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.

Background: A new recombinant activated factor VII, eptacog beta (SEVENFACT®, rFVIIa-jncw) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of bleeding events (BEs) in individuals >12 years of age with hemophilia A or B (HAB) with inhibitors. In the eptacog beta phase III trial (Wang, Haemophilia, 2017), 87% of BEs were successfully treated using two different dosing regimens within 12 hours of bleeding onset. In two studies looking at the safety of eptacog beta Ducore, Haemophilia, 2017), a total of 11 treatment-emergent adverse events (TEAEs) were reported in 42 participants, all mild and transitory. To date, no studies designed to assess safety of treatment of breakthrough BEs in people on emicizumab with eptacog beta have been performed.

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.

Background: Eptacog beta (rFVIIa-jncw) (brand name SEVENFACT®) was approved by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of bleeding events (BEs) in individuals 12 years of age and older with hemophilia A or B (HAB) complicated by inhibitors. ATHN 16: Safety of Coagulation Factor VIIa (recombinant)-jncwforthe Treatment of Bleeding Events in Patients with Hemophilia A or B with Inhibitors was designed to collect real-world evidence on the safety of eptacog beta. Objective: To evaluate the safety of eptacog beta when used to treat BEs in participants with HAB with inhibitors with or without FDA-approved prophylactic treatment. Methods: ATHN 16 (NCT04647227) is a phase IV, United States-centric multicenter, open-label safety study enrolling participants with HAB with inhibitors aged 12 years and older, who are either on an FDA-approved prophylaxis and at risk of experiencing a breakthrough BE or who are not on prophylactic treatment and may need to control a BE. Exclusion criteria include any bleeding disorder in addition to HAB, a known hypersensitivity to eptacog beta or rabbit proteins, or the inability to provide informed consent. The maximum study duration for any participant in the study will be up to 2 years from the time of enrollment. Safety of eptacog beta is evaluated based on events included in the European Haemophilia Safety Surveillance (EUHASS) protocol, including allergic or other acute events, treatment-emergent side effects, transfusion-transmitted infections, inhibitor (FVII) development, thrombosis, cardiovascular events, malignancies, neurological events, and deaths. After informed consent is obtained, demographics, bleeding disorder history, inhibitor history, baseline medical and surgical history are recorded for the baseline data. Each participant receives nine 75 µg/kg doses of eptacog beta supplied by the study funder. Eptacog beta is administered by the participant or by study staff at the time of a BE. The doses and duration of treatment are determined at the discretion of the treating physician. BE details including timing of BE, any treatments associated with the BE (including eptacog beta) and timing of resolution of the event, are collected as well as surgical procedures, EUHASS events, adverse events of special interest (AESIs), and serious adverse events (SAEs). Results: At the time of abstract submission, ATHN 16, having received central IRB approval, is rolled out to ATHN-affiliated sites across the United States. The study is currently open to enrollment at 11 sites and an additional 21 sites are proceeding with start-up approvals. A total of seven participants have been enrolled. One BE, unrelated to study product, has been reported. One SAE, unrelated to study product, has been reported. Conclusions: To date, a total of seven participants have enrolled in ATHN 16. One bleeding event has been treated with eptacog beta. The results will be updated, and all safety endpoints will be updated prior to the December 2022 meeting. 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.

INTRODUCTION/AIM:Eptacog beta is a recombinant activated human factor VII approved to treat and control bleeding in haemophilia A and B patients with inhibitors. Emicizumab is a factor VIIIa mimetic antibody approved for prophylactic treatment of haemophilia A with and without inhibitors (HAI and HA, respectively). Inhibitor patients treated with emicizumab should expect breakthrough bleeding that requires bypassing agent treatment to restore haemostasis. The aim of this study is to quantify the in vitro thrombin generation induced by the addition of eptacog beta to HAI and HA plasma containing emicizumab. METHODS:Thrombin generation assays were performed using HAI and HA plasma. Thrombin generation parameters were examined using a fixed effects model with inhibitor titre, eptacog beta concentration and emicizumab concentration as main effects, and eptacog beta concentration with inhibitor and emicizumab concentration with inhibitor as interaction effects. RESULTS:A significant increase in peak thrombin, ETP and velocity was observed when combinations of eptacog beta (0, 1, 2 or 5 µg/ml) and emicizumab (0, 50 or 100 µg/ml) were evaluated in HA and HAI plasma; the effect remained below that observed in Normal Plasma (NP). A small shortening of lag time below that of NP was observed. CONCLUSIONS:Eptacog beta and emicizumab induced thrombin generation in haemophilia A plasma (with and without inhibitors) with the thrombin generation parameters remaining below those of normal plasma. These data provide in vitro proof of concept supporting the concept of use of eptacog beta for the treatment and control of breakthrough bleeding in patients on emicizumab prophylaxis.

Introduction Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (>= 12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. Aim To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. Methods Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 mu g/kg EB initially followed by 75 mu g/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 mu g/kg (minor procedures) or 200 mu g/kg EB (major surgeries) with subsequent 75 mu g/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. Results Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. Conclusion Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.

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

Background: Gabapentin enacarbil, a transported prodrug of gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome.Objective: As part of the overall safety evaluation of gabapentin enacarbil, the present definitive QT/QTc study was conducted to assess the effects of gabapentin enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance.Methods: This randomized, double-blind, placebo-and active-controlled, crossover study enrolled 54 healthy adults. Subjects were randomly assigned to receive a single oral dose of gabapentin enacarbil 1200, 6000 mg, moxifloxacin 400 mg (active control), and placebo in a randomized sequence, with treatment periods separated by a 7-day washout. Blood samples were collected for pharmacokinetic analysis, and continuous ECG measurements were recorded using a Holter monitor. The primary end point was the time-matched difference in individualized baseline-adjusted QTc (ddQTcIb) between gabapentin enacarbil and placebo. General tolerability was also monitored.Results: Of the 54 subjects enrolled in the study (mean [SD] age, 29.2 [10.1]; 42.6% female; mean body mass index, 25.8 [3.01], 48 (88.9%) completed the study, and 6 were discontinued prematurely after having received >= 1 dose of study medication. Thus, the numbers of patients in the safety population were: gabapentin enacarbil 1200 mg, 50; gabapentin enacarbil 6000 mg, 50; moxifloxacin, 50; and placebo, 51. The maximum ddQTcIb values were 0.7 msec (upper 95% confidence limit [CL], 3.0) with gabapentin enacarbil 1200 mg; 1.3 msec (upper CL, 3.6) with gabapentin enacarbil 6000 mg; and 7.4 msec (lower CL, 5.1) with moxifloxacin. A QT-concentration relationship was reported with moxifloxacin. Gabapentin exposures were dose-proportional with gabapentin enacarbil doses of 1200 and 6000 mg. The most commonly reported adverse events with gabapentin enacarbil 6000 mg were dizziness and somnolence (60.0% and 54.0%, respectively).Conclusion: In this population of healthy adults, gabapentin enacarbil at doses of 1200 and 6000 mg was not associated with QT prolongation and was generally well-tolerated. (Clin Then 2012;34:351-362) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.

Purpose: To determine the impact of dexlansoprazole MR (DEX) on heartburn (HB) and regurgitation severity in nonerosive gastroesphophageal reflux disease (NERD) and erosive esophagitis (EE) patients.Methods: This was a post hoc analysis of patients enrolled in phase 3 studies either assessing the efficacy and safety of DEX vs placebo (PLB) for 24-hour HB relief in NERD or DEX vs lansoprazole (LAN) in EE healing.DEX 30 mg, DEX 60 mg, and PLB were administered to 315, 315, and 317 endoscopically confirmed NERD patients, respectively, in a randomized, double-blind, 4-week study.NERD patients were to have a ≥6 month history of HB.In two 8-week, double-blind, randomized healing studies, 2737 endoscopically confirmed EE patients received DEX 60 mg or LAN 30 mg.In all studies, the Patient Assessment of Upper Gastrointestinal-Symptom Severity questionnaire (PAGI-SYM) was administered at baseline to assess symptom severity.The PAGI-SYM was also completed at Weeks 2 and 4 of the NERD study, and at Weeks 4 and 8 during the EE healing trials.The PAGI-SYM, a validated questionnaire, includes items assessing severity of HB and regurgitation on a scale of 0 to 5 (no symptoms, mild, moderate, severe and very severe symptoms) yielding a HB/regurgitation subscale.Using the PAGI-SYM questions included in this subscale, we defined separate subscales for HB and regurgitation.Among patients who had both symptoms at baseline (defined as at least mild HB and at least mild regurgitation in the individual subscales), we looked at the change from baseline (CFB) in individual HB and regurgitation subscales along with the original combined HB/regurgitation subscale.Negative CFBs indicate symptom improvement.A CFB of ≥0.55 was considered the minimally important difference for the HB/regurgitation subscale score.Results: In the NERD study, 661 patients had both HB and regurgitation at baseline, as did 1909 patients in the EE study.Table 1 andTable 2 provide the mean CFB in the subscale scores for the NERD and EE patients, respectively.NERD patients receiving DEX 30 and 60 mg experienced significantly greater improvements in symptom severity for both HB and regurgitation compared to PLB.EE patients receiving DEX 60 mg had significantly greater improvements in HB/regurgitation and HB-only subscales at Week 4 compared to those receiving LAN.Conclusions: DEX appears to be effective in improving both the mechanical (regurgitation) and chemical (HB) aspects of GERD symptoms and this improvement is maintained for the duration of treatment.

Objective The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS). Methods Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n = 45), 1800 (n = 38), or 2400 mg (n = 45) or placebo (n = 41) in this 12-week, double-blind, multicenter study (NCT01332305). Clinic visits were at screening, baseline, and weeks 1, 2, 3, 4, 6, 8, 10, and 12; plasma gabapentin concentrations were measured by a validated liquid chromatography–mass spectrometry/mass spectrometry method at weeks 4 and 12. Results Exposure to gabapentin was proportional to GEn dose. Time to maximum plasma concentration was 7 to 9 hours, and elimination half-life was ∼6 hours. The mean reduction from baseline to week 12 in International Restless Legs Syndrome Rating Scale total score and proportions of subjects with "much improved"/"very much improved" Clinical Global Impression–Improvement scores (investigator and patient ratings) ranged from −12.9 to −13.9 for GEn treatment groups versus −9.3 for placebo. The 2 most commonly reported adverse events were somnolence and dizziness. Conclusions Gabapentin exposure was approximately proportional to GEn dose. Efficacy data showed that a once-daily dose of GEn 600 to 2400 mg provides greater relief of RLS symptoms than placebo; GEn was generally well tolerated with an adverse event profile consistent with gabapentin.