Treatment of severe bleeds with eptacog beta in hemophilia A or B with inhibitors: a post hoc analysis of the PERSEPT 1 and 2 trials Open Access

Development of high-titer inhibitors against factor VIII (FVIII) or factor IX (FIX) complicates the management of bleeding episodes (BEs) in individuals with hemophilia A (HA) or hemophilia B (HB), because the neutralizing antibodies render factor replacement therapy ineffective.¹ Management of BEs in inhibitor patients requires the use of bypassing agents (BPAs), such as recombinant activated human FVII (rFVIIa) products eptacog alfa (NovoSeven RT; Novo Nordisk),² eptacog beta (Sevenfact and Cevenfacta; HEMA Biologics, LLC, and Laboratoire Français du Fractionnement et des Biotechnologies [LFB] SA),^3,4 and the plasma-derived activated prothrombin complex concentrate (aPCC; FEIBA, Takeda).⁵ Although emicizumab (Hemlibra, Roche) is effective for bleed prevention in patients with HA with inhibitors,⁶ breakthrough bleeds still occur and require BPAs for hemostatic control. rFVIIa products are the recommended treatment for HA inhibitor patients experiencing breakthrough bleeds while receiving emicizumab.⁷ Concizumab has received approval for prevention of bleeding in patients with HB with inhibitors,⁸ and BPAs will be needed to address breakthrough BEs in this clinical setting as well.

For a patient with hemophilia experiencing a severe BE (ie, one that is life- or limb-threatening or otherwise holds potential for significant blood loss, extreme pain, or permanent nerve damage), the presence of inhibitors compounds an already difficult clinical situation. Treatment periods of days or weeks with eptacog alfa and aPCC for severe BEs, such as intracranial hemorrhage (ICH), abdominal or other internal bleeds, or severe joint or muscle BEs, have been described in inhibitor patients.^9-15 Extended prophylactic regimens (eg, 1-6 months or longer) after the resolution of ICH or other difficult bleeds have been recommended for inhibitor patients to prevent recurrence,¹⁶ further adding to treatment duration and burden.

Eptacog beta is a rFVIIa BPA that has been approved in the United States, Mexico, the United Kingdom, and the European Union for BE treatment in persons with HA or HB and inhibitors (PwHABIs) aged ≥12 years and in the United Kingdom and the European Union for the prevention of bleeding during surgery in inhibitor patients aged ≥12 years.^3,4,17 The pivotal phase 3 trial (PERSEPT 1; NCT02020369) in PwHABIs aged ≥12 years demonstrated eptacog beta treatment success proportions of 91% and 82% for mild or moderate BEs using 225 or 75 μg/kg initial dose regimens (IDRs), respectively, at 12 hours after the initial eptacog beta infusion.³ A subsequent phase 3 trial in PwHABIs aged <12 years (PERSEPT 2; NCT02448680) did not meet the predetermined performance criteria (the treatment success proportion and the lower bound of the 95% confidence interval being ≥55% at 12 hours for mild or moderate BEs), and therefore, eptacog beta has not been approved for use in patients aged <12 years. However, a majority of mild or moderate BEs in PERSEPT 2 were successfully treated with eptacog beta at 12 hours using an IDR of 225 or 75 μg/kg (treatment success proportions of 60% and 65%, respectively), and nearly all mild or moderate BEs were successfully treated at 24 hours (98% and 97% for 225 and 75 μg/kg IDRs, respectively).¹⁸ 

PwHABIs also experienced several severe BEs (including ICH) in PERSEPT 1 and PERSEPT 2. Consistent with accepted clinical practice, some of these BEs required extended treatment durations with eptacog beta before hemostatic control was achieved. Here, we describe the eptacog beta treatment regimens and outcomes for the most serious BEs that were encountered by adult and pediatric patients in the PERSEPT 1 and 2 trials.

The PERSEPT 1 and PERSEPT 2 trials have been previously described.^18,19 Briefly, PwHABIs in each trial were randomized to either a 75 or a 225 μg/kg IDR for BE treatment with an initial IV infusion of either 75 or 225 μg/kg eptacog beta (depending on IDR assignment), followed by additional 75 μg/kg eptacog beta as needed according to clinical response.^18,19 Patients crossed over to the alternate IDR every 3 months without a washout period. The 75 and 225 μg/kg IDRs for treating mild or moderate BEs have been previously detailed.^18,19 Pain levels were assessed using a 0- to 100-mm visual analog scale (VAS), with 0 mm corresponding to no pain, and 100 mm corresponding to worst possible pain.¹⁹ 

Treatment for severe BEs could be initiated at home using a severe BE dosing regimen with an initial dose of either 75 or 225 μg/kg eptacog beta (depending on assigned IDR), and subsequent 75 μg/kg eptacog beta infusions taking place at a hospital or hemophilia treatment center (Figure 1). All of the BEs described in this report occurred while the patients were assigned to the 225 μg/kg IDR, and therefore, only the 225 μg/kg severe BE dosing regimen was used in these trials. As such, the approved dosing recommendation for severe BEs is based on the 225 μg/kg severe BE dosing regimen.³ BE severity was determined by the site investigator. Once a BE was classified as severe, the protocol required an evaluation of eptacog beta efficacy and the need for continued treatment 6 hours after the initial infusion, with additional 75 μg/kg doses being administered every 2 hours as needed (Figure 1). If additional treatment for severe BEs was required beyond 24 hours, efficacy was assessed at least every 12 hours during eptacog beta administration and at 12 hours after the last eptacog beta infusion. Recorded efficacy assessments included those reported at 12 hours after the initial infusion, the primary efficacy time point for BEs of any severity (including severe BEs).

In the study protocol, control of severe BEs after eptacog beta treatment was rated by the treating physician according to a 4-point hemostasis evaluation scale (“excellent,” “good,” “moderate,” or “none”; Table 1), as previously described.^18,19 Treatment duration and dosing intervals could be modified at the discretion of the physician: if bleed control had improved after an eptacog beta administration (receiving an evaluation of at least “moderate” for the 75 μg/kg IDR or “good” or “excellent” for the 225 μg/kg IDR), the dosing interval could be increased to 3 hours for 1 to 2 days, after which the dosing interval could be increased to 4 to 12 hours. Eptacog beta infusions could proceed for as long as needed to control the severe bleed. In this post hoc analysis, bleed control was considered achieved as soon as a satisfactory hemostasis evaluation (“excellent” or “good”; Table 1) was obtained from either the patient or the treating physician, regardless of the time point. Bleed control of an ICH in 1 PERSEPT 2 patient was also evaluated by computed tomography (CT; see “Results”).

Study protocols were reviewed and approved by institutional review boards or independent ethics committees at each study site and were conducted in compliance with good clinical practice as described in the principles stated in the Declaration of Helsinki.²⁰ Written informed consent from the patients (or their caregivers) were obtained at trial enrollment.

Fifty-two male PwHABIs in PERSEPT 1 and PERSEPT 2 experienced 1017 BEs (1011 characterized as mild or moderate and 6 as severe). Six patients (3 from PERSEPT 1 and 3 from PERSEPT 2) each experienced a single severe BE, and another patient from PERSEPT 2 (patient 6) experienced 2 traumatic ICHs that were categorized as mild or moderate by the investigator. Given the gravity of ICHs in patients with hemophilia, these 2 ICH events were included together with the 6 severe bleeds in this post hoc analysis.

Six patients were diagnosed with severe HA and 1 patient with severe HB (Table 2). None of these patients had previously received or concurrently received immune tolerance induction therapy, and none received BPA or emicizumab prophylaxis (both PERSEPT 1 and PERSEPT 2 were completed before emicizumab approval). The elapsed time between BE onset and initial eptacog beta dose, subsequent BE management, and treatment outcomes are described in Table 3 and Figure 2.

A 34-year-old patient with HA (patient 1) experienced a traumatic soft tissue/muscle bleed resulting from a tongue bite. The bleed was considered severe by the investigator given the location and traumatic origin of the BE and required hospitalization. This BE was successfully treated with a single 225 μg/kg eptacog beta dose, with the patient reporting a hemostasis evaluation of “excellent” at 25 minutes after infusion. Antifibrinolytics were not used during treatment, and hemoglobin levels were normal. The treating physician recorded hemostasis evaluations of “excellent” at 6, 12, and 24 hours after infusion. The independent data monitoring committee (DMC) for the PERSEPT 1 trial confirmed the assessment by the investigator that the BE was severe. Both the investigator and DMC evaluations of BE severity were consistent with the trial protocol, in which BEs in the mouth and neck regions were considered severe given the potential for airway blockage due to blood loss.¹⁹ 

A 50-year-old patient with HA (patient 2) experienced a spontaneous BE in the right hip and a high level of pain at baseline (VAS score of 90 mm was reported). The BE was successfully treated with an initial 225 μg/kg eptacog beta dose, followed by additional 225 μg/kg doses at 6 and 12 hours after the initial infusion (Figure 2). This patient was monitored as an outpatient. Physician- and patient-reported responses were “good” at 6.5 and 12.5 hours and “excellent” at 24 hours. The VAS score improved to 60 mm at 6 hours, 30 mm at 12 hours, and 2 mm at 24 hours.

A 31-year-old patient with HA (patient 3) experienced hematuria from a spontaneous renal hemorrhage, which required hospitalization, and was treated with an initial 225 μg/kg dose of eptacog beta, followed by 75 μg/kg doses at 6, 8, 10, and 13 hours. Physician- and patient-reported hemostasis evaluations were “moderate” at 6 and 8 hours, “good” at 10 and 12 hours, and “excellent” at 16 and 24 hours after the initial eptacog beta infusion. An ultrasound pelvis examination revealed microscopic crystal aggregations but no stones. Treatment of the severe BE was considered successful at 10 hours, given the “good” hemostasis evaluation received at that time point.

A 9-year-old patient with HA (patient 4) experienced hematuria from a spontaneous renal hemorrhage that required hospitalization and was controlled with eptacog beta infusions over the course of 93 hours (Figure 2). The renal hemorrhage was diagnosed through urinalysis and ultrasound examination, and the treatment also included hyperhydration, methylprednisolone, trinefron, and bed rest. The patient and the treating physician provided hemostasis evaluations of “good” at 93 hours after the initial eptacog beta infusion; hemostasis evaluations were “moderate” at all earlier time points.

An 8-year-old patient with HA (patient 5) using the 225 μg/kg IDR experienced dense right hemiplegia due to a traumatic ICH that required prolonged hospitalization. A CT scan 1 day after bleed onset confirmed subarachnoid and subdural bleeding in the left middle cerebral artery area. Patient 5 received an initial 225 μg/kg eptacog beta dose, followed by a 180 μg/kg dose at 5 hours 20 minutes and a subsequent 180 μg/kg dose at 9 hours 35 minutes (Figure 2). This patient then received 75 μg/kg eptacog beta every 2 hours from 12 to 18 hours and 75 μg/kg every 3 hours from 18 to 57 hours. Physician- and patient-reported hemostasis evaluations were “none” at 3 and 12 hours, improved to “moderate” at 14 hours, and worsened to “none” at 24 hours, without subsequent improvement through the final hemostasis evaluation at 56.8 hours. Although a satisfactory (ie, “excellent” or “good”) hemostasis evaluation was not obtained with eptacog beta treatment for this ICH, repeat CT scans on days 2, 4, and 5 after BE onset showed no further active bleeding. Improvement in neuropathy was observed on day 3 after BE onset, and the patient was subsequently treated with aPCC prophylaxis (70 U/kg, every 8 hours) on day 3 for 17 more days to allow for more aggressive rehabilitation. Aggressive physiotherapy was recommended ∼6 weeks later, and patient 5 was given aPCC (70 U/kg, qd) for 4 days to support the intervention. The hemiplegia resolved ∼3 months after BE onset. The patient was subsequently discontinued from PERSEPT 2 (patient/caregiver withdrew consent).

A 1-year-old patient with severe HA (patient 6) experienced a traumatic ICH while assigned to the 225 μg/kg IDR. The patient was initially treated at home with a single dose of 225 μg/kg eptacog beta, and the caregiver recorded a hemostasis evaluation of “good” at 9 hours and “excellent” at 12 hours after the initial infusion. The bleed recurred within 22 hours, necessitating a hospital visit, where the patient received three 225 μg/kg doses of eptacog beta at 22-, 31-, and 34-hour time points. The physician-reported hemostasis evaluation at 30.8 hours was “excellent,” and the caregiver-reported hemostasis evaluations at 33.8 and 46 hours were “good” and “excellent,” respectively.

Patient 6 experienced a second traumatic ICH ∼1 week later and was treated at the hospital with 75 μg/kg eptacog beta q3h for 96 hours (Figure 2). The treating physician and the caregiver each provided a hemostasis evaluation of “good” at 3 hours after the initial infusion of eptacog beta; the caregiver provided subsequent evaluations of “good” every 3 hours through the 24-hour time point, followed by “good” evaluations every 12 hours through the 96-hour time point. Information regarding how the treating physician diagnosed either of the 2 ICH events that were experienced by patient 6 (eg, through magnetic resonance imaging, CT, or ultrasound imaging or by observing neurological signs) was unfortunately not captured in this study.

A 6-year-old patient with HB (patient 7) experienced a traumatic BE in the left elbow while assigned to the 225 μg/kg IDR; the bleed was considered severe based on the patient’s pain levels. Patient 7 received an initial 225 μg/kg eptacog beta dose at home immediately after the first symptoms, followed by a 75 μg/kg dose at 9 hours after the initial infusion, and then 75 μg/kg eptacog beta every 3 hours from 9 to 27 hours before visiting the clinic for further treatment. The patient and the treating physician recorded a hemostasis evaluation of “moderate” at 33.5 hours after the initial infusion of eptacog beta. The patient was subsequently treated with eptacog alfa (two 200 μg/kg doses, followed by a 280 μg/kg dose, every 12 hours). The left elbow was assessed as a target joint that had developed over the prior 6 months after an initial trauma. The patient was discontinued from PERSEPT 2 per physician’s decision to place the patient on prophylaxis.

Three BEs (experienced by patients 1, 3, and 5) were treated with an initial eptacog beta infusion 2 to 3 hours after bleed onset, and 4 BEs (experienced by patients 2, 4, 6, and 7) were treated with eptacog beta in less than 2 hours after BE recognition (Table 3). The time to treatment was not recorded for one of the ICHs experienced by patient 6. Eptacog beta treatment periods ranged from 25 minutes to 96 hours (Figure 3A), and the number of eptacog beta infusions received for each of these severe BEs ranged from 1 to 33 (Figure 3B). In total, the 8 bleeds were treated with 96 infusions of eptacog beta. Hemostatic control was achieved for 7 of the 8 severe or otherwise life-threatening BEs experienced by clinical trial patients aged 1 to 50 years (Table 3).

No allergic reactions, hypersensitivity, anaphylactic reactions, neutralizing anti–eptacog beta antibodies, thrombotic events, or treatment-related adverse events were observed. The investigator characterized both the hemiplegia and the intracranial bleed experienced by patient 5 as serious adverse events that were unrelated to the study drug. The eptacog beta safety profile for all patients participating in PERSEPT 1 and PERSEPT 2 has been previously described.²¹ 

Severe BEs in PwHABIs present clinical management challenges, with hemostatic control potentially taking days or weeks to achieve. In a retrospective survey of 112 ICHs in 88 patients with hemophilia in Italy, Zanon et al found a mean treatment duration of 8.3 days with eptacog alfa (range, 1-21) for 14 ICH episodes in 14 inhibitor patients; an additional ICH was treated using plasma-derived porcine antihemophilic factor for 7 days.⁹ Arkin et al describe 11 inhibitor patients (9 with HA and 2 with HB) who experienced 12 life-threatening ICHs and received a mean of 97 infusions per ICH episode (range, 6-184) of 90 to 120 μg/kg eptacog alfa over an average of 14.7 days (range, 1-32).¹⁰ Arkin et al also describe 23 patients (13 with HA, 4 with HB, and 6 with acquired inhibitors to FVIII or FIX) who experienced 35 limb-threatening joint or muscle BEs; on average, these patients received 56 infusions of 90 to 120 μg/kg eptacog alfa over 9 days (range, 1-33) for each BE.¹⁵ In this post hoc analysis, hemostatic control was achieved with eptacog beta for 7 of 8 severe or otherwise life-threatening BEs (including 3 intracranial bleeds), as determined by hemostasis evaluations and CT imaging, and in time frames consistent with treatment regimens for similar severe BEs.^9-12,15,22 Hemostatic control of the ICH in patient 5 was established on day 2 after BE onset with eptacog beta treatment and was maintained using an extended aPCC regimen.

Although relatively intense and extended treatment durations were used to control severe BEs in PERSEPT 1 and PERSEPT 2, eptacog beta was nonetheless well tolerated after each of the 96 infusions administered, with no safety issues identified. These observations are congruent with previous reports of rFVIIa safety.²³ Because eptacog beta peak plasma levels are dose proportional,²⁴ the higher 225 μg/kg eptacog beta initial dose could potentially drive a greater thrombin burst and accelerate the formation of a stable fibrin clot during severe BE treatment (a situation in which rapid BE resolution is most urgent). However, a direct comparison of 75 and 225 μg/kg severe BE dosing regimens’ efficacies was precluded in this study, because no study participants experienced severe BEs while assigned to the 75 μg/kg IDR during PERSEPT 1 or PERSEPT 2. The 225 μg/kg severe BE dosing regimen has been approved by the US Food and Drug Administration and the European Medicines Agency for gaining hemostatic control of severe BEs in adults and adolescents aged ≥12 years.^3,4 The dosing intervals and intensity for this regimen are supported by pharmacokinetic and pharmacodynamic analyses of data from a previous phase 1b clinical trial with eptacog beta.²⁴ 

Patient 7 experienced a severe left elbow bleed that did not respond sufficiently to eptacog beta treatment by 33.5 hours, and the study drug was withdrawn. Treatment response for this BE may have been influenced by a number of factors: the 225 μg/kg severe BE dosing regimen was not closely followed (longer eptacog beta dosing intervals were used), and the patient received treatment at home instead of in a hospital setting as specified per trial protocol. The observed outcome may also simply reflect the variable response to BPAs seen in inhibitor patients.^25,26 

A low number of BEs analyzed and an inconsistent adherence to the severe BE dosing regimen in a number of cases are limitations of this report. Nonetheless, the eptacog beta treatment durations needed to gain hemostatic control of challenging BEs in PwHABIs in PERSEPT 1 and PERSEPT 2 are consistent with published data and with clinical experience. None of the study patients were receiving emicizumab prophylaxis, because emicizumab had not yet been approved by the US Food and Drug Administration when the PERSEPT trials were conducted. As such, the results described here cannot guide treatment of severe breakthrough BEs in patients with HA with inhibitors using emicizumab. However, data from in vitro studies indicate that combinations of eptacog beta and emicizumab do not generate excess thrombin,²⁷ and eptacog beta has been recommended by the Medical and Advisory Scientific Committee of the National Bleeding Disorders Foundation for patients with HA with inhibitors experiencing breakthrough bleeds while receiving emicizumab.⁷ Real-world safety data of eptacog beta in inhibitor patients are currently being evaluated in the phase 4 ATHN-16 trial (NCT04647227).

Seven of 8 severe or otherwise life-threatening BEs described in this post hoc analysis (88%) were controlled with eptacog beta treatment in time frames consistent with prior similar reports, and no safety issues were identified. Although additional clinical experience will be needed to further characterize eptacog beta efficacy and safety profiles during severe BE treatment, the eptacog beta dosing regimens and corresponding treatment outcomes reported here for PwHABIs experiencing severe BEs expand on the limited available data regarding severe BE treatment with BPAs in PwHABIs.

The authors thank the participants of the PERSEPT trials, their families, and the investigators at each participating study site, without whom none of this work would be possible. The authors also thank Sonia Nasr and Thomas Wilkinson from GLOVAL LLC for assistance in editing this manuscript.

The PERSEPT program was funded by LFB SA. Partial funding was provided by LFB SA and HEMA Biologics LLC for medical writing support and for data retrieval requests by the authors.

Contribution: All authors analyzed and interpreted the data, provided critical input, edited the manuscript, reviewed and approved the final submission, and had independent and full control of the content of the manuscript.

Conflict-of-interest disclosure: G.Y. has received consulting fees from ASC Biotherapeutics, BioMarin, Centessa, CSL Behring, Genentech/Roche, HEMA Biologics/LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Genzyme, Spark, and Takeda; and funds for research support from Sanofi. J.M. has received research grants from BioMarin, Catalyst Biosciences, CSL Behring, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, and uniQure; served as a consultant or member of the scientific board for BioMarin, CSL Behring, Catalyst Biosciences, Novo Nordisk, Roche, Sanofi, Spark, and Takeda; and received speaker bureau fees from the International Society on Thrombosis and Haemostasis (ISTH), Novo Nordisk, Pfizer, Roche, Sanofi, Takeda, and the World Federation of Hemophilia (WFH). L.N.B. has received research support from Pfizer, Bayer, Octapharma, Sanofi, Principia Biopharma, LFB, and HEMA Biologics; and consulting fees from Genentech, Genzyme, Novo Nordisk, and Octapharma. M.C. has received research support from Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; and honoraria for speaking/participating in advisory boards from Bayer, LFB, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda. Y.D. has received funding for research from CSL Behring, Novo Nordisk, LFB, Bayer, Centessa, Pfizer, and Octapharma; and acted as a paid consultant to Sobi, CSL Behring, Pfizer, Roche-Chugai, LFB, Takeda, Novo Nordisk, and Octapharma. M.E. has received grants and research funding from the American Thrombosis and Hemostasis Network (ATHN), uniQure, Takeda, Bayer, Sanofi Regeneron, Novo Nordisk, Pfizer, and LFB; and honoraria and consulting fees from Takeda, Bayer, LFB, HEMA Biologics, BioMarin, Regeneron, Genentech/Roche, Sanofi, Novo Nordisk, CSL Behring, Pfizer, Kedrion, the National Hemophilia Foundation (NHF; now known as the National Bleeding Disorders Foundation), and Magellan. A.G. has served as a consultant or advisory board member for Sanofi, HEMA Biologics, Vega Therapeutics, Alexion, and Genzyme; has been a member of Data and Safety Monitoring Committee for Adrenas; and has acted as a speaker for Sanofi, Alexion, and Genzyme. C.H. has received research funding from Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Shire/Takeda, and Sobi; and honoraria and speaker bureau fees from Bayer, Belgium Red Cross Central Fractionation Facility (CAF-DCF), CSL Behring, Hoffmann-La Roche, LFB, Novo Nordisk, Octapharma, Pfizer, Shire/Takeda, Sobi, and uniQure. W.M. reports consultancy and research funding from Bayer, BioMarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, SOBI, and Takeda. D.N. has received consulting fees from HEMA Biologics. R.F.S. Jr has acted as a paid consultant for HEMA Biologics, LFB, Octapharma, Genentech/Roche, Bayer, Pfizer, Novo Nordisk, Guardian, Vega, Takeda, and Hemab; and has investigator-initiated grant funding from HEMA Biologics/LFB, Takeda, and Octapharma. M.W. has served on advisory boards for Bioverativ/Sanofi, Takeda, CSL Behring, Novo Nordisk, Bayer, Genentech, HEMA Biologics, Vega Therapeutics, and BioMarin; and served as a past investigator for HEMA Biologics and Novo Nordisk. S.W.P. has received grants/research support from Siemens and YewSavin; and served as a consultant to Apcintex, ASC Therapeutics, Bayer, BioMarin, CSL Behring, Equilibra Bioscience, GeneVentiv, HEMA Biologics, Freeline, LFB, Novo Nordisk, Pfizer, Poseida Therapeutics, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure. The remaining authors declare no competing financial interests.

Correspondence: Guy Young, Hemostasis and Thrombosis Center, Hematology/Oncology, Children’s Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027; email: gyoung@chla.usc.edu.