Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: antihemorrhagics, blood coagulation factor VIII, ATC code: B02BD02.

Mechanism of action

Turoctocog alfa pegol is a purified recombinant human factor VIII (rFVIII) product with a 40 kDa polyethylene-glycol (PEG) conjugated to the protein. The PEG is attached to the O- linked glycan in the truncated B-domain of rFVIII (turoctocog alfa). The mechanism of action of turoctocog alfa pegol is based on the replacement of the deficient or absent factor VIII in patients with haemophilia A.
When turoctocog alfa pegol is activated by thrombin at the site of injury, the B-domain containing the PEG moiety and the a3-region are cleaved off, thus generating activated recombinant factor VIII (rFVIIIa) which is similar in structure to native factor VIIIa.
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When injected into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation.
Activated factor VIII acts as a cofactor 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 results of accidental or surgical trauma. By factor VIII replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Clinical efficacy during prophylaxis and treatment of bleeding episodes 
The clinical efficacy of Esperoct for prophylaxis and treatment of bleeds was investigated in five prospective, multi-centre clinical studies in 270 previously treated patients (PTPs) with severe haemophilia A.
The haemostatic effect was confirmed in adults/adolescents and in children.

Prophylaxis in adults/adolescents

The efficacy of Esperoct for prophylaxis and treatment of bleeds was evaluated in an open- label, non-controlled trial in adolescents and adult patients with severe haemophilia A ages 12 years and above. The prophylactic effect of Esperoct was demonstrated with a dosing at 50 IU per kg body weight every 4 days or every 3–4 days (twice weekly) in 175 patients. The median annualized bleeding rate (ABR) in adults and adolescents receiving Esperoct was 1.18 (Interquartile range IQR: 0.00;4.25), whereas the spontaneous ABR was 0.00 (IQR: 0.00;1.82), traumatic ABR was 0.00 (IQR: 0.00;1.74) and joint ABR was 0.85 (IQR: 0.00;2.84). When including imputations, (replacing missing data for withdrawn patients with a substituted value) the estimated mean ABR for all bleeds was 3.70 (95% CI: 2.94;4.66). Of 
the 175 adults/adolescents on prophylaxis, 70 (40%) did not have any bleeds. The mean annual consumption for prophylaxis was 4641 IU/kg.

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

Adults/adolescents who had a low bleeding rate of 0-2 bleeding episodes during the last 6 months and had obtained at least 50 doses of Esperoct had the option of being randomised to prophylaxis treatment every 7 days (75 IU/kg every 7 days) or every 4 days (50 IU/kg every 4 days). A total of 55 of the 120 eligible patients chose to be randomised (17 to the every 4 days dosing and 38 to the 75 IU every 7 days). The ABR for randomised patients was 1.77 (0.59; 5.32) for treatment every 4 days and 3.57 (2.13; 6.00) for once weekly prophylaxis. Nine of these patients reverted back to prophylaxis every 4 days during the randomised study phase.
Overall, including all extensions parts, 31 of 61 patients on every 7 days prophylaxis switched back to every 4 days treatment.

Prophylaxis in children (below 12 years)

The efficacy and safety of Esperoct for prophylaxis treatment of bleeds were evaluated in an open-label, single-arm, non-controlled trial in 68 children below 12 years with severe haemophilia A.
The prophylactic effect of Esperoct was demonstrated with a dosing at 60 IU per kg body weight (50-75 IU/kg) twice weekly. The median and estimated mean annualised bleeding rate in children below 12 years receiving Esperoct twice weekly was 1.95 and 2.13 (95% CI: 1.48;3.06), whereas the spontaneous ABR was 0.00 and 0.58 (95% CI: 0.24;1.40), traumatic ABR was 0.00 and 1.52 (95% CI: 1.07;2.17) and joint ABR was 0.00 and 1.03 (95% CI: 0.59;1.81), respectively. Of the 68 children below 12 years on prophylaxis, 29 (42.6%) did not have any bleeds.
The mean annual consumption for prophylaxis was 6475 IU/kg.


Clinical efficacy of Esperoct in treatment of bleeding episodes and during on-demand treatment

The efficacy of Esperoct in the treatment of bleeding episodes was demonstrated in all age groups.
The vast majority of bleeds treated with Esperoct were of mild/moderate severity.
The overall success rate for the treatment of bleeds was 87.7% and 94.4% of all bleeds treated with 1-2 injections.

In 12 patients above 18 years of age, 1,126 bleedings were treated among patients receiving on-demand treatment with an average treatment dose of 38.1 IU/kg with a mean annual consumption of 1457 IU/kg. Of the total 1,126 bleeds, 86.9% were effectively treated with 1 injection and 96.8% were effectively treated with 1-2 injections of Esperoct.

Clinical efficacy of Esperoct during major surgery

Esperoct was effective in maintaining haemostasis during major surgery with a success rate of 95.6% in all major surgeries performed (43 out of 45 had the effect rated as ‘excellent‘ or ‘good‘).

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

In total, 129 single-dose pharmacokinetic (PK) profiles of Esperoct were evaluated in 86 patients (including 24 paediatric patients of 0 to below 12 years).

All pharmacokinetic studies with Esperoct were conducted in previously treated patients with severe haemophilia A (factor VIII <1%). Patients received a single dose of 50 IU/kg, and blood samples were collected prior to dosing and at multiple time points up to 96 hours after dosing.

The half-life of Esperoct was 1.6 fold longer compared to unmodified factor VIII products in adults.

Pharmacokinetic parameters

A total of 108 single dose pharmacokinetic profiles at 50 IU/kg Esperoct were evaluated in 69 patients. The single dose pharmacokinetic parameters are comparable between young children (0 to below 6 years) and older children (6 to below 12 years), and between adolescents (12 to17 years) and adults (18 years and above).
As expected incremental recovery appeared to be lower while body weight adjusted clearance appeared to be higher in children compared to adults and adolescents. In general, there was a trend of increasing incremental recovery and decreasing clearance (mL/h/kg) with age. This corresponds to a higher volume of distribution per kilo body weight in children compared to adults (table 4).
The single dose pharmacokinetic parameters determined after 28 weeks of prophylactic treatment with Esperoct were consistent with the initial pharmacokinetic parameters.

Single-dose pharmacokinetic parameters of Esperoct are listed in table 4.

Table 4         Single-dose pharmacokinetic parameters of Esperoct 50 IU/kg in children, adolescents and adults by age using the chromogenic assay
(geometric mean [CV%])
PK Parameter        0 to below 6      6 to below 12         12 to       18 years and N=No. of                years              years       below18 years        above patients                N=13               N=11             N=3             N=42 Number of                 13                11                5               79 profiles
IR (IU/dL) per        1.80 (29)          1.99 (25)        2.79 (12)       2.63 (22) (IU/kg)a
Maximum              101.2 (28)         119.6 (25)        133.2 (9)      134.4 (23) factor VIII activity
(IU/dL)a t1/2 (hours)          13.6 (20)          14.2 (26)        15.8 (43)       19.9 (34) AUCinf                2147 (47)         2503 (42)        3100 (44)       3686 (35) (IU*hour/dL)
CL                     2.6 (45)          2.4 (40)         1.5 (43)         1.4 (32) (mL/hour/kg)
Vss (mL/kg)           44.2 (34)          41.2 (25)        33.4 (10)       37.7 (27) MRT (hours)           17.0 (22)          17.3 (31)        21.7 (45)      25.2 (29)b Abbreviations: AUC = area under the factor VIII activity time profile; t1/2 = terminal half-life; MRT = mean residence time; CL = clearance;
Vss = volume of distribution at steady–state; IR = Incremental recovery.


a
Incremental recovery and factor VIII were assessed 30 min post-dosing for patients 12 years and above and 60 min post-dosing (first sample) for children below12 years.
b
Calculation based on 67 profiles.
The mean trough plasma factor VIII activity levels at steady–state during prophylactic treatment with Esperoct dosed with 50 IU/kg every 4 days is 3.0 IU/dL (95% CI: 2.6;3.4) in patients 12 years and above.
For patients under 12, who received 60 IU/kg (50 – 75 IU/kg) twice weekly, the mean steady-state factor VIII plasma activity level before administration during prophylactic treatment was 1.5 IU/dl (95% CI: 1.2; 1.9).