PB1182 - Evaluation of Factor VIII Population Pharmacokinetics and Exposure-Response to Support Dosing of Recombinant Porcine Factor VIII in Patients with Acquired Hemophilia A

Background: Recombinant porcine factor VIII (rpFVIII; susoctocog alfa) is indicated for the treatment of bleeding episodes (BEs) in acquired hemophilia A (AHA).

Aims: Factor VIII activity (FVIII:C) pharmacokinetics (PK) and exposure-response (ER) following rpFVIII were assessed to support rpFVIII dosing in AHA.

Methods: Data were from studies OBI-1-101, NCT00245245, NCT01968655 and NCT04580407 (AHA, n=28 patients; congenital hemophilia A [CHA], n=7; rpFVIII is not indicated for CHA). FVIII PK was characterized under bleeding and non-bleeding conditions using nonlinear mixed-effect modeling. The effect of porcine (p)FVIII inhibitors, human (h)FVIII inhibitors, race and bleeding on PK was evaluated. Positive pFVIII and hFVIII inhibitors comprised titers ≥0.6 BU/mL. An ER model linked FVIII exposure with the probability of efficacy response (4-point scale, Table 1) for the first BE.

Results: A 2-compartment model with linear elimination and baseline (endogenous) levels of FVIII described FVIII PK. A typical adult patient (70 kg, 65 years, with positive hFVIII and negative pFVIII inhibitors at baseline) had 10.5 dL/h FVIII clearance, 72.8 dL volume of distribution (Vc), and 6.7 h elimination half-life. Patients with bleeding and positive baseline pFVIII inhibitors (n=13) had 10-fold and 2-fold higher median FVIII clearance and Vc, respectively, than those with negative baseline pFVIII inhibitors (n=19; Table 2); patients positive for baseline hFVIII inhibitors had 3.5-fold and 2-fold higher median FVIII clearance and Vc, respectively, than those negative for baseline hFVIII inhibitors (Table 2). Race (Japanese [n=5] vs non-Japanese [n=30]) had no effect on PK. The median clearance for non-bleeding patients was 58% lower than for bleeding patients. As the majority of patients had an effective treatment response for all assessment timepoints, no significant correlation between effective response and FVIII concentrations could be drawn.

Conclusion(s): FVIII PK and ER relationships following rpFVIII administration in AHA were characterized. Findings support rpFVIII dosing in patients with AHA in the clinical setting.