Real-world effectiveness and clinical predictors of response to first-generation TTR silencers in variant ATTR amyloidosis with polyneuropathy

Abstract

Abstract 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. We conducted a multicenter retrospective study across ten Spanish referral hospitals including 98 genetically confirmed ATTRv-PN amyloidosis 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. Total responders had higher baseline CMAP amplitudes (p = 0.045), while baseline neurophysiological measures showed modest discriminatory capacity overall, with electrochemical skin conductance providing the strongest signal. Baseline renal function differed across groups (eGFR, p = 0.022), but the direction of this association was not consistent with improved response. 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. In routine practice, patisiran was associated with more favourable effectiveness and tolerability compared to inotersen. Baseline neurological preservation, particularly motor and small-fiber measures, may help identify patients more likely to benefit from treatment. However, these findings should be interpreted with caution due to the limited sample-size and the observational nature of the study.