BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. ( BACKGROUNDCurrent hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.

Key Points• BAX 855, a pegylated fulllength rFVIII with extended half-life, was highly effective in the prevention and treatment of bleeding events.• No subjects receiving BAX 855 developed FVIII inhibitory antibodies nor experienced unexpected adverse events.Current management of hemophilia A includes prophylaxis with factor VIII (FVIII) replacement every 2 to 3 days. BAX 855, Baxalta's pegylated full-length recombinant FVIII (rFVIII), was designed to increase half-life and, thus, reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy. BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years. A phase 1 study compared the pharmacokinetic (PK) profile of BAX 855 with that of licensed rFVIII (Advate). In a pivotal study, the annualized bleeding rate (ABR), PK parameters, and efficacy of bleeding treatment were assessed. In the phase 1 study, the mean half-life (T 1/2 ) and the mean residence time of BAX 855 compared with Advate were 1.4-to 1.5-fold higher. These results were confirmed in the pivotal study. The pivotal study met its primary endpoint: Prophylaxis with BAX 855 resulted in an ABR that was significantly lower than half the ABR of on-demand treatment (P < .0001). The median ABR was 1.9, and 39.6% of compliant subjects had no bleeding episodes during prophylaxis, whereas subjects treated ondemand had a median ABR of 41.5. BAX 855 was also efficacious for the treatment of bleeding episodes, with 95.9% of bleeding episodes treated with 1 to 2 infusions and 96.1% having efficacy ratings of excellent/good. No FVIII inhibitory antibodies or safety signals were identified. These studies provide evidence that BAX 855 was safe and efficacious for on-demand treatment and prophylaxis administered twice weekly in patients with hemophilia A.

Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with anaesthetic-sparing effects. We have determined the pharmacodynamic and pharmacokinetic interactions between dexmedetomidine and isoflurane in volunteers. Nine male subjects were allocated randomly to receive isoflurane anaesthesia preceded by infusion of dexmedetomidine on three separate occasions, 2 weeks apart. Dexmedetomidine target plasma concentrations were 0.0 (placebo), 0.3 ng ml-1 (low-dex) and 0.6 ng ml-1 (high-dex). End-tidal isoflurane concentrations at which gross purposeful movement and response to verbal commands occurred were identified. In the recovery period, sedation scores and digit symbol substitution tests were recorded. Venous blood samples were obtained before, during and after anaesthesia at predetermined intervals for measurement of plasma concentrations of dexmedetomidine and calculation of standard pharmacokinetic indices (AUC, Cl, Vss, T1/2 alpha, T1/2 beta). The end-tidal isoflurane concentration at which 50% of subjects first responded to the tetanic stimulus was 1.05% in the placebo group, 0.72% in the low-dex group and 0.52% in the high-dex group. We conclude that dexmedetomidine decreased isoflurane requirements in a dose-dependent manner and reduced heart rate, systolic and diastolic arterial pressures. Sedation and slight impairment of cognitive function persisted for several hours after anaesthesia and the end of infusion of dexmedetomidine. Isoflurane did not appear to influence the pharmacokinetics of dexmedetomidine.