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 (E_max ) 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 E_max model were constructed based on EXPLORER3 observations.

Results: The E_max 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.

Figure 1

Concizumab concentration and free tissue factor pathway inhibitor (TFPI) observations. Concizumab phase 1/1b data used to build an estimated exposure‐response (E _max) model for concizumab‐free TFPI are shown. The lower limit of quantification values varied between trials. Free TFPI values were generally higher in EXPLORER2 and EXPLORER3 than in EXPLORER1 and the Japanese trial. This was observed in both placebo and pre‐dose samples, as well as in post‐dose samples. This observation was included as a baseline fixed effect in the concizumab exposure‐free TFPI model

Figure 2

Relationship between concizumab exposure, free tissue factor pathway inhibitor (TFPI) and bleeding episodes. Estimated exposure‐response (E _max) model of free TFPI predictions based on all concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available are shown. Free TFPI predictions relative to the predicted baseline free TFPI concentration vs observed concizumab concentration are shown. At bleeding events in EXPLORER3 (red dots), concizumab concentration was predicted using a population pharmacokinetic model (based on all available intravenous and subcutaneous clinical data for concizumab doses >0.05 mg/kg and up to 9 mg/kg) and, subsequently, free TFPI concentration was predicted using a concizumab−free TFPI E _max model. The solid line represents predictions of free TFPI concentration vs concizumab concentration for a typical subject. A typical subject was defined as a subject from EXPLORER2 or EXPLORER3 with typical baseline TFPI concentration and EC₅₀ value. Jitter has been added to free TFPI levels for bleeds at predicted PK levels below 10 ng/mL in order to distinguish points graphically. The same has been done to observations at full reduction of free TFPI. Predictions are not shown for concizumab 9 mg/kg

Figure 3

Concizumab plasma concentration and peak thrombin generation potential in EXPLORER3. Peak thrombin generation vs concizumab concentration based on observations in the EXPLORER3 trial for the three concizumab doses tested (0.25, 0.5 and 0.8 mg/kg) are shown, excluding data obtained ≤72 h following factor VIII administration. The solid line represents predictions from an E _max model in which the peak thrombin generation logarithm was fitted with concizumab concentration as explanatory variable. The dotted horizontal lines indicate the normal range of thrombin generation potential (60‐130 nmol/L)

Figure 4

Correlation between concizumab concentration and peak thrombin generation in EXPLORER3. Based on all EXPLORER3 data for which simultaneously collected concizumab and peak thrombin generation samples were available. Observations excluding data ≤72 h following factor VIII administration due to bleeding events are shown. Peak thrombin is shown as individual values and medians (central horizontal line) with interquartile ranges (error bars). The dotted horizontal lines indicate the normal range of thrombin generation potential (60‐130 nmol/L)