BACKGROUND:

Emicizumab is approved to prevent bleeding in patients with congenital haemophilia A with or without inhibitors. However, no randomized trials addressed the efficacy of emicizumab in acquired haemophilia A (AHA).

AIMS:

To report the clinical and biochemical response of emicizumab in AHA.

METHODS:

This single-centre retrospective study included seven adults with AHA between November 2020 and May 2022. We collected patient characteristics, laboratory coagulation parameters, the use of haemostatic agents, bleeds and thrombotic events. Treatment was monitored using chromogenic FVIII assays. The assay with human reagents assesses both the emicizumab FVIII-like-activity and native patient FVIII-activity. The assay with bovine reagents only measures the patients' native FVIII-activity as emicizumab does not bind to bovine reagents.

RESULTS:

Patients presented with spontaneous hematoma (n = 7), intramuscular bleeding (n = 2), haematuria (n = 2) and/or gastro-intestinal bleeding (n = 2). Six patients had major bleedings. At diagnosis, APTT was prolonged (91 seconds, IQR 73-103), FVIII activity was 0% (IQR 0-1) and FVIII inhibitor 182 BU/mL (IQR 104-228). Emicizumab was administered weekly (3 mg/kg) for 4 weeks, and thereafter every 2 weeks until regression of the inhibitor. Three patients received activated FVIIa (cumulative dose of 1.7 mg/kg, IQR 1.2-2.2). All bleedings were controlled after treatment initiation, without further bleeds. After starting emicizumab, FVIII-like activity reached ≥5% at 12 days (IQR 7-14), whereas recovery of the intrinsic FVIII-activity ≥5% occurred at 128 days (IQR 88-173), coinciding with the disappearance of the FVIII inhibitor. There were no safety issues.

CONCLUSION:

In this AHA case series, no new clinically relevant bleeds were observed after initiation of emicizumab in conjunction with standard immunosuppressive therapy.

This study prospectively investigates the safety, FVIII immunogenicity, and hemostatic efficacy of prophylactic HEMLIBRA® given with a concomitant low dose recombinant factor VIII (rFVIII) known as NUWIQ®, in HA infants and children \<3 years old who have had little to no previous exposure to FVIII. In addition, the study investigates the safety and efficacy of a novel FVIII ITI regimen in children \<21 with existing low and high titer inhibitors (LTI and HTI).

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INTRODUCTION:

Hemophilia is a serious bleeding disorder characterized by repeated bleeding episodes into joints and muscles which can lead to permanent disabilities. Treatment with factor replacement therapy has proven to be effective at preventing these complications; however, it can lead to formation of neutralizing antibodies termed inhibitors which significantly complicate the management of the disorder. These inhibitor patients suffer from increased morbidity and mortality and there has been a major unmet need for novel therapeutic approaches. Recently, one such therapy, emicizumab, has been licensed in the United States. Areas covered: This manuscript contains a detailed discussion of the mechanism of action, the clinical trial development program as well as a review of the benefits and risks of this novel agent. In addition, practical considerations for the use of the agent are also described. Expert commentary: Emicizumab represents a new class of medication for the treatment of hemophilia A which in the past has relied on factor replacement therapy and bypassing agent (alternative factor) therapy. Emicizumab fulfills two major unmet needs in patients with hemophilia who have FVIII inhibitors. First, it provides for a much more effective therapy for the prevention of bleeding and second it substantially reduces the treatment burden.

ABSTRACT BACKGROUND:

Until recently, the treatment of people with hemophilia A and inhibitors (PwHAi) was based on the use of bypassing agents (BPA). However, the advent of emicizumab as prophylaxis has demonstrated promising results.

OBJECTIVES:

We aimed to compare the bleeding endpoints between PwHAi on BPA and those on emicizumab prophylaxis.

DESIGN AND SETTING:

Systematic review of interventions and meta-analysis conducted at the Universidade Federal de Goiás, Goiânia, Goiás, Brazil.

METHODS:

The CENTRAL, MEDLINE, Scopus, and LILACS databases were searched on February 21, 2023. Two authors conducted the literature search, publication selection, and data extraction. The selected publications evaluated the bleeding endpoints between PwHAi on emicizumab prophylaxis and those on BPA prophylaxis. The risk of bias was evaluated according to the Joanna Briggs Institute criteria. A meta-analysis was performed to determine the annualized bleeding rate (ABR) for treated bleeds.

RESULTS:

Five publications (56 PwHAi) were selected from the 543 retrieved records. Overall, bleeding endpoints were lower during emicizumab prophylaxis than during BPA prophylaxis. All the publications had at least one risk of bias. The only common parameter for the meta-analysis was the ABR for treated bleeds. During emicizumab prophylaxis, the ABR for treated bleeds was lower than during BPA prophylaxis (standard mean difference: −1.58; 95% confidence interval −2.50, −0.66, P = 0.0008; I2 = 68.4%, P = 0.0031).

CONCLUSION:

Emicizumab was superior to BPA in bleeding prophylaxis in PwHAi. However, both the small population size and potential risk of bias should be considered when evaluating these results.

SYSTEMATIC REVIEW REGISTRATION:

CRD42021278726, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278726.

Emicizumab is a monoclonal bispecific antibody with a terminal half-life of 28 days which is now licensed in the treatment of severe haemophilia A with or without inhibitors. Some heterogeneity in residual emicizumab concentrations have been reported according to age, body mass index or drug therapeutic regimen. Some cases of neutralizing antidrug antibodies have been also reported. Whether monitoring emicizumab plasma concentration could predict the residual bleeding risk under emicizumab is unknown. As conventional coagulation assays are not adapted for emicizumab monitoring, this study aims to assess the value of monitoring residual emicizumab plasma concentration by UPLC-MS/MS in bleeding risk prediction.

Introduction: Emicizumab is a subcutaneously administered, humanized bispecific monoclonal antibody that is recently approved for hemostatic prophylaxis in people with hemophilia A (PWH) with or without factor VIII inhibitors. We hypothesize that the new route and frequency of administration would lead to better treatment adherence compared to factor or bypass products in PWH outside of clinical trials. We performed the current study to test the hypothesis and to examine potential predictors of non-adherence associated with emicizumab treatment. Methods: We performed a retrospective cohort study at the Washington Center for Bleeding Disorders. Inclusion criteria included PWH with moderate to severe hereditary hemophilia (FVIII <5%), clinician recommendation for routine prophylaxis, receipt of clinical care and medication from a hemophilia treatment center (HTC), at least 12 months of prior exposure to factor or bypass products, and at least 3 months of emicizumab treatment. For patients who were previously enrolled in emicizumab clinical trials, adherence data were collected from the time of first commercial product administration. Adherence percentage (%) was estimated as days of drug dispensed / days elapsed x 100 and non-adherence % was determined as 100 - adherence %. Relevant patient, condition, treatment, and socioeconomic variable data were collected from review of medical records. To assess the difference in drug adherence, we compared the adherence % of emicizumab versus that of factor or bypass product in the same patients using the paired t test. To assess predictors of non-adherence %, we used a generalized linear model (GLM) with log link and gamma distribution to account for the right skewed distribution of the outcome. A multivariable GLM was built to incorporate the most significant predictors of non-adherence. Results: We identified 56 PWH that initiated commercial emicizumab from 1/2018 to 5/2019 at our HTC. Five patients were excluded for fewer than 3 months of follow-up on treatment and 3 patients were excluded for not having prior exposure to factor therapy. The remaining 48 patients had a median duration on emicizumab of 7 months (IQR 5-9) at the time of study. The most common dosing frequency was weekly administration (77%). The median age at treatment index date was 17 years (IQR 9-36), 65% were Caucasian, and 46% had Medicaid or Medicare insurance. The majority of patients had a diagnosis of severe hemophilia (90%), 42% had a history of inhibitor (15% active inhibitor), and 25% were previously enrolled in an emicizumab interventional trial. Prior to emicizumab initiation, 46% of patients had 5 or more self-reported annualized bleeds. The most common reason for emicizumab initiation was patient preference (35%), followed by breakthrough bleeding (33%), difficult venipuncture (21%), and shortened factor half-life (10%). Among 12 patients who previously received only on demand treatment, their adherence on emicizumab was 89%. Among 36 patients who previously received routine prophylaxis, their adherence was significantly higher on emicizumab (98%) than factor/bypass products (89%) (p=0.002). Specifically, 18 out of 48 patients (38%) had factor/bypass adherence <75% (or refused prophylaxis) and 2 out of 48 patients (4%) had emicizumab adherence <75%. Various factors were associated with increased emicizumab non-adherence (Table 1). Age group had the strongest association where young and older adult PWH had more non-adherence % than children and adolescents (Figure 1). On multivariable analysis, age group, active inhibitor, and prior factor/bypass agent non-adherence (episodic or <75% usage) were significantly associated with increased emicizumab non-adherence. Conclusions: In the current study, we found that PWH requiring routine prophylaxis were more likely to be adherent to emicizumab than previous factor or bypass agents. Age group (young adult), active inhibitor, and prior non-adherence to factor product were significant predictors for decreased emicizumab adherence but the differences were small. Given the long half-life of the drug, the significance of non-perfect adherence on bleeding outcomes needs to be studied prospectively with longer clinical follow-up. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION:

Emicizumab is a bispecific monoclonal antibody that mimics factor VIII (FVIII) by binding to factors IXa and X to promote hemostasis in haemophilia A (HA) and HA with inhibitors (HA-I). As emicizumab differs biochemically from FVIII, there is interest in its real-world haemostatic efficacy.

AIM:

To describe real-world patient experience with emicizumab by retrospective chart review.

METHODS:

We reviewed medical records of patients cared for at the Hemophilia Center of Western PA, who initiated emicizumab following its licensure, and on whom bleeding events and factor use were available. Comparisons between groups were done by Student's t test for continuous data and by chi-square or Fisher's exact test for discrete data.

RESULTS:

A total of 42 patients whose charts were reviewed included 18 (42.9%) with HA and 24 (52.1%) with HA-I. Groups were similar in age, 17 (40.5%) <18 years, race, and haemophilia severity, and initiated weekly subcutaneous emicizumab 1.5 mg/kg, following 4-week induction. Fourteen (33.3%) experienced at least one breakthrough bleed, of which 11 (44.0%) were joint bleeds, with an annualized bleed rate (ABR), 0.9 ± 0.3, not different between groups, P = .251. Surgical procedures were performed in 10 (23.8%), of whom 4 (40.0%) had postoperative bleeding and one developed postoperative thrombosis in association with FEIBA despite emicizumab discontinuation 1 month preoperatively. Local skin reactions occurred in three and headache in one. Overall, 85.0% of those who rated their health indicated it was improved.

DISCUSSION:

Despite breakthrough bleeds and postoperative thrombosis associated with emicizumab, most HA and HA-I experienced improved health.