Background
Phase 3 open-label RCT (ATLAS-A/B). 120 male patients aged ≥12 years with severe hemophilia A (FVIII <1%) or hemophilia B (FIX <1% or ≤2%) without inhibitors, previously on on-demand clotting factor concentrates. Randomized 2:1 for 9 months. Fitusiran (ALNYLAM-022) is a subcutaneous small interfering RNA (siRNA) that targets antithrombin (AT) mRNA, reducing AT production and rebalancing hemostasis toward a procoagulant state. Works independently of FVIII/FIX status, making it applicable to both hemophilia A and B. FDA approved March 2024 (Alhemo) for adults and pediatric patients ≥12 years with hemophilia A or B with or without inhibitors.
Interventions and follow up
Arm A: Fitusiran 80 mg SC once monthly
Arm B: Continue on-demand clotting factor concentrates (FVIII or FIX, per investigator direction)
Primary endpoint: Annualized bleeding rate (ABR) of treated bleeds by negative binomial model
mFollow up: 9 month
Arm B: Continue on-demand clotting factor concentrates (FVIII or FIX, per investigator direction)
Primary endpoint: Annualized bleeding rate (ABR) of treated bleeds by negative binomial model
mFollow up: 9 month
Results
Estimated mean ABR: 3.1 (95% CI 2.3–4.3) fitusiran vs 31.0 (95% CI 21.1–45.5) on-demand factor; rate ratio 0.101 (95% CI 0.064–0.159), P<.0001
Zero treated bleeds: 51% (fitusiran) vs 5% (on-demand)
Median ABR: 0.0 (fitusiran) vs 21.8 (on-demand)
Zero treated bleeds: 51% (fitusiran) vs 5% (on-demand)
Median ABR: 0.0 (fitusiran) vs 21.8 (on-demand)
Adverse events
Main adverse events: Most common: elevated alanine aminotransferase (ALT) in 23% of fitusiran patients (vs 10% on-demand). Grade ≥3 ALT elevation in ~8%. Serious AEs: 6% fitusiran vs 13% on-demand. No treatment-related thrombosis or death. Cholelithiasis/cholecystitis in 3 patients. Hypertension rare. No FVIII/FIX inhibitor development.
Conclusions
Once-monthly fitusiran prophylaxis reduced ABR by ~90% compared to on-demand factor therapy in hemophilia A and B without inhibitors, with median ABR reaching 0.0, establishing fitusiran as a factor-independent rebalancing therapy option.
Key Limitations
Key Limitations: Comparison is to on-demand factor only, not to prophylactic factor — the true standard of care for severe hemophilia. An on-demand comparator makes the relative benefit appear larger than it would vs prophylaxis. 9-month trial duration is short. ALT elevations require monitoring. Thrombosis risk (antithrombin reduction) requires careful management, especially when supplemental hemostatic agents are needed for procedures (dose modification protocol required). Monthly SC injection remains an injection burden vs oral agents.
Clinical Context
FDA approved March 2024 (Alhemo) for hemophilia A or B with or without inhibitors, with or without prophylactic factor. Fitusiran offers once-monthly SC dosing vs weekly-every-2-week injection for emicizumab (hemophilia A only). Mechanism is applicable to both hemophilia A and B, unlike emicizumab. Key safety concern is thrombosis risk with concomitant hemostatic agents — AT levels must be monitored. ATLAS-INH study confirmed efficacy in inhibitor patients (Young G et al, Lancet 2023).
References