Key Points
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Nine participants on emicizumab prophylaxis treated 33 bleeding events with initial doses of eptacog beta ranging from 56.8 to 245.1 μg/kg.
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No thrombosis or other treatment-related adverse events were noted with any eptacog beta dose used for breakthrough bleed management.
Visual Abstract
Abstract
Eptacog beta, a recombinant factor VIIa bypassing agent, has demonstrated safety and efficacy in the management of bleeding events (BEs) in people with hemophilia and inhibitors. Data describing eptacog beta use in patients receiving emicizumab prophylaxis remains limited. This interim analysis of the American Thrombosis and Hemostasis Network 16 study, a phase 4, multicenter, US based, open-label study, evaluates the safety and real-world effectiveness of eptacog beta for the treatment of BEs experienced on emicizumab prophylaxis. Nineteen participants with hemophilia A and inhibitors who agreed to treat BEs with eptacog beta were included. Eptacog beta dosing was determined by the treating physician and participant. During the interim observational period, 9 of 19 participants (47%) experienced breakthrough BEs. Thirty-three BEs were treated using eptacog beta, with 1 participant contributing 18 BEs. Initial eptacog beta doses ranged from 56.8 to 245.1 μg/kg. A single eptacog beta dose was used to manage 66.7% of BEs. All events resolved without concomitant hemostatic medications. Bleeds treated with an initial eptacog beta dose ≥76 μg/kg had higher single-dose effectiveness and required fewer total doses than bleeds treated with an initial dose <76 μg/kg; differences were not statistically significant. Two participants were treated with eptacog beta perioperatively for 3 minor surgical procedures, and 1 participant was also treated with concomitant tranexamic acid. These observations demonstrate that eptacog beta was effectively used across a range of initial doses for bleed management and perioperative hemostasis by participants receiving emicizumab prophylaxis. No treatment-related adverse events, such as thrombosis, thrombotic microangiopathy, or immune responses, were observed. This trial was registered at www.clinicaltrials.gov as #NCT04647227.
Introduction
Prophylaxis is the standard of care for people with hemophilia A and inhibitors (PwHAI) to reduce the frequency of bleeding events (BEs).1 Emicizumab (Hemlibra; Hoffmann-La Roche) is widely used for prophylaxis by PwHAI2; however, it does not prevent all BEs and may be insufficient for perioperative hemostasis.2 Bypassing agents, including recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrates may therefore be required to manage breakthrough and surgical bleeding.
Eptacog beta (Sevenfact; HEMA Biologics/LFB S.A.), a rFVIIa approved by the US Food and Drug Administration (FDA) in 2020, is the most recent addition to the bypassing agent class.3,4 Eptacog beta is approved in the United States for treating mild to moderate BEs in adults and adolescents (aged ≥12 years) with hemophilia A and B and inhibitors using 2 initial dose regimens (IDRs): an initial dose of 225 μg/kg followed at 9 hours with 75 μg/kg every 3 hours until bleed resolution, or a 75 μg/kg dose every 3 hours until bleed resolution.5 For severe BEs, an initial dose of 225 μg/kg is indicated, with additional 75 μg/kg doses every 2 hours, as required. Prescribing guidelines indicate that dose, frequency, and duration of treatment may be adjusted based on clinical response and hemostatic evaluation. Eptacog beta is also approved as Cevenfacta in Europe and Saudi Arabia for the treatment of bleeds of all severities and for perioperative management in people (aged ≥12 years) with hemophilia A or B and inhibitors.4
In a phase 3 clinical trial evaluating the safety and efficacy of eptacog beta for treatment of bleeding in people aged ≥12 years, with hemophilia and inhibitors, analyses of mild and moderate BEs showed that the 225- and 75-μg/kg IDRs achieved hemostasis in 93.2% and 84.9% of BEs, respectively, at 12 hours. A single 225 μg/kg dose achieved hemostasis in 84% of BEs at 3 hours.6
There are currently no head-to-head studies evaluating differences in efficacy and safety between eptacog beta and the rFVIIa eptacog alfa (NovoSeven RT; Novo Nordisk), first FDA-approved in 1999.7 Although, eptacog beta and eptacog alfa share the same amino acid sequence, they differ in posttranslational modifications, including N-linked glycans8,9 because of differences in manufacturing processes.9, 10, 11 These structural variations have been proposed to account for increased platelet binding and endothelial protein C receptor-dependent endothelial cell binding of eptacog beta compared with eptacog alfa.3,12 Notably, eptacog beta is not considered biosimilar to eptacog alfa because of differences in their product profiles.13
The incidence of thrombosis associated with eptacog alfa, when used as indicated with and without emicizumab prophylaxis, is considered low.1,14,15 To date, no reports of thrombosis, thrombotic microangiopathy, neutralizing anti-rFVIIa antibodies, allergic, hypersensitivity, or anaphylactic reactions have been reported with eptacog beta use without prophylaxis in phase 3 clinical trials or real-world case studies.6,16, 17, 18, 19 However, because of its more recent introduction to clinical use, evidence of eptacog beta safety and effectiveness in the context of emicizumab prophylaxis is limited.
Preliminary guidelines from the National Bleeding Disorders Foundation’s Medical and Scientific Advisory Council (MASAC) recommend treatment with eptacog alfa for acute bleeds in PwHAI receiving emicizumab prophylaxis, with an initial dose of 90 to 120 μg/kg and 0 to 2 additional doses administered at 2-hour intervals as required.20 MASAC alternatively recommends using the eptacog beta 75 μg/kg IDR with 0 to 2 additional doses. This lower recommended initial dose may impact bleed resolution and burden of treatment for PwHAI who use eptacog beta for bleed management.
In vitro studies using plasma from PwHAI have shown that peak clinical concentrations of eptacog beta enhance thrombin generation in the presence of emicizumab, although levels remain below those in normal plasma, indicating a favorable thrombotic safety profile.21 A retrospective case series of eptacog beta real-world use described treatment of 6 participants with hemophilia A and inhibitors receiving emicizumab prophylaxis, who treated 5 BEs with eptacog beta second line to eptacog alfa, and 4 BEs with first-line eptacog beta.22 For 8 of the 9 BEs (88.9%), eptacog beta provided complete and successful bleed resolution, with no safety concerns. Notably, 8 of 11 study participants (72.7%) with hemophilia A or hemophilia B and inhibitors experienced a bleed that was refractory or inadequately controlled by eptacog alfa or had a history of poor response to eptacog alfa. Although this study offers important early evidence of eptacog beta safety in combination with emicizumab prophylaxis, the number of BEs initially treated with eptacog beta was limited.
The ongoing ATHN (American Thrombosis and Hemostasis Network) 16 study is the first postapproval, phase 4 prospective evaluation of eptacog beta use. Its primary objective is to describe the safety of eptacog beta for bleed control in people with hemophilia A or B and inhibitors, with and without FDA-approved bleeding prophylaxis. In response to the recent approvals of novel rebalancing agents for hemophilia prophylaxis, ATHN 16 has been extended to broaden understanding of the clinical use of eptacog beta in combination with these new therapies. The purpose of this interim analysis is to report eptacog beta safety findings and describe exploratory objectives, including eptacog beta effectiveness and real-world use for breakthrough bleeds experienced by participants using emicizumab prophylaxis. This report provides timely real-world data supporting the safety and effectiveness of this therapeutic combination, allowing clinicians to make informed treatment decisions tailored to meet the needs of their patients.
Methods
Study design and data collection
ATHN 16 (SEVENFACT for Bleeding Events in Hemophilia with Inhibitors; ClinicalTrials.gov identifier: NCT04647227) is a phase 4, multicenter, US-based, open-label safety study tracking adverse events following eptacog beta use. The enrollment target is 28 to 55 participants. There are no prespecified efficacy end points. In this interim analysis, single-dose effectiveness and total number of eptacog beta doses were used as surrogate end points. The interim analysis was conducted using data collected from participants enrolled between August 2021 and April 2024. Only BEs experienced by participants receiving emicizumab prophylaxis are described.
At the initial study visit, participant demographics and medical history (bleeding disorder diagnosis, inhibitor status, concomitant medications, surgeries, genotype) were obtained, and a physical exam was performed or recent examination results were recorded. Participants were provided with 9 doses of eptacog beta (75 μg/kg) supplied by LFB. Eptacog beta dosing for the treatment of BEs was determined by the treating physician and participant, and administered as an IV bolus injection by either the participant or study staff. The emicizumab prophylactic regimen was continued during BE treatment.
All mild/moderate BEs were self-reported without imaging verification. Self- or clinic-reported data included adverse events, surgical procedures, and BE details including type, location, timing, and treatment use. Antidrug antibody monitoring was not included in the study protocol. Participants were monitored monthly for the first 3 months, then quarterly and ad hoc until study exit. Participants were required to alert the study site within 24 hours of a new BE and study drug administration. If not resolved within 24 hours, follow-up calls were conducted 2 to 7 days after each treatment, and all bleeds were followed until resolution. The emicizumab dose was confirmed at the most recent study visit within a maximum interval of 3 months. Bleeds treated on emicizumab prophylaxis were defined as those occurring at least 28 days after the emicizumab loading dose and up to 30 days after the last emicizumab dose.
Visits were conducted in-person or remotely by telehealth, or phone. Additional data were collected through e-consent and/or the Robust Health app (ATHN). Participants were followed until study exit or for a maximum 4-year enrollment period. The study approval was obtained from the Central Institutional Review Board/site institutional review board per site requirements and carried out in compliance with the protocol and according to the Declaration of Helsinki. All participants or their legal guardians provided written informed consent before enrollment.
Inclusion and exclusion criteria
Eligible participants were aged ≥12 years with hemophilia A or B and inhibitors, either on FDA-approved prophylaxis and at risk of breakthrough BEs, or not on prophylaxis and controlling BEs on demand. Key inclusion criteria included willingness and ability to document BEs and medication use, past or active anti-FVIII/FIX inhibitors, and ability to provide informed consent/assent with legal guardian consent for participants aged <18 years. Key exclusion criteria included additional disorders of hemostasis; intolerance or hypersensitivity to eptacog beta, rabbits, or rabbit proteins; recent investigational device implantation; use of unapproved prophylaxis or investigational drugs within 30 days of the baseline visit; planned elective surgery for the study period; or any disease or condition that could pose a hazard to the patient or interfere with study participation or outcomes.
Safety assessments
The safety analysis set included all participants who received at least 1 dose of eptacog beta during the observational period. Safety was monitored from the time of consent until 3 days after the last eptacog beta dose. Serious adverse events were defined as those resulting in death, life-threatening conditions, hospitalization, or prolongation of an existing hospitalization, disability or permanent damage, congenital anomaly, or other serious, important medical events. Adverse events were graded for severity using the Common Terminology Criteria for Adverse Events v5.0 and coded using Medical Dictionary of Regulatory Activities version 27.1.23 European Hemophilia Safety Surveillance events were also captured and reported.24
Definitions and statistical analysis
Concomitant medications were coded using the March 2024 version of the World Health Organization Drug Dictionary.25 Definitions of bleed severity6,26 and major and minor surgeries27,28 were previously described. Demographics, BE characteristics, product dosages, and adverse events were summarized using standard descriptive statistics. For analysis of categorical outcomes, including single-dose effectiveness and initial eptacog beta dose categories, generalized estimating equations (GEE) and generalized linear mixed-effects models (GLMM) were applied with subject as a random effect to account for correlation between BEs within participants. Spearman's rank correlation coefficient was used to assess the relationship between initial eptacog beta dose amount and total number of eptacog beta doses administered. Data were analyzed using SAS Version 9.4 (SAS Institute, Cary, NC). Data analysis was performed by the study sponsor (ATHN) and funder (LFB). This post hoc analysis was conceived and executed by the study authors. All authors had access to the primary data.
Results
Participant demographics and emicizumab use
At the time of the interim analysis, 19 PwHAI (8 adolescents aged 12-17 years and 11 adults aged ≥18 years) were enrolled in the ATHN 16 study (Figure 1; Table 1), with additional participants enrolled to date. Participants had a median baseline FVIII:C level of 1.0 IU/mL (range, 1.0-5.0). Two participants exited the study because of nonadherence to the protocol or relocation outside the study catchment area; however, data collected from these participants before their exit were included in the interim analysis. The primary objective of this study was to evaluate safety in participants who used at least 1 dose of eptacog beta. Nine participants used eptacog beta to treat a breakthrough BE, and 2 used eptacog beta for perioperative bleed control during the interim observational period. No treatment-related adverse events occurred.
Figure 1.
ATHN 16 participant disposition. At the time of interim data analysis, 19 participants had been enrolled in the ATHN 16 study who were using emicizumab prophylaxis. Of these, 8 participants did not use eptacog beta during the interim observational period and were not included in the safety analysis set. One participant (Participant 2) used eptacog beta for on-demand bleed control and for breakthrough bleeds experienced on emicizumab prophylaxis. In addition, 8 participants used eptacog beta to manage breakthrough BEs while on continuous emicizumab prophylaxis, and 2 participants on emicizumab prophylaxis used eptacog beta for perioperative bleed control. A total of 11 participants used at least 1 dose of eptacog beta and were included in the safety analysis set. Only BEs that occurred while participants were using emicizumab prophylaxis are described in this report.
Table 1.
Participant demographic information
| Participants using emicizumab prophylaxis (N = 19) | |
|---|---|
| Male sex at birth, n (%) | 19 (100) |
| Age, y | |
| Mean ± SD | 27.3 ± 14.69 |
| Median (range) | 21.0 (13.0-55.0) |
| Race, n (%) | |
| American Indian or Alaska Native | 1 (5.3) |
| Asian | 2 (10.5) |
| Black or African American | 5 (26.3) |
| White | 11 (57.9) |
| Ethnicity, n (%) | |
| Hispanic, Latino/a, or Spanish origin | 2 (10.5) |
| Not Hispanic, Latino/a, or Spanish origin | 17 (89.5) |
| Baseline weight, kg | |
| Mean ± SD | 85.2 ± 20.56 |
| Median (range) | 85.0 (56.7-119.7) |
| Baseline height, cm | |
| Mean ± SD | 175.7 ± 7.83 |
| Median (range) | 175.3 (154.3-191.3) |
| Body mass index, kg/m2 | |
| Mean ± SD | 27.6 ± 6.39 |
| Median (range) | 28.9 (18.7-37.1) |
| Primary diagnosis, n (%) | |
| Hereditary FVIII deficiency | 19 (100) |
| FVIII level at baseline, % | |
| Mean ± SD | 1.3 ± 1.0 |
| Median (range) | 1.0 (1.0-5.0) |
| FVIII inhibitor status, n (%) | |
| <5 BU | 3 (15.8) |
| ≥5 BU | 6 (31.7) |
| Unknown | 10 (52.6) |
| Type of F8 gene mutation, n (%) | |
| Frameshift | 1 (5.3) |
| Intron 22 inversion | 7 (36.8) |
| Inversion (other) | 1 (5.3) |
| Missense | 1 (5.3) |
| Nonsense | 1 (5.3) |
| Predicted null mutation | 1 (5.3) |
| Unknown/not identified | 7 (36.8) |
| Emicizumab treatment, n (%) | |
| Once-weekly | 15 (78.9) |
| Once every 2 weeks | 5 (26.3) |
Participant age was collected at the time of informed consent. One participant used both once-weekly and once every 2 week emicizumab treatment regiments.
BU, Bethesda units; SD, standard deviation.
Fifteen participants followed a once-weekly emicizumab dosing schedule, and 5 used a once every 2 weeks dosing schedule; Participant 2 used both treatment schedules. Eighteen participants received continuous emicizumab prophylaxis. Participant 2, who had a clinical history of intracranial hemorrhage (ICH), used intermittent emicizumab prophylaxis. This participant entered the study using eptacog beta for on-demand bleed control. After 215 days, this participant commenced emicizumab prophylaxis in preparation for surgery but discontinued 70 days later because of malaise and chronic flu-like symptoms (Figure 2). The surgery was canceled, and on-demand treatment was resumed. On day 567, this participant experienced a life-threatening ICH, and emicizumab prophylaxis was resumed. For this interim analysis, only bleeds experienced by Participant 2 during emicizumab prophylaxis (28 days after the emicizumab loading dose and up to 30 days after the last emicizumab dose) were included. Details of the on-demand treatment of BEs experienced by Participant 2, including management of the severe ICH, will be described separately.
Figure 2.
Swimmer plot showing emicizumab treatment period and key clinical events for participants who treated at least 1 breakthrough BE during the interim observational period. Severe BEs included a groin bleed experienced by Participant 1, an ICH experienced by Participant 2 that occurred during a period without emicizumab prophylaxis, and an elbow hemarthrosis experienced by Participant 77. For Participant 2, gray bars indicate periods of emicizumab use, defined as 28 days after the emicizumab loading dose and up to 30 days after the last emicizumab dose. All other participants used emicizumab continuously throughout the interim observational period, with emicizumab exposure defined from the day of enrollment through study exit or interim analysis cut-off date.
Breakthrough BEs during emicizumab prophylaxis
Among the 19 study participants using emicizumab prophylaxis, 9 (47.4%) experienced a total of 36 BEs, of which 33 were treated with eptacog beta (Table 2). Dosing of eptacog beta was at the discretion of the participant and treating physician. The remaining 10 participants (52.6%) did not experience a BE during the interim observational period (Figure 3A). Of the 33 BEs treated with eptacog beta, 31 were considered mild or moderate and 2 were considered severe (Figure 3B). Overall, 18 BEs were experienced by Participant 2, whereas the remaining study participants experienced 15 BEs combined. Because of differences in emicizumab use (intermittent vs continuous), age, and clinical history of severe ICH, Participant 2 was evaluated separately from the rest of the cohort.
Table 2.
Summary of nonsurgical BEs
| All participants excluding Participant 2 (N = 8) | Participant 2 (N = 1) | Total (N = 9) | |
|---|---|---|---|
| No. of BEs | |||
| Total, N | 18 | 18 | 36 |
| Treated with eptacog beta, n | 15 | 18 | 33 |
| Untreated, n | 3 | 0 | 3 |
| Length of time on study, d | |||
| Mean ± SD | 488.3 ± 267.21 | 694.0 ± NE | — |
| Median (range) | 546.5 (77.0-918.0) | 694.0 (NE) | — |
| No. of BEs per participant, n (%) | |||
| 0 | 10 (52.6) | — | 10 (52.6) |
| 1 | 5 (26.3) | — | 5 (26.3) |
| 2 | 1 (5.3) | — | 1 (5.3) |
| 4 | 2 (10.5) | — | 2 (10.5) |
| >4 | — | 1 (5.3) | 1 (5.3) |
| Type of bleed, n (%) | |||
| Activity or exercise | 6 (40.0) | 13 (72.2) | 19 (57.6) |
| Spontaneous | 2 (13.3) | 2 (11.1) | 4 (12.1) |
| Trauma/injury | 7 (46.7) | 3 (16.7) | 10 (30.3) |
| Anatomic location, n (%) | |||
| Ankle/foot | 4 (26.7) | 0 | 4 (12.1) |
| Elbow | 1 (6.7) | 3 (16.7) | 4 (12.1) |
| Knee | 3 (20.0) | 2 (11.1) | 5 (15.2) |
| Shoulder | 0 | 1 (5.6) | 1 (3.0) |
| Soft tissue/muscle | 3 (20.0) | 2 (11.1) | 5 (15.2) |
| Wrist/hand | 1 (6.7) | 0 | 1 (3.0) |
| Other | 3 (20.0) | 10 (55.6) | 13 (39.4) |
| Joint location, n (%) | |||
| Yes | 9 (60.0) | 6 (33.3) | 15 (45.5) |
Joint bleeds are defined as those located in the ankle/foot, elbow, hip, knee, shoulder, or wrist.
NE, not estimable; SD, standard deviation.
Figure 3.
Summary of study events. (A) The 19 participants enrolled in the ATHN 16 study treated 33 nonsurgical BEs with eptacog beta. Of these, 10 participants did not experience a bleed during the interim observational period, 6 participants experienced 1 or 2 BEs, 2 participants (participants 1 and 4) experienced 4 BEs each, and 1 participant (Participant 2) experienced 18 BEs. (B) Of the 33 BEs treated with rFVIIa during the interim observational period, 31 were considered mild/moderate and 2 were severe BEs. In addition, 2 participants on emicizumab prophylaxis used eptacog beta for perioperative bleed control for 3 minor surgical procedures.
Among the 8 study participants (excluding Participant 2) who treated ≥1 BEs with eptacog beta during the interim observational period, the median age was 16.0 years (range, 13-35). A total of 15 BEs (13 mild/moderate and 2 severe) were treated with eptacog beta over a median observational period of 546.5 days (range, 77-918) (Table 2). Overall, 9 of 15 BEs (60%) were located in joints and 6 of 15 BEs (40%) were nonjoint bleeds (Table 2). In addition, 6 of 15 BEs (40%) involved activity/exercise, 7 of 15 BEs (46.7%) involved trauma/injury, and 2 of 15 BEs (13.3%) were spontaneous (Table 2).
Participant 2, aged 51 years, experienced 18 mild/moderate breakthrough BEs during the 231-day period of emicizumab prophylaxis (Table 2). Although this rate was higher than the rest of the cohort, it remained within the expected range for comparably aged PwHAI.1,6 Joint bleeds accounted for 6 of 18 BEs (33.3%) experienced by this participant (Table 2). Thirteen of 18 BEs (72.2%) were attributed to activity or exercise, related in part to physical therapy rehabilitation after ICH, 3 of 18 (16.7%) were trauma- or injury-related, and 2 of 18 (11.1%) were spontaneous (Table 2).
Treatment of breakthrough BEs using eptacog beta
The 8 study participants (excluding Participant 2) used a median initial eptacog beta dose of 75.1 μg/kg (range, 56.8-209.1). Five of 15 BEs (33%) were treated with a single eptacog beta dose, using a median of 3.0 doses per bleed (range, 1-8) (Figure 4A; Table 3). The median additional dose was 75.1 μg/kg (range, 56.8-139.4). No concomitant hemostatic medications were used for bleed control, although 1 participant used 2 doses of standard half-life rFVIII (101.4 U/kg) during treatment of a single BE for maintenance of immune tolerance induction.
Figure 4.
Number of eptacog beta doses used to treat breakthrough BEs experienced on emicizumab prophylaxis. (A) Comparison of single-dose effectiveness for bleeds experienced by Participant 2 vs all other participants using GEE and GLMM statistical analyses (GEE, P < .0001; GLMM, P = .0901). Participant 2 treated 17 of 18 BEs (94.4%) with a single dose of eptacog beta, whereas all other participants combined treated 5 of 15 BEs (33.3%) with a single dose of eptacog beta. (B) Total number of eptacog beta doses administered per bleeding event. A total of 22 BEs were treated with a single eptacog beta dose, whereas the remaining BEs were treated using 2 to 8 total eptacog beta doses.
Table 3.
Summary of eptacog beta use for nonsurgical bleeding episodes
| All participants excluding participant 2 (n = 8) | Participant 2 (n = 1) | Total (N = 9) | |
|---|---|---|---|
| No. of BEs treated with eptacog beta | 15 | 18 | 33 |
| Emicizumab treatment regimen, n | |||
| Once weekly | 3 | 1 | 4 |
| Once every 2 weeks | 5 | 1 | 6 |
| Eptacog beta initial dose, μg/kg | |||
| Mean ± SD | 88.5 ± 42.52 | 143.0 ± 51.48 | 118.2 ± 54.37 |
| Median (range) | 75.1 (56.8-209.1) | 122.5 (61.3-245.1) | 122.5 (56.8-245.1) |
| No. of eptacog beta doses per BE | |||
| Mean ± SD | 2.8 ± 1.93 | 1.1 ± 0.24 | 1.8 ± 1.56 |
| Median (range) | 3.0 (1.0-8.0) | 1.0 (1.0-2.0) | 1.0 (1.0-8.0) |
| No. of BEs treated with a single eptacog beta dose, n (%) | 5 (33.3) | 17 (94.4) | 22 (66.67) |
| Additional eptacog beta dose, μg/kg | |||
| Mean ± SD | 75.9 ± 14.02 | 245.1 ± NE | 81.9 ± 34.81 |
| Median (range) | 75.1 (56.8-139.4) | 245.1 (NE) | 75.1 (56.8-245.1) |
| Time between bleed start and initial eptacog beta dose, h | |||
| Mean ± SD | 3.9 ± 6.65 | 0.1 ± 0.28 | 1.9 ± 4.80 |
| Median (range) | 1.8 (0.0-21.0) | 0.0 (0.0-1.1) | 0.0 (0.0-21.0) |
| Time between initial eptacog beta dose and first additional dose, h | |||
| Mean ± SD | 15.1 ± 7.96 | 6.0 ± NE | 14.3 ± 8.03 |
| Median (range) | 15.3 (4.0-26.0) | 6.0 (NE) | 13.0 (4.0-26.0) |
Participant 2 used once-weekly and once-biweekly emicizumab prophylaxis regimens.
NE, not estimable; SD, standard deviation.
Participant 2 treated breakthrough BEs using a median initial eptacog beta dose of 122.5 μg/kg (range, 61.3-245.1), and for 17 of 18 BEs (94.4%), a single dose was sufficient to control the bleed (Figure 4A; Table 3). The median number of eptacog beta doses used per bleed was 1.0 (range, 1-2). A single left elbow bleed (a target joint) was treated with an initial 245.1 μg/kg eptacog beta dose followed at 6 hours by an additional 245.1 μg/kg dose, with no thrombotic complications reported. No concomitant hemostatic medications were used by this participant for bleeds experienced on emicizumab prophylaxis.
Management of severe BEs with eptacog beta
In total, 2 severe BEs were experienced by participants using continuous emicizumab prophylaxis during the interim observational period. Participant 1, aged 14 years, experienced a groin muscle injury while playing football. Two days later, this participant developed groin swelling and pain. This participant subsequently treated at home with an initial eptacog beta dose of 75.08 μg/kg and presented to the emergency department for evaluation. Ultrasound and radiograph were unremarkable. The participant declined to be admitted for magnetic resonance imaging and observation and was discharged against medical advice. Bleed management was continued using 4 additional 75.08 μg/kg doses of eptacog beta administered at 3.0- to 16.2-hour intervals. Participant 77, aged 14 years, experienced a right elbow hemarthrosis, likely related to a pillow fight with his siblings. After 2 days, this participant was treated inpatient using a single 173.01 μg/kg dose of eptacog beta.
Surrogate measures of eptacog beta effectiveness
Substantial variability was observed in eptacog beta single-dose effectiveness and total number of doses used to treat on-study bleeds (Figure 4). To better understand factors influencing these outcomes, bleed characteristics, initial eptacog beta dose, bleed location, and bleed type were evaluated. As 26 of 33 BEs (78.9%) were attributed to 3 participants (Participant 1, 4 BEs; Participant 2, 18 BEs; and Participant 4, 4 BEs), GEE and GLMM statistical methods were used to account for possible correlation between bleeding episodes within each participant.
Participant 2 experienced a higher rate of single-dose effectiveness (17/18, 94.4%) than the 8 other participants combined (5/15, 33.3%) (Figure 4A; GEE, P < .0001; GLMM, P = .091). Notably, Participant 2 treated BEs with a higher median initial eptacog beta dose (median, 122.5 μg/kg; range, 61.3-245.1) than other participants (median, 75.1 μg/kg; range, 56.8-209.1) (Table 3), which may partially explain the increased single-dose effectiveness.
The impact of eptacog beta initial dose on single-dose effectiveness and total number of doses administered was further evaluated by categorizing initial doses as either <76 μg/kg, consistent with current MASAC recommendations and accounting for provider preference and fixed vial size,20 or ≥76 μg/kg. Twelve BEs were treated using an initial eptacog beta dose of <76 μg/kg using a median initial dose of 72.45 μg/kg (range, 56.77-75.19), whereas 21 BEs were treated with an initial eptacog beta dose of ≥76 μg/kg using a median initial dose of 122.55 μg/kg (range, 79.44-245.10) (Figure 5A). Notably, eptacog beta initial doses were clustered within participants and therefore not considered independent. Participant 2 contributed 17 of 21 BEs (81.0%) that were treated with an initial eptacog beta dose of ≥76 μg/kg and only 1 of 12 BEs (9.1%) treated with <76 μg/kg (Figure 5B). Participants 1 and 4 each contributed 4 of 12 BEs (33.3%) treated with an initial eptacog beta dose of <76 μg/kg.
Figure 5.
Influence of the initial eptacog beta dose on single-dose effectiveness and total number of eptacog beta doses used. The impact of the initial eptacog beta dose on single-dose effectiveness and total number of doses administered was further evaluated by categorizing initial doses as either <76 μg/kg, consistent with current MASAC recommendations,20 or ≥76 μg/kg. (A) Distribution of initial eptacog beta doses by <76 μg/kg or ≥76 μg/kg initial dose category. (B) Contribution of BEs to the <76 μg/kg or ≥76 μg/kg initial dose categories by each participant (Participant 1, 4 BEs; Participant 2, 18 BEs; Participant 4, 4 BEs; all other participants, 7 BEs). (C) Proportion of BEs treated with a single eptacog beta dose by <76 μg/kg or ≥76 μg/kg initial dose category. Statistical significance was evaluated using GEE and GLMM statistical analyses (GEE, P = .3427; GLMM, P = .9343). (D) Number of additional eptacog beta doses administered by eptacog beta initial dose category (GEE, P = .0915; GLMM, P = .5156). (E) Moderate negative correlation between eptacog beta initial dose and total number of doses (Spearman's r = -0.4207).
Overall, 4 of 12 BEs (33.3%) treated with an initial eptacog beta dose <76 μg/kg were managed using a single dose, whereas 15 of 18 BEs (85.7%) treated with an initial eptacog beta dose ≥76 μg/kg used a single dose (Figure 5C). This apparent trend was not considered statistically significant after accounting for within-subject correlation (GEE, P = .3427; GLMM, P = .9343). A similar result was observed when the number of additional eptacog beta doses used was analyzed. Bleeds treated with an initial eptacog beta dose of <76 μg/kg used a median of 1.0 additional doses (range, 0-4), whereas bleeds treated with an initial eptacog beta dose of ≥76 μg/kg used a median of 0 additional doses (range, 0-7) (Figure 5D; GEE, P = .0915; GLMM, P = .5156). A moderate negative correlation was observed between the initial eptacog beta dose and the total number of eptacog beta doses used (Figure 5E; r = ˗0.4207).
For joint bleeds, 8 of 15 bleeds (53.3%) were treated with a single eptacog beta dose compared with 11 of 18 (61%) nonjoint bleeds (61%) (Figure 6A; GEE, P = .043; GLMM, P = .3367). When bleed type was evaluated, 14 of 19 bleeds (73.7%) activity or exercise-related bleeds, 6 of 10 (60.0%) trauma- or injury-associated bleeds, and 1 of 4 (25.0%) spontaneous bleeds were treated with a single eptacog beta dose (Figure 6B; GEE, P = .552; GLMM, P = .099).
Figure 6.
Relationship between bleed characteristics and eptacog beta single-dose effectiveness and total number of doses used. The association between bleed characteristics and eptacog beta single-dose effectiveness was evaluated using GEE and GLMM statistical modeling and total number of doses administered was assessed descriptively. (A) Effect of joint vs nonjoint bleed location on single-dose effectiveness (GEE, P = .0443; GLMM, P = .3367). (B) Effect of bleed type on single-dose effectiveness (GEE, P = .552; GLMM, P = .099).
Eptacog beta use for perioperative bleed control
Two participants using once-weekly emicizumab underwent 3 minor surgical procedures that were successfully managed with eptacog beta. Of these, 1 participant had 2 procedures related to ingrown toenails, and each was managed using a single 225.66 μg/kg dose of eptacog beta. The second participant underwent a circumcision using a single 223.81 μg/kg dose of eptacog beta along with 7 doses of tranexamic acid.
Safety
Eleven participants used at least 1 dose of eptacog beta during the interim observational period (n = 9 for breakthrough bleed control, n = 2 for perioperative hemostasis) and were included in the safety analysis set. A total of 4 adverse events were reported in 3 participants, all of which were considered unrelated to the study medication (Tables 4 and 5). Of the 4 adverse events, 3 were considered serious adverse events, all of which were severe bleeding episodes. The groin and hemarthrosis severe bleeds, experienced by Participant 1 and Participant 77 are described in the severe bleed section. Participant 2 experienced an ICH while treating bleeds on demand; this event will be described in detail in a separate publication. Participant 2 also experienced a lower respiratory tract lung infection (pneumonia) during the interim observational period. No treatment-related adverse events, European hemophilia safety surveillance events, allergic, hypersensitivity or anaphylactic events, neutralizing antihuman rFVIIa antibodies, thrombosis, thrombotic microangiopathy, or participant deaths were observed.
Table 4.
Overall summary of adverse events in the safety analysis set
| Safety analysis set (n = 11) | |
|---|---|
| All adverse events | |
| No. of events | 4 |
| No. of participants | 3 |
| Treatment-related adverse events | |
| No. of events | 0 |
| No. of participants | 0 |
| Serious adverse events | |
| No. of events | 3 |
| No. of participants | 3 |
| Allergic/hypersensitivity/anaphylactic events | |
| No. of events | 0 |
| No. of participants | 0 |
| EUHASS events | |
| No. of events | 0 |
| No. of participants | 0 |
The safety analysis set was defined as all participants who received at least a single dose of eptacog beta during the interim observational period, including 9 participants who treated ≥1 breakthrough BEs with eptacog beta and 2 participants who used eptacog beta for perioperative bleed control. None of the serious adverse events were considered related to eptacog beta use.
EUHASS, European Hemophilia Safety Surveillance.
Table 5.
Adverse events by MedDRA system organ class and preferred terms in the safety analysis set
| Safety analysis set (n = 11) | AE/SAE | Grade | Outcome | |
|---|---|---|---|---|
| Blood and lymphatic system disorders, no. of events | ||||
| Groin bleed | 1 | SAE | 3 | Resolved |
| Infections and infestations, no. of events | ||||
| Pneumonia | 1 | AE | N/A | Resolved |
| Musculoskeletal and connective tissue disorders, no. of events | ||||
| Hemarthrosis | 1 | SAE | 3 | Resolved |
| Nervous system disorders, no. of events | ||||
| Hemorrhage, intracranial | 1 | SAE | 3 | Resolving/recovering |
The safety analysis set was defined as all participants who received at least a single dose of eptacog beta during the interim observational period, including 9 participants who treated ≥1 breakthrough BEs with eptacog beta and 2 participants who used eptacog beta for perioperative bleed control.
AE, adverse event; SAE, serious adverse event; N/A, not available.
Discussion
Eptacog beta has demonstrated a favorable safety profile for the management of acute BEs and perioperative hemostasis in phase 3 clinical trials and real-world case reports.6,18,22 However, additional safety data are needed to better inform treatment decisions when using eptacog beta with emicizumab prophylaxis. This interim analysis of the ATHN 16 study provides the first postapproval prospective evaluation of the safety and real-world use of eptacog beta in people receiving emicizumab prophylaxis.
In this report, 9 participants on emicizumab prophylaxis used a total of 61 eptacog beta doses to manage 33 BEs. All BEs were treated using eptacog beta alone, and no events required the use of concomitant hemostatic medications for bleed control. One participant used 2 doses of standard half-life rFVIII for maintenance of immune tolerance induction during a single BE. In addition, 2 study participants on emicizumab prophylaxis underwent 3 minor surgical procedures using 1 dose each of eptacog beta, and 1 participant also used 7 doses of tranexamic acid for perioperative bleed control. Overall, no treatment-related adverse events, including thrombosis or thrombotic microangiopathy, were observed in association with eptacog beta use in single or multiple doses, in combination with emicizumab, or with concomitant hemostatic agents.
The interim findings of the ATHN 16 study are consistent with a recent retrospective case series describing the use of eptacog beta by PwHAI receiving emicizumab prophylaxis. In that series, 6 participants successfully treated 8 of 9 BEs (88.9%) using eptacog beta with a range of initial doses (60-225 μg/kg) and 0 to 17 follow-up doses. In addition, 3 participants effectively used eptacog beta (75-225 μg/kg initial dose and 0-4 follow-up doses) for perioperative bleed control.22 In the retrospective case series, no adverse events were reported when eptacog beta was used with emicizumab or off-label eptacog beta prophylaxis, or with concomitant hemostatic medications including rFVIIa, activated prothrombin complex concentrates, aminocaproic acid, and tranexamic acid.22 The ATHN 16 study interim safety observations further align with the reported safety of other rFVIIa products when used with emicizumab prophylaxis.1,14,15
Although the primary end point of the ATHN 16 study was safety, exploratory surrogate markers of effectiveness, including single-dose effectiveness and total number of eptacog beta doses used, were also evaluated. A descriptive trend suggested that a higher (≥76 μg/kg) initial eptacog beta dose was associated with increased single-dose effectiveness and fewer additional eptacog beta doses (Figure 5C-E); however, Participant 2, who used higher initial eptacog beta doses than other study participants, contributed disproportionately to the total number of BEs. When within-participant correlation was accounted for using GEE and GLMM statistical models, these associations were not statistically significant. Notably, because model-based sensitivity is a function of the number of analysis units (BEs), the GLMM yielded more conservative test results. Although the generalizability of these nonstatistically significant real-world observations is limited, they align with the findings from PERSEPT 1, where the 225 μg/kg IDR demonstrated statistically greater efficacy and a higher rate of single-dose bleed control compared with the 75 μg/kg IDR.6 Taken together, these data suggest that higher initial doses of eptacog beta may decrease the treatment burden and potentially reduce the time to bleed resolution for PwHAI.
Limitations of this study include sample size, number of total BEs, and the disproportionate contribution of BEs by 3 participants. There may also be variability in treatment selection because of real-world use, such as limiting doses to full vials and provider preferences. In addition, the low rate of breakthrough BEs presents a challenge in achieving sufficient statistical power to detect rare safety signals, prompting the need to continue collecting data through the ATHN data set and systems that are available in other countries. Efforts are ongoing to expand the ATHN 16 study enrollment to include participants with hemophilia B and participants using other FDA-approved prophylactic agents.
This interim report contributes to the growing body of real-world evidence supporting the safety of eptacog beta for the management of acute and perioperative bleeding in PwHAI using emicizumab prophylaxis.22 Study participants treated with a range of eptacog beta initial doses, consistent with previous observations that eptacog beta dose, frequency, and duration of treatment can be adjusted to meet patient needs. Ongoing assessments from the ATHN 16 study will provide broader real-world data with other nonfactor therapies and in patients with hemophilia B. Full results will be reported at a later date.
Conflict-of-interest disclosure: T.C.-S. has acted as a paid consultant to Octapharma, Bayer, Novo Nordisk, CSL Behring, Kedrion, Genentech, BioMarin, Takeda, HEMA Biologics LLC, and Pfizer; received honoraria from Octapharma, HEMA Biologics LLC, Genentech, BioMarin, Novo Nordisk, CSL Behring, Takeda, Grifols, and Pfizer; participates in the Global Blood Therapeutics/Pfizer advisory board; and is a leader for National Medical Advisory Council, Make-A-Wish, and the American Heart Association New Orleans. S. Acharya has received consulting fees for participation in advisory boards with HEMA Biologics LLC. S. Ahuja has served on medical advisory boards for Novo Nordisk, Pfizer, Genentech/Roche, XaTek, Sanofi Genzyme/Bioverativ, HEMA Biologics LLC, and BioMarin; acted as a consultant to Novo Nordisk and XaTek; participated in the speakers’ bureau for Sanofi Genzyme/Bioverativ; conducted clinical research in collaboration with Novo Nordisk, Genentech/Roche, XaTek, Sanofi Genzyme/Bioverativ, Regeneron, HEMA Biologics LLC, Hemab Therapeutics, and Be Biopharma; served as a board member for Innovative Hematology; and is a member of the Blood Products Advisory Committee for the US Food and Drug Administration. L.E.A. has received honorarium from Bayer; and has served on the speakers’ bureau for Sanofi. M.C. has received investigator-initiated research grants from Genentech, Novartis, and Agios Pharmaceuticals; served on the speakers’ bureau for Kedrion, Novo Nordisk, and Sanofi; and received honoraria for participation on advisory boards for Novo Nordisk, Genzyme Corp, Sanofi, Bio Products Laboratory Inc, Takeda, and CSL Behring. M.E. has received honoraria for consulting and/or speaking from Takeda, Sanofi, CSL Behring, Bayer, Novo Nordisk, Regeneron, Genentech/Roche, BioMarin, Magellan, HEMA Biologics LLC, LFB S.A., and the National Hemophilia Foundation. The University of Texas has participated in research funded by Takeda, Novo Nordisk, Bayer, Sanofi, Regeneron, CSL Behring, and LFB S.A. S.G. has received speaker honoraria from Sanofi and Novo Nordisk. S.N. has acted as a paid consultant to HEMA Biologics LLC and LFB S.A. R.K.P. has received honoraria for attending advisory boards from CSL Behring, Genentech, Bayer Healthcare AG, HEMA Biologics LLC, Instrumentation Laboratory, BioMarin, and Sanofi; and has consulted for Merck. M. Recht is on the board of directors of Partners in Bleeding Disorders. A.R. is an employee of LFB S.A. D.V.Q. has received honoraria for consulting and/or advisory board participation from Bayer, BioMarin, CSL Behring, HEMA Biologics LLC/LFB S.A., Genentech/Roche, Novo Nordisk, Pfizer, Sanofi, and Takeda; and served on the speakers’ bureau for CSL Behring, HEMA Biologics LLC/LFB S.A., Novo Nordisk, Pfizer, and Sanofi. A.P.W. has participated in advisory boards and/or received honoraria from Novo Nordisk, Hemab Therapeutics, Pfizer, Genentech, Takeda, and CSL Behring. M. Reding has received institutional research support from Bayer, BioMarin, and Be Biopharma; served on advisory boards for Bayer, CSL Behring, Genentech, HEMA Biologics LLC, Novo Nordisk, Sanofi, and Takeda; and served on the speakers’ bureau for Bayer, CSL Behring, Sanofi, and Takeda. The remaining authors declare no competing financial interests.
Acknowledgments
The authors thank Laura Swystun of Gloval LLC for providing drafts and editorial assistance to the authors during preparation of the manuscript.
The study was sponsored by American Thrombosis and Hemostasis Network, with funding, study product, and medical writing support provided by LFB S.A.
The study funder had no involvement in the design of the analysis or in decisions regarding data inclusion for this report.
Authorship
Contribution: M. Recht designed the study; T.C.-S. and M. Reding served as coprincipal investigators; C.F. oversaw project management; N.D. and A.R. performed data analysis; and all authors critically reviewed the manuscript in development, approved the final submission, and conceived and executed the post hoc analysis.
Footnotes
The data that support the findings of this study are available from the corresponding author, Tammuella Chrisentery-Singleton (tsingleton@athn.org), on reasonable request.
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