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

Abstract

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).

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

“…The trough levels of emicizumab in plasma at clinically therapeutic doses have been estimated to be approximately 30 to 80 μg/mL. [14][15][16][17][18] In the present study, to reflect pathogenic mechanism(s) of TMA and to evaluate current risk management for emicizumab-related TMA in clinical settings, a concentration of 100 µg/mL as the maximum dose, comparable to the plasma emicizumab concentration at a high-dose regimen (C3-cohort) in the phase 1/2 study, 12,13 was chosen.…”

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

“…To date, clinical experience on the use of emicizumab for the treatment of PUPs with HA is only described in a single PUP who was enrolled at 4 months of age in the Q4W cohort of the HOHOEMI clinical trial. 33 This PUP experienced no bleeds during a 24-week period followup. Although this result seems promising, prospective studies using emicizumab prophylaxis in PUPs may be required to better assess the outcome of such novel therapeutic strategy in pediatric patients with severe HA (Table 2).…”

“…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.…”

“…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.…”

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

“…At present, clinical experience with noninhibitor pediatric patients receiving emicizumab prophylaxis is available from only a small number of centers. We have recently reported the interim results from a multicenter open‐label phase 3 study of pediatric noninhibitor patients <12 years old treated with emicizumab every 2 and 4 weeks 48 . In this study, the median age of participants was 6.6 years (1.5‐10.7) in the every 2 weeks cohort and 4.1 years (0.3‐8.1) in the every 4 weeks cohort.…”