A New, Viable Approach in Hemophilia: Inhibition of Activated Protein C

SerpinPC is a covalent inhibitor of activated protein C (APC) currently in clinical development for the management of hemophilia. New preclinical data from a mouse model study, published in Blood Advances, add to the evidence supporting this novel treatment approach in the disease.

“SerpinPC has a unique mode of action and preclinical profile, which potentially differentiates it from other nonfactor therapies approved or in development,” wrote first author for the study James A Huntington, PhD, of the University of Cambridge, United Kingdom.

The agent is designed to restore hemostasis in patients by inhibiting circulating APC, thereby increasing the amount of thrombin produced during the initiation stage of hemostasis. In a preclinical mouse tail clip model to evaluate this mechanism in hemophilia A, 48 factor-VIII deficient mice were administered subcutaneous SerpinPC injections over 56 days.

The investigators found that the SerpinPC injections fully normalized hemostasis in the study mice. At all tested doses, the injections reduced blood loss, and blood loss in the hemophilia A mice fell to levels comparable to those in wild-type (WT) mice. The investigators noted that the reduction in blood loss with SerpinPC was dose- and time-dependent, and in each relationship, they were able to identify a plateauing point for the reduction effect.

“We have demonstrated that SerpinPC was capable of fully correcting hemostasis at low doses in hemophilia models, and high doses were not associated with overcorrection,” Dr. Huntington wrote.

In a modified study model, the investigators found that SerpinPC could treat ongoing active bleeds in hemophilia A mice. Over the course of several weeks in older mice, they observed that prophylactic injections of the agent prevented spontaneous internal bleeding. From their evaluation of SerpinPC’s ability to reverse the effect of apixaban on blood loss, they also determined the agent might have use as a hemostatic agent in cases of bleeding due to over-anticoagulation.

Among the investigators’ other findings, SerpinPC was well tolerated at high doses in WT mice and not associated with increased inflammatory response. In their work with peripheral blood mononuclear cells from a cohort of 50 healthy European and North American donors, the investigators also found a low immunogenicity risk of SerpinPC.

Clinical evaluations of SerpinPC in patients with severe hemophilia are currently underway.

Reference

Huntington JA, et al. Blood Adv. 2025;9(10):2402-2409. doi:10.1182/bloodadvances.2024015201