Susoctocog alfa

Susoctocog alfa is a recombinant, B-domain deleted, porcine sequence Factor VIII. 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 susoctocog alfa. Susoctocog alfa temporarily replaces the inhibited endogenous Factor VIII that is needed for effective haemostasis.

Pharmacokinetic data from 5 subjects with acquired haemophilia whilst in a non-bleeding state are presented in thw following table.

Individual pharmacokinetic data for factor VIII activity after administration of the final dose of susoctocog alfa to 5 subjects with acquired haemophilia. Subjects were in a non-bleeding state. Factor VIII activity was measured by the one-stage clotting assay:

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.

Inhibitory antibodies against susoctocog alfa 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 susoctocog alfa 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 susoctocog alfa at doses of 75, 225 and 750 U/kg/day tended to increase over time.

Animal reproduction studies have not been conducted with susoctocog alfa.