Real-World Effectiveness and Clinical Predictors of Response to First-Generation TTR Silencers in Variant ATTR Amyloidosis with Polyneuropathy

Background: Transthyretin (TTR) gene-silencing therapies have transformed the management of variant transthyretin amyloidosis with polyneuropathy (ATTRv-PN). However, real-world evidence on effectiveness, safety, and durability is limited. Methods: We conducted a multicenter retrospective study across ten Spanish referral hospitals including 98 genetically confirmed ATTRv-PN patients treated with patisiran (n=81) or inotersen (n=17). Patients were classified as total, partial, or non-responders according to clinical evolution and Neuropathy Impairment Score (NIS). Baseline clinical, neurophysiological (CMAP, SNAP, ESC), and biochemical parameters were analyzed. Longitudinal NIS changes, treatment persistence, and safety were assessed. Results: Total responders had higher baseline CMAP amplitudes (p=0.045) and better renal function (eGFR, p=0.022). Compared with inotersen, patisiran showed a higher total response rate (59.3% vs. 23.5%), slower NIS progression (median +0.31 vs. +4.00 points/year; p=0.011), and greater treatment persistence (log-rank p=0.0005). No discontinuations due to adverse events occurred with patisiran, versus 41.2% with inotersen. ESC showed the highest predictive value (AUC 0.681 overall; 0.783 in the patisiran subgroup), while baseline NIS was less informative. Conclusions: In routine practice, patisiran demonstrated superior efficacy, safety, and durability compared with inotersen. Baseline motor nerve function and renal status may help guide therapeutic decisions, supporting early and personalized treatment strategies.