The TRUST Trial: Anti-Drug Antibody Formation In a Patient With Hemophilia With Inhibitors After Receiving The Activated Factor VII Product Bay 86-6150

Up to 30% of patients with hemophilia A and 5% of patients with hemophilia B develop neutralizing antibodies (inhibitors) against replacement factor VIII or factor IX, respectively. Acute bleeding episodes in these patients with inhibitors are treated with bypassing agents, which include activated recombinant factor VII (rFVIIa). BAY 86-6150 is a modified rFVIIa which in preclinical studies was shown to have prolonged half-life and improved potency compared with currently available rFVIIa. In a phase 1, randomized, double-blind trial, BAY 86-6150 was not associated with any clinically significant adverse events (AEs). We report the immunologic response to BAY 86-6150 in a phase 2/3 clinical trial in patients with hemophilia with inhibitors.

TRUST (Treatment with Unique Recombinant FVII Study) was a multicenter, open-label, 2-part study (part A and part B) which included males aged 12−62 years with moderate or severe hemophilia A or B, with a history of high-titer inhibitors (≥5 Bethesda units), and ≥4 bleeding episodes in the 6 months prior to enrollment. Part A was a sequential dose-escalation study of 4 BAY 86-6150 dose levels (6.5, 20, 50, and 90 μg/kg body weight; n≥10/cohort). Dose escalation was dependent on both efficacy and an Independent Data Monitoring Committee (IDMC) approval of safety in 10 patients per cohort who had ≥1 bleeding episode treated with BAY 86-6150. Part B was designed as a single-arm investigation of the efficacy and safety of the recommended dose of BAY 86-6150 determined in all patients from Part A. Safety endpoints were AEs and immunogenicity. Anti-drug antibody testing was performed at screening (prior to exposure), after the second exposure, then every fifth exposure, and at the end of study visit in both part A and part B. Anti-BAY 86-6150 binding antibodies were measured using a validated enzyme-linked immunosorbent assay (ELISA). Samples that revealed a specific immunoreactivity in this assay were further characterized for neutralizing activity using a validated platelet-activated clotting assay. Additional functional assays were performed to determine the cross-reactive neutralizing effect on rFVIIa (NovoSeven^®) of any detected anti-BAY 86-6150 antibodies. The presence of neutralizing antibodies was considered a serious adverse event (SAE) requiring prompt IDMC review.

In cohort 1, 10 patients (mean age, 27.4 years) were treated with 6.5 mg/kg BAY 86-6150. These patients had a total of 73 bleeding events and received a total of 84 study drug injections. No anti-drug antibodies or anti-FVIIa was detected in the patients at screening prior to exposure to the study drug. BAY 86-6150 was well tolerated in all patients with no clinical or laboratory symptoms or signs of venous thromboembolism. Binding antibodies to BAY 86-6150 were detected on a scheduled screening visit in 1 patient after 3 exposures to BAY 86-6150; these anti-BAY 86-6150 antibodies displayed neutralizing activity against BAY 86-6150 and were also cross-reactive and neutralizing for rFVIIa. The affected patient had received rFVIIa before entry into the study. At the time of diagnosis of binding and neutralizing antibodies, the affected patient was not bleeding and did not require emergency treatment. Exposure to BAY 86-6150 was stopped and the trial was terminated at the first cohort. Subsequent bleeding episodes in this patient were successfully managed with FEIBA^TM (Factor Eight Inhibitor Bypass Activity). No other treatment-related AEs or SAEs were reported in this study. Additionally, the IDMC has recommended safety follow-up assessments for all the patients who actively participated in the trial.

The TRUST trial has been discontinued as a precautionary measure because of potential safety concerns related to the detection of the antidrug antibodies in 1 patient. Development of neutralizing antibodies against BAY 86-6150 that had a cross-reactive neutralizing effect on rFVIIa was considered a serious risk because of the limited treatment options in patients with inhibitors. These results underline the fact that it is currently not possible to predict immunologic response based on preclinical and phase 1 studies.

Hardtke:Bayer Pharma AG: Employment. Schroeder:Bayer Pharma AG: Employment.