Fitusiran is a subcutaneous investigational small interfering RNA therapeutic targeting antithrombin, to rebalance haemostasis in patients with haemophilia A or haemophilia B. In the phase III ATLAS-INH trial, researchers investigated the efficacy and safety of fitusiran as a prophylactic bypassing agent. The results of this multicentre, randomised, open-label study were published in The Lancet and show that subcutaneous fitusiran prophylaxis resulted in a statistically significant reduction in the annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds.
Haemophilia A and haemophilia B are bleeding disorders caused by the absence of the blood clotting protein factor VIII (haemophilia A) or factor IX (haemophilia B). Patients can develop antibodies, so-called inhibitors, against factor replacement therapy, making them resistant to standard treatment with prophylaxis of factor VIII or IX clotting factor. The current treatment for patients with inhibitors is the on-demand use of bypassing agents, including recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrate (aPCC) or factor VIII inhibitor bypass activity (FEIBA). Prophylactic treatment with fitusiran, a newly developed RNA interference therapeutic targeting antithrombin, has shown promising results by increasing thrombin generation and clotting factor levels.1
In total, 26 sites in 12 countries, primarily secondary or tertiary centres, contributed to this study. Eligible participants were male (≥12 years) with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents. These patients were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. Eighty-five participants were screened for inclusion and 57 were included. Nineteen participants were randomly assigned to the bypassing agent on-demand, 38 were assigned to fitusiran prophylaxis. The primary endpoint was the mean annualised bleeding rate during the efficacy period, estimated by the negative binominal model. Adverse events were registered to assess safety as a secondary endpoint.
The negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1.7 [95%CI: 1.0–2.7]) compared to the bypassing agents on-demand group (18.1 [10.6–30.8]), corresponding to a 90.8% (95% CI 80.8-95.6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0.0001). Twenty-five (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) participants. There were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group compared to none in the bypassing agents on-demand group. No deaths were reported.
In this study, a monthly prophylactic dose of subcutaneous fitusiran was compared to bypassing agents used on-demand. Fitusiran significantly decreased annualised bleeding rates when compared to bypassing agents used on-demand. Moreover, two-thirds of participants treated with fitusiran had zero bleeds. In short, fitusiran prophylaxis shows haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors, indicating it is a suitable alternative to bypassing agents for haemophilia patients with inhibitors.