Silencing TTR, distinct signals: safety profiles of small interfering RNA therapies in amyloidosis
J Gu, W Tan, S TanAbstract
Background
Vutrisiran and patisiran are small interfering RNA (siRNA) agents approved for the treatment of transthyretin-mediated amyloidosis. Their use in patients with cardiac amyloidosis has expanded, yet post-marketing safety data remain limited.
Methods
We conducted a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) to characterize adverse event (AE) profiles of vutrisiran and patisiran in patients with cardiac amyloidosis from 2020 to 2025. Disproportionality was assessed with reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs).
Results
Among reports involving vutrisiran, the most frequent AEs were fatigue (19.4%) and product use in unapproved indications (16.1%). The strongest disproportionality signals were for product use in unapproved indications (ROR 10.76, 95% CI 4.03, 28.75) and fatigue (ROR 4.54, 95% CI 1.84, 11.17). For patisiran, the most frequently reported AEs were death (12.5%), infusion-related reaction (9.4%), and atrial fibrillation (9.4%). The most significant disproportionality was observed for infusion-related reactions (ROR 51.24, 95% CI 17.66, 148.64), followed by atrial fibrillation (ROR 1.81, 95% CI 0.77, 4.25), while death was reported less often than expected (ROR 0.44, 95% CI 0.21, 0.93).
Conclusion
Vutrisiran and patisiran demonstrate distinct and non-overlapping safety signals in patients with cardiac amyloidosis. Vutrisiran was frequently reported in unapproved clinical scenarios, underscoring gaps between trial design and real-world use. In contrast, patisiran was strongly associated with infusion-related reactions. These findings highlight the importance of post-marketing surveillance to better inform clinical decision-making and the need for further investigation of long-term safety in this population.