Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial

• Published in: The Lancet (British edition) Vol. 401; no. 10386; pp. 1427 - 1437
• Main Authors: Young, Guy, Srivastava, Alok, Kavakli, Kaan, Ross, Cecil, Sathar, Jameela, You, Chur-Woo, Tran, Huyen, Sun, Jing, Wu, Runhui, Poloskey, Stacey, Qiu, Zhiying, Kichou, Salim, Andersson, Shauna, Mei, Baisong, Rangarajan, Savita
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 29.04.2023; Elsevier Limited
• Subjects: Adult; Adverse events; Alanine; Alanine Transaminase; Antibodies; Antithrombin; Bleeding; Consent; Disease prevention; Effectiveness; Factor IX deficiency; Female; Hemophilia; Hemophilia A - complications; Hemophilia A - drug therapy; Hemophilia B - complications; Hemophilia B - drug therapy; Hemorrhage - epidemiology; Humans; Inhibitors; International organizations; Laboratories; Male; Men; Prophylaxis; Quality of life; RNA, Small Interfering - therapeutic use; Safety; siRNA; Statistical analysis; Thromboembolism; Transaminases; Venous access; Young Adult; Young adults
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(23)00284-2

Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents 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. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5–33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0–2·7]) than in 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). 25 (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%) of 41 participants in the safety population; 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. No deaths were reported. Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. Sanofi.