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).

Keywords: bispecific antibody; emicizumab; haemophilia A; non-inhibitor; paediatrics; prophylaxis.

Figure 1

Study design. QW, every week; Q2W, every 2 weeks; Q4W, every 4 weeks. The study design is open‐label, non‐randomized. Patients in the Q4W cohort were enrolled after the completion of enrolment in the Q2W cohort. ^aPatients who experienced ≥2 bleeding events treated with coagulation factors during the last 8 wk of the first 12 wk of treatment were eligible for up‐titrating the maintenance dose to 3 mg/kg QW. After the first 12 wk of treatment, patients who experienced ≥2 bleeding events treated with coagulation factors during any consecutive 12 wk were eligible for the dose up‐titration. ^bPatients with sustained clinical benefit during the first 24 wk of treatment could continue emicizumab prophylaxis afterwards

Figure 2

Number of patients participating in physical activity and mean time spent on physical activity. The upper panel shows the numbers of patients participating in each category of physical activity among all 13 enrolled patients in the indicated weeks. The lower panel shows the arithmetic mean times spent participating in each category of physical activity among all 13 enrolled patients in the indicated weeks. If a patient did no activity, time was set to zero for that patient. Activities with low risk include, for example, walking and swimming during which acute injury or collision is considered unlikely. Activities with moderate risk include, for example, soccer and basketball during which acute injury or collision is possible but not likely. Activities with high risk include, for example, rugby and wrestling during which acute injury or collision is likely. The baseline activity level was defined as the activity level during the first week of emicizumab prophylaxis. The data of activities with low risk are not shown in the panels

Figure 3

Reasons for caregivers' preference for emicizumab. All caregivers preferred emicizumab prophylaxis to the patient's previous haemophilia treatment. Each reason for the preference was ranked by caregivers. The proportions of the rankings given for each reason are presented here. Of note, the responses from the caregiver of a 4‐month‐old patient untreated with FVIII previously were based on the caregiver's experience of treatment for the patient's elder brother with severe haemophilia A

Figure 4

Time courses of trough plasma concentrations of emicizumab. Q2W, every 2 weeks; Q4W, every 4 weeks. Circles indicate the means, and bars on or under the circles indicate the standard deviations