Evaluation of Pharmacokinetics, Efficacy and Safety of a New Human Fibrinogen Concentrate in Patients with Congenital Fibrinogen Deficiency

Introduction: Congenital fibrinogen deficiencies (CFD) are rare coagulopathies characterized by impaired hemostasis and moderate to severe bleeding manifestations due to a deficiency or absence of fibrinogen. Fibrinogen concentrates are indicated for treating CFD. The aim of this trial was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) parameters, surrogate efficacy and safety of a novel plasma-derived human fibrinogen concentrate (HFC) (BT524, Biotest AG) in patients with congenital afibrinogenemia or severe congenital hypofibrinogenemia.

Methods: This was a prospective, multi-national, open label, single arm interventional PK/PD, efficacy and safety trial in patients with congenital fibrinogen deficiency (EudraCT:2011-004154-25). The trial was divided into part 1 (phase I) that focused on the single-dose PK/PD of BT524 and part 2 (phase III) that evaluated the efficacy and safety of BT524 used as on-demand treatment or prophylaxis of bleeding events (multiple doses). In part 1, patients were treated with a single fixed dose of 70 mg/kg bodyweight of HFC. The primary objective was to investigate the PK of HFC following single IV infusion. PK/PD parameters were obtained using population PK/PD modelling and non-compartmental analysis from plasma concentration of fibrinogen antigen levels (immunonephelometry) and fibrinogen activity (Clauss assay). Mean change in maximum clot firmness (MCF) was assessed in plasma samples by rotational thromboelastometry as surrogate efficacy endpoint following a single infusion. Safety parameters were evaluated for 49 days.

Results: Twenty-seven patients (adults, n=15; 12 to <18 years, n=3; 6 to <12 years, n=3; and <6 years, n=6) were treated with the HFC. For fibrinogen antigen levels, mean (SD) PK parameters were as follows: C_max 1.81 (0.42) g/L, AUC_0-∞ 173 (45.4) g*h/L, and t_1/2 67.9 (15.3) h. For fibrinogen activity, mean (SD) C_max was 1.26 (0.4) g/L, AUC_0-∞ 104 (33.5) g*h/L, t_1/2 of 60.3 (13.3) h. The incremental in-vivo recovery (IVR) of fibrinogen activity was 1.88 (0.61) mg/dL per mg/kg, and classical IVR, 84.8 (27.5) %. At pre-dose, the MCF was below the detection limit. In adults, MCF significantly increased 1 h after HFC infusion (mean [SD] change 11.1 [5.1] mm, P<0.0001, 95% CI: 9.33-14.47). Similarly, the mean MCF increase across pediatric groups ranged from 9.3 to 16.5 mm. This increase was sustained for 8 h, with levels ranging between 8.7 (2.52) mm, in the 12 to <18 years group, and 12.7 (4.68) mm, in adults (P<0.0001). A total of 31 treatment-emergent adverse events (TEAEs) were reported in 15 (55.6%) patients. The incidence of related TEAEs was very low, with only one mild related TEAE being reported in one patient (3.7%). Three serious adverse events occurred in 2 (7.4%) patients, but none of them were assessed as related to trial drug. No thromboembolic events occurred in any patient.

Conclusions: This trial showed the PK/PD profile of this novel HFC in patients with CFD. The HFC effectively increased antigen levels and activity, restored clot formation, and demonstrated a favorable safety and tolerability profile across all age groups.