Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial
rVIII-SingleChain is a new recombinant Factor VIII (F.VIII) molecule in which the heavy and light chains are fused to achieve a single protein, which is indistinguishable from endogenous F.VIII. It has an increased binding to von Willebrand factor (vWF) leading to a potentially increased half life and decreased risk of F.VIII inhibitors.
This prospective phase III trial recruited previously treated pediatric patients (younger than 12 years) with no personal or family history of inhibitors. They received either prophylaxis or on-demand therapy and were dosed at investigator's discretion. Efficacy and safety were regularly assessed, and inhibitor screening was performed. Pharmacokinetic evaluation was done using the chromogenic substrate assay, which has been shown to be more accurate with this molecule.
84 patients were followed across 19 countries: PK studies showed a mean half life of just over 10 hours. Efficacy was demonstrated for treatment of acute bleeds, and there were no safety concerns or development of new inhibitors. For patients on prophylaxis, the annualized bleeding rate (ABR) was 3.69, and the annualized spontaneous bleeding rate was 0. The ABR was noted to be slightly higher in the 6-12 year old group, likely reflecting their increased activity. Many patients were able to decrease the frequency of their prophylactic injections, although a few required more frequent infusions.
Since the treatment regimen, including dosing, was left to the discretion of the investigator, there is a significant potential for bias. It also makes it challenging to compare the ABR across the different prophylactic groups.