Neutralizationof Porcine Recombinant Factor VIII (Susoctocog Alfa) in Acquired Hemophilia A (AHA): Data from the GTH-AH 01/2010 Study

Susoctocog Alfa (Obizur) is licensed for the treatment of acute bleeds in acquired hemophilia A (AHA). The drug is able to restore hemostasis in the presence of neutralizing anti-human factor VIII (FVIII) antibodies (inhibitors) because of low or absent cross-reactivity with porcine recombinant FVIII. In the pivotal clinical trial, anti-porcine antibody cross-reactivity ranged between 0 and >100% with no apparent effect on clinical response to treatment with susoctocog alfa. However, patients with cross-reacting antibodies had lower FVIII activity (FVIII:C) on treatment and higher product consumption compared to patients without cross-reacting antibodies. Here, we studied cross-reactivity of inhibitors with susoctocog alfa in the framework of the prospective GTH-AH 01/2010 study. 70 patients were enrolled, including 26 females and 44 males, with a mean age of 70 (range 26–94) years. AHA was associated with underlying disorders in 30%, such as autoimmunity (17%), malignancy (11%) and pregnancy (4%). Median residual FVIII:C at presentation was 1.4% (range 0–31%); median inhibitor titer as measured by local laboratories was 17 Bethesda units (BU)/ml (range 1.3–1449 BU/ml). Backup samples were used to perform central laboratory Nijmegen-modified Bethesda assays against human FVIII (standard plasma, Siemens Healthcare) or porcine FVIII (susoctocog alfa laboratory standard, provided by Shire Deutschland GmbH). Limit of detection was 0.5 BU/ml for both assays. All patients were tested positive for human inhibitors, ranging between 0.7 and 3891 BU/ml. 39 patients (56%) did not inhibit susoctocog alfa (anti-porcine antibody titer <0.5 BU/ml); porcine inhibitor titers ranging between 0.5 and 3.1 BU/ml were found in 30 patients (43%); a single patient with a very high anti-human antibody titer (3891 BU/ml) also tested highly positive for porcine inhibitors (471 BU/ml). There was poor correlation between human and porcine titers. However, patients without cross-reactivity (anti-porcine antibody titer <0.5 BU/ml) tended to have lower human inhibitor titers (median 5.4 vs. 27.8 BU/ml, p<0.01) and higher FVIII:C (2.6 vs. <1%, p<0.01). Receiver-operator curve (ROC) analysis demonstrated that cross-reactivity could be excluded with 90% sensitivity if the human inhibitor titer was <3.8 BU/ml. The likelihood of any degree of cross-reactivity was 90% if the anti-human antibody titer was >50 BU/ml. In conclusion, this unbiased, prospective cohort study of patients with AHA found absent or low cross-reactivity of inhibitors to Susoctocog alfa in 56% and 43% of patients, respectively. High levels of cross-reactivity were very rare (1 of 70 patients). Cross-reactivity cannot be predicted based on the antihuman Bethesda titer, although it tended to be more likely in patients with high antihuman antibody titers.

No conflict of interest has been declared by the author(s).