment or increasing the level of bleed protection. Plain Language Summary Coagulation factor VIII (FVIII) replacement therapy is the mainstay of haemophilia A treatment; FVIII prophylaxis is the standard of care for severe disease. EHL rFVIII products have been developed to decrease the burden and/or increase the effectiveness of prophylaxis compared with conventional FVIII/rFVIII products which, due to their shorter half-lives, require more frequent injections. Efmoroctocog alfa (Elocta ® , Eloctate ® , Eloctate™), a first-in-class rFVIII-Fc fusion protein with a half-life ≈ 1.4−1.8 times longer than that of conventional FVIII/rFVIII preparations, is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in various countries worldwide. The efficacy of efmoroctocog alfa has been demonstrated in phase III trials in patients with severe haemophilia A, and its effectiveness, particularly as FVIII prophylaxis, has been confirmed in numerous studies in clinical practice. The rate of formation of neutralizing anti-FVIII antibodies (inhibitors) with efmoroctocog alfa is similar to that with other FVIII/rFVIII products. Based on a large body of clinical trial and real-world data, efmoroctocog alfa is an established and effective EHL FVIII replacement therapy for the management of haemophilia A.

Limited studies investigated the low dose emicizumab prophylaxis, especially in patients switched from pharmacokinetic (PK)-guided FVIII prophylaxis. A retrospective study was conducted among inhibitor-free boys with severe hemophilia A (SHA). They received PK-guided FVIII prophylaxis for six months and then switched to low dose emicizumab regimen for one year. The patients’ demographic data, PK profiles and clinical outcomes (annualized bleeding rates and zero bleeding proportions) were collected from six-month pre-switch to one-year post-switch. The target joints and direct cost of treatment were also calculated. Twenty boys with SHA were enrolled and the median age was 4.3 years (IQR 3.1–5.8). With a median dose and infusion frequency of 25.3 IU/kg and 3.5 infusions per week, their trough FVIII level is 3.5 IU/dL with range of 2.0-5.8 IU/dL. After their switch to emicizumab, the median dose was 3.5 mg/kg/month with range of 3.0–4.0 mg/kg/month. Significantly improved annualized bleeding rate [0(0, 0.75) vs. 2(2,4), P  < 0.0001], annualized treated bleeding rate [0(0, 0.75) vs. 1.0 (0, 3.5), P  < 0.01], annualized joint bleeding rate [0(0,0) vs. 0(0, 3.5), P  < 0.05] and zero bleeding proportion [75% vs. 20%, P  < 0.01] were observed. Compared with FVIII, low dose emicizumab showed a much lower direct cost [median, 26676 vs. 35568 dollars yearly, P  < 0.01]. Participants received well improved clinical outcomes of reduced annualized bleeding rates and increased zero bleeding proportions. The emicizumab prophylaxis demonstrated a significant decrease in direct cost of 25% compared with FVIII infusions. PK-guided individualized emicizumab prophylaxis could be expected to enhance cost-effectiveness further.

Damoctocog alfa pegol (BAY 94-9027, Jivi ), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate ), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta ; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate /Adynovi ; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate ; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences.