<b>

BACKGROUND:

</b>Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors.<b>

METHODS:

</b>We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study.<b>

RESULTS:

</b>A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors.<b>

CONCLUSIONS:

</b>Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).

BACKGROUND:

The genetically engineered, humanized, bispecific monoclonal antibody emicizumab (Hemlibra) that mimics the cofactor activity of activated factor VIII (FVIII) has been approved for treatment of hemophilia A patients with and without inhibitor. In the pivotal premarketing clinical trials, emicizumab prophylaxis significantly reduced bleeding rates compared with previous treatments and was well tolerated. However, a consequence of this novel therapy may be the host immune response to a foreign protein.

OBJECTIVE:

Characterization of the neutralizing anti-emicizumab antibody associated with the loss of treatment efficacy.

PATIENT:

A pediatric hemophilia A patient with inhibitor enrolled in the HAVEN2 (Study of Emicizumab Administered Subcutaneously (SC) in Pediatric Participants With Hemophilia A and Factor VIII (FVIII) Inhibitors) clinical trial.

METHODS:

The anti-emicizumab antibody has been characterized with Western blot and enzyme-linked immunosorbent assay (ELISA). The antibody was affinity purified and sequenced. Binding affinity to full-length and papain-digested emicizumab was analyzed using surface plasmon resonance and byo-layer interferometry.

RESULTS:

The neutralizing anti-emicizumab antibody was highly polyclonal with high-affinity binding mainly to the Fab portion of emicizumab with a small amount of binding to the Fc portion. Molecular interaction experiments between emicizumab and the purified antibody indicated the presence of at least two components with similar affinities.

CONCLUSIONS:

Although the incidence of neutralizing anti-emicizumab antibody is rare, this study highlights the importance of a close monitoring and the need of a simple laboratory assay to promptly detect these antibodies in patients with a history of poor drug efficacy.

This study aims to examine the real-life experience and impact of using emicizumab in a cohort of patients with haemophilia and inhibitors, who were prescribed emicizumab as part of the early access to medicine schema (EAMS),those who have been in clinical trials and those now receiving emicizumab as part of routine haemophilia care.

The Investigators also intend to capture the impact of emicizumab use on the lives of close family members (parents/carers/children/partners/siblings). Each participant and his family members will be deemed a study \'dyad\'.

This is a prospective, observational cohort qualitative research study to be conducted among patients using emicizumab in routine clinical practice.

The study is designed to allow English-speaking patients and their families to tell their own life stories through narrative accounts. The narratives represent a true sharing of experiences and therefore offers insight into how these patients and families cope with haemophilia.

[Formula presented] Introduction Emicizumab is a recombinant humanized monoclonal antibody that bridges factor IXa and Factor Xa and is administered via subcutaneous injection. After initial FDA approval for patients with hemophilia A (HA) and inhibitors, it was approved in October 2018 for prophylaxis in patients with HA without inhibitors of all ages. In clinical trials of subjects without inhibitors, emicizumab was studied only in those >12 years of age. The primary objective of this study was to report our “real-world”, post-licensure experience with emicizumab across a more heterogenous patient population, comparing annualized bleeding rates prior to and after initiating emicizumab. Secondary objectives included evaluating for serious adverse events including death, thrombosis or drug discontinuation. Methods We conducted a multi-center observational study at 3 federally funded Hemophilia Treatment Centers: Children's Hospital of Philadelphia, Virginia Commonwealth University and Children's National Health System. Inclusion criteria included patients with HA initiated on emicizumab prior to May 15th 2019. Data extraction included: demographics, diagnosis, prior HA history (inhibitor, prophylaxis treatment regimen), emicizumab dosing data, bleeding events (all bleeds, treated bleeds, joint bleeds, traumatic bleeds) and thrombotic events from the 6 months prior to emicizumab until July 15th 2019. Annualized bleeding rates (ABR) were calculated to account for variable follow up. Wilcoxon Sign-Rank Difference Test was used to test the difference in number of bleeds and McNemar's test was used to test the difference in proportions of patients with ABR=0. Results Ninety-two patients met inclusion criteria: 89 male and 89 with severe HA (3 moderate HA) (Table 1). Age at initiation of emicizumab ranged from 5 weeks to 55 years; median 8.6 yrs (IQR 4.8-13.5 yrs). Nineteen patients had an active inhibitor at the time of starting emicizumab; the remaining 73 did not have an inhibitor, and most (86%) were on prophylaxis prior to emicizumab. Sixty-two patients were < 12 years of age (13 with inhibitors). Median duration of emicizumab therapy was 48 weeks (inhibitors) and 22 weeks (non-inhibitors), with a total follow up of 53.3 patient years. In patients with inhibitors, the ABR (treated bleeds) prior to emicizumab was 6.2 events (95% CI, 0.98 to 11.4) compared to 0.3 events (95% CI, 0 to 0.73) on emicizumab, p=0.002. In subjects without inhibitors, the ABR prior to emicizumab was 1.8 events (95% CI, 0.66 to 2.96) compared to 0.22 events (95% CI, 0.05 to 0.39) on emicizumab, p<0.001. Additional data on bleeding events is provided in Table 1. The proportion of patients with ABR=0 increased in both inhibitor (from 46% to 74%, p=0.06) and non-inhibitor subjects (from 60 to 78%, p=0.015). All patients received 1.5 mg/kg weekly x 4 loading doses, followed by either weekly (27%), every other week (70%), or monthly (3%) dosing; patients with inhibitors were more likely to receive weekly dosing. No patients who initiated emicizumab discontinued the drug or developed a neutralizing antibody to FVIII or emicizumab, although patients have not been consistently screened for these antibodies. No thrombotic or thrombotic microangiopathy events or death have occurred. Conclusions Our favorable clinical experience with emicizumab post-licensure in patients with HA is similar to that reported in the clinical trials. Although excluded from the clinical trials, patients with HA without inhibitors < 12 years accounted for the majority (67%) of our cohort. As anticipated, these younger patients appear to experience the same benefit as patients > 12. No serious drug-related adverse events were reported, although the overall study period is relatively short. Ongoing follow up of these patients, and others, will be important to assess the ongoing safety and efficacy profile of this novel therapy. Updated data on this cohort will be presented at the ASH meeting [Formula presented] Disclosures: Guelcher: NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board; Takeda: Other: Advisory Board; Genetech: Other: Advisory Board. Butler: pfizer: Other: Advisory board; Hema-Biologics: Consultancy; genetech: Other: Advisory board. Guerrera: Genetech: Other: Advisory Board; Kendrion: Other: Advisory Board; Shire: Other: Advisory Board; Bayer: Other: Advisory Board; Bioverativ: Consultancy; Pfizer: Other: Advisory Board; Novo Nordisk: Consultancy. Raffini: Roche: Other: Advisory Board; Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board.

BACKGROUND:

As the first non-factor replacement therapy for persons with congenital hemophilia A (PwcHA), emicizumab's safety profile is of particular interest to the community.

OBJECTIVES:

We applied an algorithm for categorization of fatal events contemporaneous to emicizumab using reporter-assessed causality documented in the Roche Emicizumab Global Safety Database.

PATIENTS/METHODS:

All fatalities in PwcHA reported to the database (from clinical trials, pre-market access, and spontaneous post-marketing reports) were categorized into: associated with hemophilia A-hemorrhagic, thrombotic, human immunodeficiency virus (HIV)/hepatitis C virus (HCV), hepatic (non-HCV); associated with general population-trauma/suicide, non-HA-associated conditions; or, unspecified. Reported cause of death was not reassessed.

RESULTS:

As of cut-off May 15, 2020, 31 fatalities in PwcHA taking emicizumab were reported. Median age at death was 58 years; 51% had factor VIII inhibitors. Fifteen fatalities were considered associated with HA; overall, the most frequent category was hemorrhage (11/31). Of these, six had a history of life-threatening bleeds, and four had a history of intracranial hemorrhage. The remaining HA-associated fatalities were related to HIV/HCV (3/31) and other hepatic causes (1/31). No cases were categorized as thrombotic. Of 10 cases considered not associated with HA, two were categorized as cardiovascular (non-thrombotic), five as infection/sepsis, and one each of trauma/suicide, pulmonary, and malignancy. Six cases were unspecified.

CONCLUSIONS:

No unique risk of death was associated with emicizumab prophylaxis in PwcHA. The data reveal that mortality in PwcHA receiving emicizumab was primarily associated with hemorrhage or non-HA-associated conditions, and was not reported by treaters to be related to emicizumab treatment.

Assessment of the outcomes of prophylaxis with Emicizumab in children with severe hemophilia A in Ivory Coast

Introduction Emicizumab is A humanized monoclonal antibody that showed high efficacy in preventing bleeds in patients with hemophilia A and inhibitors aged > 12 years (HAVEN 1 study, Oldenburg et al. NEJM 2017). Thrombotic microangiopathy and thrombosis were reported in patients who received multiple doses of > 100 IU/kg activated prothrombin complex concentrate (aPCC) for breakthrough bleeds. The surgical setting represents A challenge in hemophilia management due to the risk of peri-operative bleeding especially in inhibitor patients in whom intensive by-passing therapy is usually required with unpredictable and sometimes suboptimal efficacy. Here we present the management of A major non-elective orthopaedic surgery performed in one patient enrolled in the HAVEN 1 study at our Institution. Methods: As per protocol, the patient received emicizumab 3 mg/kg subcutaneously once weekly for the first 4 weeks followed by 1.5 mg/kg/week. During the trial, right hip replacement was required due to displacement of the screws used to fix A previous femoral fracture. He continued emicizumab prophylaxis throughout the peri-and post-operative period. Based on our practice and protocol recommendations, we chose recombinant FVIIa (rFVIIa) as the hemostatic by-passing agent to manage the surgical procedure. FVIII replacement was considered as alternative option in the presence of an inhibitor titer < 5 BU/mL. No tromboprophylaxis was given. Anti-FVIII inhibitors were measured by chromogenic assay using bovine substrates (Chromogenix, Coamatic® Factor VIII, IL) and therapeutic FVIII levels by chromogenic assay with human substrates (Biophen

FVIII:

C, Hyphen BioMed). Cell blood count, D-dimer, fibrinogen, LDH, haptoglobin and blood film were monitored peri-and post-operatively. Thrombin generation assay (Thrombinoscope™ Thrombinoscope BV) was performed on platelet-rich and platelet-poor plasma pre-and post-operatively. Results: Medical history: the patient, aged 56 years, had high-responding inhibitors since childhood (peak titer: 126 BU/mL) and treated bleeds with aPCC, plasma-derived porcine FVIII and rFVIIa. He previously underwent femur fracture fixation and total knee replacement that were both managed with rFVIIa by continuous infusion and high-dose boluses (140-190 mcg/kg every 2 hours for the first 48h), respectively. Both procedures were complicated by severe bleeding (blood loss > 1500 mL) and controlled by repeated high-dose rFVIIa boluses and sequential treatment with bypassing agents (alternate dosing of aPCC and rFVIIa), respectively. Surgical management during HAVEN 1 trial: rFVIIa 100 mcg/kg was administered pre-operatively. Surgery lasted 1,5h and was uneventful with an intraoperative blood loss of 650 mL (as expected). During Day 0 rFVIIa was continued at 80 mcg/kg every 3 h and hemoglobin (Hb) level and platelet count dropped (Table 1). Schistocytes were never detected and haptoglobin always normal. On Day 1 A right thigh hematoma developed and Hb levels further dropped despite packed red blood cells transfusions. Inhibitor titer at that time was 2 BU/mL therefore we chose FVIII therapy (Klott, Kedrion) to control bleeding rather than intensify rFVIIa regimen. He received 115 IU/kg by bolus followed by continuous infusion at 3.3-4 IU/kg/h. FVIII levels were maintained above 70 IU/dL until Day 7 when FVIII decreased to 24 IU/dL despite increasing FVIII infusion rate up to 6 IU/kg/h. Platelet count progressively improved during FVIII treatment. The patient was switched back to rFVIIa 80 mcg/kg every 4-8h in association with antifibrinolytic therapy until discharge on Day 13, in this period platelet count were in the normal range. Thrombin generation parameters were in the normal range during emicizumab prophylaxis as well as during the peri-and post-operative period. Conclusion In this patient A low-dose rFVIIa regimen was used for hip replacement without thrombotic microangiopathy or thrombosis and it was not sufficient to prevent bleeding. Bleeding was controlled by FVIII therapy to avoid intensive rFVIIa treatment or other by-passing agents owing to the concern of thrombotic risk. FVIII replacement therapy in association with emicizumab was safe and effective under proper laboratory monitoring. In conclusion, major orthopaedic surgery in patients on emicizumab requires expert multidisciplinary team supported by specialized coagulation laboratory.

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Background Patients with severe hemophilia A may develop inhibitors against factor VIII (FVIII) in around 30% of cases. Recently, the introduction of non-replacement therapies such as emicizumab, a FVIII-mimicking agent administered as a subcutaneous injection, has revolutionized the treatment of patients with inhibitors. However, although rarely, some patients may develop antibodies against this drug. If neutralizing, these antibodies interfere with the activity of the drug, making it ineffective. Mim8 (Novo Nordisk®) is a novel experimental FVIII-mimetic human bispecific antibody that has a similar function as emicizumab, by bridging activated FIX (FIXa) and FX to activate FX, although with a different molecular structure compared to emicizumab. It is currently in phase II clinical trial for subcutaneous treatment of patients with hemophilia A with or without FVIII inhibitors (1, 2). It is currently unknown whether the antibodies developed against emicizumab by patients with hemophilia A could cross-react with Mim8. Aim Our aim was to study the cross-reactivity of anti-emicizumab antibodies developed by patients with hemophilia A against Mim8 with an in-house detection method. Methods We studied the serum of three patients who developed anti-emicizumab antibodies. Plasma from one patient with persistent inhibiting antibodies was collected both during the treatment (thus also containing emicizumab at steady-state levels) and two years after treatment discontinuation due to inefficacy (neutralizing persistent antibodies). Plasma from two patients who developed transient antibodies against emicizumab were also tested in the course of treatment with emicizumab (non-neutralizing transient antibodies). The plate was coated both with emicizumab and with Mim8 provided by the pharmaceutical companies for research purposes. Plasma samples, diluted 1/20, were loaded into the coated wells and incubated 90 min at 37°C. The cross-reactivity to Mim8 was evaluated also by using the affinity purified anti-emicizumab IgG, which was loaded at 5 ug/mL. A properly adapted ELISA method already described (3) was used as reference assay. Then, biotinylated-emicizumab (1.5 ug/mL) or biotinylated-Mim8 (at 2 and 4 ug/mL) were added and the plate incubated 1 hour at 37°C. Moreover, a competition test was performed by using a mixture of biotinylated-emicizumab (1.5 ug/mL) and an excess of Mim8 (at 4, 8 and 40 ug/mL) in the detection phase. Results The Mim8 molecule - either alone, or matched with emicizumab - used both in the capture phase and in the detection phase did not bind to neither patient's plasma antibodies nor to anti-emicizumab purified IgG, which were instead revealed with the reference assay. The binding of the anti-emicizumab antibodies to biotinylated-emicizumab was not inhibited by the addition of Mim8, even at 40 ug/mL. Conclusions Our in-house method showed that anti-emicizumab antibodies do not react with Mim8 in vitro. Observational studies to test whether Mim8 can be used safely in patients with anti-emicizumab antibodies are needed to confirm our findings in vivo as well. References 1. Østergaard et al. A FVIIIa-mimetic bispecific antibody (Mim8) ameliorates bleeding upon severe vascular challenge in hemophilia A mice. Blood. 2021;blood.2020010331. doi:10.1182/blood.2020010331. 2. Valsecchi C et al. J Thromb Haemost. 2021;19(3):711-718. Disclosures: Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Von Willebrand Disease (VWD) is the most common inherited bleeding disorder affecting up to 0.1% of the population, is usually characterized by mucocutaneous bleeding, HMB, surgical bleeding or other hemostatic challenges. Severe bleeding events require VWF concentrates administered solely through intravenous access. Emicizumab (Hemlibra) is a monoclonal bispecific antibody developed to bind activated FIX and FX and mimic FVIII cofactor functionality. Hemlibra is administered via subcutaneous injection rather than intravenous infusion. The hypothesis of this study is that Emicizumab is safe and efficacious for prophylaxis in severe VWD and concomitant VWD/hemophilia patients.