Hemostatic efficacy of marstacimab alone or in combination with bypassing agents in hemophilia plasmas and a mouse bleeding model

Abstract

Background Patients with hemophilia have deficiencies in intrinsic coagulation factors and can develop inhibitors that limit the effectiveness of replacement coagulation factors. Marstacimab, a human monoclonal antibody, binds and inhibits the human tissue factor pathway inhibitor. Marstacimab is currently under development as a potential prophylactic treatment to prevent bleeding episodes in patients with hemophilia A and B. Objective To assess the effects of marstacimab alone or in combination with the bypassing agent recombinant factor FVIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC) on thrombin generation and bleeding. Methods Marstacimab and/or rFVIIa or aPCC were added to hemophilic A or B plasma or nonhemophilic plasma in vitro. Hemostatic activity was measured using the thrombin generation assay. In vivo effects were assessed using a mouse acute bleeding model. Male hemophilia A mice were dosed with marstacimab plus aPCC before tail clip; blood loss was quantified by measuring hemoglobin. Results Marstacimab plus rFVIIa or aPCC slightly increased peak thrombin levels compared with either agent alone. This increase was within the reported range for nonhemophilic plasma and did not exceed levels observed in nonhemophilic plasma treated with marstacimab alone. Hemophilia A mice that received 200 U/kg aPCC had significantly reduced bleeding (62%) compared with vehicle‐treated mice ( p < 0.05), and marstacimab plus aPCC reduced bleeding by 83.3% compared with vehicle ( p = 0.0009). Conclusions Marstacimab alone or with bypassing agents increased hemostasis in hemophilia plasma without generating excessive thrombin. The hemostatic activity of marstacimab plus aPCC was confirmed in hemophilia A mice.

Updates on Novel Non-Replacement Drugs for Hemophilia

“…This increase was within the reported range for nonhemophilic plasma. In addition, this increase did not exceed levels observed in nonhemophilic plasma treated with marstacimab alone [ 64 ]. In another study, participant plasma samples spiked with marstacimab exhibited improvements in thrombin generation parameters, including reduced lagtime and increased peak thrombin concentrations.…”

Long‐term safety and efficacy of the anti‐tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results

“…10 It is intended to reduce the inhibition of FXa by TFPI, thereby augmenting haemostasis through the extrinsic pathway. 11 …”

“…Marstacimab (formerly PF‐06741086; Pfizer Inc.), an investigational human immunoglobulin G1 monoclonal antibody, targets the K2 domain of TFPI (Figure S1). 10 It is intended to reduce the inhibition of FXa by TFPI, thereby augmenting haemostasis through the extrinsic pathway 11 …”

“…10 It is intended to reduce the inhibition of FXa by TFPI, thereby augmenting haemostasis through the extrinsic pathway. 11 Safety and efficacy of SC marstacimab were previously evaluated in a short-term (85-day treatment period), phase Ib/II, multiple ascending dose study (NCT02974855) in participants with severe haemA or haemB with or without inhibitors, with weekly marstacimab doses ranging from 150 to 450 mg. 12 In that study, SC marstacimab was well tolerated and effective at reducing mean ABRs.…”