A Specific Coagulation Factor X Activator for on-Demand Treatment in Hemophilia with Inhibitors

Background Bemiltenase alfa targeting factor X (FX), purified from Daboia russelii siamensis venom, is developed as a hemostatic agent for hemophilia A or B with inhibitors (HAwI and HBwI). Methods This is a prospective, multicenter, open-label, phase Ib/II trial evaluating the safety and efficacy of bemiltenase alfa for on-demand treatment in HAwI and HBwI patients (Clinicaltrials.gov NCT05027230). Adults (18-65 years) male HAwI and HBwI patients were enrolled to achieve multiple doses of bemiltenase alfa in stage 1 (0.10 U/kg dose cohort) and stage 2 (0.10 U/kg cohort and 0.16 U/kg dose cohort). The primary endpoints were safety and hemostatic efficacy. The secondary endpoints were pharmacokinetic (PK) and pharmacodynamic (PD) profiles, alleviation of clinical symptoms of bleeding events, and the dosage of bemiltenase alfa needed to achieve hemostasis. Results Between October 2021 and July 2023, 80 patients were assessed for eligibility and 70 were enrolled. The 0.16 U/kg dose group (n=37) achieved an effective hemostasis rate of 96.48% (95% confidence interval: 92.89% to 98.57%) in 199 bleeding events, while the 0.10 U/kg dose group (n=20) showed a comparable rate of 94.07% (88.66% to 97.41%) in 135 bleeding events. The clinical remission rate also showed the same trend. For bleeding events, the 0.16 U/kg cohort required fewer number of injections (1.7±0.9 vs. 2.1±1.1, respectively P<0.001). Four patients in 0.16U/kg cohorts experienced grade one asymptomatic venous thromboembolisms. No drug-related serious adverse events or anti-drug antibodies were observed. PK findings showed that plasma drug concentrations increased with consecutive doses. The PD results indicated bemiltenase alfa can dramatically improve the activated partial thromboplastin time, peak height and endogenous thrombin-generating potential of thrombin generation assay. Conclusion Our study indicates that FX as a novel target in treating bleedings showed good efficacy. We also demonstrated for the first time that FX activator from snake venom showed good safety and strong therapeutic effect which supports its potential as a hemostatic treatment for HAwI and HBwI patients.