INTRODUCTION:Eptacog beta is a novel human recombinant FVIIa approved for use in the United States, European Union, United Kingdom and Mexico for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors (≥12 years). It is also indicated for perioperative care in the same patient population in Europe and the United Kingdom. AIM:To assess the incidence of rebleeding and review treatment outcomes in subjects with haemophilia with inhibitors enrolled in the phase 3 PERSEPT 1 clinical trial. METHODS:To treat mild/moderate bleeding episodes (BEs), subjects administered an initial 75  or 225µg/kg dose of eptacog beta, followed (if necessary) by additional 75µg/kg doses at predefined intervals until bleed control. This analysis used subject-reported rebleeding to determine a rebleeding incidence for the first 24 h. Rebleeding through later timepoints was an exploratory, intention-to-treat analysis of bleed treatment data. RESULTS:Four hundred and sixty-five BEs were analysed. Through 24 h, the proportion of rebleeds was 0% (initial 75µg/kg dose) and 0.5% (initial 225µg/kg dose). Through 48 h, the proportion of rebleeds was 3.2% (75µg/kg initial dose) and 5.6% (225µg/kg initial dose); the difference between initial dose strategies was not statistically significant. The majority of rebleeds were controlled with a single dose of eptacog beta and no subject who treated a rebleed required hospitalization. CONCLUSION:Subjects with haemophilia with inhibitors who used eptacog beta to treat mild/moderate BEs experienced a low incidence of rebleeding. Rebleeds that did occur were effectively controlled with eptacog beta (median, one dose) without the need for hospitalization.

Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older.

Introduction Bleeding episodes (BEs) into joints and muscles cause acute pain that can be reduced by quick and efficient treatment. Eptacog beta is a new recombinant coagulation factor VIIa approved by the EMA for the treatment of BEs in patients (≥12 years of age) with congenital hemophilia A or B with inhibitors (CHABwI) and for the prevention of bleeding in those undergoing surgery or invasive procedures. We herewith describe the impact of eptacog beta treatment on pain relief across two different age groups using data from the pivotal clinical trials.

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. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses.

Abstract Introduction Following treatment with a bypassing agent, parents or caregivers often face difficulties in determining bleeding episode (BE) resolution in children with hemophilia A or B and inhibitors (CwHABI), potentially contributing to a longer treatment duration in children as compared to adults (Valentino et al, Haemophilia 2012; 18:554-60. Gruppo et al, Haemophilia 2013; 19:524-32). Eptacog beta is a new recombinant activated human factor VII proven to be safe and effective for the treatment and control of BEs in patients with hemophilia A or B with inhibitors (≥12 years of age). The pivotal phase 3 trial (PERSEPT 1; NCT02020369) included subjects from ages 12 to <18 years, in addition to adult subjects. A subsequent phase 3 trial (PERSEPT 2; NCT02448680) further examined the safety and efficacy of eptacog beta for bleed treatment in CwHABI <12 years of age. Within this population, we hypothesized that caregivers could better ascertain treatment success in older children, which would manifest as increasing eptacog beta efficacy measurements and tighter 95% confidence intervals (CIs) with increasing subject age. We explored this question by analyzing BE treatment success in three age subgroups within PERSEPT 1 and PERSEPT 2. Aims The study objective is to evaluate and compare the clinical response to eptacog beta for BEs in CwHABI at 12 and 24 hours after initial dose of eptacog beta in 3 pediatric age subgroups (<6 years, 6 to <12 years, and 12 to <18 years). Methods PERSEPT 1 and PERSEPT 2 were prospective, global, open-label trials of eptacog beta using two initial dose regimens (IDRs) of 75 and 225 µg/kg in a randomized, non-blinded, crossover design. Subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (determined by clinical response) to treat BEs (Figure 1). Treatment success for mild or moderate BEs was defined as obtaining a hemostasis evaluation of "excellent" or "good" 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. Evaluations were provided by the parent/caregiver in conjunction with the study participant when possible, depending upon subject age and verbal capacity. Written informed consent from the participants' parents/legal guardians were obtained at enrollment. Results Thirty subjects were assessed (25 from PERSEPT 2 [13 subjects, 0 to <6 years; 12 subjects, 6 to <12 years] and 5 from PERSEPT 1 [ages 12 to <18 years]). These subjects experienced 628 mild/moderate BEs. No subject was receiving emicizumab prophylaxis. Nearly all BEs in every pediatric age subgroup were successfully treated by 24 hours after initial eptacog beta infusion (Figure 2). At 12 hours, BE treatment success proportions in the 0 to <6 year, 6 to <12 year, and 12 to <18 year subgroups for the 75 µg/kg IDR were 58%, 72%, and 93%, respectively. Corresponding treatment success proportions for the 225 µg/kg IDR in the 0 to <6 year, 6 to <12 year, and 12 to <18 year subgroups were 58%, 63%, and 89%, respectively. The increased treatment success proportions seen for the 12 to <18 year subgroup over those seen for the 0 to <6 year and 6 to <12 year subgroups were statistically significant for both IDRs (p < 0.05; Figure 2). Differences in treatment success between the 0 to <6 year and 6 to <12-year subgroups were not statistically significant for either IDR. Treatment success point estimates at 12 hours in the 0 to <6 years age group showed the widest CIs among the various subgroups (Figure 2). Conclusions Eptacog beta treatment of BEs in this pediatric population yielded remarkable (>95%) treatment success proportions in both IDRs by 24 hours after initial eptacog beta infusion of 75 or 225 µg/kg. Differing age group pharmacokinetics could contribute to the observed increase in treatment efficacy at 12 hours with increasing subject age. In addition, when taken together with the wide CIs associated with treatment success point estimates at 12 hours for the 0 to <6 year subgroup, these results are consistent with well-known challenges that drive pediatric dosing of bypassing agents: chiefly, that of caregivers experiencing uncertainty with regard to BE resolution in young children. The high efficacy and narrow 95% CIs seen at 24 hours further indicate that caregivers had achieved clarity regarding BE resolution by the 24-hour timepoint. Figure 1 Figure 1. Disclosures Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Pipe: Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Castaman: Uniqure: Honoraria; Bayer: Honoraria; Sobi: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Kedrion: Honoraria; LFB: Honoraria; Grifols: Honoraria; Werfen: Honoraria; Biomarin: Honoraria; Sanofi: Honoraria; F Hoffmann-La Roche Ltd: Honoraria. Davis: Genentech, Spark Therapeutics, BioMarin, Bayer: Consultancy; Takeda, Sanofi: Honoraria; Genentech, Sanofi, Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Ducore: Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria. Dunn: Sanofi, Takeda, Freeline, BioMarin, ATHN, Novo Nordisk: Research Funding; Genentech, Kedrion, CSL Behring, BioMarin: Consultancy; UniQure, CSL Behring, World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria. Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Khan: Genentech, Octapharma, BioMarin, CSL Behring, HEMA Biologics, Kedrion, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mahlangu: Bayer, Biogen, BioMarin, CSL, Novo Nordisk, Sobi, Roche, and UniQure: Research Funding; Amgen, Bayer, Biotest, Biogen, Baxalta, CSL Behring, Catalyst Biosciences, Novo Nordisk, Roche, and Spark: Membership on an entity's Board of Directors or advisory committees; Alnylam, Bayer, Biotest, Biogen, Novo Nordisk, Pfizer, Sobi, Shire, Roche, ISTH, and WFH: Speakers Bureau. Meeks: Sangamo Therapeutics: Consultancy; Spark Therapeutics: Consultancy; National Hemophilia Foundation: Research Funding; Pfizer: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Takeda: Consultancy; Hemophilia of Georgia: Research Funding; National Institutes of Health: Research Funding. Négrier: UniQure: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Recht: Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment. Chrisentery-Singleton: Biomarin: Speakers Bureau; Spark: Consultancy, Research Funding; Takeda: Consultancy, Speakers Bureau; Kedrion: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy; Hema Biologics: Consultancy; Grifols: Consultancy; CSL Behring: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau. Stasyshyn: CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Shire: Consultancy. Wang: Octapharma: Other; Pfizer/Spark: Other: clinical trial investigator; uniQure: Consultancy, Other: Clinical trial investigator; Hema Biologics: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator; Genentech: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy, Other: Clinical trial investigator; CSL Behring: Consultancy, Other: Clinical trial investigator; Bioverativ: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy, Other: Clinical trial investigator; BioMarin: Consultancy, Other: Clinical trial investigator. Windyga: Alnylam Pharmaceuticals: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Octapharma: Research Funding, Speakers Bureau; Rigel: Research Funding; Roche: Research Funding, Speakers Bureau; Sanofi/Genzyme: Research Funding, Speakers Bureau; Shire/takeda: Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Speakers Bureau; Werfen: Speakers Bureau. Alexander: HEMA Biologics: Consultancy, Ended employment in the past 24 months. Al-Sabbagh: LFB: Current Employment. Bonzo: LFB: Current Employment. Macie: HEMA Biologics: Current Employment. Mitchell: HEMA Biologics: Consultancy, Current Employment. Wilkinson: GLOVAL, LLC: Consultancy. Shapiro: Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Glover Blood Therapeutics: Research Funding; Kedrion Biopharma: Research Funding; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; Takeda: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; OPKO: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Prometric BioTherapeutics: Research Funding; Pfizer: Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Novartis: Research Funding; BioMarin: Research Funding; Agios: Research Funding.

Introduction Eptacog beta [Sevenfact®, coagulation factor VIIa (recombinant)-jncw] (HEMA Biologics and LFB) is a human rFVIIa variant indicated for the treatment and control of bleeding events (BEs) in adults and adolescents with hemophilia A or B and inhibitors. In a phase 3 clinical trial (PERSEPT 1, NCT02020369) two initial dose regimens of eptacog beta (75 µg/kg q3h; and 225 µg/kg followed by 75 µg/kg q3h after 9 hours if necessary) demonstrated hemostatic efficacy at 12 hours (82% and 91% respectively) in inhibitor-related mild or moderate bleeding with a very low incidence of rebleeding. Two additional phase 3 trials have been completed and a phase 4 trial is planned. Emicizumab (Hemlibra®, Genentech) is a bispecific antibody indicated for prophylaxis in persons with hemophilia A (with or without inhibitors) to reduce the frequency of bleeding. Emicizumab cannot treat a BE; instead, persons with hemophilia A or B with inhibitors require the use of a bypassing agent (BPA). In clinical trials and post-marketing surveys, thromboembolic events (TEs), including thrombotic microangiopathy have been observed with the concomitant use of aPCC (Feiba®, Shire) (>100 U/kg/day for >1 day) and emicizumab. These TEs have not been observed with emicizumab and eptacog alfa (rFVIIa, NovoSeven® RT, Novo Nordisk) alone. Aims To determine the in vitro procoagulant activity of eptacog beta alone and in combination with emicizumab utilizing a thrombin generation (TG) assay with hemophilia A (HA) and hemophilia A inhibitor (HAI) plasma. The in vitro TG attributed to the combined products will be used to gauge the potential safety and efficacy of eptacog beta for the treatment of BEs in persons with hemophilia A with inhibitors managed with this type of prophylaxis. Methods TG assays were performed according to the method developed by Hemker et al using a Fluoroskan Ascent fluorometer (Thermo Labsystems). TG curves, peak thrombin, endogenous thrombin potential (ETP), lag time and velocity index were determined for severe HA plasma (10 samples) and HAI plasma (4 high titer samples) using both platelet-poor plasma (phospholipid and tissue factor initiator) and platelet-rich plasma (tissue factor initiator). Eptacog beta concentrations (1 µg/mL and 2 µg/mL) were selected to reflect the approximate peak plasma levels observed in the phase 1b trial [NCT01708564; 75 µg/kg dose (0.72 µg/mL) and 225 µg/kg dose (1.9 µg/mL)]; eptacog beta (5 µg/mL) was also examined. Emicizumab (50 µg/mL and 100 µg/mL) concentrations reflect the approximate maximum steady state levels observed when dosed at 1.5 mg/kg (55 µg/mL) and 6 mg/kg (67 µg/mL). Results When no procoagulants were added to HA and HAI plasma, peak thrombin, ETP and velocity index were reduced, and lag time was increased compared to normal pooled plasma (NPP). Addition of emicizumab (50 or 100 µg/mL) and/or eptacog beta (1, 2, or 5 µg/mL) induced a concentration-dependent increase in peak thrombin, ETP, and velocity index. Notably, the effect was lower than that seen with normal plasma: peak thrombin, ETP and velocity index for all combinations and single agents in HAI plasma were significantly lower than those observed in NPP (P<0.001, P-values from t-tests comparing NPP mean TG parameters with the corresponding parameters from HAI plasma). A slight shortening of the lag time below that observed in NPP was observed when both eptacog beta and emicizumab were jointly present in the assay. Conclusions These in vitro data show that clinically relevant combinations of eptacog beta and emicizumab result in a concentration-dependent increase in thrombin generation that remains below that observed in normal pooled plasma. This observation is comparable to that reported for eptacog alfa/sequence identical analog emicizumab (SIA-emicizumab), which was used to explain the clinical safety of the combination and rationalize the lack of TEs. The similarity of these results further suggests that eptacog beta could be used as an alternate BPA for the treatment of a breakthrough BE in inhibitor patients utilizing emicizumab prophylaxis. A clinical trial to investigate this observation is planned. Figure Disclosures Pipe: Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy. Recht:Spark: Research Funding; BioMarin: Research Funding; Genentech: Consultancy, Other: personal fees, Research Funding; Pfizer: Consultancy, Other: personal fees; uniQure: Consultancy, Other: personal fees, Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; CSL Behring: Consultancy, Other: personal fees; Novo Nordisk: Consultancy, Other: personal fees, Research Funding. Callaghan:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Other, Speakers Bureau; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sancillio: Other; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau. Sidonio:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Biomarin: Consultancy, Honoraria, Speakers Bureau; Uniqure: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Grifols: Research Funding. Grandoni:LFB: Ended employment in the past 24 months. Duretz:LFB: Current Employment. Bonzo:International Association for Statistical Computing: Other; International Statistics Institute: Other; American Statistical Association: Other; LFB USA, Inc.: Current Employment. Plantier:LFB: Current Employment. Evans:LFB: Current Employment. Mitchell:HEMA Biologics: Consultancy. Hermans:Bayer: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; LFB: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau; EAHAD: Other; WFH: Other.

Introduction Joint bleeding events (BEs) have cumulative, irreversible and debilitating consequences for persons with hemophilia A or B with inhibitors (PwHABI) due to synovitis and joint iron deposition. To limit the long-term consequences of bleeding into joints, early bleed resolution is a primary treatment goal. Eptacog beta (Sevenfact®, HEMA Biologics and LFB) is a new bypassing agent indicated for the treatment and control of BEs in adults and adolescents with hemophilia A or B with inhibitors. In a prospective, randomized, cross-over, phase 3 clinical trial (PERSEPT 1, NCT#02020369) in the first 24 hours following bleed onset, eptacog beta demonstrated dose-dependent improvements in successful clinical response with 2 initial dose regimens (IDRs) (75 µg/kg IDR: 75 µg/kg q3h; and 225 µg/kg IDR: 225 µg/kg followed by 75 µg/kg q3h after 9 hours if necessary; Figure 1). 91% of all mild or moderate BEs achieved hemostatic efficacy at 12 hours (225 µg/kg IDR), as did 82% at 12 hours in the 75 µg/kg IDR. The majority (85%) of mild/moderate BEs treated in PERSEPT 1 were joint BEs. Aims A subset analysis of mild or moderate joint BE data from the PERSEPT 1 trial was performed to investigate the effect of 2 IDRs on clinical response at 3, 9, 12 and 24 hours on joint BEs in PwHABI. IRB approval and informed consent were obtained. Methods At enrollment, male PwHABI (n=27) were randomized to receive BE treatment on either the 75 µg/kg IDR or the 225 µg/kg IDR (Figure 1) for the first 3 months of treatment; subjects were crossed over to the alternate IDR every 3 months. The 12-hour composite endpoint subset analysis for joint BEs used the same success criteria that were used for the primary efficacy endpoint (for all BEs at 12 hours) in PERSEPT 1. Hemostatic efficacy at all other intermediate timepoints and at 24 hours was assessed using a 4-point evaluation scale (an excellent or good evaluation being considered hemostatic efficacy, and moderate or poor being considered a lack of hemostatic efficacy.) BE treatment continued until bleeding ceased as determined by the subject or physician to discontinue treatment. Results A subset of 396 mild/moderate joint BEs were analyzed. The proportion of successfully treated BEs (composite endpoint) at 12 hours was 91.5% [95% CI: 83.4%, 99.6%] on the 225 µg/kg IDR and 80.6% [95% CI: 69.6%, 91.6%] on the 75 µg/kg IDR. At 9 hours, the proportion of BEs with hemostatic efficacy (using the 4-point evaluation scale) from the first dose in the 225 µg/kg IDR was 86.5%; 3- and 24-hour data are shown in Table 1. Conclusions The joint BE success proportion following a first dose in the 225µg/kg IDR at 3 hours was 85.2%; joint BEs treated by the 75µg/kg IDR demonstrated a 26.4% 3-hour success proportion. These success proportions demonstrate a dose-dependent onset of action; this effect on efficacy was also observed in the 12- and 24-hour data. At 9 hours, sustained hemostatic efficacy from a single 225 µg/kg dose was observed (86.5%). Overall, both initial dose regimens showed successful resolution of joint BEs with early hemostatic success proportions. Further, the onset of action data supports the concept that a larger initial thrombin burst may result in an earlier effective clot that drives earlier bleed resolution. Further observations of this type are needed to understand the role of rFVIIa in hemostatic clot formation. Disclosures Hermans: Bayer: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; LFB: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau; EAHAD: Other; WFH: Other. Ducore:Octapharma: Consultancy; Bayer: Consultancy, Honoraria, Speakers Bureau; HEMA Biologics: Consultancy, Honoraria. Escobar:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Young:BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Bayer, CSL Behring, Freeline, UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Wang:Bayer: Honoraria; Takeda: Honoraria; Genentech: Honoraria; Biomarin: Honoraria; CSL Behring: Honoraria; Bioverativ Inc: Honoraria. Quon:Shire/Takeda: Speakers Bureau; Octapharma: Honoraria; Biomarin: Honoraria, Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Bayer: Honoraria; Orthopaedic Institute for Children: Current Employment; Bioverativ/Sanofi: Honoraria, Speakers Bureau. Alexander:HEMA Biologics, LLC: Current Employment, Patents & Royalties: No royalties or benefits. Mitchell:HEMA Biologics: Consultancy. Al-Sabbagh:LFB: Current Employment. Bonzo:International Association for Statistical Computing: Other; International Statistics Institute: Other; American Statistical Association: Other; LFB USA, Inc.: Current Employment.

Introduction Eptacog beta [Sevenfact®, coagulation factor VIIa (recombinant)-jncw] (HEMA Biologics and LFB) is a human rFVIIa variant indicated for the treatment and control of bleeding events (BEs) in adults and adolescents with hemophilia A or B with inhibitors. Eptacog beta has not yet been approved for perioperative management; therefore, a phase 3 trial (PERSEPT 3, NCT02548143) was initiated to evaluate the safety and efficacy of eptacog beta for the prevention of excessive bleeding and achievement of hemostasis in persons with hemophilia A or B with inhibitors (PwHABI) undergoing elective surgery or other invasive procedures. Aims To determine the perioperative safety and efficacy of eptacog beta in major and minor elective procedures in PwHABI. Methods PERSEPT 3 was a global, multicenter, single-arm, phase 3 trial that enrolled male PwHABI who required elective minor or major procedures. IRB approval was obtained, and all subjects provided informed consent. Immediately prior to the start of the procedure, subjects undergoing minor invasive procedures were administered an initial dose of 75 µg/kg eptacog beta and those undergoing major invasive procedures were administered an initial dose of 200 µg/kg eptacog beta. Additional eptacog beta (75 µg/kg) was administered during the procedure and post-operatively (Table 1). Hemostatic efficacy was assessed using a 4-point evaluation scale during the procedure, immediately following the procedure, at regular post-operative intervals, and 48 hours following the last dose of eptacog beta (hemostatic evaluations were recorded as excellent, good, moderate and poor). The primary efficacy endpoint was the percentage of good and excellent responses (ie, successes) at 48 (±4) h following the final dose of eptacog beta and was based upon the investigators' integrated assessment; taking into consideration the investigators' intraoperative hemostatic assessment; the number of postoperative bleeding events and interventions, and blood transfusions; and the amount of eptacog beta used. Results Twelve male subjects (age 2-56 years; median 20 years) were enrolled at 8 sites in 5 countries; all subjects had severe hemophilia A with inhibitors. Six minor procedures [circumcision (3) and tooth extraction (3)] and 6 major procedures (left transtibial amputation, hip replacement, orthopedic knee surgery, amputation of the left leg, left knee joint endoprosthesis removal, and left ankle achilloplasty) were evaluated. The primary efficacy endpoint is shown in Table 2: the success proportion was 67% for major procedures and 100% for minor procedures. The intraoperative efficacy of eptacog beta was rated as good or excellent in all 12 procedures (100% success); mean estimated actual intraoperative blood loss was lower than the mean maximum predicted blood loss for a patient without a bleeding disorder undergoing the same procedure. Efficacy 24 hours following procedure completion was rated as good or excellent in all procedures where data were reported (major, 4/4; minor, 6/6). One subject (major procedure) was withdrawn from the study due to an adverse event (postprocedural hematoma); this subject subsequently received aPCC and NSAIDs and experienced blood loss anemia and GI hemorrhage. One subject (minor procedure) withdrew consent. Other nontreatment-related adverse events included postoperative anemia, post-procedural hemorrhage, procedural pain, wound secretion and hemorrhage. No allergic, hypersensitivity, or anaphylactic events were reported; no anti-eptacog beta antibodies were observed; and no thromboembolic events occurred. Conclusions This controlled study demonstrated the efficacy and safety of 2 different dose regimens of eptacog beta in minor and major elective procedures. The intraoperative hemostatic efficacy of eptacog beta was rated as good or excellent in all major and minor procedures, and the success proportion 48h following the final dose (primary efficacy endpoint) was 82% overall. The breadth of procedures examined (ranging from circumcision and tooth extraction to amputation and hip replacement), low mean blood loss, and high intraoperative efficacy suggests that eptacog beta may be successfully utilized in a variety of minor and major procedures. This study provides useful perioperative data for providers who manage congenital hemophilia A or B patients with inhibitors. Disclosures Escobar: National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Quon:Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Shire/Takeda: Speakers Bureau; Octapharma: Honoraria; Bayer: Honoraria; Biomarin: Honoraria, Speakers Bureau; Orthopaedic Institute for Children: Current Employment; Bioverativ/Sanofi: Honoraria, Speakers Bureau. Leissinger:Bayer: Consultancy; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; HEMA Biologics: Consultancy; Takeda: Consultancy; Uniqure: Consultancy; Kedrion: Consultancy; Spark: Consultancy. Luck:Orthopaedic Institute for Children: Research Funding; National Hemophilia Foundaton: Honoraria, Speakers Bureau; Board of Trustees, Orthopaedic Institute for Children: Membership on an entity's Board of Directors or advisory committees. Al-Sabbagh:LFB: Current Employment. Bonzo:LFB USA, Inc.: Current Employment; American Statistical Association: Other; International Statistics Institute: Other; International Association for Statistical Computing: Other. Mitchell:HEMA Biologics: Consultancy. Alexander:HEMA Biologics, LLC: Current Employment, Patents & Royalties: No royalties or benefits. Hermans:Bayer: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; LFB: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau; EAHAD: Other; WFH: Other. OffLabel Disclosure: SEVENFACT(R) [eptacog beta, coagulation factor VIIa (recombinant)-jncw] is a human rFVIIa variant indicated for the treatment and control of bleeding events (BEs) in adults and adolescents with hemophilia A or B with inhibitors. Eptacog beta is not yet indicated for perioperative management

Bypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high-titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case-by-case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once-weekly or every-other-week prophylactic dosing in inhibitor patients. Other non-traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non-factor-based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents.

IntroductionHaemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20years. 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. AimEvaluate 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). MethodsA 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 75g/kg or 225g/kg initial doses with 75g/kg subsequent doses by schedule were administered until clinical response. ResultsThe primary endpoint was sustained clinical response within 12hours, determined by a composite of objective and pain measures. In the 75g/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225g/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. ConclusionThe 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.