Emicizumab Lowers Bleeding Rates in Children With Hemophilia A and Inhibitors

Once-weekly treatment with emicizumab prophylaxis led to low bleeding rates in children with hemophilia A and factor VIII (FVIII) inhibitors, with more than three-quarters of patients experiencing an annualized bleeding rate (ABR) of zero, according to findings from the phase III HAVEN 2 study published in Blood. The results also suggest that efficacy was maintained even at less frequent emicizumab dosing schedules.

Currently, prophylactic infusions of FVIII are the standard-of-care treatment for pediatric patients with congenital hemophilia A. However, up to 30% of previously untreated patients develop FVIII inhibitors, the authors, led by Guy Young, MD, from Children’s Hospital Los Angeles, wrote. Options for managing hemophilia A with FVIII inhibitors in pediatric patients include immune tolerance induction (ITI) and prophylactic or episodic use of bypassing agents (BPAs), “whose efficacy can be suboptimal and unpredictable.”

The open-label, nonrandomized HAVEN 2 study explored whether emicizumab, a bispecific humanized monoclonal antibody that restores the function of missing FVIIIa in hemophilia A by bridging activated factor IX and factor X, could offer a safe, effective prophylactic treatment option for these patients.

Eligible participants were between the ages of 2 and 11, with congenital hemophilia A and a history of high-titer FVIII inhibitors (≥5 Bethesda units/mL) and were receiving prophylactic treatment with BPAs at the time of enrollment. Children between the ages of 12 and 17 also were eligible if they weighed <40 kg and met the other inclusion criteria; patients younger than age 2 could enroll if the investigator determined there was a high unmet medical need.

A total of 88 male patients were enrolled in three treatment arms and received subcutaneous emicizumab in the following schedules:

  • group A: emicizumab in four 3-mg/kg once-weekly loading doses, followed by 1.5 mg/kg weekly as maintenance (n=68)
  • group B: emicizumab 3 mg/kg every 2 weeks (n=10)
  • group C: emicizumab 6 mg/kg every 4 weeks (n=10)

Participants were treated for up to 52 weeks. Groups B and C were recruited to the study after group A was fully enrolled to investigate flexible dosing possibilities.

Nearly all patients (97%) had severe hemophilia A. The majority had previously undergone ITI (76%) and were receiving prophylactic BPAs (75%). The median participant age was 7 years (range = 1-15 years). Twenty-three participants had target joints at baseline, and 43 started the study with a central venous access device (CVAD).

The researchers observed 712 adverse events (AEs), the most common of which were nasopharyngitis (37.5%) and local injection-site reactions (30.7%). These resolved without treatment and did not require discontinuation of emicizumab. Of 21 serious AEs, only development of antidrug antibodies with neutralizing potential, which occurred in two participants, was considered to be related to emicizumab. No thrombotic events occurred, and no deaths were reported during the study.

Three patients left the study to switch to commercial emicizumab (n=2, group A) or because of a lack of efficacy (n=1, group C).

During study follow-up, patients <12 years in group A experienced a mean ABR of 0.3 (95% CI 0.17-0.50) and a median ABR of 0. Fifty participants (77%) had no treated bleeding events. Overall, 22 treated bleeding events were reported in 15 participants, 91% of which were considered “traumatic.” ABRs were similarly low in groups B and C, at 0.2 (95% CI 0.03-1.72) and 2.2 (95% CI 0.69-6.81), respectively. Also, 90% of participants in group B and 60% in group C reported zero treated bleeding events (TABLE).

Emicizumab prophylaxis also appeared to effectively lower the risk of treated bleeds in patients with target joints (defined as major joints in which ≥3 bleeding events had occurred over a 24-week period prior to study). Of the 23 participants who had a total of 45 target joints at baseline, all were resolved. Eighty-seven percent of participants did not have target joint bleeding events while on emicizumab. In addition, 21 of the 43 participants (49%) who started the study with a CVAD had it removed during follow-up. Most of these removals (81%) were performed without BPA prophylaxis. However, one participant experienced a post-operative bleeding event.

The study did not include a comparator arm, but an intra-individual comparison among 15 participants who had participated in a noninterventional study “showed a substantially lower bleeding rate with once-weekly emicizumab compared with prior standard prophylaxis, which included [BPAs].”

Less frequent dosing of emicizumab appeared to be as effective as weekly dosing, with all participants experiencing ≤3 treated bleeding events.

As a secondary endpoint, patient caregivers completed the Adapted Health-Related Quality of Life in Haemophilia Patients with Inhibitors (Inhib-QoL) questionnaire to determine whether the lower treatment burden associated with subcutaneous emicizumab improved patients’ health-related quality of life. In group A, 28% of the 89% of caregivers who completed the Adapted Inhib-QoL questionnaire said their child had not missed any school or daycare days in the previous four weeks. By week 13, this proportion increased to 61%.

Less frequent dosing in groups B and C appeared to be as effective as weekly dosing, with all participants experiencing ≤3 treated bleeding events. “Clinically meaningful efficacy and pharmacokinetic results were achieved with all three dosing regimens assessed, suggesting the potential for reduced treatment burden,” the authors concluded.

Limitations of this study include the later addition of groups B and C, which resulted in smaller numbers and shorter follow-up in those groups. The nonrandomized design and reliance on data from a separate noninterventional study as a comparator group also may have limited these findings.

The authors report relationships with Genentech/Roche and Chugai Pharmaceuticals, which sponsored this trial.


Young G, Liesner R, Chang T, et al. A multicenter, open-label, phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019 October 10. [Epub ahead of print]