Fitusiran, a small interfering RNA (siRNA) molecule targeting antithrombin, has demonstrated significant efficacy in managing hemophilia A and B, according to data presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition. The ATLAS-OLE clinical trial (NCT03754790) assessed fitusiran as a prophylactic agent in combination with adjusted bleed management guidelines for breakthrough bleeding.
ATLAS-OLE Trial Results
Steven W. Pipe, MD, professor of pediatric hematology/oncology at CS Mott Children’s Hospital, presented findings from the open-label extension (OLE) study, highlighting the benefits of antithrombin-guided dosing of fitusiran. The study included over 200 patients who were shifted from a fixed dose of 80 mg monthly to a new regimen targeting antithrombin levels between 15% and 35% of normal. This revised strategy was implemented to mitigate thrombotic risks observed with lower antithrombin levels.
Reduced Bleed Rates and Factor Consumption
The data revealed that fitusiran was highly effective as a prophylactic agent, showing a 70% reduction in breakthrough treated bleeds compared to bypassing agent prophylaxis. Protection from bleeding was comparable to standard of care factor VIII (FVIII) or factor IX (FIX) prophylaxis. Importantly, when breakthrough bleeds did occur, the vast majority of patients achieved control with substantially reduced doses of factor products or bypassing agents, often requiring only a single dose.
"Fitusiran is a highly effective prophylactic agent, and the modulation of thrombin generation allows for achieving effective bleed control with substantially lower doses of factor and bypassing agents, as well as fewer infusions," said Dr. Pipe. The study reported between a 64% and almost 98% reduction in the amount of factor needed to treat breakthrough bleeding across hemophilia A and B, with or without inhibitors.
Optimized Dosing Strategy
Early in the clinical trial program, a voluntary hold was implemented due to thrombotic complications. Concerns arose that combining procoagulants with antithrombin knockdown could generate excessive thrombin burst. In response, bleed management guidelines were developed, recommending substantially reduced doses of FVIII, FIX, activated prothrombin complex concentrates (APCCs), and recombinant factor VIIa, with more protracted intervals between doses.
The revised dosing strategy, targeting antithrombin levels between 15% and 35%, was informed by the observation that the risk of thrombotic events increased when antithrombin levels were less than 10%. By maintaining levels above this threshold, the benefit-risk profile of fitusiran prophylaxis was optimized.
Improved Patient Experience
The findings suggest that fitusiran offers an improved patient experience. Effective prophylaxis reduces the frequency of infusions, and when breakthrough bleeds occur, they can often be managed with a single, lower dose of factor or bypassing agent. This represents a significant advancement in the management of hemophilia A and B.
