Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data

Abstract

Introduction Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose‐dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. Aim Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. Methods Free TFPI predictions were generated using an estimated concizumab‐free TFPI exposure‐response (Emax) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. Results The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re‐established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab‐free TFPI and concizumab‐TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once‐daily dosing would minimize within‐patient concizumab PK variability. Conclusion Concizumab phase 2 trials will target an exposure ≥100 ng/mL, with a once‐daily regimen.

An in vitro pharmacodynamic spiking study of befovacimab, a tissue factor pathway inhibitor monoclonal antibody, in blood samples from patients with severe FVIII deficiency

“…These differences may be explained by the dual mechanism of befovacimab which targets the K1 and K2 domains of TFPI that leads to greater FVIIa‐TF and FXa generation versus simply targeting the K2 domain alone which only enhances FXa generation. Finally, the changes in dPT between befovacimab and marstacimab 17 were similar. At the highest concentrations tested with both molecules (100 nM), the median dPT values were 87 and 100 s, respectively, which is likely not clinically relevant.…”

Prophylaxis Using a Mixture of Plasma-Derived Activated Factor VII and Factor X (pdFVIIa/FX) in a Patient with Hemophilia B Complicated by Inhibitors and Allergy to Factor IX Concentrates: A Case Report

“…Hope is also offered by developments in gene therapy [12, 13]. Moreover, recently, non-factor products such as concizumab [14, 15] and fitusiran [16] are under development. Concizumab is anti-tissue factor pathway inhibitor monoclonal antibody, and fitusiran is an RNA interference therapy that targets antithrombin.…”

Current progress and future direction in the treatment for hemophilia

“…In subsequent trials (eg. EXPLORER 3) [15,16] there was a trend towards a lower ABR at higher concentrations of concizumab, especially over 100 ng/mL Inverse d-dimer and prothrombin fragment 1 + 2 levels have been reported, and depressed fibrinogen levels have been observed at the highest dose in the dose-escalation studies and in the intravenous cohort at the highest doses (1000 or 3000 μg/kg). One healthy subject developed thrombophlebitis.…”