Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

Background: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors.
Methods: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete.
Findings: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported.
Interpretation: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia.
Funding: Sanofi.
Competing Interests: Declaration of interests AS is a member of advisory boards and grant review committees for Sanofi, Takeda, Novo Nordisk, Roche, Pfizer, and Bayer Healthcare and has received research funding from Roche, Novo Nordisk, Sanofi, and Pfizer. SR has received honoraria for consulting from Reliance Life Sciences; participated in a speakers bureau for Takeda; and has been a member of advisory boards for Pfizer, Sanofi, and Sigilon Therapeutics. KK has received honoraria from and attended speakers bureaus for Pfizer, Bayer, Takeda, Roche, and Novo Nordisk and is on advisory committees for Pfizer, Bayer, Takeda, Roche, and Novo Nordisk. RK has received research funding from Bayer and LEO Pharma; received honoraria from Bayer, Biotest, BioMarin Pharmaceutical, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, LEO Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda; and attended speakers bureaus for Bayer, Biotest, BioMarin Pharmaceutical, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, and Takeda. GK consults for Alnylam Pharmaceuticals, Bayer, BioMarin Pharmaceutical, CSL Behring, Novo Nordisk, OPKO Biologics, Pfizer, Takeda, Roche, Sanofi, and uniQure; has received research funding from Alnylam, Bayer, Bio Products Laboratory, OPKO Biologics, Pfizer, Roche, and Takeda; has attended speakers bureaus for Bayer, Pfizer, CSL Behring, Shire Pharmaceuticals, Novo Nordisk, and Roche; and is on advisory committees for Alnylam, Bayer, BioMarin Pharmaceutical, CSL Behring, Novo Nordisk, OPKO Biologics, Pfizer, Takeda, Roche, Sanofi, and uniQure. LK has received research funding from Roche and honoraria from Sanofi, Novo Nordisk, and Roche; has participated in speakers bureaus for Roche, Sanofi, Novo Nordisk, and Takeda; and is on advisory committees for Roche, Sanofi, and Novo Nordisk. C-YC has received research funding from Bayer and Sanofi and honoraria from Bayer, Sanofi, Novo Nordisk, Takeda, Chugai Pharmaceutical, and Pfizer; and has participated in advisory boards for Sanofi, Novo Nordisk, Bayer, and Chugai Pharmaceutical. NM has received research funding for clinical research yet to be conducted and is vice-chair of St Francis Hospice, South Africa. LF has received research funding from Pfizer, Roche, Sobi, and CSL Behring. OS has received research funding and honoraria from Novo Nordisk, Shire Pharmaceuticals, CSL Behring, Sanofi, Pfizer, and LFB and has participated in speaker bureaus for Novo Nordisk, Pfizer, Shire Pharmaceuticals, Octapharma and Roche. SP, ZQ, and SA are current employees of, and equity holders in, Sanofi. BM was an employee of and equity holder in Sanofi at the time of the study and has divested equity in Sanofi in the past 24 months; he is currently an employee of Editas Medicine. SWP has received consultancy fees from ApcinteX, ASC Therapeutics, Bayer, BioMarin Pharmaceutical, CSL Behring, GeneVentiv, HEMA Biologics, Freeline Therapeutics, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure; has received research funding from Siemens; and is a member of a scientific advisory committee for GeneVentiv. C-WY, WX, and CNB declare no competing interests.
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