Factor X Activator for Hemophilia Patients with Inhibitors: A Phase 1, First-in-Human, Multi-Center, and Open-Label Trial

Background Bleeding episodes of hemophilia A (HA) or B (HB) patients with inhibitor are difficult to control. Bypass treatment agents have been widely used as hemostatic treatment agents, which provide imperfect treatment for bleeding episodes. Non-factor replacement treatments with different mechanisms have also been explored. There are still some limitations whether in terms of complications or efficacy. Blood coagulation factor Xa (FXa) is straightforward and faster acting for boosting thrombin generation in hemophilia patients, then STSP-0601, a specific FX activator purified from the venom of Daboia Russellii siamensis was developed. Methods This is a phase I, first-in-human, multi-center, open-label, dose-escalation study to investigate the safety, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of STSP-0601. This study was divided into two parts, the single-dose part (Part A) and the multiple-dose part (Part B). Both HA and HB patients with inhibitors were eligible for this study. Patients received a single intravenous injection of STSP-0601 (0.01 U/kg, 0.04 U/kg, 0.08 U/kg, 0.16 U/kg, 0.32 U/kg or 0.48 U/kg) in Part A or at a maximum six injections of STSP-0601(0.16U/kg) every four hours in Part B in non-bleeding state. This study was registered at www.clinicaltrials.gov with trial number as NCT-04747964 and NCT-05027230. Findings A total of 16 inhibitor patients were enrolled in Part A and 7 inhibitor patients enrolled in Part B. Eight (22.2%) adverse events (AE) in Part A and 18 (75%) AEs in Part B were reported to related to STSP-0601. The most common AEs were increased level of D-Dimer and fibrin and fibrinogen degradation products (FDP). All of these AEs (100%) in Part A and 94.4% (17/18) in Part B were grade 1. Neither serious adverse event (SAE) nor dose-limiting toxicity (DLT) events were reported in both Parts. The change of coagulation factor X compared with the baseline was still within 10% in single dose and 20% in multi-dose administrations. Anti-drug antibody of the administration of STSP-0601 was not detected. In Part A, STSP-0601 exhibited a linear PK profile. Maximum plasma concentration (Cmax) was 110.04±32.03 pg/mL at 0.16U/kg, 163.51±50.79 pg/mL at 0.32U/kg and 296.48±122.65 pg/mL at 0.48U/kg. The elimination half-life (t1/2) were 7.33±0.55h, 8.33±0.41h and 7.57±0.68h respectively. In Part B, the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) was 3342.02 h*pg/mL, and the t1/2 was 8.40 h. In Part A and B, both peak height and endogenous thrombin-generating potential (ETP) of thrombo-generation assay (TGA) increased in a dose-dependent manner and reached a maximum value 5-10min after STSP-0601 administration. After four doses of STSP-0601, the increase of TG peak height and the shortening of APTT reached the plateau stage. Compared to the baseline, the decreased value of APTT reached a maximum of 36.2% in 0.48U/kg dose cohort in Part A and 42.8% in Part B after 4 doses. Interpretation Both single and multiple injections of STSP-0601are safe and well tolerated. Starting from the single dose of 0.16 U/kg, STSP-0601 significantly improved the coagulation-related laboratory indicators. These results indicate that STSP-0601 has potential to be used as a hemostatic treatment for bleeding episodes in HA or HB patients with inhibitor.