S303: A PHASE 3 STUDY (ATLAS-PPX) TO EVALUATE EFFICACY AND SAFETY OF FITUSIRAN IN PEOPLE WITH HAEMOPHILIA A OR B WHO HAVE SWITCHED FROM PRIOR CLOTTING FACTOR CONCENTRATE OR BYPASSING AGENT PROPHYLAXIS
Makaleler > Tam Makale · 2023
Yazarlar: Gili Kenet, Beatrice Nolan, Bulent Zulfikar, Bulent Antmen, Peter Kampmann, Tadashi Matsushita, Chur-Woo You, Kateryna Vilchevska, Catherine N. Bag, Azizan Sharif, Flora Peyvandi, Guy Young, Claude Negrier, Christian Sussebach, Fadi Shammas, Shauna Andersson, Baisong Mei, Kaan Kavakli
HemaSphere, Uluslararası, Wos, 2023, cilt 7, ss e643526e-e643526e
DOI: 10.1097/01.hs9.0000968124.64352.6e
Özet
Background: Fitusiran, a subcutaneous (SC) investigational siRNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or B (PwHA/B), irrespective of inhibitor status. In previous Phase 3 trials, once-monthly fitusiran prophylaxis significantly reduced annualised bleeding rate (ABR) in PwHA/B, with or without inhibitors versus episodic/on-demand treatment. Aims: To evaluate the efficacy and safety of fitusiran versus prior clotting factor concentrate (CFC)/bypassing agent (BPA) prophylaxis in PwHA/B, with or without inhibitors. Methods: This Phase 3, multinational, open-label study (NCT03549871) included males aged ≥12 years with hemophilia A or B, with or without inhibitors, who had prior CFC/BPA prophylaxis. Participants continued CFC/BPA prophylaxis (6 months) before switching to once-monthly 80 mg SC fitusiran prophylaxis (7 months). Primary endpoint was ABR in the CFC/BPA prophylaxis period (Day 168 to Day 1) and fitusiran efficacy period (Day 29 to Day 190). Secondary endpoints included spontaneous ABR (AsBR), joint ABR (AjBR), and health-related quality of life (HRQoL). Safety and tolerability were assessed. Results: Of 80 enrolled participants, 65 (inhibitor/non-inhibitor, n=19/46; haemophilia A/haemophilia B, n=50/15) were eligible for ABR analyses. Median observed (IQR) ABRs were 4.4 (2.2; 10.9) with CFC/BPA and 0.0 (0.0; 2.3) with fitusiran prophylaxis; 41 participants (63.1%) experienced zero treated bleeds with fitusiran. Fitusiran achieved statistically significant reductions in estimated ABR, AsBR and AjBR versus CFC/BPA prophylaxis (Table 1). Fitusiran significantly improved HRQoL versus CFC/BPA as measured by Haem-A-QOL total score (LS mean difference -4.6 [95% CI: -7.6; -1.5; p<0.01]). Serious adverse events (SAEs) occurred in 5/65 participants (7.7%) with CFC/BPA and 9/67 (13.4%) with fitusiran prophylaxis. A total of 17 (25.4%) participants experienced alanine aminotransferase or aspartate transaminase elevations >3x the upper limit of normal in the fitusiran prophylaxis period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Summary/Conclusion: Once-monthly fitusiran prophylaxis significantly reduced bleeding versus CFC/BPA prophylaxis with a median ABR of zero in PwHA/B with and without inhibitors, resulting in a meaningful improvement in HRQoL. Reported AEs were generally consistent with previously identified risks of fitusiran.Keywords: Hemophilia