PB0168 - In vitro assessment of clinical coagulation assays in the presence of concizumab

Background: Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in phase 3 clinical development as a once-daily subcutaneous prophylaxis in patients with haemophilia A/B (HA/HB) with or without inhibitors.

Aims: To evaluate the impact of concizumab on coagulation assays validated for use in clinical monitoring, in order to inform potential future clinical monitoring of patients treated with concizumab prophylaxis.

Methods: Concizumab was added to normal human plasma, haemophilia plasma or relevant control plasma. Plasma samples ± concizumab (250–16000 ng/mL) were analysed on an Atellica COAG 360 analyser (Siemens) using commercially available diagnostic kits and calibrators.

Results: Differences in measurements with concizumab were within ±25% of measurements without concizumab for most standard coagulation assays (Table 1). Concizumab resulted in < 20% increased recovery of factor (F) VIII and FIX when measured in the respective one-stage clot assays (OSAs). In the respective chromogenic substrate assays (CSAs), no influence of concizumab on FIX activity was detected; however, decreased recovery (-6%) of FVIII was observed. Concizumab had no effect on Bethesda assays for neutralising anti-FVIII or FIX antibodies (OSAs and CSAs).
In the prothrombin time (PT)-based FVII OSA, addition of concizumab increased recovery of FVII, with a difference in measurements with and without concizumab >25%. This assay interference is in accordance with concizumab’s mechanism of action: in the presence of tissue factor (TF) and activated FVII (FVIIa), FX is converted to active FX (FXa), initiating coagulation. TFPI normally binds and inhibits both FXa and the TF-FVIIa-FXa complex, however, when concizumab is present, this inhibition is prevented, giving increased FXa activity. Hence, shorter clot times are observed in the PT-based FVII OSA, with an apparent increase in FVII activity.

Conclusion(s): The presence of concizumab had minimal impact on most standard clinical coagulation assays and is therefore not expected to interfere with clinical decision-making.