Abstract

Introduction: Concizumab is a humanized monoclonal antibody (mAb) that enhances thrombin generation (TG) potential by inhibiting tissue factor pathway inhibitor (TFPI). explorer™3 (NCT02490787) was a phase 1b, double-blind, multiple-dose escalation trial of subcutaneously administered concizumab in patients with severe hemophilia A without inhibitors in which the safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of concizumab were assessed. Three dose cohorts (0.25, 0.5, 0.8 mg/kg every fourth day) of eight participants were included. The primary analysis of explorer™3 raised no safety concerns and a PK/PD relationship among concizumab dose, unbound TFPI and TG was confirmed. Here, we present results from exploratory PK/PD analyses that aimed to determine the association between concizumab exposure and PD markers (unbound TFPI, reported bleeding episodes and peak TG).

Methods :Predictions of unbound TFPI (i.e., not bound to concizumab) were generated using an estimated exposure-response (Emax) model between concizumab and unbound TFPI. Concizumab concentration at the time of a bleeding episode was predicted using a PK model. The level of unbound TFPI at the time of a bleeding episode was predicted using the estimated concizumab concentration and the unbound TFPI model. The PK model was based on available data for clinically relevant doses of concizumab (>50 µg/kg), using both intravenous and subcutaneous administration. Data were best described by a 2-compartment model, with both linear and non-linear clearance components. Classical disposition parameters (clearance and volume) were comparable to those reported for other mAbs (Dirks NL, Meibohm B. Clin Pharmacokinet 2010; 49[10]: 633−59). Variability simulations were performed using individually estimated parameters, and by repeating inter-occasion variability components as estimated within patients. Plots of unbound TFPI and peak TG versus concizumab concentrations were constructed based on observations in the explorer™3 trial.

Results : Following the principle of target-mediated drug disposition (TMDD), a dose-dependent but non-linear increase in concizumab exposure was documented. Dose-dependent between-patient concizumab concentration variability was observed. In the higher dose cohorts, large within-patient, peak-to-trough and other residual variability were also observed. The PK model predicted that once-daily dosing would minimize between-patient PK variability by minimizing the peak-to-trough differences observed in the highest dose cohort in explorer™3, and by minimizing the influence of absorption variability. TheEmax model showed a tight PK/PD relationship between concizumab exposure and unbound TFPI, with unbound TFPI decreasing with increasing concizumab concentration. A correlation between the frequency of bleeding episodes and concizumab concentration was indicated, with the least frequent bleeding in patients with a concizumab concentration >100 ng/mL and no apparent effect for exposures <100 ng/mL. There was also a strong correlation between concizumab concentration and peak TG, with concizumab >100 ng/mL re-establishing TG potential to within the normal reference range (60−130 nM). Median (interquartile range [IQR]) peak thrombin was 15 (10−24), 31.5 (17.25−61) and 81 (65.5−100) nM for concizumab ≤20, >20 to ≤100 and >100 ng/mL, respectively. As shown in earlier clinical trials, patients with the highest exposure (up to 5000 ng/mL) showed increased levels of D-dimer and prothrombin fragment 1+2.

Conclusions : Post-hoc, explorer™3 PK/PD analyses indicated a clinically relevant prophylactic effect for patients with hemophilia A without inhibitors based on the decrease in reported bleeding episodes at estimated concizumab exposure levels >100 ng/mL. Additionally, at these exposure levels, the TG potential was predominantly within the normal range. The phase 2 clinical development program has therefore been designed to target a concizumab exposure of at least 100 ng/mL, and a once-daily, efficacy-based, individual, optional dose-escalation regimen has been selected to reduce exposure variability. The minimum concizumab exposure level required to achieve sufficient efficacy will be fine-tuned following the availability of phase 2 clinical data. These data will also help to firmly establish the therapeutic window for concizumab.

Disclosures

Eichler: Pfizer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Honoraria, Research Funding. Kavakli: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Knöbl: Novo Nordisk: Consultancy. Windyga: Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Baxter Healthcare: Honoraria, Research Funding; Biogen Idec: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. Jimenez-Yuste: Novo Nordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Friedrich: Novo Nordisk: Employment. Andersen: Novo Nordisk: Employment, Equity Ownership. Chowdary: Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy.

Author notes

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Asterisk with author names denotes non-ASH members.