Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Novo Nordisk A/S, Novo Alle 1, DK-2880 Bagsvaerd, Denmark
Pharmacotherapeutic group: antihaemorrhagics, other systemic haemostatics
ATC code: B02BX10
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.
The NN7415-4311 trial was a multi-national, multi-centre, open-label phase 3 trial to investigate efficacy and safety of concizumab for prophylaxis of bleeding episodes in 91 adults (58 HAwI and 33 HBwI) and 42 adolescents (22 HAwI and 20 HBwI) male patients with haemophilia A or B with inhibitors.
The trial was comprised of 4 arms, including two non-randomised arms:
Patients were aged ≥12 years of age and body weight >25 kg, with congenital Haemophilia A or B of any severity with documented history of inhibitor (≥0.6 BU), who had been prescribed, or in need of, treatment with bypassing agents in the last 24 weeks prior to screening. The patients received a dose regimen in line with the SmPC recommendations.
The primary objective of the study was to compare the effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with bypassing agents) in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A or B with inhibitors (see Table 3). Using a negative binomial model, a ratio of the annualised bleeding rates (ABR) was estimated to 0.14 (p<0.001), corresponding to a reduction in ABR of 86% for subjects on concizumab prophylaxis compared to no prophylaxis. An additional analysis including all available information following the ITT principle shows an estimated ABR ratio of 0.20 (95% CI [0.09;0.45], p<0.001).
Additionally, the number of patients with zero bleeds has been calculated.
Median ABRs and number of patients with zero bleeds are shown in Table 3.
Efficacy was also assessed when all patients in arm 2, 3 and 4 had completed at least 56 weeks of treatment, and the results were consistent with results presented in Table 3.
Table 3. Annualised bleeding rate with concizumab prophylaxis versus no prophylaxis in patients with haemophilia A with inhibitors and Haemophilia B with inhibitors ≥12 years of age (NN7415-4311, arms 1 and 2):
| HAwI and HBwI concizumab prophylaxis N=33 | HAwI and HBwI no prophylaxis N=19 | ABR ratio [95% CI] | |
|---|---|---|---|
| Treated spontaneous and traumatic bleeds | |||
| Estimated mean ABR [95% CI] | 2.1 [1.32; 3.46] | 14.8 [8.96; 24.35] | 0.14 [0.07; 0.29] P<0.001 |
| Median (Min; Max) ABR | 0.00 (0.0; 66.4) | 9.76 (0.0; 94.7) | |
| # patients with 0 bleeds who completed 24 weeks of treatment (%) | 17 (51.5%) | 1 (5.3%) | |
| # patients with 0 bleeds who didn’t complete 24 weeks of treatment (%) | 4 (12.1%) | 1 (5.3%) | |
| Treated joint bleeds | |||
| Estimated mean ABR [95% CI] | 1.7 [1.00; 2.97] | 11.4 [6.60; 19.68] | 0.15 [0.07; 0.32] |
| Treated target joint bleeds | |||
| Estimated mean ABR [95% CI] | 1.4 [0.40; 4.80] | 6.8 [2.00; 22.87] | 0.21 [0.04; 1.17] |
| Treated and untreated bleeds | |||
| Estimated mean ABR [95% CI] | 5.2 [3.43; 8.02] | 15.8 [9.59; 26.10] | 0.33 [0.17; 0.64] |
# – Number of; HAwI – Haemophilia A with inhibitors; HBwI – Haemophilia B with inhibitors; ABR – Annualised bleeding rate; Bleed definitions were according to World Federation of Haemophilia criteria.
Efficacy was evaluated in haemophilia A and B patients with inhibitors when all patients in arms 1 and 2 had completed the main part of the trial (at least 24 or at least 32 weeks, respectively), by comparing the number of treated bleeding episodes between concizumab prophylaxis (arm 2) and no prophylaxis (arm 1).
Estimated mean ABRs and associated ABR ratios are based on a negative binomial regression with the patient’s number of bleeds analysed as a function of the randomised treatment regimen, type of haemophilia (HAwI or HBwI) and bleeding frequency (<9 or ≥9 bleeding episodes during the past 24 weeks prior to screening) and the logarithm of the length of the observation period included as an offset in the model. The estimated mean ABRs are marginal estimates based on the covariate distribution present in the study population. The model is based on all patients randomised and accounts for the use of ancillary therapy. The statistical model for the treated target joint bleeds is only fitted for the patients having target joints at baseline.
Increased levels of fibrin D-dimer and fragment 1.2 were reported across the multiple dose trials. Concizumab plasma concentration is positively correlated with fibrin D-dimer and prothrombin fragments 1.2 indicating haemostatic effect of concizumab.
No clinically significant changes were seen in fibrinogen, anti-thrombin and platelets.
While using concizumab dosing regimen and the breakthrough bleed guidance in section 4.2 bleeds were effectively and safely treated with no thromboembolic events observed. The safety and efficacy of concomitant use of concizumab prophylaxis dosing regimen and breakthrough bleed treatment were confirmed in trial NN7415-4311. A total of 408 bleeding episodes were treated with rFVIIa (majority) and FEIBA (≥56 weeks for concizumab treatment arms).
During the treatment periods in trials NN7415-4159 (11 weeks), NN7415-4310 and NN7415-4255 (≥76 weeks), NN7415-4311 (≥56 weeks for concizumab treatment arms) and NN7415-4307 (≥32 weeks for concizumab treatment arms), 68 out of 320 concizumab treated patients (21.3%) tested positive for anti-concizumab antibodies, of which 17 patients (5.3%) tested positive for in vitro-neutralising antibodies. In 1 (1.5%) of the 68 patients testing positive for anti-concizumab antibodies, the in vitro-neutralising antibodies co-occurred with restoration of free TFPI levels. In the remaining 67 patients (98.5%), there was no identified clinically significant effect of the antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of concizumab.
The European Medicines Agency has deferred the obligation to submit the results of studies with concizumab in one or more subsets of the paediatric population in the treatment of congenital haemophilia A with inhibitors and the treatment of congenital haemophilia B with inhibitors (see section 4.2 for information on paediatric use).
Pharmacokinetic trials have shown that systemic exposure to concizumab, as measured by AUC and Cmax, 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 Table 4. The pre-dose (trough) plasma concentrations remained stable throughout 56 weeks of treatment.
Table 4. Steady state concizumab concentrations during 24 hours dosing interval at week 24 (NN7415-4311):
| Parameters | All maintenance doses N=99* |
|---|---|
| Cmax,ss (ng/mL), geometric mean (CV) | 1 167.1 (1.3) |
| Ctrough,ss (ng/mL), geometric mean (CV) | 665.4 (2.2) |
| Cmax/Ctrough ratio, mean (SD) | 2.2 (5.2) |
Cmax,ss = maximum plasma concentration at steady state.
Ctrough,ss = pre-dose (trough) plasma concentration at steady state.
* on concizumab dosing regimen
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 (tmax) was in the range from 8 hours to 99 hours (4.1 days).
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.
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.
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.
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.
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 AUC0-24h).
Studies in animals to evaluate the carcinogenic potential of concizumab, or studies to determine the effects of concizumab on genotoxicity have not been performed.
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 AUC0-24h), 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.
No data are available with respect to potential side effects of concizumab on embryofoetal development.
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 AUC0-24h.
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