Research in context
Evidence before this study
We searched PubMed for clinical trials published in English from database inception to July 1, 2022, using the terms “siRNA OR RNAi”, “haemophilia OR hemophilia”, and “clinical trial”; no published trials of siRNA molecules other than fitusiran in haemophilia were found. In phase 1/2 studies of fitusiran prophylaxis, dose-dependent lowering of antithrombin resulted in increased thrombin generation and marked reductions in the number of bleeding events in people with haemophilia A or B, with or without inhibitors.
Added value of this study
The phase 3 ATLAS-A/B trial was designed to investigate fitusiran prophylaxis versus episodic (on-demand) treatment with clotting factor concentrates in people with haemophilia A or B without inhibitors. Our findings show that subcutaneous fitusiran prophylaxis provides sustained protection against bleeding and results in markedly improved bleeding phenotype in participants with haemophilia A or B without inhibitors, with approximately 50% of participants having no bleeding events with fitusiran prophylaxis. These efficacy outcomes were accompanied by a meaningful improvement in quality of life and an overall reduction of both treatment and disease burden. Reported treatment-emergent adverse events were generally consistent with previously reported risks of fitusiran or those anticipated in an adult and adolescent population with severe haemophilia A or B.
Implications of all the available evidence
The evidence from available phase 3 studies of fitusiran (NCT03417102, NCT03549871, and this study NCT03417245) suggests that subcutaneous fitusiran prophylaxis provides effective bleed protection for all people with haemophilia—type A or B, with or without inhibitors—resulting in a reduced treatment burden. Fitusiran has the potential to be the first prophylactic therapy that is effective in all people with haemophilia, irrespective of subtype, thereby potentially advancing health equity and progress in closing the quality-of-life gap between people with and without haemophilia.