Preclinical studies and a phase 1 clinical trial have demonstrated that, in patients with hemophilia with inhibitors, Staidson protein-0601 (STSP-0601) is beneficial for the activation of blood coagulation factor X (FX) and has a good safety profile. The findings were recently published in the Journal of Thrombosis and Haemostasis.
STSP-0601 is a specific FX activator purified from the venom of Daboia russelii siamensis. Patients with hemophilia A and hemophilia B exhibit deficiencies in factor VIII (FVIII) and factor IX (FIX), respectively. Although treatment in these individuals involves the replacement of the missing factor, some patients will develop inhibitors of exogenous FVIII or FIX. In patients with inhibitors, hemostatic therapy and eradication of the inhibitors are the key treatment approaches.
To date, immune tolerance induction (ITI) is the only approach proven to be successful in the eradication of inhibitors. A considerable proportion of patients with hemophilia A (30%) and hemophilia B (70%), however, do not respond to ITI.
Recognizing that bleeding episodes in patients with hemophilia with inhibitors are difficult to control, the researchers sought to explore the efficacy and safety of STSP-0601 in these individuals. Initially, they conducted in vitro and in vivo preclinical studies using FVIII knockout hemophilic mice.
Next, a phase 2, first-in-human, open-label, multicenter study was conducted in patients with hemophilia A or hemophilia B with inhibitors. The study was performed at the Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences in Tianjin, China, and at the Henan Cancer Hospital in Zhengzhou, China (NCT04747964 and NCT05027230).
FVIII/FIX inhibitor positivity was defined as “having an inhibitor titer of ≥0.6 BU/mL as measured by the Bethesda assay or the Nijmegen-modified Bethesda assay.” Eligible participants comprised individuals aged 18 to 65 years with moderate or severe hemophilia A or hemophilia B (ie, factor activity levels of <5 IU/dL) with FVIII and FIX inhibitors.
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The phase 1 clinical study was divided into Part A and Part B. In Part A, participants received a single intravenous injection of STSP-0601 of 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 B, patients received a maximum of 6 4-hourly injections of 0.16 U/kg. The primary study endpoint for the 2 parts was the number of adverse events (AEs) from baseline to 168 hours following STSP-0601 administration.
Results of the preclinical studies demonstrated that treatment with STSP-0601 was associated with the ability to activate FX in a dose-dependent fashion. Regarding the results of the clinical study, of 16 participants enrolled in Part A and 7 participants enrolled in Part B, 22.2% of AEs reported in Part A and 75.0% of AEs reported in Part B were linked to STSP-0601.
There were no severe AEs, dose-limiting toxicity events, or thromboembolic events reported. Additionally, the antidrug antibody of STSP-0601 was not detected.
“In summary, STSP-0601 specifically activated FX in a dose-dependent manner in preclinical studies,” the authors indicated. “STSP-0601 might also be a rapid and versatile hemostatic agent for treating patients with bleeding conditions other than hemophilia,” they concluded.
Liu W, Xue F, Fu R, et al. Preclinical studies of a factor X activator and a phase 1 trial for hemophilia patients with inhibitors. J Thromb Haemost. Published online February 14, 2023. doi:10.1016/j.jtha.2023.01.040