Patients: 15 previously treated male patients aged 21 to 55 years with hemophilia B. Patients had FIX activity ≤2 IU/dL and at least 150 exposure days to any FIX product.⁸

Study design: Data from the above patients, who participated in the first human-dose (FHD) trial for Rebinyn^® (Negrier 2011), were used to generate population pharmacokinetic models for Rebinyn^® (n=15), pdFIX (n=7), and rFIX (n=8). The model was validated by simulating data from the FHD trial 1000 times and comparing the model’s output to the observed data from the trial.^1,8

Primary endpoint: To simulate different dose levels and dosing frequencies for Rebinyn^® and inform the design of phase 3 pivotal and surgical trials investigating Rebinyn^® dosing regimens.¹

Patients: 15 previously treated male patients aged 18 to 70 years with hemophilia B who had participated in the paradigm 7 clinical trial. Patients had FIX activity ≤2 IU/dL and at least 150 exposure days to any FIX product. During paradigm 7, patients received single 50 IU/kg doses of Rebinyn^® and rFIXc at least 21 days apart, with blood samples collected at 14 time-points across 10 days following each dose.⁷

Study design: Population pharmacokinetic models were built using data from paradigm 7 and validated against data from paradigm 2 (n=59). Model selection was guided by visual inspection of goodness-of-fit plots, plausibility of parameter estimates, and changes in –2 Log Likelihood. A P-value of 0.001 was used in model extension/reduction criteria throughout the analysis.²

Primary endpoint: Simulate plasma FIX activity following dosing with Rebinyn^® and rFIXc for surgery and on-demand treatment of bleeds.²

Patients: 74 male patients aged 13 to 70 years with hemophilia B. Patients had FIX activity ≤2 IU/dL, no history of inhibitors to FIX, and at least 150 exposure days to any FIX product.

Study design: Patients were selected for prophylaxis or on-demand treatment at screening. On-demand patients participated in the trial for 28 weeks and received a single dose of 40 IU/kg for bleeding episodes (80 IU/kg for severe bleeding episodes). Prophylaxis patients participated for 52 weeks. Prophylaxis patients were randomly divided into groups of 10 IU/kg once weekly and 40 IU/kg once weekly. Patients were blinded to the prophylaxis dose. The investigator was blinded but could become unblinded if it became necessary to measure a patient’s FIX activity. A pharmacokinetic assessment of the two prophylactic doses was conducted using a subset of these patients. Pharmacokinetic assessments were based on a 1-stage clotting assay and performed at trial initiation (single dose assessments) and after 12 to 44 weeks of prophylaxis (steady state assessments) with both trial doses. The assessments included 7 sampling points up to 168 hours post injection.

Primary endpoint: Safety of Rebinyn^®, measured by factors including development of FIX inhibitors (per Nijmegan modified Bethesda assay), adverse events, noninhibitory binding antibodies against Rebinyn^®, and antibodies against host cell proteins.

Secondary endpoints: Efficacy and prophylactic effect of Rebinyn^® when treating spontaneous or traumatic bleeding episodes. Assessment included number of doses, amount of product used, duration of bleed, and annual bleed rate.

Patients: 25 previously treated children with severe or moderately severe hemophilia B. Children were ≤12 years old, had an FIX activity level of ≤2%, had a history of ≥ 50 exposure days to other FIX products, and weighed ≥10 kg.

Study design: International, multicenter, open-label, non-controlled, single-arm trial designed following EMA guidelines. Patients were stratified into two age groups: 0–6 years and 7–12 years. The trial consisted of a main phase of 52 weeks, and an extension phase, which is still ongoing. All patients received a fixed dose of 40 IU/kg of Rebinyn^® intravenously once weekly for prophylaxis. A pharmacokinetic (PK) assessment was conducted after the first dose of Rebinyn^®, with the last PK sample collected 1 week after that dose and just prior to administration of the second dose. Breakthrough bleeds were treated with a single dose of 40 IU/kg of Rebinyn^® (mild-to-moderate bleeds) or 80 IU/kg of Rebinyn^® (severe bleeds).

Primary endpoint: Immunogenicity of Rebinyn^® as measured by the occurrence of FIX inhibitors (≥0.6 BU) over at least 50 exposure days.

Secondary endpoint: Efficacy of Rebinyn^® in long-term prophylaxis as assessed by the estimated number of bleeds per year, success in treating breakthrough bleeds, and safety other than immunogenicity. FIX activity was also a secondary endpoint, measured after the first single-dose exposure and again at steady state.

Patients: 15 previously treated male patients aged 18 to 70 years with hemophilia B. Patients had FIX activity ≤2 IU/dL and at least 150 exposure days to any FIX product.

Study design: Patients were randomly assigned a single 50 IU/kg dose of either Rebinyn^® or rFIXFc, followed by a 50 IU/kg dose of the other product at least 21 days later. Pharmacokinetic (PK) assessment was performed on blood samples drawn over 10 days postdose for each product, using both 1-stage and chromogenic assays.

Primary endpoint: Area under the FIX activity-time curve for each product.

Secondary endpoints: PK endpoints including maximum FIX activity dose-normalized to 50 IU/kg, terminal half-life, and incremental recovery at 30 minutes.