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.

Autor:	Young G; Hemostasis and Thrombosis Center, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA. Electronic address: gyoung@chla.usc.edu., Srivastava A; Department of Haematology, Christian Medical College & Centre for Stem Cell Research, a unit of inStem, Bengaluru, Christian Medical College Campus, Vellore, India., Kavakli K; Department of Pediatric Hematology and Oncology, Ege University Faculty of Medicine Children's Hospital, Izmir, Turkey., Ross C; Department of Hematology, St John's Medical College Hospital, Bangalore, India., Sathar J; Department of Haematology, Ampang Hospital, Kuala Lumpur, Malaysia., You CW; Department of Pediatrics, Eulji University School of Medicine, Seoul, South Korea., Tran H; Ronald Sawers Hemophilia Treatment Center, The Alfred, Monash University, Melbourne, Victoria, Australia., Sun J; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China., Wu R; National Center for Children's Health, Beijing Children's Hospital, Beijing, China., Poloskey S; Pharmacovigilance, Sanofi, Cambridge, MA, USA; Clinical Development, Sanofi, Cambridge, MA, USA., Qiu Z; Biostatistics & Programming, Sanofi, Bridgewater, NJ, USA., Kichou S; Clinical Development, Sanofi, Paris, France., Andersson S; Clinical Development, Sanofi, Cambridge, MA, USA., Mei B; Clinical Development, Sanofi, Cambridge, MA, USA., Rangarajan S; Advanced Centre for Oncology, Haematology & Rare Diseases KJ Somaiya Super Specialty, Hospital, Mumbai, India; Faculty of Medicine, University of Southampton, Southampton, UK.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2023 Apr 29; Vol. 401 (10386), pp. 1427-1437. Date of Electronic Publication: 2023 Mar 29.
DOI:	10.1016/S0140-6736(23)00284-2
Abstrakt:	Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Sanofi. Competing Interests: Declaration of interests GY reports grants from Genentech/Roche, Grifols, and Takeda; and speaking and consultancy fees from Apcintex, BioMarin, Genentech/Roche, Grifols, Hema Biologics/ Laboratoire français du Fractionnement et des Biotechnologies biomedicaments, Novo Nordisk, Pfizer, Rani, Sanofi, Spark, Takeda, and UniQure. AS reports membership on advisory committees or grant review committees for Sanofi, Takeda, Novo Nordisk, Roche, Pfizer, and Bayer Healthcare and reports research funding from Roche, Novo Nordisk, Sanofi, and Pfizer. KK reports grants and consultancy fees from Novo Nordisk, Roche, and Takeda. JSa is the president of the Malaysian Society of Patient Blood Management. HT reports grants or honorarium from Sanofi, Takeda, Roche, and CSL Behring. SP, ZQ, and SK are employees and equity holders in Sanofi. BM was an employee and equity holder in Sanofi at the time of the study and has divested equity in Sanofi in the past 24 months; he is an employee of Editas Medicine. SA is an employee and equity holder in Sanofi, and a member of the WEST advisory committee. SR reports consultancy fees from Reliance Life Sciences; grants for conference attendance from Takeda; and fees for attendance at advisory board meetings from Pfizer, Sanofi, Sigilon, and Takeda. All other authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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