Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04.

Mechanism of action
Refixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG) conjugated to the protein. The average molecular weight of Refixia is approximately 98 kDa and the molecular weight of the protein moiety alone is 56 kDa. Upon activation of Refixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated factor IX molecule.

Factor IX is a single chain glycoprotein. It is a vitamin-K dependent coagulation factor and it is synthesised in the liver. Factor IX is activated by factor XIa and by factor VII/tissue factor complex.
Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX 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 IX are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Clinical efficacy
The completed clinical trial programme included one phase 1 trial and four phase 3 multicentre, non- controlled trials.

Prophylaxis
Fifty-four of the patients across all age-groups were treated with a weekly prophylactic dose of 40 IU/kg where 23 (43%) of these patients had no bleeding episodes.

Pivotal trial
The pivotal trial included 74 adolescent (13–17 years) and adult (18–65 years) previously treated patients. The trial included one open-label on-demand arm with treatment for approximately 28 weeks and two prophylaxis treatment arms with single-blind randomisation to either 10 IU/kg or 40 IU/kg once-weekly for approximately 52 weeks. When comparing the 10 IU/kg and 40 IU/kg treatments, the annualised bleeding rate for patients in the 40 IU/kg arm was found to be 49% lower than the bleeding rate (95% CI: 5%;73%) for patients in the 10 IU/kg arm (p<0.05).

The median (IQR) overall annual bleeding rate (ABR) in patients (13–65 years) treated with a prophylactic dose of 40 IU/kg once weekly was 1.04 (0.00; 4.01) whereas the traumatic ABR was 0.00 (0.00; 2.05), joint ABR was 0.97 (0.00; 2.07) and spontaneous ABR was 0.00 (0.00; 0.99).
Of note, ABR is not comparable between different factor concentrates and between different clinical trials.

In this pivotal trial in adolescent and adult patients, there were 70 breakthrough bleeding episodes for 16 out of 29 patients in the 40 IU/kg prophylaxis arm. The overall success rate for treatment of breakthrough bleeds was 97.1% (67 out of 69 evaluated bleeds). A total of 69 (98.6%) of the 70 bleeding episodes were treated with one injection. Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds.

In 29 adult and adolescent patients treated, 13 patients with 20 target joints were treated for one year with a weekly prophylactic dose of 40 IU/kg. Eighteen out of these 20 joints (90%) were no longer considered target joints at the end of the trial.

On-demand treatment
In the pivotal trial there was a non-randomised arm where 15 patients were treated in an on-demand regimen with 40 IU/kg for mild or moderate bleeds and 80 IU/kg for severe bleeds. The overall success rate (defined as excellent or good) for treatment of bleeds was 95% with 98% of the bleeds treated with one or two injections.

Children and adolescents

A trial including 25 paediatric previously treated patients (ages 0–12 years) who received a prophylactic dose 40 IU/kg once weekly was performed.
In children aged 0–12 years, the median (IQR) annualised bleeding rate was 1.0 (0.00; 2.06) and the spontaneous bleeding rate was 0.00 (0.00; 0.00).

For treatment of bleeds in paediatrics, the overall success rate (defined as excellent or good) was 93% (39 out of 42 bleeds), where 36 (86 %) of the bleeds were resolved with 1 injection, and 5 (12%) of the bleeds were resolved with 2 injections of Refixia.

The European Medicines Agency has deferred the completion of the study with Refixia in previously untreated patients (see section 4.2 for information on paediatric use).
Overall haemostatic efficacy
Bleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds or 80 IU/kg for severe bleeds, where one bleed was evaluated as severe. An overall assessment of haemostatic efficacy was performed by the patient or caretaker (for home treatment) or study site investigator (for treatment under health care professional supervision) using a 4-point scale of excellent, good, moderate, or poor.
The overall success rate (defined as excellent or good) for treatment of bleeds was 93% (551 out of 591). Of the 597 treated bleeds observed in 79 (75%) of the 105 patients, 521 (87%) of the bleeds were resolved with 1 injection and 60 (10%) of the bleeds were resolved with 2 injections of Refixia.

The success rate and dose needed for treatment of the bleeding episodes were independent of the localisation of the bleed. The success rate for treatment of bleeding episodes was also independent of whether the bleed was traumatic or spontaneous of nature.

Surgery
Three trials, of which one trial was a dedicated surgery trial, included in total 15 major and 26 minor surgery procedures (patients aged 13 to 56 years). Haemostatic effect of Refixia during surgery was confirmed with a success rate of 100% in the 15 major surgeries in the trials. All evaluated minor surgeries were performed successfully.

In a dedicated surgery trial, the efficacy analysis included 13 major surgical procedures performed in 13 previously treated adult and adolescent patients. The procedures included 9 orthopaedic, 1 gastrointestinal, and 3 surgeries in the oral cavity. The patients received 1 pre-operative injection of 80 IU/kg on the day of surgery, and post-operatively, injections of 40 IU/kg. A pre-operative dose of 80 IU/kg Refixia was effective and no patients required additional doses on the day of surgery. In the post-surgery period Day 1 to 6 and Day 7 to 13, the median number of additional 40 IU/kg doses administered was 2.0 and 1.5, respectively. The mean total consumption of Refixia during and after surgery was 241 IU/kg (range: 81–460 IU/kg).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Refixia has a prolonged half-life compared to unmodified factor IX. All pharmacokinetic studies with Refixia were conducted in previously treated patients with haemophilia B (factor IX ≤2%). The analysis of plasma samples was conducted using the one-stage clotting assay.

Steady state pharmacokinetic parameters for adolescents and adults are shown in Table 4 
Table 4  Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescents and adults (geometric mean (CV%))
PK Parameter                          13–17 years                 ≥18 years N=3                         N=6
Half-life (t1/2) (hours)                             103 (14)                           115 (10) Incremental Recovery (IR) (IU/ml per                 0.018 (28)                         0.019 (20) IU/kg)
Area under the curve (AUC)0-168h                     91 (22)                            93 (15) (IU*hours/ml)
Clearance (CL) (ml/hour/kg)                          0.4 (17)                           0.4 (11) Mean residence time (MRT) (hours)                    144 (15)                           158 (10) Volume of distribution (Vss) (ml/kg)                 61 (31)                            66 (12) Factor IX activity 168 h post dosing                 0.29 (19)                          0.32 (17) (IU/ml)
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation.

All patients assessed in the steady state pharmacokinetic session had factor IX activity levels above 0.24 IU/ml at 168 hours post dosing with a weekly dose of 40 IU/kg.

Single-dose pharmacokinetic parameters of Refixia are listed by age in Table 5. The use of Refixia in children below 12 years is not indicated.

Table 5        Single-dose pharmacokinetic parameters of Refixia (40 IU/kg) by age (geometric mean (CV%))
PK Parameter           0–6 years        7–12 years 13–17 years ≥18 years N=12             N=13       N=3         N=6

Half-life (t1/2)       70 (16)          76 (26)        89 (24)          83 (23) (hours)

Incremental       0.015 (7)             0.016 (16)     0.020 (15)       0.023 (11) Recovery (IR)
(IU/ml per IU/kg)

Area under the         46 (14)          56 (19)        80 (35)          91 (16) curve (AUC)inf
(IU*hours/ml)

Clearance CL           0.8 (13)         0.6 (22)       0.5 (30)         0.4 (15) (ml/hour/kg)

Mean residence         95 (15)          105 (24)       124 (24)         116 (22) time (MRT)
(hours)

Volume of          72 (15)              68 (22)        59 (8)           47 (16) distribution (Vss)
(ml/kg)

Factor IX activity 0.08 (16)            0.11 (19)      0.15 (60)        0.17 (31) 168 h post dosing
(IU/ml)
Clearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of distribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation.

As expected, body weight adjusted clearance in paediatric and adolescent patients was higher compared to adults. No dose adjustment was required for paediatric or adolescent patients in clinical trials.

The mean trough levels at steady state are presented in Table 6; based on all pre-dose measurements taken every 8 weeks at steady state for all patients on once weekly dosing of 40 IU/kg. The use of Refixia in children below 12 years is not indicated.

Table 6        Mean of trough levels* of Refixia (40 IU/kg) at steady state 0–6 years                 7–12 years              13–17 years             18–65 years N=12                      N=13                    N=9                     N=20 
Estimated mean         0.15                      0.19                    0.24                    0.29 factor IX trough       (0.13;0.18)               (0.16;0.22)             (0.20;0.28)             (0.26;0.33) levels IU/ml
(95% CI)
* Factor IX trough levels = factor IX activity measured prior to next weekly dose (5 to 10 days post dosing) at steady state.

Pharmacokinetics were investigated in 16 adult and adolescent patients of which 6 were normal weight (BMI 18.5–24.9 kg/m2) and 10 were overweight (BMI 25–29.9 kg/m2). There were no apparent differences in the pharmacokinetic profiles between normal weight and overweight patients.