Emicizumab in children: bleeding episodes and outcome before and after transition to Emicizumab.

PURPOSE: Real-world data and study data regarding therapy with Emicizumab in pediatric cohorts with haemophilia A is scarce. Especially, data on previously untreated pediatric patients (PUPs) and minimally treated patients (MTPs) are missing. METHODS: Thirteen pediatric patients with haemophilia A and treatment with Emicizumab were retrospectively evaluated for Annual Bleeding Rates (ABR) pre-and post-Emicizumab treatment. Safety data and data on management of minor surgery as well as laboratory results were collected. Additionally, we describe the clinical features of two PUPs and one MTP that are included in our cohort. RESULTS: Median age at initiation of Emicizumab was 5.3 (range: 0.26-17.5) years, three patients were younger than one year at initiation of treatment with Emicizumab. Median follow-up time on Emicizumab was 23.8 (range: 0.7-40) months. Total ABR (p = 0.009) as well as spontaneous (p = 0.018), traumatic (p = 0.018), and joint (p = 0.027) ABR reduced significantly post-Emicizumab transition. Safety profile was favourable as only one local site reaction occurred; no cessation of treatment was necessary. Surgery was successfully performed in three patients receiving rFVlla pre- and post-surgery. Emicizumab trough levels showed a median of 43.2 µg/ml (range: 23.9-56.8) after three doses of 3 mg/kg and 51.9 µg/ml (range: 30.4-75) at first follow-up with 1.5 mg/kg. CONCLUSION: Emicizumab is safe and efficient in pediatric patients with and without inhibitors. More data on larger multicenter cohorts and especially on PUPs/MTPs are still needed.

Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

INTRODUCTION: The factor VIII mimetic emicizumab (Hemlibra, Hoffman-la Roche, Basel, Switzerland) has a novel mode of action that affects the laboratory monitoring of patients receiving this treatment. AIM: This guideline from the United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO) aims to provide advice for clinical and laboratory staff on appropriate use of laboratory assays in patients with Haemophilia A treated with emicizumab. METHODOLOGY: The guideline was prepared by a review of the available literature and discussion and revision by the authors. RESULTS: The guideline describes the effect of emicizumab on commonly used coagulations tests and provides recommendations on the use of assays for measurement of factor VIII and factor VIII inhibitor in the presence of emicizumab. The guideline also provides recommendations on measurement of emicizumab. CONCLUSION: Knowledge of the effect of emicizumab on coagulation tests and factor assays is required to ensure appropriate testing and monitoring of therapy in patients receiving this drug.

Evaluation of an e-Learning Program for Community Pharmacists for Dispensing Emicizumab (Hemlibra) in France: Nationwide Cross-Sectional Study.

BACKGROUND: Since June 2021, patients with hemophilia A with antifactor VIII inhibitors and those with severe hemophilia A without antifactor VIII inhibitors treated with Hemlibra have had to choose between a community or hospital pharmacy. The French reference center for hemophilia developed the HEMOPHAR e-learning program for community pharmacists for dispensing emicizumab. OBJECTIVE: This study aims to evaluate the efficiency and safety of this new care pathway by assessing the HEMOPHAR e-learning program. METHODS: The methodology is based on Kirkpatrick's model for evaluating the immediate reaction of trained community pharmacists (level 1), their level of acquired knowledge (level 2), and their professional practice after 3 months of dispensation (level 3). RESULTS: The HEMOPHAR e-learning program reached a large audience, with 67% (337/502) of the eligible community pharmacists following it. The immediate reaction was overall satisfying. High rates of engagement were reported with 63.5% (214/337) to 73.3% (247/337) of completed training modules, along with high rates of success with quizzes of 61.5% (174/337) to 95.7% (244/337). We observed that 83.9% (193/230) of the community pharmacists needed less than 2 attempts to pass the quiz of the module related to professional practice, while the other quizzes required more attempts. Advice on compliance and drug interactions were most frequently provided to patients by the community pharmacists. CONCLUSIONS: This study suggests ways to improve the training of community pharmacists and to optimize coordination with treatment centers. This study also reports on the feasibility of switching to a community pharmacy in a secure pharmaceutical circuit, including in the context of a rare bleeding disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT05449197; https://clinicaltrials.gov/study/NCT05449197. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/43091.

Chromogenic Factor VIII Assay for Patients with Hemophilia A and on Emicizumab Therapy.

This chapter will describe a method for measuring endogenous and infused Factor VIII (FVIII) in patients on emicizumab therapy (Hemlibra, Genetec, Inc). Emicizumab is a bispecific monoclonal antibody used in patients with hemophilia A, with or without inhibitors. The mechanism of action for emicizumab is novel and mimics the role that FVIII plays in vivo by binding and bridging FIXa and FX. It is vital that the laboratory understands the effect this drug has on coagulation tests and uses a suitable chromogenic assay which is not affected by emicizumab, for determination of FVIII coagulant activity and inhibitors.

Hemophilia A: Emicizumab monitoring and impact on coagulation testing.

Hemophilia A is an X-linked recessive bleeding disorder characterized by absent or ineffective coagulation factor VIII, a condition that could result in a severe and potentially life-threatening bleed. Although the current standard of care involves prophylactic replacement therapy of factor VIII, the development of neutralizing anti-factor VIII alloantibody inhibitors often complicates such therapeutic treatment. Emicizumab (Hemlibra®), a novel recombinant therapeutic agent for patients with hemophilia A, is a humanized asymmetric bispecific IgG4 monoclonal antibody designed to mimic activated factor VIII by bridging factor IXa and factor X thus effecting hemostasis. Importantly, this drug eliminates the need for factor VIII and complications associated with inhibitor generation. Emicizumab has been approved for use in several countries including the United States and Japan for prophylaxis of bleeding episodes in hemophilia A with and without FVIII inhibitors. Therapy is also approved in the European Union for routine prophylaxis of bleeds in hemophilia A with inhibitors or severe hemophilia A without inhibitors. Unfortunately, emicizumab therapy presents unique challenges for routine and specialty coagulation tests currently used to monitor hemophilia A. In this review, hemophilia A is presented, the biochemistry of factor VIII is discussed, and the impact of the therapeutic agent emicizumab is highlighted.

Budget Impact of Emicizumab for Routine Prophylaxis of Bleeding Episodes in Patients With Hemophilia A With Inhibitors.

OBJECTIVES: To examine the budget impact of emicizumab as prophylactic therapy in reducing the frequency of bleeding episodes in patients with hemophilia A with inhibitors in Malaysia. METHODS: A budget impact model was built to assess the cost implication of introducing emicizumab for routine prophylaxis of bleeding episodes in people with hemophilia A with inhibitors. It was based on the public healthcare system in Malaysia over a 5-year duration. The primary analysis computed healthcare costs for emicizumab compared with no prophylactic regimen to calculate the budget needed to treat all patients with hemophilia A with inhibitors. RESULTS: The introduction of emicizumab resulted in a total incremental budget of Malaysian Ringgit (RM) 20 356 897 ($4 917 125) during the first year. The total cost for the current situation (no prophylaxis) was RM13 425 941 ($3 242 981), whereas the total cost for the new situation (prophylaxis with emicizumab) was RM33 782 838 ($8 160 106). The 5-year cumulative incremental budget impact from 2021 to 2025 was RM97 205 459 ($23 479 579) with an uncertainty range from -RM4 869 886 (-$1 176 301) to RM138 035 597 ($33 341 932) and a total of 72 patients treated with emicizumab. In a sensitivity analysis, the use of emicizumab was cost saving if the annual bleeding rate was greater than 16 instead of 6 times per year. CONCLUSION: The 5-year budget impact might be considered reasonable and possibly cost saving. The model and approach used in this study to obtain relevant parameters where scarce data exist may help other jurisdictions with future adaptation.

Bispecific antibody characterization by a combination of intact and site-specific/chain-specific LC/MS techniques.

Bispecific antibodies (bsAbs) are considered as an important class of biopharmaceutical drugs, with about 160 products in clinical trials. From an analytical point of view, the correct chain-association is one of the most critical challenge to monitor during bsAbs development and production. In the present study, a full analytical workflow has been developed based on the use of various chromatographic modes: size exclusion chromatography (SEC), ion exchange chromatography (IEX), reversed phase liquid chromatography (RPLC), and hydrophilic interaction chromatography (HILIC), all combined with high resolution mass spectrometry (MS). This analytical strategy was applied to Hemlibra® (emicizumab), which is certainly the most successful commercial bsAb to date. Using this strategy, it was possible to monitor the presence of mispaired bsAb species and detect and identify additional post-translational modifications (PTMs).