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

Haemophilia. 2019 Jan;25(1):60-66. doi: 10.1111/hae.13627. Epub 2018 Nov 8.

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.

Keywords: concizumab; haemophilia; modelling; pharmacodynamics; pharmacokinetics; phase 1.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Coagulants / pharmacokinetics
  • Coagulants / therapeutic use*
  • Double-Blind Method
  • Half-Life
  • Hemophilia A / drug therapy*
  • Hemophilia B / drug therapy*
  • Hemorrhage / pathology
  • Humans
  • Placebo Effect
  • Thrombin / analysis
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Coagulants
  • concizumab
  • Thrombin

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