Fitusiran Antithrombin-Based Regimen Ensures Effective Bleed Control in Hemophilia: ATLAS-OLE Study

"In male participants aged ≥12 years with severe hemophilia A or B, with or without inhibitors, the fitusiran antithrombin-based dose regimen—designed to maintain antithrombin activity between 15% and 35%—exhibited a favorable safety profile. The regimen achieved a median annualized bleeding rate of 3.7, demonstrating superior efficacy compared to on-demand treatments by reducing bleeding rates by more than 70%," the researchers reported in Blood Journal.

Fitusiran, an RNA interference therapeutic, works by reducing antithrombin levels to enhance thrombin generation, thereby promoting clot formation in people with hemophilia. Guy Young, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California, United States, and colleagues researchers conducted this phase 3 open-label extension study (ATLAS-OLE) to assess the safety and efficacy of an antithrombin-based dose regimen (AT-DR) in males aged ≥12 years with severe hemophilia A or B, with or without inhibitors.

For this purpose, the researchers optimized the original 80 mg monthly (QM) dose regimen (ODR) to an antithrombin-based dose regimen (AT-DR) targeting antithrombin activity levels of 15–35% to reduce thrombotic risk. The adjusted regimen began with a starting dose of 50 mg once every two months (Q2M), with individualized adjustments to 20 mg Q2M or 20/50/80 mg QM as needed.

Safety and efficacy were evaluated as the primary and secondary endpoints, respectively. Integrated safety analyses assessed the safety of both AT-DR and ODR across all fitusiran studies, while integrated efficacy analyses compared AT-DR efficacy in ATLAS-OLE with phase 3 parent study control groups.

The study revealed the following findings:

• At the interim data cut-off, 213 participants were enrolled in the AT-DR regimen, with 78% receiving Q2M dosing.
• Integrated safety analyses of 286 participants receiving AT-DR confirmed that the regimen was well tolerated.
• In ATLAS-OLE, the observed median annualized bleeding rate (ABR) with AT-DR was 3.7.
• Integrated efficacy analyses showed that AT-DR was superior to on-demand clotting factor concentrates (CFCs), with a 71% mean ABR reduction.
• AT-DR also demonstrated a 73% mean ABR reduction compared to on-demand bypassing agents (BPAs).
• A 70% mean ABR reduction was observed when compared to BPA prophylaxis.
• ABR outcomes with AT-DR were comparable to those achieved with CFC prophylaxis.

The findings showed that fitusiran lowers antithrombin levels to enhance thrombin generation and restore hemostasis in individuals with hemophilia A or B, regardless of inhibitor status. The antithrombin-based dose regimen was well tolerated and provided meaningful bleed protection with as few as six injections per year.

The study authors confirmed that these findings align with previous fitusiran research, reinforcing its potential as an effective subcutaneous prophylactic option for hemophilia management.

Reference:

Guy Young, Kaan Kavakli, Robert Klamroth, Tadashi Matsushita, Flora Peyvandi, Steven W. Pipe, Savita Rangarajan, Ming-Ching Shen, Alok Srivastava, Jing Sun, Huyen A Tran, Chur-Woo You, Bulent Bülent Zülfikar, Laurel A. Menapace, Chuanwu Zhang, Yuqian Shen, Marja Puurunen, Marek Demissie, Gili Kenet; Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: the ATLAS-OLE study. Blood 2025; blood.2024027008. doi: https://doi.org/10.1182/blood.2024027008