Efficacy and safety of recombinant porcine factor VIII in Japanese patients with acquired hemophilia A.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies inhibiting human factor VIII (hFVIII). This phase II/III open-label study evaluated the safety and efficacy of recombinant porcine factor VIII (rpFVIII, susoctocog alfa) in adults with AHA and severe bleeding episodes in Japan (NCT04580407). The initial rpFVIII dose was 200 U/kg, with subsequent doses based on clinical measures including plasma FVIII activity. The primary efficacy endpoint was the proportion of severe bleeding episodes with a positive response to rpFVIII therapy 24 h after treatment initiation. Five patients were eligible for, and completed, rpFVIII treatment (age group: 60s-80s; median hFVIII inhibitor: 52 BU/mL; porcine FVIII [pFVIII] inhibitor: 3/5 patients). The median (range) total dose/patient was 548.4 (198-1803) U/kg with a median 3.0 infusions/patient. All patients responded positively to rpFVIII therapy at 24 h regardless of baseline pFVIII inhibitor status. rpFVIII treatment was well tolerated with no adverse events of special interest such as thromboembolic events or de novo pFVIII inhibitors. This study supports the use of rpFVIII as a novel therapy in the clinical management of patients with AHA in Japan. rpFVIII was approved for treating bleeding episodes in adults with AHA in Japan in 2024.

P53 negatively regulates the transcriptional activity of FOXO3a under oxidative stress.

Transcription factors P53 and FOXO are both activated in response to stresses via protein-protein interactions, leading to events such as cell survival or apoptosis. To clarify the mechanisms that regulate FOXO activity, we analyzed the intermolecular interaction of FOXO3a and P53. FOXO3a and P53 interacted in COS-7 cells, and transcriptional activity of FOXO3a was suppressed by P53, but P53 was not affected by FOXO3a. RT-PCR revealed that expression of the endogenous apoptosis-inducible genes Bim and Bcl6 was decreased markedly by co-expression of P53 with them, but expression of p27 and CyclinG2 was not. In addition, treatment with 500 microM H2O2 for 30 min to 1h to mimic oxidative stress promoted protein binding. Serum deprivation and drug treatment also affected the binding of FOXO3a and P53. These findings suggest that FOXO3a controls cellular function by changing its molecular interaction with P53 to mediate transcription factor activity under stress stimuli.