PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding

Abstract

Introduction Haemophilia A or B patients with inhibitors have been treated with FVIIa‐containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. Aim Evaluate the dose‐dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). Methods A Phase 3, randomized, cross‐over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on‐demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response. Results The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 μg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. Conclusion The dose‐dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.

Safety and dose‐dependency of eptacog beta (activated) in a dose escalation study of non‐bleeding congenital haemophilia A or B patients, with or without inhibitors

“…A dose‐escalation study was performed to assess the safety, pharmacokinetic profile (PK), and laboratory pharmacodynamic markers (PD) of rhFVIIa activity in non‐bleeding subjects with haemophilia A or B, with or without inhibitors. Computationally modelled pharmacokinetic behaviour supported the selection of doses for Phase 3 clinical trials of rhFVIIa for the treatment of bleeding episodes in patients with inhibitors …”

The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors

“…Two early investigational variants, vatreptacog alfa and BAY 86-6150, had increased biological activity from specific amino acid mutations; however, both failed in clinical trials due to the observation of antidrug antibodies. 49,50 Eptacog beta also showed increased efficacy and a reduction in time to haemostasis with a higher initial dose compared with multiple smaller doses. 48 Two investigational variants continue to show promising clinical data: eptacog beta (on-demand) and marzeptacog alfa (prophylaxis); neither product is currently indicated for use.…”

“…51,52 The clinical development of a glycopegylated variant with an extended half-life (N7-GP) was similarly halted due to the lack of a dose-response and inferior activity compared with eptacog alfa. 49 Marzeptacog alfa has sevenfold increased in vitro activity and a 9.5 hours half-life (subcutaneous administration). Eptacog beta is a variant with a unique post-translational modification profile; based on 468 treated bleeds in 27 subjects, it has a high single dose haemostatic success rate (85%) and a low rebleeding rate at 24 hours (0.2%), possibly due to its increased EPCR activity.…”

Optimizing bleed prevention throughout the lifespan: Womb to Tomb

“…Other agents targeting different factors in the coagulation cascade are being developed, including fitusiran (antithrombin), TFPI inhibitors, APC inhibitors, Super FVa and long-acting and/or more potent rFVIIa variants(Table 2) [86][87][88][102][103][104]. TFPI can also directly inactivate FXa.…”