Use of emicizumab in patients with acquired hemophilia A: An interim safety analysis of a large-scale post‑marketing surveillance study

Abstract Background: Acquired hemophilia A (AHA) is a rare autoimmune disorder in which autoantibodies neutralize coagulation factor VIII (FVIII), causing bleeding. Treatment focuses on bleeding control using bypassing agents and elimination of FVIII inhibitors via immunosuppressive therapy (IST). Emicizumab is a recombinant humanized bispecific monoclonal antibody that mimics activated FVIII (FVIIIa) by bridging FIXa and FX to promote hemostasis. Its safety and efficacy in congenital HA have been established. Following the Phase 3 AGEHA trial (Shima, JTH 2023), emicizumab was approved in Japan in 2022 for AHA. While strict discontinuation criteria for emicizumab are not defined, the manufacturer suggests considering it when FVIII activity exceeds 50 IU/dL, as in AGEHA. This post-marketing surveillance study aimed to monitor the safety of emicizumab, and indirectly assess its effectiveness, for patients with AHA in real-world clinical practice. Methods: This ongoing observational study (UMIN000048156) includes a longitudinal series of patients with AHA treated with emicizumab from August 2022 to July 2025. This planned interim analysis was conducted after 50 patients completed the observation period. Each patient was followed from first emicizumab dose until 4 weeks after last administration, with a maximum observation period of 24 months. Inclusion criteria were confirmed AHA diagnosis and emicizumab treatment at one of 37 medical institutions. The primary endpoint was adverse events (AEs); if a causal relationship with emicizumab could not be ruled out, the event was classed as an adverse drug reaction (ADR). Results: At the time of this interim analysis, 110 patients were enrolled in the study; 51 completed observation and are included here. Of these, 34 (66.7%) were male; median age was 76.0 years (range: 33–91). All 51 patients received IST, most commonly prednisolone monotherapy (n=29; 56.9%). Median initial prednisolone dose for AHA treatment, either as monotherapy or IST combination, was 0.93 mg/kg (mean SD: 0.79 0.32 mg/kg). Median FVIII activity before emicizumab was 1.0 IU/dL (range: 0.0–15.0); at treatment end, it was 59.1 IU/dL (15.1–103.0). Median FVIII inhibitor titer decreased from 34.1 BU/mL (1.3–401.4) to 0.9 BU/mL (0.0–48.8). AEs occurred in 25 (49.0%) patients, totaling 63 events (45 serious), with infection the most common (n=10; 19.6%). One thromboembolism (cerebral infarction) was deemed unrelated to emicizumab by the investigator. Two ADRs were reported by investigators, both classed as serious: acute pyelonephritis and hemorrhoidal hemorrhage.Nine (17.6%) patients died during the observation period; causes of death were infection (n=4; 7.8%), hemorrhage (n=3; 5.9%), interstitial lung disease (recurrent lung cancer; n=1), and cholangiocarcinoma with liver metastases (n=1). Hemorrhage-related deaths included: upper gastrointestinal bleeding (treated with 23 doses of rFVIIa and red blood cell RBC and platelet transfusions), bladder hemorrhage (treated with 8 doses of rFVIIa and RBC transfusion), and gastric ulcer bleeding (treated with 1 dose of rFVIIa and RBC transfusion). All three patients, who had multiple comorbidities, received prednisolone monotherapy, but FVIII activity had not recovered. A causal relationship with emicizumab was ruled out in all deaths. During emicizumab treatment, 21/51 (41.2%) patients used rFVIIa, 9/51 (17.6%) had transfusions, and 7/51 (13.7%) received other hemostatic agents (FXIII, tranexamic acid). No patient received activated prothrombin complex concentrate or FVIIa/FX. Hemostatic treatment declined over time. Among 38 patients who did not receive rFVIIa in the first week after emicizumab initiation, 30/38 (78.9%) required no rFVIIa throughout the study, indicating prevention of new treated bleeds in almost 80% of cases. Of 301 rFVIIa doses administered following initiation of emicizumab, 181 were given to 4 patients for treatment of bleeds: gastrointestinal (n=2), iliopsoas/retroperitoneal/catheter removal (n=1), and unknown location (n=1). Conclusions: In this large-scale post-marketing study, emicizumab demonstrated a favorable safety profile in real-world clinical practice. While the study was not specifically designed to evaluate efficacy, the consistently low incidence of bleeding events observed supports the potential role of emicizumab in effectively preventing bleeds in patients with AHA, reinforcing its positive risk–benefit profile at this interim analysis.