Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors

Abstract

Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remaining short. In cohorts 1, 2, and 3, respectively, median ABRs remained low at 1.4, 0.2, and 0 compared with 4.4, 0, and 0 in the 12-week study. Overall, 8 patients experienced no bleeding events (6 patients with and 2 patients without FVIII inhibitors); dose up-titration resulted in further reduction in ABRs in patients with suboptimal bleeding control; and the episodic use of clotting factors to control bleeding was reduced. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. This study was registered at www.clinicaltrials.jp as #JapicCTI-132195.

Graphical abstract

Figure 1.

Study design schematic of the extension study following the first-in-patient study. SC, subcutaneous; QW, once weekly. *Loading dose. †Maintenance dose. ‡Dose escalation within patient may be allowed (decided by efficacy and safety evaluation committee).

Figure 2.

PK and PD of emicizumab during once-weekly subcutaneous administrations of emicizumab. Mean (± standard deviation) time courses of plasma emicizumab concentration (A), aPTT (B), peak height of FXIa-triggered TG (C). The reference ranges for aPTT and peak height of FXIa-triggered TG are 25.4 to 37.2 seconds and 341 to 489 nmol/L, respectively, which were derived from healthy Japanese participants. All data collected after dose up-titrations were excluded; the number of patients for this summary was 6 per cohort. Data points where the number of patients with quantifiable measurement was ≥2 and not less than half of the number of observed patients were plotted.

Figure 3.

Median ABR for each dose cohort during once-weekly subcutaneous administration of emicizumab. (A) Bleeding events at any site. (B) Joint bleeding events. All data collected after dose up-titrations were excluded; the number of patients for this summary was 6 per cohort. Cohort 1 included 4 patients with and 2 without inhibitors at study enrollment and data cutoff; cohort 2 included 4 patients with and 2 without inhibitors at study enrollment, and 3 patients with and 2 without inhibitors at data cutoff; cohort 3 included 3 patients with and 3 without inhibitors at study enrollment, and 3 patients with and 2 without inhibitors at data cutoff.