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

Young G 1 , Srivastava A 2 , Kavakli K 3 , Ross C 4 , Sathar J 5 , You CW 6 Show all authors , Tran H 7 , Sun J 8 , Wu R 9 , Poloskey S 10 , Qiu Z 11 , Kichou S 12 , Andersson S 13 , Mei B 13 , Rangarajan S 14

Affiliations 

  • 1 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
  • 2 Department of Haematology, Christian Medical College & Centre for Stem Cell Research, a unit of inStem, Bengaluru, Christian Medical College Campus, Vellore, India
  • 3 Department of Pediatric Hematology and Oncology, Ege University Faculty of Medicine Children's Hospital, Izmir, Turkey
  • 4 Department of Hematology, St John's Medical College Hospital, Bangalore, India
  • 5 Department of Haematology, Ampang Hospital, Kuala Lumpur, Malaysia
  • 6 Department of Pediatrics, Eulji University School of Medicine, Seoul, South Korea
  • 7 Ronald Sawers Hemophilia Treatment Center, The Alfred, Monash University, Melbourne, Victoria, Australia
  • 8 Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 9 National Center for Children's Health, Beijing Children's Hospital, Beijing, China
  • 10 Pharmacovigilance, Sanofi, Cambridge, MA, USA; Clinical Development, Sanofi, Cambridge, MA, USA
  • 11 Biostatistics & Programming, Sanofi, Bridgewater, NJ, USA
  • 12 Clinical Development, Sanofi, Paris, France
  • 13 Clinical Development, Sanofi, Cambridge, MA, USA
  • 14 Advanced Centre for Oncology, Haematology & Rare Diseases KJ Somaiya Super Specialty, Hospital, Mumbai, India; Faculty of Medicine, University of Southampton, Southampton, UK
Lancet, 2023 Mar 29.
PMID: 37003287 DOI: 10.1016/S0140-6736(23)00284-2

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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