Once-monthly prophylactic treatment with subcutaneous fitusiran reduced the risk of bleeding in patients with severe hemophilia A or B without inhibitors, compared with once-daily treatment. In addition, the reduction in bleeding risk was associated with improvements in health-related quality of life (HRQoL). Alok Srivastava, MD, FRACP, FRCPA, FRCP, presented these findings at the 2021 ASH Annual Meeting.
Fitusiran is an investigational siRNA therapeutic agent targeting antithrombin to enhance thrombin production potential and rebalance hemostasis in patients with hemophilia, regardless of inhibitor status. To evaluate the safety and efficacy of fitusiran, Dr. Srivastava and colleagues enrolled 120 male patients aged 12 years and older with severe hemophilia A (n=93) or B (n=27) without inhibitors in the phase III ATLAS-A/B study. Previously, patients had been receiving once-daily treatment.
Patients were randomized 2:1 to receive either:
- fitusiran 80 mg once monthly (n=80)
- factor concentrates for treatment of bleeding episodes once daily (n=40)
The treatment period was nine months. The annualized bleeding rate (ABR) during the efficacy period (day 29 after the first fitusiran dose through day 246) represented the primary endpoint of the study. Secondary endpoints were annualized spontaneous bleeding rate (ASBR) and annualized joint bleeding rate (AJBR) during the efficacy period and HRQoL (measured by Haem-A-QoL) during the treatment period.
In the fitusiran arm, the median observed ABR was 0, compared with 21.8 in the daily factor concentrates arm, for an 89.9% reduction in estimated ABR (p<0.0001). About half of patients in the fitusiran arm (50.6%; n=40) experienced no bleeding events requiring treatment with once-daily factor concentrates.
Estimated ASBR was reduced by 91.7% in the fitusiran arm, compared with the factor concentrates cohort. The median observed ASBR for patients receiving fitusiran was 0 versus 16.1 in the daily treatment arm. There was also a significant 90.3% reduction in estimated AJBR for patients treated with fitusiran compared with factor concentrates. Transformed total and physical health scores were significantly improved in the fitusiran cohort compared with the factor concentrates group.
No new safety signals associated with fitusiran emerged during the trial. At least one treatment-emergent adverse event (AE) was reported in 62 patients (78.5%) in the fitusiran arm and 18 patients (45%) in the daily treatment arm. In the fitusiran and concentrate treatment arms, five patients each (6.3% and 12.5%, respectively) experienced serious treatment-emergent AEs, including cholelithiasis (n=2), cholecystitis (n=1), lower respiratory tract infection (n=1), and asthma (n=1). In two cases, patients discontinued fitusiran because of treatment-emergent AEs (cholecystitis and increased alanine aminotransferase). No treatment-emergent AEs were fatal.
“With the aim of further enhancing the benefit-risk profile of fitusiran, a revised regimen with reduced dose and frequency is currently being evaluated in ongoing clinical studies,” Dr. Srivastava wrote.
Study authors report relationships with Sanofi and Genzyme, which sponsored this trial.
Reference
Srivastava A, Rangarajan S, Kavakli K, et al. Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: First Results from a Phase 3 Study to Evaluate Efficacy and Safety in People with Hemophilia a or B without Inhibitors (ATLAS-A/B). Abstract LBA-3. Presented at the 2021 ASH Annual Meeting, December 11-14, 2021.
