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. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Introduction: VONCENTO (R) (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate, which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and a VWF/factor VIII (FVIII) ratio of similar to 2.4:1, similar to Haemate (R) P (CSL Behring).Methods: The pharmacokinetic, efficacy and safety profiles of VONCENTO (R) were investigated in this multicentre, double-blind, randomised study. Subjects aged >= 12 years with haemophilia A who required treatment of non-surgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmaco-kinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO (R) or BIOSTATE (R) reference product (Biostate-RP) (Day 1; Day 8 [n = 16], repeated on Day 180 [VONCENTO (R) only; n = 15]). Efficacy and safety analyses were performed either during on-demand treatment (n = 52) or prophylaxis (n = 29) for >= 6 months and >= 50 exposure days, respectively.Results: Besides the confirmation of bioequivalence between VONCENTO (R) and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either 'excellent' or 'good' in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0-34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013). VONCENTO (R) was well tolerated and no inhibitory antibodies were identified during the study period.Conclusions: This study demonstrated the bioequivalence of VONCENTO (R) to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects. (C) 2015 Published by Elsevier Ltd.

SummaryHaemostatic management of haemophilia B patients undergoing surgery is critical to patient safety. The aim of this ongoing prospective trial was to investigate the haemostatic efficacy and safety of a recombinant factor IX (rFIX) (Bax326) in previously treated subjects (12–65 years, without history of FIX inhibitors) with severe or moderately severe haemophilia B, undergoing surgical, dental or other invasive procedures. Haemostatic efficacy was assessed according to a predefined scale. Blood loss was compared to the average and maximum blood loss predicted preoperatively. Haemostatic FIX levels were achieved peri‐ and postoperatively in 100% of subjects (n = 14). Haemostasis was ‘excellent’ intraoperatively in all patients and postoperatively in those without a drain, and ‘excellent’ or ‘good’ at the time of drain removal and day of discharge in those with a drain employed. Following the initial dose, the mean FIX activity level rose from 6.55% to 107.58% for major surgeries and from 3.60% to 81.4% for minor surgeries. Actual vs. predicted blood loss matched predicted intraoperative blood loss but was equal to or higher than (but less than 150%) the maximum predicted postoperative blood loss reflecting the severity of procedure and FIX requirements. There were no related adverse events, severe allergic reactions or thrombotic events. There was no evidence that BAX326 increased the risk of inhibitor or binding antibody development to FIX. BAX326 was safe and effective for peri‐operative management of 14 subjects with severe and moderately severe haemophilia B.

SummaryThe Pro‐FEIBA study reported health‐related quality of life (HRQoL) improved following 6‐month of Factor Eight Inhibitor Bypassing Activity (FEIBA) prophylaxis. This study investigates whether 12‐month of FEIBA prophylaxis improved HRQoL in haemophilia patients with inhibitors. Thirty‐six subjects in a 1‐year prospective, randomized, open‐label, parallel‐design study were randomized to prophylaxis (85 ± 15 U kg−1 every other day) or on‐demand treatment. HRQoL was assessed at screening, 6 and 12‐month termination using the EQ‐5D, Haem‐A‐QoL, Haemo‐QoL and a general pain visual analog scale (VAS). To evaluate changes, paired t‐tests and criteria for minimally important differences were applied. Repeated measures regression tested the association between annualized bleeding rate (ABR) and physical HRQoL. At 6 and 12 months, prophylaxis subjects reported clinically meaningful improvement in EQ‐5D index (mean improvement, 0.10 and 0.08, respectively) and both clinically meaningful and statistically significant improvements in EQ‐VAS scores (16.9 and 15.7, respectively; P < 0.05) vs. baseline. General pain was significantly reduced during prophylaxis at each follow‐up (mean improvement, 20.3 and 23.2, respectively; both P <0.05). At 12 months, prophylaxis subjects achieved significant improvements in Haem‐A‐QoL Total Score and in four domains: Physical Health, Feeling, View, and Work and School (all P < 0.05). No statistically significant changes, except for Haem‐A‐QoL Physical Health at 6 months, were observed with on‐demand treatment. ABR was decreased by 72.5% with prophylaxis vs. on‐demand treatment (P = 0.0003) and reduced ABR was associated with better physical HRQoL (P < 0.05). FEIBA prophylaxis significantly reduced ABR and improved HRQoL in inhibitor patients. Subjects with lower ABR reported better physical HRQoL.

SummaryFactor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti‐inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high‐titre inhibitors or low‐titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1‐year period, 17 subjects were treated prophylactically (85 ± 15 U kg−1 every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on‐demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms (P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode‐free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on‐demand therapy than prophylaxis (P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on‐demand treatment, and the safety of prophylaxis is comparable to that of on‐demand treatment.

Summary BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12–65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non‐serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence ( n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC 0–72 h per dose. Twice‐weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg −1 per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on‐demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.