Anti-Thrombin siRNA Reduces Bleeding in Severe Hemophilia Without Inhibitors

Monthly prophylaxis injections of fitusiran, an siRNA therapeutic targeting antithrombin, reduced bleeding in people with hemophilia A and B without inhibitors compared to on-demand treatment, according to data from the phase 3 ATLAS/B study (NCT03417245).

These data were presented at the 63rd Annual American Society of Hematology (ASH) Meeting, December 11-14, 2021, by Alok Srivastava, MD, professor, hematology, and head, Centre for Stem Cell Research, Christian Medical College, Vellore, India.

“Fitusiran is a subcutaneously administered investigational siRNA therapeutic agent which targets antithrombin to enhance thrombin generation potential and rebalance hemostasis in people with hemophilia, irrespective of inhibitor status,” Srivastava and colleagues wrote.

The randomized, open-label, ATLAS A/B enrolled 120 patients with severe hemophilia A or B without inhibitors, 80 of which were randomized to the fitusiran arm and 40 of which were randomized to the OD arm. Overall, 79 patients (98.8%) in the fitusiran arm and 27 patients (92.5%) in the OD arm completed the study. Most participants (n = 93) had hemophilia A (fitusiran n = 62; OD n = 31) and 27 participants had hemophilia B (fitusiran n = 18; OD n = 9).

Investigators found that the median observed annualized bleeding rate (ABR) was 0.0 (interquartile range [IQR], 0.0-3.4) in the fitusiran arm and 21.8 (IQR, 8.4-41.0) in the OD arm. In the fitusiran arm, 40 participants (50.6%) had no bleeds that required OD treatment. Estimated ABR was significantly reduced in the fitusiran arm compared to the OD arm (89.9% [95% CI, 84.1-93.6]; P <.0001). 

Observed annualized spontaneous bleeding rate (AsBR) was also significantly lower in the fitusiran arm (median, 0.0; IQR, 0.0-1.7) compared to the OD arm (median, 16.2 [IQR, 3.4-27.6]) with a 91.7% reduction (95% CI, 85.9-95.1; P <.0001) in estimated AsBR between arms. Similarly, observed annualized joint bleeding rate (AJBR) was significantly lower in the fitusiran arm (median, 0.0; IQR, 0.0-3.4) compared to the OD arm (median, 15.9; IQR, 4.2-33.5), with a 90.3% reduction (95% CI, 83.9-94.1; P <.0001) in estimated AJBR between arms.

Health scores were also assessed, and investigators found a significant improvement in the transformed total and physical health score in the fitusiran arm (least square means difference [LSM], –7.07 [95% CI, –11.23 to –2.90]) compared to the OD arm (LSM, –19.75 [95% CI, –27.00 to –12.50]; P <.0011).

Treatment emergent adverse events (TEAEs) were common, with 62 patients (78.5%) in the fitusiran arm and 18 patients (45%) in the OD arm experiencing at least 1 TEAE. Serious TEAEs, including cholelithiasis (n = 2; 2.5%), cholecystitis (n = 1; 1.3%), lower respiratory tract infection (n = 1; 1.3%), and asthma (n = 1; 1.3%) were reported in 5 patients (6.3%) in the fitusiran arm. Two participants, those that experienced cholecystitis and increased alanine aminotransferase, discontinued treatment. In the OD arm, 9 serious TEAEs were reported in 5 participants (12.5%).

“Once-monthly 80 mg subcutaneous fitusiran prophylaxis demonstrated a significant reduction in ABR, AsBR and AJBR (all ~90%) in people with severe hemophilia A or B without inhibitors compared with OD treatment. This reduction in bleeding was associated with a meaningful improvement in health-related quality of life... 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,” Srivastava and colleagues concluded.

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