Background: Prophylaxis is the standard of care for people with severe hemophilia A or B to prevent bleeding, but the treatment burden can be high, and breakthrough bleeding can still occur, particularly in patients with inhibitors. Fitusiran, a small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis, offering a novel prophylactic approach. This systematic review and meta-analysis aim to evaluate the efficacy and safety of Fitusiran prophylaxis in this population.

Aim: To systematically review and meta-analyze the efficacy and safety of Fitusiran prophylaxis compared to control in people with hemophilia A or B, with or without inhibitors.

Methods: A systematic literature search was conducted across PubMed, Cochrane, ScienceDirect, Web of Science, and Scopus to identify randomized controlled trials (RCTs) comparing Fitusiran with control (placebo or bypassing agents on-demand) in patients with hemophilia A or B. The primary efficacy outcomes were the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), and annualized joint bleeding rate (AjBR). Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent severe adverse events (TESAEs), and specific adverse events of interest such as elevated liver enzymes. Data from RCTs were pooled using a random-effects model. Mean difference (MD) was used for continuous outcomes and odds ratio (OR) for dichotomous outcomes, with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic.

Results: Three RCTs were included in this meta-analysis, ATLAS-INH 2023, ATLAS-PPX 2024, and ATLAS A/B 2023, with a combined sample size of (N=311). In patients with inhibitors, Fitusiran significantly reduced ABR (MD: -11.70, 95% CI: [-18.55, -4.85]; P=0.0008), AsBR (MD: -9.40, 95% CI: [-18.63, -0.18]; P=0.05), and AjBR (MD: -8.49, 95% CI: [-14.92, -2.05]; P=0.01). In patients without inhibitors, no statistically significant reduction was observed for ABR (P=0.25), AsBR (P=0.26), or AjBR (P=0.28). Fitusiran was associated with a significantly higher odds of any TEAE (OR: 5.11, 95% CI: [3.05, 8.56]; P<0.00001) and increased alanine aminotransferase (ALT) (OR: 17.80, 95% CI: [4.88, 64.92]; P<0.0001). There was no statistically significant difference in the odds of increased aspartate aminotransferase (AST) (P=0.06), upper respiratory tract infection (P=0.12), arthralgia (P=0.23), nasopharyngitis (P=0.15), or TESAEs (OR: 0.84, 95% CI: [0.35, 2.00]; P=0.69). Heterogeneity for all outcomes was low.

Conclusion: Fitusiran prophylaxis is an effective therapy for reducing bleeding rates in patients with hemophilia A or B with inhibitors. While a similar trend was observed in patients without inhibitors, the result was not statistically significant. The safety profile indicates an increased risk of TEAEs, most notably transient elevations in ALT, but not an increase in severe adverse events. These findings support Fitusiran as a promising prophylactic option, especially for the difficult-to-treat inhibitor population and underscore the importance of monitoring liver function during treatment.

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2025
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