Inhibitor development in previously untreated patients with severe hemophilia A treated with human-cl rhFVIII, a new generation recombinant FVIII of human origin

A. Russo1, C. Altisent2, A. Borel-Derlon3, H. Chambost4, M. Gattens5, Y. Gruel6, A. Klukowska7, C. Koenigs8, T. Lambert9, R. J. Liesner10, M. Sigaud11, M. Abashidze12, O. Aleinkova13, M. J. Belletrutti14, M. Carcao15, A. K. C. Chan16, L. Dubey17, J. Ducore18, N. A. Fouzia19, N. Kavardakova20, M. El Khorassani21, S. Lohade22, V. Turea23, J. K. M. Wu24, V. Vdovin25 (1Mainz, Germany, 2Barcelona, Spain, 3Caen, France, 4Marseille, France, 5Cambridge, United Kingdom, 6Tours, France, 7Warsaw, Poland, 8Frankfurt am Main, Germany, 9Le Kremlin Bicetre, France, 10London, United Kingdom, 11Nantes, France, 12Tbilisi, Georgia, 13Minsk, Belarus, 14Edmonton, Canada, 15Toronto, Canada, 16Hamilton, Canada, 17Lviv, Ukraine, 18Sacramento, US, 19Vellore, India, 20Kiev, Ukraine)

Bleeding disorders, coagulation and fibrinolytic factors
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: Studies have shown that the incidence of inhibitor development varies between FVIII concentrates. In the SIPPET study, the cumulative incidence of high-titre inhibitors with hamster-cell derived recombinant FVIII (rFVIII) products was 28.4% vs 18.6% for plasma-derived von Willebrand factor-containing FVIII products (Peyvandi F et al. N Engl J Med 2016;374:2054-2064). However, new generation rFVIII products produced in human cell lines were not included. Human-cl rhFVIII (Nuwiq®) is the first and only rFVIII produced in human cells without chemical modification or protein fusion. No inhibitors were reported in 201 previously treated patients with severe haemophilia A treated with human-cl rhFVIII. The immunogenicity, efficacy and safety of human-cl rhFVIII in PUPs with severe haemophilia A is being assessed in the NuProtect study (initiated 2013).

Methods: NuProtect is ongoing in 17 countries and 38 centres worldwide. One hundred evaluable male PUPs of all ages and ethnics are being studied for 100 exposure days (EDs) or 5 years. No prior treatment with FVIII concentrates or other blood products containing FVIII is permitted. Primary objective is to assess the immunogenicity of human-cl rhFVIII by determining inhibitor activity (≥0.6 BU) using the Nijmegen modified Bethesda assay.

Results: Data for 66 PUPs with ≥20 EDs (the time by which inhibitors are most likely to arise) were analysed in the first pre-planned interim analysis (May 2016). The median age at first treatment was 13 months (range: 3–135). Of 59 patients with available F8 gene mutation analysis, 1 (1.7%) had no identifiable mutation, 44 (74.6%) had high-risk mutations and 47 (81.0%) had null mutations. High-titre inhibitors developed in 8 of 66 patients after a median of 11.5 EDs (range 6–24). Five patients developed a low-titre inhibitor (4 transient). Only 2 patients developed an inhibitor (1 high-titre) after 20 EDs. The cumulative incidence of high-titre inhibitors was 12.8% (95% CI: 4.49–21.15), of low-titre inhibitors it was 8.4% (95% CI: 1.28–15.59) and of all inhibitors it was 20.8% (95% CI: 10.68–30.95). Twelve of 13 inhibitor patients had identifiable F8 gene mutation, all were null, and all but one were high-risk.

Conclusion: These interim data support the low rate of inhibitor development in PUPs treated with human-cl rhFVIII. Final data are expected in 2018.