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.