Emicizumab Prophylaxis Administered Once-weekly or Every Two Weeks Provides Effective Bleed Prevention in Persons with Hemophilia A (PwHA) without Inhibitors - Results from the Phase III HAVEN 3 Study

Objectives: Subcutaneous once-weekly (QW) prophylaxis with emicizumab - a bispecific humanized monoclonal antibody - is effective in PwHA with inhibitors. The HAVEN 3 (NCT02847637) study was designed to assess the efficacy, safety, and pharmacokinetics (PK) of emicizumab prophylaxis QW and every 2 weeks (Q2W) in adolescent/adult PwHA without inhibitors.

Methods: Severe haemophilia A patients without inhibitors aged ≥12 years were enrolled. Patients on prior episodic FVIII, with ≥5 bleeds over the previous 24 weeks, were randomized (2:2:1) to emicizumab prophylaxis: 3 mg/kg QW for 4 weeks, followed by 1.5 mg/kg QW (Arm A) or 3 mg/kg Q2W (Arm B) maintenance; or to no prophylaxis (Arm C). The primary efficacy objective compared treated bleed rates (Arm A vs C; Arm B vs C). Patients previously on FVIII prophylaxis received 1.5 mg/kg QW emicizumab maintenance in Arm D; those from a non-interventional study (NIS; NCT02476942) were included in intra-individual comparisons.

Results: Overall, 152 patients aged 13–77 years (median: 38) were enrolled. Statistically significant and clinically meaningful reductions of ≥94% were observed in treated, all, treated spontaneous, joint and target joint bleeds with emicizumab QW or Q2W versus no prophylaxis ([Table 1]); >55% of patients receiving emicizumab QW or Q2W had zero treated bleeds and >91% had ≤3 treated bleeds. An intra-individual comparison showed a 68% reduction in treated bleed rate with QW emicizumab versus prior FVIII prophylaxis observed during the NIS ([Table 1]). Emicizumab was well tolerated; the most common AE was injection-site reaction (25%). As of the clinical cut-off date of 15 September, 2017, no thrombotic events, ADAs or de novo FVIII inhibitors had occurred. Sustained emicizumab trough concentrations were achieved with both regimens.

Conclusions: Emicizumab prophylaxis QW or Q2W significantly reduced bleed rates in PwHA without inhibitors, with a favorable safety profile. Most notably, an intra-individual comparison demonstrated superiority of emicizumab over previous FVIII prophylaxis. Subcutaneous emicizumab prophylaxis could provide a highly efficacious and flexible management option, with reduced treatment burden for PwHA without inhibitors.

Table 1 Bleeding events in HAVEN 3 study