Concizumab

Concizumab is an anti-tissue factor pathway inhibitor (anti-TFPI) antibody. TFPI is an inhibitor of factor Xa (FXa). Concizumab binding to TFPI prevents TFPI inhibition of FXa. The increased FXa activity prolongs the initiation phase of coagulation and allows sufficient thrombin generation for effective haemostasis. Concizumab acts independently from FVIII and FIX.

In the NN7415-4311 trial, mean free TFPI (plasma TFPI not bound to concizumab) for patients on concizumab prophylaxis decreased by 87% within 24 hours following administration of the concizumab loading dose and remained stable over time. Concizumab re‐established thrombin generation capacity reflected by mean thrombin peak within the range of normal plasma, and 94% of patients having thrombin peak values within the range of normal plasma (26–147nM) at the 56-week cut-off. Transiently, moderately elevated thrombin peak levels were reported in 37.6% of patients with no associated safety concerns.

Pharmacokinetic trials have shown that systemic exposure to concizumab, as measured by AUC and C_max, increased with increasing dose in a greater than dose-proportional manner. This non-linear pharmacokinetic behaviour is caused by target-mediated drug disposition (TMDD) which occurs when concizumab binds to endothelial cell-anchored TFPI with subsequent elimination of the drug-target complex. This is a saturable process and the extent of concizumab elimination by TMDD is determined by the amount of endothelial cell-anchored TFPI. This results in a fast elimination/high clearance at low concizumab concentrations (where the non-linear pathway is dominant) and a slower elimination/lower clearance at higher concizumab concentrations (where the linear pathway is dominant).

The concizumab exposure was similar between haemophilia A and B with inhibitors. Geometric mean steady state concizumab concentrations at week 24 are shown in the following table. The pre-dose (trough) plasma concentrations remained stable throughout 56 weeks of treatment.

Steady state concizumab concentrations during 24 hours dosing interval at week 24 (NN7415-4311):

C_max,ss = maximum plasma concentration at steady state.
C_trough,ss = pre-dose (trough) plasma concentration at steady state.
^* on concizumab dosing regimen

Absorption

Following a single-dose subcutaneous administration of 0.05–3 mg/kg concizumab in healthy and haemophilia subjects, the time to maximum plasma concentration of concizumab (t_max) was in the range from 8 hours to 99 hours (4.1 days).

Biotransformation

Concizumab is an antibody and like other large proteins these are mainly catabolised by lysosomal proteolysis into amino acids, which are subsequently excreted or reused by the body. Concizumab is expected to follow this catabolic pathway both for the non-linear elimination pathway via TMDD and for the linear elimination pathway via Fc receptor binding which is common for antibodies.

Elimination

Both linear and non-linear pathways contribute to the elimination of concizumab. A terminal half-life in healthy and haemophilia subjects dosed a single subcutaneous dose of 0.25–3 mg/kg was measured in the range from 39 hours (1.6 days) to 195 hours (8.1 days). At steady state levels, where the linear elimination becomes dominant, the total half-life can be longer.

Special populations

Age

Age had no effect on the concizumab exposure in patients with haemophilia A or B with inhibitors. The study population was within the age range 12−61 years.

Renal impairment

Limited data is available on renal impairment. Of the 112 patients treated with concizumab dosing regimen in NN7415-4311, 4 patients had mild renal impairment (eGFR between 60 and 90 mL/min/1.73 m²) and 1 patient had moderate renal impairment (eGFR between 30 and 60 mL/min/1.73 m²) at the time when the loading dose was administered. No impact on exposure of concizumab was observed. No data is available on severe renal impairment.

Hepatic impairment

Limited or no data is available on hepatic impairment. Of the 112 patients treated with concizumab dosing regimen in NN7415-4311, 4 patients had elevated liver enzymes (ALT or AST ≥1.5 x ULN) at the time when the loading dose was administered. No impact on exposure of concizumab was observed.

Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicology.

Pharmacology mediated formation of thrombi was observed in a 52-week toxicology study in cynomolgus monkeys at subcutaneous doses of ≥1 mg/kg/day (corresponding to 300-fold the human exposure based on AUC_0-24h).

Carcinogenicity

Studies in animals to evaluate the carcinogenic potential of concizumab, or studies to determine the effects of concizumab on genotoxicity have not been performed.

Fertility

In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3 400-fold the human exposure, based on AUC_0-24h), concizumab did not affect fertility (testicular size, sperm functionality or menstrual cycle duration) and did not cause any changes in the male or female reproductive organs.

Teratogenicity

No data are available with respect to potential side effects of concizumab on embryofoetal development.

Drug-drug interaction

In a 28-day drug-drug interaction toxicity study in cynomolgus monkeys with daily dosing of 1 mg/kg concizumab to achieve steady state, three consecutive intravenous doses of up to 1 mg/kg rFVIIa were administered with 2-hour intervals to the concizumab dosed animals. No adverse findings were observed at a concizumab exposure corresponding to 200-fold the human exposure, based on AUC_0-24h.