Eptacog Beta (rFVIIa) Has a Low Incidence of Spontaneous Rebleeding through 24 and 48 Hours in Adult and Adolescent Patients with Hemophilia A or B with Inhibitors

Introduction Bypassing agents (BPAs [ie, recombinant FVIIa (rFVIIa) or activated prothrombin complex concentrate]) are the primary treatment option to control breakthrough bleeding episodes (BEs) in persons with hemophilia A or B with inhibitors (PwHABI). BPAs can have variable efficacy that may lead to rebleeding following initial successful hemostasis; this can result in additional product usage for rebleed treatment or prevention, delayed recovery, and possible re-hospitalization or prolonged hospitalization.

Eptacog beta (SEVENFACT®; HEMA Biologics and LFB) is a human rFVIIa that is approved for use in the US for the treatment and control of BEs in PwHABI (aged ≥12 years). In the PERSEPT 1 trial (PwHABI aged ≥12 years), 2 dosing regimens were investigated for the treatment of mild/moderate BEs: the 225µg/kg initial dose regimen (IDR) and the 75µg/kg IDR (Fig 1). Efficacy at 12h was 91% (225µg/kg IDR) and 82% (75µg/kg IDR); efficacy at 24h was 99.5% (225µg/kg IDR) and 96.7% (75µg/kg IDR). The median number of doses to treat a mild/moderate BE were 1 (225µg/kg IDR) and 2 (75µg/kg IDR). No thrombotic events were observed.

Aims The aim of this analysis is to examine the incidence of rebleeding in PwHABI ≥12 years when using eptacog beta to treat mild/moderate BEs.

Methods PERSEPT 1 (NCT02020369) was a prospective, randomized, crossover trial that investigated eptacog beta (225µg/kg and 75µg/kg IDRs). Informed consent/assent was obtained.

Subjects with hemophilia A or B with inhibitors (who were not using prophylaxis) received an initial dose of eptacog beta (225µg/kg or 75µg/kg) for BE treatment followed by 75µg/kg doses at predefined intervals determined by clinical response (Fig. 1). Treatment success for mild/moderate BEs was defined as a patient-reported hemostasis evaluation of excellent or good (using a predefined 4-point scale) with no use of additional eptacog beta, alternative hemostatic agents or blood products, and no increase in pain following the first excellent or good assessment.

Rebleeding through the first 24h was reported by the subject and defined as a BE in the same anatomical location after an initial excellent/good assessment.

Rebleeding through 48h was an exploratory analysis of all BE data on a subject-by-subject basis: if subsequent bleeds occurred in the same anatomical location, and the initial doses of eptacog beta for each BE were administered within 48h of each other, then the latter BE was considered a rebleed.

Results Twenty-seven subjects (aged 12-54) enrolled in PERSEPT 1; 465 mild/moderate bleeds were reported. Subjects used the same IDR to treat both the initial BE and the rebleed. All rebleeds were reported as mild/moderate.

During the first 24h of BE treatment a single rebleed was reported (1/465; 0.2% incidence; Table 1).

During the first 48h following initial treatment of a BE, this intention-to-treat analysis identified 19 rebleeds at the same anatomical location (incidence of 4.1%) in 11 subjects; the incidence by IDR is shown in Table 1. The majority (91%) of rebleeds through 48h treated with the 225µg/kg IDR were controlled with a single 225µg/kg dose (1 rebleed required an additional 75 µg/kg dose); 50% (4/8) of those treated with the 75µg/kg IDR required a single 75µg/kg dose to achieve bleed control (the remainder required 2 or 3 75µg/kg doses). All rebleeds achieved hemostasis by 12h and none required a hospital/HTC visit.

A second analysis that excluded 2 rebleeds in 1 subject who was removed from the trial due to lack of treatment adherence and 1 rebleed in a 2nd subject that was a result of traumatic reinjury, resulted in a 3.4% incidence of rebleeding during the first 48h (Table 1).

Conclusion Eptacog beta has a low incidence of rebleeding through 24h (0.2%) and 48h (4.1%) as observed in PERSEPT 1; in the few cases where rebleeding did occur, the majority of rebleeds required a single dose of only eptacog beta to achieve hemostasis and none required a hospital/HTC visit.

In hemophilia without inhibitors, it is typical to be able to administer a minimal number of FVIII/FIX doses to control a BE and have a low risk of rebleeding; the data reported in PERSEPT 1 suggest a similar outcome for the control of mild/moderate BEs in inhibitor patients with eptacog beta. These new data may permit providers to make informed treatment decisions for inhibitor patients to reduce or avoid the possibility of rebleeding without the need for additional doses and their associated cost.

Dunn:CSL Behring: Consultancy; Biomarin: Consultancy, Research Funding; Kedrion: Consultancy; Genentech: Consultancy; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; American Society of Thrombosis and Hemostasis: Research Funding; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees. Abajas:HEMA Biologics: Honoraria. Castaman:Alexion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: satellite symposia; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: satellite symposia; uniQure: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee; Sanofi: Membership on an entity's Board of Directors or advisory committees; Werfen: Other: satellite symposia; Kedrion: Other: satellite symposia; LFB: Membership on an entity's Board of Directors or advisory committees; Grifols: Other: satellite symposia; BioMarin: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: satellite symposia; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: satellite symposia. Giermasz:Pfizer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; ATHN: Consultancy, Research Funding; LFB: Other: co-investigator in research funded by ; Hema Biologics: Consultancy; Sangamo: Research Funding; Adrenas: Consultancy; Genentech: Consultancy, Speakers Bureau; uniQure: Research Funding; Sanofi Genzyme: Consultancy, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau. Lewandowska:Agios: Consultancy, Other: Writing support; Genentecch: Other: Writing support; Octapharma: Speakers Bureau; Spire: Other: Instructor. Mahlangu:Novo Nordisk: Consultancy, Other: advisory board and principal investigator, Research Funding, Speakers Bureau; Spark Therapeutics: Consultancy, Other: advisory board; Takeda: Consultancy; BioMarin Pharmaceutical Inc.: Other: principal investigator, Research Funding; SOBI: Other: principal investigator, Research Funding, Speakers Bureau; uniQure: Other: principal investigator, Research Funding; Alnylam: Speakers Bureau; Amgen: Consultancy, Other: advisory board; Bayer: Consultancy, Other: advisory board, Research Funding, Speakers Bureau; Biotest: Consultancy, Other: advisory board, Speakers Bureau; Biogen: Consultancy, Other: advisory board, Research Funding, Speakers Bureau; Baxalta: Consultancy, Other: advisory board; Pfizer: Speakers Bureau; Shire: Speakers Bureau; ISTH: Speakers Bureau; WFH: Speakers Bureau; F. Hoffman-La Roche Ltd.: Consultancy, Other: advisory board and Principal Investigator, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Other: advisory board and Principal Investigator, Research Funding; Catalyst BioSciences: Consultancy, Other: Advisory board. Meeks:Novo Nordisk: Consultancy, Other: advisory board; Takeda: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: advisory board, Research Funding; Spark: Consultancy; Pfizer: Consultancy; Shire: Consultancy, Other: advisory board; Octapharma: Research Funding. Miesbach:Biomarin: Consultancy; Sobi: Consultancy; Takeda: Consultancy; Freeline: Consultancy; Roche: Consultancy; LFB: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; CSL Behring: Consultancy; Chugai: Consultancy; Biogen: Consultancy; Bayer: Consultancy; Alnylam: Consultancy; uniQure: Consultancy. Recht:Catalyst Biosciences, CSL Behring, Genentech, Grifols, Hema Biologics, Novo Nordisk, Pfizer, Sanofi, Takeda, uniQure: Consultancy; Bayer, Biomarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark Therapeutics, Takeda, uniQure: Research Funding; Foundation for Women and Girls with Blood Disorders; Partners in Bleeding Disorders: Thrombosis and Hemostasis Societies of North America: Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Ended employment in the past 24 months; American Thrombosis and Hemostasis Network; Yale University School of Medicine: Current Employment. Chrisentery-Singleton:HEMA Biologics: Consultancy, Other: advisory board; Kedrion: Consultancy, Other: advisory board; Pfizer: Consultancy, Honoraria, Other: advisory board, Research Funding; Genentech: Consultancy, Honoraria, Other: advisory board, Speakers Bureau; Biomarin: Consultancy, Honoraria, Other: advisory board, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Other: advisory board, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Other: advisory board, Speakers Bureau; Grifols: Honoraria, Speakers Bureau; Spark: Research Funding, Speakers Bureau; BPL: Honoraria; Takeda: Consultancy, Honoraria, Other: advisory board, Speakers Bureau; Bayer: Consultancy, Other: advisory board; Octapharma: Consultancy, Honoraria, Other: advisory board, Speakers Bureau. Wang:LFB-USA, Inc.: Current Employment. Mitchell:HEMA Biologics: Consultancy, Current Employment. Young:Biomarin: Consultancy, Honoraria, Speakers Bureau; Genentech/Roche: Consultancy, Honoraria; Genentech: Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria; Grifols: Research Funding; Spark: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Hema Biologics: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria; LFB: Consultancy; Viatris: Patents & Royalties.