Abstract
Background: Fitusiran is a prophylactic investigational therapeutic comprised of synthetic small interfering ribonucleic acid (siRNA) that targets antithrombin to enhance thrombin generation and rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. In previous Phase 3 trials, once-monthly fitusiran prophylaxis significantly improved HRQoL in PwHA/B, with or without inhibitors versus episodic/on-demand treatment
Objective: We present health-related quality of life (HRQoL) results from the phase 3 ATLAS-PPX study (NCT03549871) comparing fitusiran prophylaxis versus prior prophylaxis with clotting factor concentrates (CFC) or bypass agents (BPA) in PwHA/B with or without inhibitors.
Methods: This multicenter, multinational, open-label, Phase 3 study recruited male patients aged ≥12 years with severe hemophilia A or B, with or without inhibitors. Participants continued factor/BPA prophylaxis (6 months between month -6 and Day 0) before switching to once-monthly 80 mg SC fitusiran prophylaxis (7 months between Day 1 and month 7). Aside from annualized bleeding rates (ABR), the study assessed HRQoL at Month -6, Day 1 (baseline) and Month 7, during factor/BPA prophylaxis and during treatment with fitusiran using the following questionnaires: Hemophilia Quality of Life Questionnaire (Haem-A-QoL & Haemo-QoL; lower scores = improved HRQoL), Hemophilia Activity List (HAL & PedHal; range 0-100, higher scores = improved HRQoL), EuroQoL-5 Dimension 5-Level (EQ-5D-5L; index score ranges 0-1, higher scores = improved HRQoL), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and the Hemophilia Joint Health Score (HJHS).
Results: A total of 80 participants were enrolled and 65 were evaluable for efficacy analyses (inhibitor/non-inhibitor, n=19/46; hemophilia A/hemophilia B, n=50/15). At enrollment (Month -6), the mean (SD) age was 24.8 (11.2) years, transformed Haem-A-QoL physical health and total scores were 32.87 (23.68) and 31.63 (18.54) respectively, EQ-5D-5L index score was 0.83 (0.13), HAL total score was 79.11 (20.29) and TSQM-9 baseline score for effectiveness, convenience and satisfaction were 66.76 (18.06), 61.29 (17.97) and 69.35 (15.91), respectively. Fitusiran achieved the study primary endpoint and significantly reduced the frequency of bleeding episodes; observed median (IQR) ABR for treated bleeds was 0.0 (0.0; 2.3) in the fitusiran efficacy period and 4.35 (2.2; 10.9) in the factor /BPA prophylaxis period. The least squares (LS) mean difference between change from Month -6 to baseline (Day 1) and change from Month -6 to Month 7 in Haem-A-QoL scores demonstrated significant improvement in transformed total score with fitusiran treatment vs factor/BPA prophylaxis (-4.55 [95% CI: -7.56, -1.54]) and nominal improvement in physical health score in favor of fitusiran (-3.60 [95%-CI: -10.52, 3.33]). In addition to showing a good functional ability to perform activities of daily living, patients rated an even better physical ability over the two periods of assessment of the study as evidenced by changes in HAL scores: mean (SD) changes in total score were 3.05 (20.04) and 2.45 (19.42) for fitusiran and factor/BPA prophylaxis, respectively. Similar to the results from disease specific questionnaire, fitusiran also demonstrated nominal improvements in the EQ-5D-5L index score versus factor/BPA prophylaxis, with mean (SD) changes from Month -6 to Month 7/ Day 1of 0.04 (0.13) versus 0.0 (0.13). Overall results of the mean (SD) TSQM-9 score consistently favored fitusiran prophylaxis versus factor/BPA prophylaxis in all three domains of effectiveness, convenience, and global satisfaction (Table 1).
Conclusions: Associated with a marked ABR reduction, PwHA/B with or without inhibitors on fitusiran prophylaxis consistently improved all HRQoL endpoints, demonstrating added value in PwHA/B beyond the improvement in bleeding phenotype.
Disclosures
Kenet:BPL: Consultancy, Research Funding; Alnylam: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Shire: Research Funding; Opko Biologics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; ASC Therapeutics: Consultancy; Novo Nordisk: Consultancy, Honoraria; BioMarin Pharmaceutical Inc.: Consultancy, Honoraria; Sanofi-Genzyme: Consultancy, Honoraria; UniQure, SPark, Sobi, CSL: Honoraria. Matsushita:Fujimoto: Honoraria; Bayer Yakuhin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; KM biologics Co.: Honoraria; Sanofi: Honoraria; Japan Blood Products: Honoraria; CSL Behring: Honoraria; Sysmex Corp.: Honoraria. Young:Grifols: Research Funding; Bayer: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Roche: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria; Spark: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Honoraria; Biomarin: Consultancy, Honoraria, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Hema Biologics: Consultancy, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; LFB: Consultancy; Viatris: Patents & Royalties. Quan:Sanofi: Current Employment. Cano:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Sussebach:Sanofi: Current Employment. Andersson:Sanofi: Current Employment. Afonso:Sanofi: Current Employment. Kavakli:Bayer: Other: participated in advisory board; Novo Nordisk: Other: participated in advisory board; Takeda: Other: participated in advisory board; Pfizer: Other: participated in advisory board; Roche: Other: participated in advisory board.
