Novel human-cell derived recombinant Factor VIII product limits inhibitor development

SAN DIEGO — A novel antihemophilic factor recombinant product derived from human cells demonstrated a low rate of inhibitor development among previously untreated patients with severe hemophilia A, according to study results presented at the ASH Annual Meeting and Exposition.

“Studies have shown that the incidence of inhibitor development varies between Factor VIII concentrates, with some suggesting that recombinant Factor VIII concentrates produced in hamster cell lines pose a greater risk of inhibitor development than plasma-derived von Willebrand factor–containing Factor VIII products,” the researchers wrote.

However, none of these studies included new generation recombinant Factor VIII (FVIII) products manufactured in human cell lines. The ongoing, phase 3 NuProtect study aims to examine the efficacy, safety and immunogenicity of human coagulation FVIII (rDNA), simoctocog alfa (Nuwiq, Octapharma), a new-generation recombinant FVIII produced in human cells without chemical modification or protein fusion, in previously untreated patients with severe hemophilia A.

The study, which began in 2013, is being conducted in 17 countries and 38 centers throughout the world. One hundred previously untreated men of all ages and ethnicities (out of 110 enrolled) are being evaluated for 100 exposure days or a maximum participation period of 5 years. Patients previously exposed to FVIII concentrates or other blood products containing FVIII were not eligible for enrollment.

Raina Liesner, MD, of the Great Ormond Hospital for Children NHS Trust Haemophilia Centre in London, and colleagues examined data from the first pre-planned interim analysis of the NuProtect study in May 2016, which included 85 previously untreated patients with severe hemophilia A. At that point, 66 of the previously untreated patients had 20 or more exposure days, which is when most inhibitors would have been likely to develop.

The immunogenicity of Nuwiq was evaluated by determining inhibitor activity (≥ 0.6 BU/mL) with the Nijmegen modified Bethesda assay. Screening for inhibitors was conducted every 3 to 4 exposure days until 20 exposure days, every 10 to 12 exposure days until 100 exposure days and every 3 months until the end of the study. F8 gene mutation analysis was conducted in all patients.

Median age at first treatment with Nuwiq was 13 months (range, 3 to 135). Among the patients in whom F8 gene mutation analysis was available (n = 59), 1 (1.7%) had no identifiable mutation; 44 (74.6) had mutations that conferred a high risk of inhibitor development and 47 (81%) had null mutations.

Interim analysis

Data examined by Liesner and colleagues demonstrated that 8 of the 66 previously untreated patients receiving Nuwiq for 20 or more exposure days developed a high-titer inhibitor following a median of 11.5 exposure days (range, 6 to 24). Five patients developed low-titer inhibitors; 4 of these (80%) were transient. Two patients developed an inhibitor after 20 exposure days, although only one was a high-titer inhibitor.

The cumulative incidence of high-titer inhibitors among previously untreated patients receiving Nuwiq was 12.8% (95% CI, 4.49 to 21.15) for high-titer inhibitors, 8.4% (95% CI, 1.28 to 15.59) for low-titer inhibitors and 20.8% (95% CI, 10.68 to 30.95) for all inhibitors. No inhibitors were observed after 25 exposure days and the rate of inhibitor development has been consistent since the study was initiated.

Among patients in whom F8 gene mutation analysis was available (n = 59), 1 patient had no identifiable mutation (1.7%). Mutations associated with a high risk of inhibitor development were noted in 44 patients (74.6%); null mutations were identified in 47 patients (81%). The causative F8 gene mutation was seen in 12 of 13 patients who developed inhibitors, all of which were null; all but one were high-risk mutations.

“Previously untreated patients treated with Nuwiq for [20 or more] exposure days had a 12.8% cumulative incidence of high-titer inhibitors at the time of interim analysis, despite the fact that 81% of patients had gene mutations known to be associated with increased inhibitor risk (eg, null mutations),” the researchers wrote. “These interim data support the low rate of inhibitor development in previously untreated patients treated with Nuwiq, a human-cell derived recombinant FVIII.” – by Julia Ernst, MS

Reference:

Liesner R, et al. Abstract 327. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosures: Leisner reports receiving consulting fees, honoraria and research funding from Baxalta Innovations GmbH, a wholly owned, indirect subsidiary of Shire; consulting fees, honoraria and speakers bureau fees from Bayer; consulting fees, honoraria and research funding from Biogen; consulting fees, honoraria and research funding from BPL; research funding from Cangene; consulting fees, honoraria and research funding from CSL Behring; consulting fees and honoraria from Grifols; consulting fees, honoraria, research funding and speakers bureau fees from Octapharma; consulting fees, honoraria and research funding from Pfizer; and consulting fees, honoraria, research funding and speakers bureau fees from Sobi. Please see the full study for a list of all other researchers’ relevant financial disclosures.