A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors

Young, Guy; Liesner, Ri; Chang, Tiffany; Sidonio, Robert F.; Oldenburg, Johannes; Jiménez‐Yuste, Víctor; Mahlangu, Johnny; Kruse‐Jarres, Rebecca; Wang, Michael; Uguen, Marianne; Doral, Michelle Y.; Wright, Lilyan Y; Schmitt, Christophe; Lévy, Gallia; Shima, Midori; Mancuso, Maria Elisa

doi:10.1182/blood.2019001869

Cited by 274 publications

(534 citation statements)

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“…The final concentration of aPCC or rFVIIa in whole blood was calculated using the following formula: therapeutic dose (U/kg or μg/kg)/80 ¼ final concentration (U/mL or μg/mL, respectively). In this experiment, we utilized higher concentrations of emicizumab (100 μg/mL) than clinically therapeutic concentrations (30 À 80 μg/mL) [14][15][16][17][18] to ensure maximum activity for thrombus formation ex vivo. Reactions on the collagen that was coated on the surface under these conditions represented thrombus formation at high shear.…”

Section: Perfusion Chamber Experimentsmentioning

confidence: 99%

Emicizumab Augments Thrombus Formation in Whole Blood from Patients with Hemophilia A under High Shear Flow Conditions

Yaoi

Shida

Kitazawa³

et al. 2020

Thromb Haemost

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Background Emicizumab is a bispecific antibody to factor (F) IXa and FX that mimics the FVIIIa cofactor function. Emicizumab prophylaxis markedly decreases bleeding episodes in patients with hemophilia A (PwHAs), irrespective of the presence of FVIII inhibitors. However, thrombotic microangiopathy (TMA) was reported when repeated high doses of activated prothrombin complex concentrates (aPCC) were concomitantly used with emicizumab. Although bypassing agents (BPAs) are vital in the hemostatic treatment for PwHAs with inhibitors, the mechanism of emicizumab-related TMA remains unclear. Aim To assess the risk of excessive thrombus formation associated with BPAs and emicizumab under high shear conditions. Methods Perfusion flow-chamber experiments under high shear conditions were performed using whole blood from PwHAs in the presence of emicizumab without or together with FVIII or BPAs ex vivo. Results Emicizumab (100 μg/mL) added ex vivo to whole blood from PwHAs improved defective thrombus formation in a similar manner to that observed with the addition of recombinant FVIII at the early phase, while FVIII continued to be important at the later stages. aPCC (1.2 U/mL equivalent to 100 U/kg) or recombinant FVIIa (1.1 µg/mL; equivalent to 90 µg/kg) together with emicizumab further promoted platelet interactions and fibrin formation ex vivo but did not induce excessive thrombus formation. Conclusion Emicizumab enhanced thrombin generation at local sites and improved defective hemostasis in whole blood from PwHAs under high shear conditions. Simple concomitant use of BPAs with emicizumab did not mediate excessive thrombus formation and remains an option for hemostatic management of emicizumab-treated PwHAs with inhibitors.

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Section: Perfusion Chamber Experimentsmentioning

confidence: 99%

Emicizumab Augments Thrombus Formation in Whole Blood from Patients with Hemophilia A under High Shear Flow Conditions

Yaoi

Shida

Kitazawa³

et al. 2020

Thromb Haemost

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“…Consequently, rFVIIa has been recommended as first‐line therapy for breakthrough bleeding during emicizumab prophylaxis. The occurrence of ADAs has also been identified as a rare SAE, including 2 pediatric patients who developed neutralizing ADAs in the HAVEN 2 studies 25 . The frequency of ADAs in these circumstances appears to be low compared to that reported with other antibody drugs.…”

Section: Summary Of Clinical Trialsmentioning

confidence: 99%

Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

Shima

2020

Research and Practice in Thrombosis and Haemostasis

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Regular prophylaxis has markedly improved the treatment for patients with hemophilia A, especially after the introduction of highly purified factor VIII (FVIII) concentrates. However, frequent intravenous infusions and the development of FVIII inhibitors remain as unsolved difficulties. To overcome these unmet needs, a bispecific antibody mimicking activated FVIII has been developed in Japan. This bispecific antibody, emicizumab, recognizes activated factor IX (FIXa) and activated factor X (FXa), and promotes FIXa‐catalyzed activation of FX in the absence of FVIII. Emicizumab initially reacts with FIXa generated by the action of factor VIIa/tissue factor complexes. Subsequently, thrombin generation is enhanced in the presence of higher amounts of FIXa derived from FXIa‐dependent mechanisms. Hence, emicizumab‐driven FXa and thrombin generation is maintained by a FXI activation loop in the intrinsic coagulation pathway. Reactions downstream of emicizumab are regulated by natural anticoagulants including activated protein C, antithrombin, and tissue factor pathway inhibitor. Phase 3 studies (HAVEN 1‐4 and HOHOEMI studies) demonstrated a remarkable reduction in bleeding rates together with a high percentage of patients with zero treated bleeds irrespective of the presence of inhibitors. In general, emicizumab proved to be well tolerated, although isolated thromboembolic and thrombotic microangiopathic complications were observed in the HAVEN 1 studies, and 3 out of a total of 400 patients developed neutralizing antidrug antibodies. In addition, several questions remain to be discussed with respect to open‐use clinical practice, including when to start treatment, how to monitor therapy, and optimum dosage for surgical procedures and immune tolerance induction.

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“…HAVEN 2 is a non-randomized, open-label, multicenter, phase 3 clinical trial designed to evaluate the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis in children <12 years of age (12 to 17 years, if bodyweight < 40 kg) with HA and high-titer FVIII-inhibitors (≥5 BU/mL), previously treated with BPAs. 32 First cohort of patients (n=68) received subcutaneous injections of loading dose emicizumab 3 mg/ kg QW for 4 weeks, followed by maintenance dose 1.5 mg/kg QW thereafter. Two additional nonrandomized cohorts were subsequently opened to enroll patients to receive similar loading dose regimen, followed by maintenance dose 3 mg/kg Q2W (n=10 patients), or 6 mg/kg Q4W (n=10 patients).…”

Section: Pharmacology Mode Of Action and Pharmacokinetics Of Emicizmentioning

confidence: 99%

“…Results were concordant with those observed in adult patients, revealing that through plasma emicizumab concentrations were maintained at approximately 50 µg/mL, 45 µg/mL, and 38 µg/mL with QW, Q2W, and Q4W dosing, respectively (Figure 1). 32 Recently, the HOHOEMI study, a Japanese multicenter non-randomized trial, reported pharmacokinetic data of emicizumab administered subcutaneously at a maintenance dose of 3 mg/kg Q2W (n=6 patients) or 6 mg/kg Q4W (n=7 patients) in HA pediatric patients without FVIII-inhibitors, 33 including only one previously untreated patient (PUP), after receiving a loading dose of 3 mg/kg QW subcutaneously for the first 4 weeks of treatment. The mean trough plasma concentrations of emicizumab were approximately 48 μg/mL at the completion of the loading dose in both cohorts, which were comparable with those in adult and adolescent patients receiving the same Q2W or Q4W regimen in HAVEN 2, HAVEN 3 and HAVEN 4 studies.…”

Section: Pharmacology Mode Of Action and Pharmacokinetics Of Emicizmentioning

confidence: 99%

“…22 Mean trough emicizumab concentrations with Q4W emicizumab prophylaxis were slightly lower than those obtained with QW or Q2W emicizumab in HA adults/adolescents and children. 27,32,33 Therefore, we can speculate that choosing the QW emicizumab regimen would be more appropriate in children in order to provide better long-term protection from bleeding, especially in these patients who are more prone to be highly active and to participate in high-impact activities and sports.…”

Section: Pharmacology Mode Of Action and Pharmacokinetics Of Emicizmentioning

confidence: 99%

See 1 more Smart Citation

<p>Clinical Evidence and Safety Profile of Emicizumab for the Management of Children with Hemophilia A</p>

Quellec¹

2020

DDDT

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Emicizumab is a bispecific, humanized, monoclonal antibody mimicking the factor (F) VIII cofactor activity in mediating the generation of FXa by FIXa in patients with hemophilia A (HA). This subcutaneous non-factor agent has been recently extensively approved for the prophylaxis of patients of HA patients with and without FVIII-inhibitors of all ages, although few data are currently available in children. In Phase 3 clinical trials and case series, emicizumab prophylaxis significantly reduced bleeding rates compared to previous treatment in HA adolescents and children with or without FVIIIinhibitors and was generally well tolerated. In addition, subcutaneous administration of emicizumab provided beneficial effects on health-related quality of life, and lessened the burden of the disease in HA patients as well as in their caregivers. However, additional prospective studies are required to evaluate the long-term safety of emicizumab prophylaxis in very young patients, including previously untreated patients. The aim of this paper was to review the limited data available on the use of emicizumab prophylaxis in children and to highlight the need for further studies to address remaining concerns.

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A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors

Abstract: In a Plenary Paper, Young et al describe impressive favorable outcomes of emicizumab prophylaxis in children with hemophilia A and factor VIII inhibitors, reporting a 99% reduction in annualized bleeding, with 77% of patients having no treated bleeding events.

Cited by 274 publications

References 30 publications

Emicizumab Augments Thrombus Formation in Whole Blood from Patients with Hemophilia A under High Shear Flow Conditions

Emicizumab Augments Thrombus Formation in Whole Blood from Patients with Hemophilia A under High Shear Flow Conditions

Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

<p>Clinical Evidence and Safety Profile of Emicizumab for the Management of Children with Hemophilia A</p>

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