Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

SUMMARY Background

Aim: N8-GP (turoctocog alfa pegol) is a glycoPEGylated, extended half-life human recombinant factor VIII (FVIII) shown to be an efficacious treatment for patients with haemophilia A. Accurate monitoring of replacement therapy helps ensure proper dosing, leading to better patient care. The objective of this field study was to evaluate the accuracy and intra-and inter-laboratory variabilities of N8-GP and rAHF (Advate ® ) FVIII activity (FVIII:C) measurements in clinical laboratories using their routine methods and reagents.Methods: Laboratories measured plasma samples spiked with 0.03, 0.2, 0.6 and 0.9 IU/mL N8-GP or rAHF. Samples were blinded, and laboratories were instructed to perform evaluations using their routine FVIII activity assays and calibrators. Results:Of the 67 participating laboratories from 25 countries, 60 used a one-stage assay, 36 used a chromogenic assay, and 29 used both one-stage and chromogenic assays. Participating laboratories used nine different activated partial thromboplastin time (aPTT) reagents, the most common being SynthASil ® and Actin ® FS. Most aPTT reagents recovered N8-GP close to target. Three silica-based aPTT reagents (APTT-SP, TriniCLOT™ and STA ® PTT-Automate) underestimated N8-GP, recovering 40%-83% of target concentration. For chromogenic assays, N8-GP and rAHF recoveries were comparable at all concentrations, with overall mean recoveries for both products close to 130%. Assay variability was similar for both assay types and both products; inter-laboratory variability was greater than intra-laboratory variability and highest at 0.03 IU/mL. Conclusions:Most clinical laboratories accurately measured N8-GP and rAHF when using their in-house one-stage or chromogenic FVIII:C assays. However, three silicabased aPTT reagents underestimated N8-GP recovery. K E Y W O R D S chromogenic assay, clinical laboratory techniques, factor VIII activity assay, haemophilia A, one-stage assay, postadministration monitoring S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Tiefenbacher S, Clausen WHO, Hansen M, Lützhøft R, Ezban M. A field study evaluating the activity of N8-GP in spiked plasma samples at clinical haemostasis laboratories. Haemophilia. 2019;25:893-901.

N9-GP has the potential to shift previously treated haemophilia B patients from a severe/moderate disease state into a mild- or non-haemophilic range for most of the dosing interval, which is expected to reduce the number of bleeding episodes.

On day 15 BIAsp70 was associated with a shorter Tmax, and more than 40% elevated Cmax. Comparing with BIAsp30, AUC(0-24 h) and AUCdinner(0-6 h) were increased by 25% and 28%, respectively, but AUCdinner (6-14 h) was markedly lower for BIAsp70 [BIAsp30/BIAsp70: 1.9; 95% CI (1.42, 2.55)]. Similar findings were also observed on day 1. The fasting or pre-meal serum insulin levels on day 15 tended to be higher with BIAsp30, but the differences were not statistically significant. CONCLUSIONS The pharmacokinetic properties of BIAsp30 and 70 remain constant during 2 weeks of daily administration in patients with Type 1 diabetes. In comparison with BIAsp30, the administration of BIAsp70 results in a shorter time to and larger maximum insulin aspart concentration. Furthermore, total and early post-dinner insulin AUC were greater, whereas late-phase insulin exposure was lower with BIAsp70.