Novel, human cell line‐derived recombinant factor VIII (Human‐cl rhFVIII, Nuwiq^®) in children with severe haemophilia A: efficacy, safety and pharmacokinetics

Abstract

Introduction:Nuwiq â (Human-cl rhFVIII) is a new-generation recombinant factor VIII (rFVIII) protein, without chemical modification or fusion to any other protein, produced in a human cell line. Aim/Methods: This prospective, open-label, multinational phase III study assessed the efficacy and safety of Human-cl rhFVIII in 59 previously treated patients (PTPs) with severe haemophilia A aged 2-12 years (2-5 [N = 29]; 6-12 [N = 30]) during standard prophylaxis (≥50 exposure days and ≥6 months). Efficacy in treating breakthrough bleeds and during surgical prophylaxis was also assessed. Results: An initial pharmacokinetic assessment (N = 13 per age subgroup) demonstrated comparable results with the one-stage and chromogenic assays. Mean (SD) half-life was 11.9 (5.4) and 13.1 (2.6) hours in children aged 2-5 years and 6-12 years respectively (one-stage assay). Prophylactic efficacy, based on mean monthly bleeding rate, was 'excellent' or 'good' in 91.5% of children for all bleeds and in 96.6% of children for spontaneous bleeds. Mean (SD) annualized bleeding rate was 4.12 (5.22) [median 1.9] for all bleeds, 1.50 (3.32) [median 0] for spontaneous bleeds and 2.34 (3.54) [median 1.57] for traumatic bleeds. There were no major, life-threatening bleeds. Efficacy was 'excellent' or 'good' in the treatment of 82.4% of breakthrough bleeds. Overall efficacy during five major surgeries was rated as 'excellent'. There were no FVIII inhibitors or treatment-related serious adverse events. Conclusion: These results in paediatric PTPs indicate that Human-cl rhFVIII is effective for the prevention and treatment of bleeds.

PK‐guided personalized prophylaxis with Nuwiq® (human‐cl rhFVIII) in adults with severe haemophilia A

“…In these studies, patients received 'standard' prophylaxis with Nuwiq â . The mean (standard deviation, SD) half-life using the one-stage assay in registration studies in PTPs was 17.1 (11.2) h in adults and adolescents, 11.9 (5.4) h in children aged 2-5 years and 13.1 (2.6) h in children aged 6 to ≤12 years [25,28]. Based on the half-life of Nuwiq â and considerable interpatient variability in FVIII half-life observed with Nuwiq â and across products [25,[28][29][30][31][32], a personalized prophylaxis study applying individually appropriate two-, one-or noncompartmental PK methods (NuPreviq approach) was initiated to evaluate the opportunity for extended dosing intervals during PK-guided personalized prophylaxis in adult PTPs with severe haemophilia A.…”

“…Nuwiq â has been shown to be effective in the prevention and treatment of bleeds in clinical trials including both paediatric and adult previously treated patients (PTPs) with severe haemophilia A [24][25][26][27]. In these studies, patients received 'standard' prophylaxis with Nuwiq â .…”

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

“…60 To date, clinical studies with this human cell line-derived rFVIII, involving 59 and 32 previously treated children and adult hemophiliacs, respectively, have shown no FVIII inhibitors. 73,74 As the chaperone of FVIII in plasma, the role of VWF in FVIII immunogenicity cannot be ignored. It has been proposed that VWF may serve an immunoprotective role in 2 ways.…”

Production of recombinant coagulation factors: Are humans the best host cells?

“…The purification process includes 5 chromatographic steps, including a affinity chromatography step with a recombinant protein as ligand, and 2 virus clearance steps with solvent/detergent treatment and nanofiltration to destroy/remove any theoretically occurring enveloped or non-enveloped viruses. 24 Until now, no treatment related adverse effect or inhibitor formation was reported after Nuwiq Ò prophylaxis or on-demand treatment in children 44 and adults. 45,46 with severe hemophilia A.…”