Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.

Safety and Efficacy of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Untreated Patients with Hemophilia B.

Introduction Recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) has been shown to be an effective, well-tolerated treatment for patients with severe hemophilia B who had previously received factor replacement therapy. This study investigated the safety and efficacy of rIX-FP in previously untreated patients (PUPs). Methods Patients with moderately severe/severe hemophilia B (≤2% FIX) previously untreated with FIX replacement products received rIX-FP (25-75 IU/kg) prophylaxis weekly or on-demand treatment over ≥50 exposure days (EDs). Primary outcomes were the number of patients who developed FIX inhibitors and mean incremental recovery (IR) following a 50 IU/kg dose of rIX-FP. Secondary outcomes included incidence of adverse events (AEs) and annualized bleeding rates (ABRs). Results In total, 12 PUPs with a median age of 0 years (range, 0-11 years) were treated with rIX-FP for a median of 50 EDs (6/12 prophylaxis; 6/12 on-demand then prophylaxis). Overall, 11/12 patients did not develop FIX inhibitors; one 11-year-old patient developed an inhibitor against FIX after 8 EDs and was ultimately withdrawn. Mean (standard deviation) IR was 1.2 (0.4, n = 8) (IU/dL)/(IU/kg). Of the 137 treatment-emergent AEs recorded, five were attributed to rIX-FP. On the prophylaxis regimen, median ABR was 1.0 (range, 0-3.9, n = 12). No thromboembolic events or deaths occurred during the study. Conclusion This study provides data to support the safety and efficacy of rIX-FP in PUPs requiring on-demand or prophylactic treatment for moderately severe/severe hemophilia B, consistent with results in previously treated patients. Overall, 1/12 patients developed an inhibitor against FIX.

Extended half-life factor IX prophylaxis up to every 21 days in hemophilia B: a longitudinal analysis of the efficacy and safety in selected adult patients.

Background: Extended half-life factor IX (FIX) products have revolutionized prophylactic treatment for patients with hemophilia B as patients maintain protective FIX levels with minimal occurrence of spontaneous bleeding. rIX-FP is an extended half-life FIX product that allows prolonged dosing intervals. Objectives: To assess individualized and prolonged prophylactic dosing interval up to 21 days in adult patients (≥18 years) with hemophilia B in the rIX-FP clinical trial program. Methods: Patients who were included in the PROLONG-9FP phase III study or who received rIX-FP during surgery could continue into an extension study for long-term assessment. Patients began 7-day prophylaxis with rIX-FP, and after 6 months, they could extend dosing intervals to every 14 days. In the extension study, adult patients could switch to a 21-day regimen if well-controlled on a 14-day regimen. Results: Eleven patients transitioned from a 7-day prophylaxis regimen to a 14-day regimen and finally to a 21-day regimen, 5 of whom were treated on demand at enrollment. Patients who switched to the 21-day regimen had a median annualized spontaneous bleeding rate of 0.0 across all regimens. The median observed FIX activity remained >5 IU/dL until day 21 after a single 100-IU/kg dose of rIX-FP. After 6 months on the 21-day regimen, 2 patients switched back to a 14-day regimen. No inhibitors, anaphylactic reactions, or thromboembolic events occurred. Conclusion: Patients who are well controlled on a once-weekly regimen might extend their treatment interval to 14 days, and in adult patients, further extension to up to 21 days (100 IU/kg) may be considered.