Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Baxalta Innovations GmbH, Industriestrasse 67, A-1221, Vienna, Austria
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation Factor VIII, porcine sequence
ATC code: B02BD14
Obizur is a recombinant, B-domain deleted, porcine sequence Factor VIII (susoctocog alfa). It is a glycoprotein. Immediately after release in the patient’s circulation, Factor VIII binds to von Willebrand factor (vWF). 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, which ultimately converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.
Acquired haemophilia is a rare bleeding disorder in which patients with normal Factor VIII genes develop inhibitory autoantibodies directed against Factor VIII. These autoantibodies neutralize circulating human Factor VIII thus creating a deficiency of available Factor VIII. Circulating antibodies (inhibitors) targeted against human Factor VIII have minimal or no cross reactivity against OBIZUR. OBIZUR temporarily replaces the inhibited endogenous Factor VIII that is needed for effective haemostasis.
The safety and efficacy of OBIZUR for the treatment of serious bleeding episodes in subjects with acquired haemophilia with autoimmune inhibitory antibodies to human Factor VIII was investigated in a prospective, non-randomised, open-label trial of 28 subjects (18 Caucasian, 6 Black, and 4 Asian). The trial included subjects presenting with life and/or limb threatening bleeding requiring hospitalisation.
All initial bleeding episodes had a positive response to treatment at 24 hours after initial dosing as assessed by the primary investigator. A positive response was one where bleeding had stopped or was reduced, with clinical improvement or with Factor VIII activity above a pre-specified target.
A positive response was observed in 95% (19/20) of subjects evaluated at 8 hours and 100% (18/18) at 16 hours. In addition to response to treatment, the overall treatment success was determined by the investigator based on his/her ability to discontinue or reduce the dose and/or dosing frequency of OBIZUR. A total of 24/28 (86%) had successful control (resolution) of the initial bleeding episode. Of those subjects treated with OBIZUR as first-line therapy, defined as no immediate previous use of anti-haemorrhagic agents prior to the first OBIZUR treatment, 16/17 (94%) had eventual treatment success reported. Eleven subjects were reported to have received anti-haemorrhagic agents (eg. rFVIIa, activated prothrombin-complex concentrate, tranexamic acid) prior to first treatment with OBIZUR. Of these 11 subjects, eight had eventual successful treatment (73%).
The median dose per injection to successfully treat the primary bleed was 133 U/kg and the median total dose was 1523 U/kg for a median of 6 days. The median number of daily infusions per subject was 1.76 (range: 0.2 to 5.6). In the initial 24 hour period, the median total dose of 493 U/kg were utilized in the clinical study with a median of 3 infusions. When treatment was required beyond 24 hours, a median total dose of 1050 U/kg were utilized with a median of 10.5 infusions (median dose 100 U/kg) to control a bleeding episode.
The European Medicines Agency has waived the obligation to submit the results of studies with OBIZUR in all subsets of the paediatric population in treatment of acquired haemophilia (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
Pharmacokinetic data from 5 subjects with acquired haemophilia whilst in a non-bleeding state are presented in Table 1.
Table 1. Individual pharmacokinetic data for factor VIII activity after administration of the final dose of OBIZUR to 5 subjects with acquired haemophilia. Subjects were in a non-bleeding state. Factor VIII activity was measured by the one-stage clotting assay:
| Subject | Dose (U) | Dose (U/kg) | Baseline hFVIII activity (%) | t½ (h) | Tmax (h) | Amax (%) | AUC0-t (%·t) | AUC0-∞ (%·t) |
|---|---|---|---|---|---|---|---|---|
| 1 | 5,000 | 76.7 | 89 | 17 | 0.42 | 213 | 3,124 | 4,988 |
| 2 | 2,934 | 30.0 | 18 | 4.6 | 0.42 | 100 | 694 | 712 |
| 3 | 7,540 | 144.2 | 3 | 5.3 | 0.45 | 74 | 473 | 492 |
| 4 | 9,720 | 206.8 | 0 | 1.8 | 0.50 | 53 | 122 | 135 |
| 5 | 10,000 | 133.3 | N/A | 4.2 | 0.75 | 178 | 1,583 | 1,686 |
The mean recovery rate after the initial dose of 200 U/kg was 1.06 ± 0.75 U/ml per U/kg (range 0.10-2.61) measured with the one stage coagulation assay.
Although factor VIII activity determined by the chromogenic assay is generally lower than the Factor VIII activity determined by the one-stage clotting assay, post-infusion Factor VIII activities in patients with acquired haemophilia in clinical study OBI-1-301 tended to be higher when determined with the chromogenic assay than with the one-stage clotting assay (see section 4.4).
Inhibitory antibodies against OBIZUR were measured using a modification of the Nijmegen variation of the Bethesda assay method. Three subjects included in pharmacokinetic analysis had a detectable anti-porcine factor VIII inhibitor titre at baseline (≥0.6 Bethesda Units (BU)/mL). Three of the five subjects had no detectable anti-porcine Factor VIII titres post-treatment (<0.6 BU/mL based on the last reported result), two subjects had a detectable anti-porcine Factor VIII titre (≥0.6 BU/mL).
The mean half-life of OBIZUR in nine evaluable subjects in the bleeding state was (about) 10 hours (range 2.6 to 28.6 hours).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology or repeated dose toxicity.However, in repeated dose toxicity studies, the incidence and severity of glomerulopathy observed in monkeys intravenously administered OBIZUR at doses of 75, 225 and 750 U/kg/day tended to increase over time.
Animal reproduction studies have not been conducted with OBIZUR.
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