Real-World Data of the Hemostatic Efficacy of Recombinant Human Factor VIIa Eptacog Beta for Acute Bleeding Events in Patients with Hemophilia a and B with Inhibitors

Introduction: Activated prothrombin complex concentrate (FEIBA, Takeda) and recombinant factor VIIa (rFVIIa, Novoseven, NovoNordisk) remain the primary bypassing agents (BPA) available for bleeding management in patients with hemophilia and inhibitors. Eptacog beta [rFVIIa-B, Coagulation factor VIIa (recombinant)-jncw, Sevenfact, HEMA Biologics & LFB] is a recombinant human FVIIa approved by the FDA in 2020 for the treatment of acute bleeding events in adult and adolescent patients ≥12 years old with hemophilia A or B with inhibitors. rFVIIa-B demonstrated hemostatic efficacy of 86% in a phase 3, randomized cross-over study of 465 mild/moderate bleeding events in 27 patients with hemophilia A and B with inhibitors. The purpose of this study is to report real-world data on the hemostatic efficacy of rFVIIa-B for acute bleeding management in patients with hemophilia A and B with inhibitors. Methods: This is a retrospective chart-review of individuals ≥12 years of age with severe hemophilia A (factor VIII <1%) or hemophilia B (factor IX <1%) with an active inhibitor from 3 U.S. hemophilia treatment centers who utilized rFVIIa-B for acute bleed management. Results: Seven bleeds were treated among the 3 patients identified. Patient characteristics and bleeding events are summarized in Table 1. The 3 patients were 12, 13, and 31 years of age. Two patients had hemophilia A and 1 patient had hemophilia B. The 2 patients with hemophilia A were on emicizumab prophylaxis per standard dosing regimens for bleeding prevention. The individual patient with hemophilia B had a history of anaphylaxis at inhibitor development and received on-demand BPA for acute bleeding events. All 7 bleeds consisted of hemarthroses with the knee being the primary site in 57% of the bleeds. Five of the 7 bleeds (71%) received a severe bleeding dose of 210-225 microgram per kilogram (mcg/kg) for the initial rFVIIa-B dose followed by 70-75 mcg/kg for subsequent doses. Final dosing regimens were dependent on available vial sizes. rFVIIa-B resulted in complete resolution of all bleeds (100%) at a median of 4 doses (range 1-8 doses) and a median of 24 hours (range 3-48 hours). There were no failures in bleeding resolution following treatment. No adverse events with infusions were reported including infusion-related reactions, hypersensitivity reactions, thrombosis, or thrombotic microangiopathy. Conclusions: Administration of rFVIIa-B in the real-world setting appears to demonstrate hemostatic efficacy in a cohort of pediatric and adult patients with hemophilia A and B with inhibitors and may serve as an alternative human rFVIIa therapy for the management of acute bleeds in this population. Further post-marketing studies are warranted to expand the indication to younger children (<12 years of age) and to continue to monitor drug efficacy and adverse events in a larger population of patients over time including individuals on non-factor therapies such as emicizumab. Figure 1 Figure 1. Disclosures Batsuli: Bio Product Laboratory: Honoraria; Kedrion: Honoraria. Tran: HEMA Biologics: Honoraria. Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Sidonio: Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Biomarin: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Genentech: Consultancy, Research Funding.

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Background Management of severe hemophilia A includes on-demand treatment or prophylaxis with replacement factor VIII (FVIII) concentrate. FVIII inhibitors can develop following exposure to exogenous FVIII in approximately 30% of previously untreated patients (PUPs), typically in the first 50 exposure days (EDs), with serious complications. This is the first study evaluating the safety, immunogenicity, and hemostatic efficacy of rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA), an extended half-life (EHL) recombinant FVIII, in PUPs with severe hemophilia A. Methods This prospective, open-label, multi-center, phase 3 study (NCT02615691) was conducted in patients ˂6 years of age with severe hemophilia A (FVIII <1%). Patients were previously untreated, or had <3 EDs to rurioctocog alfa pegol, octocog alfa, or plasma transfusion at any time prior to screening. Patients with detectable FVIII inhibitory antibodies at screening or a history of FVIII inhibitory antibodies prior to screening (≥0.6 Bethesda units) were not eligible. Patients received intravenous rurioctocog alfa pegol as prophylaxis (25-50 IU/kg, up to 80 IU/kg ≥1 × weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). Prophylaxis was started before 3 years of age or after a maximum of 2 joint bleeds, whichever occurred first. The primary endpoint was the incidence of FVIII inhibitor development. Secondary endpoints included safety and efficacy (annualized bleeding rate [ABR] and hemostatic efficacy). This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing an inhibitor to FVIII or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. Demographic and baseline characteristics were summarized using continuous and categorical data. The incidence of FVIII inhibitor development was calculated using the Clopper Pearson exact 95% CI computed for the proportion of patients who developed FVIII inhibitors during the study. ABR was analyzed by point and interval estimates derived from a negative binomial model with treatment regimen as a covariate. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) was recorded for all patients receiving rurioctocog alfa pegol. Informed consent and ethics approval were obtained. Results As of the data cut-off, 59 (73.8%) of 80 enrolled patients had received ≥1 dose of rurioctocog alfa pegol; 18 patients (screen failures) did not meet the eligibility criteria and 4 discontinued prior to treatment. 54 patients received prophylaxis and 35 received on-demand treatment at any time during the study period. The mean (SD) patient age at baseline was 11.8 (8.2) months. The number of patients with 0 EDs prior to screening was 36 (61.0%), with 9 (15.3%) patients having 1 ED and 14 (23.7%) having 2 EDs. Overall, 32 patients had a family history of hemophilia A. A large deletion, intron 1 or intron 22 inversion, or substitution nonsense hemophilia gene mutation was present in 29 (49.2%) patients and 21 (35.6%) had either a small deletion, small duplication, or substitution missense gene mutation. Of the 52 patients who qualified for this interim analysis, 10 developed an inhibitory antibody to rurioctocog alfa pegol during the study; the incidence of inhibitor development was 0.192 (95% CI, 0.096-0.325) (10/52). Rurioctocog alfa pegol exposure data and ABRs for patients receiving prophylaxis or on-demand treatment are presented in Table 1. At bleed resolution, hemostatic efficacy was rated by patients as "excellent" for 88/269 bleeds (32.7%) and "good" for 73/269 bleeds (27.1%). Overall, 52 (88.1%) patients receiving rurioctocog alfa pegol experienced a total of 283 AEs, and 13 patients experienced 14 rurioctocog alfa pegol-related AEs (including 10 SAEs). SAEs occurred in 24 patients, 10 of whom experienced 10 treatment-related SAEs of FVIII inhibitor development. Discussion This is the first prospective study of the EHL recombinant FVIII rurioctocog alfa pegol for the treatment of PUPs with severe hemophilia A. These preliminary results demonstrate a relatively low inhibitor rate compared with other EHL recombinant FVIII products and a safety and efficacy profile consistent with that previously observed for rurioctocog alfa pegol in the treatment of bleeding episodes in patients with hemophilia A. Figure 1 Figure 1. Disclosures Sidonio: Guardian Therapeutics: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biomarin: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst: Consultancy. Peyvandi: Takeda: Honoraria; Spark: Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Honoraria; Bioverativ: Honoraria; Grifols: Honoraria. Stasyshyn: Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding; Shire: Consultancy; Grifols: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Antmen: Takeda: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy. Yeoh: Takeda: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Grifols: Honoraria. Maggiore: IQVIA: Current Employment. Engl: Baxalta Innovations GmbH, a Takeda company: Current Employment; Takeda: Current equity holder in publicly-traded company. Allen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Tangada: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc: Current Employment.

Hemostatic efficacy of two topical adjunctive hemostats in a porcine spleen biopsy punch model of moderate bleeding

Topical hemostatic agents have become essential tools to aid in preventing excessive bleeding in surgical or emergency settings and to mitigate the associated risks of serious complications. In the present study, we compared the hemostatic efficacy of SURGIFLO® Hemostatic Matrix Kit with Thrombin (Surgiflo—flowable gelatin matrix plus human thrombin) to HEMOBLAST™ Bellows Hemostatic Agent (Hemoblast—a combination product consisting of collagen, chondroitin sulfate, and human thrombin). Surgiflo and Hemoblast were randomly tested in experimentally induced bleeding lesions on the spleens of four pigs. Primary endpoints included hemostatic efficacy measured by absolute time to hemostasis (TTH) within 5 min. Secondary endpoints included the number of product applications and the percent of product needed from each device to achieve hemostasis. Surgiflo demonstrated significantly higher hemostatic efficacy and lower TTH (p < 0.01) than Hemoblast. Surgiflo-treated lesion sites achieved hemostasis in 77.4% of cases following a single product application vs. 3.3% of Hemoblast-treated sites. On average, Surgiflo-treated sites required 63% less product applications than Hemoblast-treated sites (1.26 ± 0.0.51 vs. 3.37 ± 1.16). Surgiflo provided more effective and faster hemostasis than Hemoblast. Since both products contain thrombin to activate endogenous fibrinogen and accelerate clot formation, the superior hemostatic efficacy of Surgiflo in the porcine spleen punch biopsy model seems to be due to Surgiflo’s property as a malleable barrier able to adjust to defect topography and to provide an environment for platelets to adhere and aggregate. Surgiflo combines a flowable gelatin matrix and a delivery system well-suited for precise application to bleeding sites where other methods of hemostasis may be impractical or ineffective.

Hemostatic Efficacy and Biocompatibility Evaluation of a Novel Absorbable Porous Starch Hemostat

Background A novel absorbable porous starch hemostat (APSH) based on calcium ion-exchange crosslinked porous starch microparticles (Ca2+CPSM) was developed to improve hemostasis during surgeries for irregular cuts. The aim of this study was to compare its hemostatic efficacy and biocompatibility in a standard rat liver injury model relatively to Arista AH, Quickclean, and crosslinked porous starch microparticles (CPSM, without calcium ion). Methods 72 Wistar rats (220g–240 g) were randomly assigned to six groups (Arista, Quickclean, CPSM, Ca2+CPSM, native potato starch, and untreated control group, n =12 per group). 30 mg of each hemostatic agent was applied to a standard circular liver excision (8 mm in diameter and 3 mm deep) in rats. Following their hemostatic efficacy, in vivo biocompatiblity evaluation was examined. The native potato starch (NPS) group was used as the negative group. Results Ca2+CPSM had almost the same hemostatic efficacy compared with Arista; meanwhile, all the 4 hemostatic agents had good blood compatibility. In terms of in vivo tissue compatibility, Ca2+CPSM had relatively fast degradation and absorption rate with good histocompatibility. As the morphological, anatomic observation and H&E staining of liver defects after implantation, Ca2+CPSM was almost completely absorbed by liver tissue after 14 days. Conclusion According to our study, Ca2+CPSM could effectively achieve hemostasis in the standard rat liver injury model and exhibited good blood compatibility and in vivo tissue compatibility. These finding suggested that Ca2+CPSM as a new kind of APSH had its extensive clinical application value.

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage

Background and Purpose: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). Methods: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. Results: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). Conclusions: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02329327.

Real-Life Applications and Challenges of Andexanet Alfa for Life-Threatening Bleeding and Reversal Prior to Surgery

Andexanet alfa is a targeted reversal agent for apixaban and rivaroxaban for life-threatening or uncontrolled bleeding. There are few multicenter, real world studies that also include patients with off-label use who require emergent surgery. The objective was to describe hemostatic efficacy, thrombotic events, clinical applications, pharmaceutical challenges, and mortality associated with reversing apixaban and rivaroxaban with andexanet alfa in clinical practice. Retrospective descriptive observational cohort study of andexanet alfa use at 2 academic medical centers in the United States from July 1, 2018 to September 30, 2019. Ninety patients received 91 doses of andexanet alfa including 6 for reversal prior to surgery. Effective hemostasis was achieved in 72.9% of bleeding episodes and all patients that received andexanet alfa preoperatively were deemed to have effective hemostasis. Thrombotic events occurred in 7 of 90 patients (7.7%) and 2 of these events occurred the day after administration. Incorrect high-dose andexanet alfa was given 11 times with an estimated excess expenditure of $272,250. Thirty-two of 90 (35.5%) patients died, and most deaths occurred during the initial hospitalization. Our real-world experience with andexanet alfa in bleeding patients is similar to the non-comparative trial that led to Food and Drug Administration approval, and our findings show good hemostatic efficacy in a small number of patients requiring emergent surgery. We highlight the importance of appropriate dose based on time of ingestion and factor Xa inhibitor dose. Our 2 institutions spent over a quarter of a million dollars on excess andexanet alfa in a year and a half.