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Emicizumab: a highly effective treatment option for paediatric patients with haemophilia A and inhibitors

Results of the phase III HAVEN-2 study, evaluating the bispecific humanized monoclonal antibody emicizumab in children with haemophilia A and inhibitors, demonstrate that emicizumab prophylaxis effectively prevents, or substantially reduces the rate of bleeding. Moreover, the drug was well tolerated in this patient population and led to a substantial improvement in the quality of life of the children in the study.

Patients with haemophilia A produce extremely low levels of the blood clotting factor VIII (FVIII). As a result, these patients can suffer debilitating bleeding events multiple times per month, especially in the joints. The latter causes significant pain in the short term and eventually leads to irreversible joint defects. Currently, the best available treatment to prevent bleeds involves frequent intravenous infusions of FVIII. With this treatment the disease can effectively be controlled in most patients. However, some patients develop antibodies (referred to as inhibitors) that bind to the standard replacement therapy and render it ineffective. Emicizumab is a subcutaneously administered, bispecific humanized monoclonal antibody that bridges FIXa and FX. As such, emicizumab is able to restore the function of missing FVIIIa, which results in a decreased bleeding incidence.

The phase III HAVEN-2 study enrolled 60 paediatric patients with haemophilia A. In order to be eligible for the study, patients had to be 2–12 years of age (or 12–17 years if they weigh less than 40 kg) and had to be on episodic or prophylactic treatment with bypassing agent(s) (BPAs). The study is currently also enrolling patients younger than 2 years of age. Patients in the study were treated with emicizumab prophylaxis for ≥52 weeks. Of note, the patients’ caregiver could administer the subcutaneous drug at home. The efficacy analyses included annual bleeding rate (ABR) and the bleed reduction compared to ABR on prior BPA treatment from a prospective non-interventional study. In addition to this, Health-Related Quality of Life (HRQoL), aspects of caregiver burden and safety parameters were also assessed.In a previously reported interim analysis of the HAVEN 2 study (n=20), presented at ISTH 2017, once-weekly emicizumab prophylaxis was shown to successfully prevent or reduce bleeds and provided clinically meaningful reductions in the ABR versus BPA treatment.

During the 2017 Annual meeting of the American Society of Hematology (ASH), updated results of this study were presented with 40 additional patients (60 patients in total).

The median age of the 60 haemophilia A patients in the study was 7 years (range 1-15) and 57 patients were younger than 12. Three patients aged ≥12 years and <40kg were also enrolled. The majority of patients had severe haemophilia A (N=57), 71.1% previously received therapy to eradicate the inhibitors and 73.3% received prophylactic BPA therapy. In the 24 weeks prior to study entry, patients had a median of 6 bleeding episodes (range 0-155) and 65% of patients had more than 1 target joint (i.e. a joint that keeps bleeding). The median observation time for this analysis was 9 weeks (range 1.6 to 41.6 weeks). In total, 20 patients had been observed for at least 24 weeks.

Overall, 54/57 (94.7%) patients had zero treated bleeds. Only three patients experienced bleeding events requiring treatment and all three were safely treated with recombinant FVIIa (1 spontaneous bleed). Overall 37/57 patients (64.9%) reported no bleeds at all. A total of 65 bleeds were reported in 20 patients. Twenty-three patients were followed for at least 12 weeks and these patients were included in the ABR population calculation. The analysis revealed an ABR of only 0.2 (95%CI: 0.06; 0.62). Thirteen patients who had been on HAVEN 2 for ≥12 weeks and who were previously enrolled in a previous prospective non-interventional study with BPA, were included in the intra-individual comparison. This analysis showed a substantial reduction in ABR of 99% with emicizumab prophylaxis compared to prior BPA treatment. Finally, considerable improvements in HRQoL, and aspects of caregiver burden were observed.

Previous emicizumab trials conducted in adults and adolescents raised safety concerns over adverse events that occurred after patients experienced bleeding while on the drug. However, in HAVEN-2, emicizumab was well tolerated with viral upper respiratory tract infection and injection site reactions (16.7% of patients each) being the most common adverse events. No thromboembolic events were reported.

In summary, HAVEN-2 demonstrates that emicizumab prophylaxis prevents or substantially reduces bleeds in children with haemophilia A and inhibitors. As such, weekly subcutaneous emicizumab has the potential to reduce overall treatment- and disease burden and may provide a new standard of care for these patients.


Young G, Sidonio R, Oldenburg J, et al. HAVEN 2 Updated Analysis: Multicenter, Open-Label, Phase 3 Study to Evaluate Efficacy, Safety and Pharmacokinetics of Subcutaneous Administration of Emicizumab Prophylaxis in Pediatric Patients with Hemophilia A with Inhibitors. Presented at ASH 2017; Abstract #85.

Speaker Guy Young


Guy Young, MD, Children's Hospital Los Angeles, Los Angeles, CA


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