Low Rebleed Incidence with Eptacog Beta Treatment through 24 and 48 Hours in Children (

Abstract

Introduction Persons with hemophilia A or B and inhibitors (PwHABI) who are not on prophylaxis may have high rates of bleeding, and, if not treated effectively, may have significant morbidity related to rebleeding. Dosing strategies of bypassing agents (BPAs) are variable in clinical practice, and following a period of initial bleed control, rebleeding may occur. The development of additional bypassing agents that can minimize the incidence of rebleeding in this patient population is an important medical need. Eptacog beta is a recombinant activated human factor VII approved in the US and Mexico (Sevenfact®, 2020), as well as the EU and UK (Cevenfacta®, 2022) as a BPA for the treatment of bleeding episodes (BEs) in PwHABI aged 12 years and older using two initial dose regimens (IDRs) of 75 or 225 µg/kg. In the EU and UK, eptacog beta is also indicated for preventing bleeding in the setting of surgery and other invasive procedures. Approval in the US and Mexico was based on demonstrated efficacy in the pivotal phase 3 PERSEPT 1 trial (NCT02020369), which included 27 adolescent and adult PwHABI who treated 465 mild or moderate BEs. Bleed resolution at 24 hours post-initial infusion was 96.7% and 99.5% for 75 and 225 µg/kg IDRs, respectively, with a single bleed recurrence observed before 24 hours. The subsequent phase 3 PERSEPT 2 trial (NCT02448680) enrolled 25 PwHABI <12 years of age who treated 546 mild or moderate BEs. Bleed resolution at 24 hours post-initial infusion in these pediatric patients was 97.4% and 98.0% for 75 and 225 µg/kg IDRs, respectively. The objective of this analysis is to evaluate the incidence of rebleeding when treating mild or moderate BEs in PwHABI <12 years of age with eptacog beta during PERSEPT 2 at 24 and 48 hours post-initial dose. Methods PwHABI in PERSEPT 2 were randomized to either the 75 or the 225 µg/kg IDR to treat BEs and were crossed over to the alternate IDR every 3 months. No subjects in PERSEPT 2 were using prophylaxis. Subjects assigned to the 75 µg/kg IDR treated BEs with initial doses of 75 µg/kg eptacog beta followed by 75 µg/kg q3h as needed. Subjects assigned to the 225 µg/kg IDR treated BEs with an initial 225 µg/kg eptacog beta dose, followed after 9 hours by 75 µg/kg q3h as needed. Mild or moderate BE treatment success at a given time point was assessed by the patient or caregiver and was defined as obtaining a hemostasis evaluation of “excellent” or “good” on a 4-point scale with no additional eptacog beta being infused, no alternative hemostatic agents or blood products being used, and no increase in pain following the first “excellent” or “good” assessment. For this analysis, a BE was considered a rebleed if occurring at the same anatomical location as the original bleed, and within 24 or 48 hours of the initial infusion for the original bleed. Results During the study, subjects treated 546 BEs. Nine rebleeds occurred among 4 of the 25 children within 24 hours, and 13 rebleeds occurred among 6 children within 48 hours. The rebleed incidence and 95% confidence intervals (CIs) through 24 hours was 1.3% [95% CI: 0.0%, 3.6%] for the 75 µg/kg IDR and 2.0% [95% CI: 0.0%, 3.9%] for the 225 µg/kg IDR. The corresponding rebleed incidence and 95% CIs through 48 hours for the 75 and 225 µg/kg IDRs were 2.1% [95% CI: 0.0%, 4.5%] and 2.6% [95% CI: 0.4%, 4.9%], respectively. The differences in rebleed incidence between the two IDRs were not statistically significant at either 24 or 48 hours (Figure 1). The overall rebleed incidence in PERSEPT 2 was 1.6% [95% CI: 0.0%, 3.7%] through 24 hours and 2.4% [95% CI: 0.2%, 4.5%] through 48 hours. No treatment-related adverse events or thrombotic complications were observed. Conclusions Eptacog beta demonstrated a low overall incidence of rebleeding through 24 hours (1.6%) and 48 hours (2.4%) in PwHABI <12 years of age during PERSEPT 2. Rebleeding was similarly low for either IDR at both time points. These findings align with those previously reported for PERSEPT 1 in adolescent and adult patients. Combined with the high efficacy at 24 hours (>96%) observed in both trials and both IDRs, these results suggest that eptacog beta can provide clinicians and caregivers with a treatment option that can establish and maintain hemostatic control of mild or moderate BEs in PwHABI of all ages.