Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, ATC code: B02BD02.

Mechanism of action
NovoEight contains turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B- domain. This glycoprotein has the same structure as human factor VIII when activated, and post- translational modifications that are similar to those of the plasma-derived molecule. The tyrosine sulphation site present at Tyr1680 (native full length), which is important for the binding to von Willebrand factor, has been found to be fully sulphated in the turoctocog alfa molecule. When infused into a haemophilia patient, factor VIII binds to endogenous von Willebrand Factor in the patient’s circulation. The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of bleeding tendencies.

Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.

Clinical efficacy
Four multi-centre, open-labelled, non-controlled trials have been conducted to evaluate the safety and efficacy of NovoEight in the prevention and treatment of bleeds and during surgery in patients with severe haemophilia A (FVIII activity ≤1%). Three of these trials were performed in previously treated patients and the fourth in previously untreated patients. The trials included 298 exposed patients; 175 adolescents or adult patients without inhibitors from the age of 12 years (≥150 exposure days), 63 previously treated paediatric patients without inhibitors below 12 years of age (≥50 exposure days) and 60 previously untreated patients below 6 years of age.

188 out of 238 previously treated patients continued in the safety extension trial. Treatment with NovoEight was shown to be safe and had the intended haemostatic and preventive effect. Of the 3,293 reported bleeds observed in 298 of the patients, 2,902 (88.1%) of the bleeds were resolved with 1-2 infusions of NovoEight.

Table 3 Consumption of NovoEight and haemostatic success rates in previously untreated patients (PUP) and previously treated patients (PTP)
Younger Younger           Older       Adolescents Adults        Total children children         children    (12 –        (≥18 years)
(0 –       (0 –           (6 –        <18 years)   PTP
<6 years) <6 years)       <12 years)  PTP
PUP        PTP            PTP
Number of        60         31             32          24           151          298 patients
Dose used for prevention per patient
(IU/kg BW)
Mean (SD)        45.2       41.5 (8.1)     38.4 (9.4)  28.5 (9.3)   28.5 (8.3)   32.8 (10.9) Min ; Max        (14.4)     3.4 ; 196.3    3.2 ; 62.5  17.4 ; 73.9  12.0 ; 97.4 3.2 ; 363.8 4.5 ;
363.8
Dose used for treatment of bleed (IU/kg
BW)              43.6       44.0 (12.6)    40.4 (10.5) 29.3 (10.3) 35.0 (12.3) 37.5 (13.4) Mean (SD)        (15.2)     21.4 ; 193.8   24.0 ; 71.4 12.4 ; 76.8  6.4 ; 104.0 6.4 ; 193.8 Min ; Max        11.9 ;
118.9
Success ratea % 87.0%       92.2%          88.4%       85.1%        89.6%        88.9% 
BW: Body weight, SD: Standard deviation a
Success is defined as either 'Excellent' or 'Good'.

Pre-authorisation clinical data were corroborated by a non-interventional, post-authorisation safety study conducted in order to provide additional documentation of the immunogenicity, and efficacy and safety of NovoEight in routine clinical practice. In total 68 previously treated patients (>150 EDs), of which 14 patients were <12 years and 54 patients were ≥12 years, received either on-demand (N=5) or prophylactic (N=63) treatment for a total of 87.8 patient years and 8967 EDs.

Surgery
A total of 30 surgeries were performed in 25 patients of which 26 were major surgeries and 4 were minor. Haemostasis was successful in all surgeries and no treatment failures were reported.

Data on Immune Tolerance Induction (ITI) has been collected in patients with haemophilia A who had developed inhibitors to factor VIII. During clinical trial in PUPs, 21 patients were treated with ITI and 18 (86%) patients completed ITI with a negative inhibitor test result.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
All pharmacokinetic (PK) studies with NovoEight were conducted after i.v. administration of 50 IU/kg NovoEight in previously treated patients with severe haemophilia A (FVIII ≤1%). The analysis of plasma samples was conducted using both the one-stage clotting assay and the chromogenic assay.

The assay performance of NovoEight in FVIII:C assays was evaluated and compared to a marketed full length recombinant FVIII product. The study showed that comparable and consistent results were obtained for both products and that NovoEight can be reliably measured in plasma without the need of a separate NovoEight standard.

The single dose pharmacokinetic parameters of NovoEight are listed in Table 4 for the one-stage clotting assay and in Table 5 for the chromogenic assay.

Table 4 Single-dose pharmacokinetics parameters of NovoEight (50 IU/kg) by age - one stage clotting assay - Mean (SD)
Parameter                0 − <6 years        6 − <12 years ≥12 years n=14                n=14             n=33
Incremental recovery     1.8 (0.7)           2.0 (0.4)        2.2 (0.4) (IU/dl)/(IU/kg)
AUC ((IU*h)/dl)          992 (411)           1109 (374)       1526 (577) CL (ml/h/kg)             6.21 (3.66)         5.02 (1.68)      3.63 (1.09) t½ (h)                   7.65 (1.84)         8.02 (1.89)      11.00 (4.65) Vss (ml/kg)              56.68 (26.43)       46.82 (10.63) 47.40 (9.21) Cmax (IU/dl)             100 (58)            107 (35)         123 (41) Mean residence time      9.63 (2.50)         9.91 (2.57)      14.19 (5.08) (h)
Abbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminal half-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity.

Table 5 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by age - chromogenic assay - Mean (SD)
Parameter                0 − <6 years        6 − <12 years ≥12 years n=14                n=14             n=33
Incremental recovery     2.2 (0.6)           2.5 (0.6)        2.9 (0.6) (IU/dl)/(IU/kg)
AUC ((IU*h)/dl)          1223 (436)          1437 (348)       1963 (773) CL (ml/h/kg)             4.59 (1.73)         3.70 (1.00)      2.86 (0.94) t½ (h)                   9.99 (1.71)         9.42 (1.52)      11.22 (6.86) Vss (ml/kg)              55.46 (23.53)       41.23 (6.00)     38.18 (10.24) Cmax (IU/dl)             112 (31)            125 (27)         163 (50) Mean residence time      12.06 (1.90)        11.61 (2.32)     14.54 (5.77) (h)
Abbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminal half-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity.

The pharmacokinetic parameters were comparable between paediatric patients below 6 years of age and the paediatric patients from 6 to below 12 years of age. Some variation was observed in the pharmacokinetic parameters of NovoEight between paediatric and adult patients. The higher CL and the shorter t½ seen in paediatric patients compared to adult patients with haemophilia A may be due in part to the known higher plasma volume per kilogram body weight in younger patients.