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Background: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. Aim: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. Methods: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg À1 octocog alfa (Advate â ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg À1 rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. Results: rVIII-SingleChain had a longer mean half-life (t 1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h À1 kg À1), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUC inf (2090 vs. 1550 IU·h dL À1 ) than octocog alfa, respectively. The mean AUC inf after rVIII-SingleChain infusion was~35% larger than after octocog alfa. A similar pattern was observed for AUC 0-last . No serious adverse events or inhibitors were reported. Conclusions: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t 1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.

Haemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium. Joint damage is the hallmark of the disease. Despite its frequency and severity, the pathobiology of blood-induced joint disease remains obscure. Although bleeding into the joint is the ultimate provocation, the stimulus within the blood inciting the process and the mechanisms by which bleeding into a joint results in synovial inflammation (synovitis) and cartilage and bone destruction (arthropathy) is unknown. Clues from careful observation of patient material, supplemented with data from animal models of joint disease provide some clues as to the pathogenesis of the process. Among the questions that remain to be answered are the following: (i) What underlies the phenotypic variability in bleeding patterns of patients with severe disease and the development of arthropathy in some but not all patients with joint bleeding? (ii) What is the molecular basis underlying the variability? (iii) Are there strategies that can be developed to counter the deleterious effects of joint bleeding and prevent blood-induced joint disease? Understanding the key elements, genetic and/or environmental, that are necessary for the development of synovitis and arthropathy may lead to rational design of therapy for the targeted prevention and treatment of blood-induced joint disease.

Introduction Haemophilia A or B patients with inhibitors have been treated with FVIIa‐containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. Aim Evaluate the dose‐dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). Methods A Phase 3, randomized, cross‐over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on‐demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response. Results The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 μg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. Conclusion The dose‐dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.