TY - JOUR
T1 - Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B)
T2 - a multicentre, open-label, randomised, phase 3 trial
AU - Srivastava, Alok
AU - Rangarajan, Savita
AU - Kavakli, Kaan
AU - Klamroth, Robert
AU - Kenet, Gili
AU - Khoo, Liane
AU - You, Chur Woo
AU - Xu, Weiqun
AU - Malan, Niel
AU - Frenzel, Laurent
AU - Bagot, Catherine N.
AU - Stasyshyn, Oleksandra
AU - Chang, Chia Yau
AU - Poloskey, Stacey
AU - Qiu, Zhiying
AU - Andersson, Shauna
AU - Mei, Baisong
AU - Pipe, Steven W.
N1 - Funding Information:
We thank the participants, their families, and the investigators and staff from participating sites involved in this trial; Sajida Iqbal for contributions to the analysis and interpretation of pharmacodynamics and antidrug antibody analysis; José Bartelt-Hofer for analysis and interpretation of the health-related quality of life data; and Julia Xiong and Yue Cui for contributions to the statistical analysis and critical review of the manuscript. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Jack Wigham of Ashfield MedComms, an Inizio company, and funded by Sanofi in accordance with Good Publication Practice guidelines.
Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
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U2 - 10.1016/S2352-3026(23)00037-6
DO - 10.1016/S2352-3026(23)00037-6
M3 - Article
C2 - 37003278
AN - SCOPUS:85151379771
SN - 2352-3026
VL - 10
SP - e322-e332
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 5
ER -
