Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study

Pipe, Steven W.; Shima, Midori; Lehle, Michaela; Shapiro, Amy D.; Chebon, Sammy; Fukutake, Katsuyuki; Key, Nigel S.; Portron, Agnès; Schmitt, Christophe; Podolak-Dawidziak, Maria; Bienz, Nives Selak; Hermans, Cédric; Campinha‐Bacote, Avrita; Kiialainen, Anna; Peerlinck, Kathelijne; Lévy, Gallia; Jiménez‐Yuste, Víctor

doi:10.1016/s2352-3026(19)30054-7

Cited by 302 publications

(489 citation statements)

References 31 publications

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“…51 The dosing and duration of radiotherapy are variable and should be guided by local experience. 51 The dosing and duration of radiotherapy are variable and should be guided by local experience.…”

Section: Radiotherapymentioning

confidence: 99%

Characteristics and management of the haemophilia‐associated pseudotumours

2019

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| INTRODUC TI ONHaemophilia-associated pseudotumours (HPT) were first described by Starker in 1918 and are a continuing cause of severe morbidity and mortality for patients with congenital haemophilia. 1 The prevalence of HPT has been described between 1% and 2% of patients with haemophilia with similar levels persisting despite the use of recombinant factor replacement over the last decades. 2,3 The clinical course of HPT can be heterogenous due to a variety of factors including age of onset, disease severity, presence of an inhibitor and inadequate factor replacement. 4 They can result in a variety of problems including bleeding, organ compression and loss of function, bone destruction and fistula formation.HPT typically develops at a site of injury such as a bone fracture, or from spontaneous bleeding in subperiosteal and soft tissues. A preceding traumatic event has been described in 57%-75% of patients with HPT. 3,5 Subsequent bleeding, inadequate blood reabsorption and capsular formation around the haematoma lead to progressive enlargement of the HPT. This can ultimately lead to the eventual mass effect on local structures or bone and skin AbstractThe management of haemophilia-associated pseudotumours presents an ongoing challenge to the haematologist, surgeon and interventional radiologist alike. There is a range of therapeutic approaches including factor replacement, embolization, radiotherapy and a variety of surgical interventions. However, there remains little evidence regarding the most appropriate treatment. We aimed to evaluate the available options of management for the haemophilia-associated pseudotumour. A literature review was performed using relevant terminology and reviewed for treatment approaches and outcomes. The results demonstrated that most of the data is from single case reports with a small number of single-and multicentre case series. In total, 133 patients with 134 described pseudotumours were identified. Adequate haemostatic control with factor replacement was a key component to successful treatment. Surgical excision was the most commonly reported surgical intervention with various composites used for filling of the surgical cavity. The use of radiotherapy has been described particularly in the paediatric population and sites of difficult surgical access. Embolization can be considered as a method of presurgical optimization.Patients with both factor inhibitors and pseudotumours have poorer postoperative outcomes. This review demonstrates that although a lack of large-centre, randomized studies, timely surgical intervention with adequate haemostatic support and the consideration adjuvant therapies in selected cases can achieve acceptable outcomes in this cohort of patients. K E Y W O R D Scomplication, haemophilia A, haemophilia B, pseudotumour, surgery S U PP O RTI N G I N FO R M ATI O NAdditional supporting information may be found online in the Supporting Information section.

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Section: Radiotherapymentioning

confidence: 99%

Characteristics and management of the haemophilia‐associated pseudotumours

2019

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“…1 However, despite the regular prophylaxis with FVIII given once or more times per week, the majority of patients are still at the risk of bleeding. 8,9 Another study (HAVEN 2) was conducted in paediatric patients with inhibitors. 6 In adult and adolescent patients with or without inhibitors, clinically meaningful efficacy of emicizumab for bleeding prevention was demonstrated with a subcutaneous maintenance dose of 1.5 mg/kg every week (QW) in the HAVEN 1 and HAVEN 3 studies, 7,8 and similar efficacy profiles were confirmed with less frequent subcutaneous maintenance doses of 3 mg/kg every 2 weeks (Q2W) and 6 mg/kg every 4 weeks (Q4W) in the HAVEN 3 and HAVEN 4 studies, respectively.…”

Section: Introductionmentioning

confidence: 99%

A multicentre, open‐label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors

Shima

Nogami

Nagami³

et al. 2019

Haemophilia

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195

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Introduction Emicizumab is a recombinant humanized bispecific monoclonal antibody mimicking the cofactor function of activated factor VIII. Aim In this multicentre, open‐label study (HOHOEMI), we evaluated the efficacy, safety and pharmacokinetics of emicizumab in Japanese paediatric patients aged <12 years with severe haemophilia A without factor VIII (FVIII) inhibitors. Methods Emicizumab was administered subcutaneously, with four loading doses of 3 mg/kg every week followed by maintenance doses of 3 mg/kg every 2 weeks (Q2W) or 6 mg/kg every 4 weeks (Q4W) in 6 and 7 patients, respectively. Results All patients completed at least 24 weeks of treatment. Baseline ages ranged from 4 months to 10 years, and all patients had been treated with FVIII prophylaxis prior to enrolment except a 4‐month‐old patient untreated with FVIII previously. In the respective Q2W and Q4W cohorts, 2/6 and 5/7 patients experienced no treated bleeding events, and annualized bleeding rates for treated bleeding events were 1.3 (95% confidence interval [CI], 0.6‐2.9) and 0.7 (95% CI, 0.2‐2.6). All caregivers preferred emicizumab to the patient's previous treatment. Only one related adverse event (injection site reaction) was observed. There were no thromboembolic events or thrombotic microangiopathy. Individual trough plasma concentrations of emicizumab were within the variability observed in preceding adult/adolescent studies. All patients tested negative for anti‐emicizumab antibodies. Conclusions Emicizumab administered Q2W or Q4W was efficacious and safe in paediatric patients with severe haemophilia A without inhibitors. This study was registered at http://www.clinicaltrials.jp (JapicCTI‐173710).

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“…Measurements were then recorded after the addition of 20 µL reagent containing CaCl 2 and fluorogenic substrate (f.c. 16.7 and 2.5 mmol/L, respectively). The development of fluorescent signals was monitored using a Fluoroscan Ascent microplate reader (Thermo Fisher Scientific).…”

Section: Low Concentration Tf-triggered Thrombin Generation Assaymentioning

confidence: 88%

“…9,10 In phase 1/2 and 3 clinical trials, subcutaneous administration of emicizumab substantially diminished bleeding episodes in congenital HA in the presence and absence of inhibitors. [11][12][13][14][15][16] The product has received international regulatory approval for routine prophylaxis in HA.…”

Section: Introductionmentioning

confidence: 99%

An anti‐factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A

Takeyama

Nogami

Matsumoto

et al. 2020

Journal of Thrombosis and Haemostasis

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Introduction Acquired hemophilia A (AHA) is caused by autoantibodies against factor (F)VIII, and is characterized by severe, spontaneous bleeding, which can be life‐threatening. Emicizumab, an anti‐FIXa/FX bispecific antibody, significantly reduces bleeding events in congenital hemophilia A (HA) with and without inhibitors. The known pathophysiological mechanisms and current preclinical data in HA suggest that emicizumab could provide effective treatment for AHA, but the coagulation activities of emicizumab in these patients remain unknown. Aim To evaluate the coagulant effects of emicizumab in plasma from AHA patients. Methods and Results Tissue factor‐triggered thrombin generation assays using normal plasma preincubated with anti‐FVIII monoclonal antibodies recognizing different epitopes demonstrated that 20 µg/mL emicizumab recovered the depressed peak levels of thrombin generation to 46% to 72%. Further studies were devised, therefore, to simulate the clinical course in AHA patients, including during the acute phase for severe bleeding requiring FVIII‐bypassing therapy, and during the subacute/chronic phase with less bleeding. Various concentrations of emicizumab were used to represent the potential changes in plasma levels based on the half‐life of the antibody (~30 days). The ex vivo addition of emicizumab to plasma samples from AHA patients (n = 16) increased peak thrombin in all cases, irrespective of the inhibitor epitope specificity. Thrombin generation at 20 and 100 µg/mL emicizumab was restored to (median) 43.9% and 92.2%, respectively. Differences were evident in some cases, however, and recovery rates appeared likely to be greater in patients with type 2 inhibitor than those with type 1. Conclusion Emicizumab improved ex vivo coagulation potential in plasma from AHA patients.

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Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study

Cited by 302 publications

References 31 publications

Characteristics and management of the haemophilia‐associated pseudotumours

Characteristics and management of the haemophilia‐associated pseudotumours

A multicentre, open‐label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors

An anti‐factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A

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