Post‑Marketing Surveillance of the Safety and Effectiveness of Emicizumab in Japanese Patients with Congenital Hemophilia A with Inhibitors

Introduction: Congenital hemophilia A (HA) is a hereditary bleeding disorder resulting from deficiencies in blood coagulation factor (F)VIII. Approximately 15–30% of patients with severe or moderately severe HA who receive FVIII replacement therapy develop inhibitors to their treatment, which poses an additional therapeutic challenge. Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that substitutes for the cofactor function of activated FVIII, thereby facilitating coagulation. Since its approval in Japan in 2018, the long-term safety and effectiveness of emicizumab prophylaxis in Japanese clinical practice have been monitored via continued surveillance. The main safety concern related to emicizumab treatment is the potential risk of thromboembolic events (TEs) and thrombotic microangiopathy (TMA) during concomitant use of bypassing agents, such as activated prothrombin complex concentrate (aPCC). This all-case post-marketing surveillance study (PMSS) was conducted to monitor the long-term safety and effectiveness of emicizumab, including appropriate concomitant use of bypassing agents, in Japan.

Methods: This observational PMSS was conducted between May 2018 and January 2023 in Japanese patients with congenital HA with inhibitors receiving emicizumab. Patients were registered regardless of age or HA severity, and had initiated emicizumab between the launch of the drug in May 2018 and June 2019. Patients who had previously participated in a clinical trial of emicizumab were included from the date of switch to the marketed product. The target duration of observation for each patient was 3 years after emicizumab initiation. The primary objectives were to evaluate the percentage of patients with adverse events (AEs) and adverse drug reactions (ADRs), including the onset time, outcome and treatment of any TE or TMA, and to determine the treatment status of patients receiving emicizumab and bypassing agents experiencing bleeds and/or TE and TMA. Secondary objectives were to measure FVIII inhibitor titers over time, and to calculate the annualized bleeding rate (ABR) post emicizumab treatment initiation for all bleeds and for bleeds requiring treatment intervention (treated bleeds).

Results: In total, 138 patients were registered, all of whom were male. Of these, 134 formed the safety analysis set (SAS) and 101 were eligible for inclusion in the effectiveness analysis set (EAS). In the SAS, median age at the start of emicizumab treatment was 17.0 years (range: 0−78); 9 patients each (6.7%) had mild or moderate congenital HA and 116 (86.6%) had severe congenital HA. Mean (standard deviation) duration of emicizumab treatment was 145.5 (34.8) weeks. Thirty-three (24.6%) patients had previously participated in an emicizumab clinical trial. Overall, 17 patients (12.7%) discontinued emicizumab treatment for reasons including AEs (n=4; 3.0%), lack of efficacy (n=1; 0.7%), and death (n=6; 4.5%). A causal relationship between emicizumab treatment and death was ruled out in 5 patients. In total, 112 AEs occurred in 47 patients (35.1%) and 22 ADRs occurred in 12 patients (9.0%), including 8 serious ADRs in 4 patients (3.0%). No TEs or TMAs associated with concomitant use of emicizumab and aPCC or activated FVII (FVIIa)/FX occurred; 2 cases of lacunar infarction were reported as AEs. FVIII inhibitor levels remained constant or decreased in most patients. In total, 319 treated or untreated bleeds occurred in 79 patients (59.0%). Bypassing agents were administered to 68 patients (50.7%) for bleeding that occurred during emicizumab treatment: 68 received recombinant FVIIa, 5 received FVIIa/FX, and none received aPCC. In the 101 patients included in the EAS, mean ABR for all bleeds following emicizumab initiation was 1.41 (95% confidence interval [CI]: 0.89−2.25). The mean ABR for treated bleeds was 1.31 (95% CI: 0.81−2.12).

Conclusions: This study comprises the longest post-marketing surveillance dataset for emicizumab and includes more than 100 participants from the Japanese patient population, who started treatment with emicizumab within the first year of availability in Japan and were observed for up to 3 years after treatment initiation. No TEs/TMA associated with concomitant use of emicizumab and bypassing agents occurred. The results provide further evidence that emicizumab is well tolerated in Japanese patients with congenital HA and FVIII inhibitors.