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Abstract Background Patients with hereditary transthyretin amyloidosis (ATTRv) frequently experience symptoms of polyneuropathy (PN) that worsen over time and impair daily functioning. Previous analyses supported efficacy of inotersen, an antisense oligonucleotide, to slow neuropathic progression in patients with ATTRv-PN, as indicated by larger mean changes, relative to placebo, in total score and several subscales of the Neuropathy Impairment Score (NIS), and for the subset of NIS items specific to lower limbs (NIS-LL) for the overall study sample. A key objective of the current study was to evaluate efficacy of inotersen for slowing neuropathic progression in NIS/NIS-LL within key clinical subgroups of patients with ATTRv-PN. Additionally, for this study, responder definition (RD) thresholds were estimated for NIS/NIS-LL total and subscale scores, for the purpose of evaluating clinically meaningful benefit of inotersen at the individual patient-level. Methods Post hoc analyses used data from the NEURO-TTR phase 3 trial of inotersen in patients with ATTRv-PN (NCT01737398). Treatment differences in mean changes on NIS/NIS-LL total and subscale scores from baseline to week 65 were examined within patient subgroups defined by clinical characteristics. Anchor- and distribution-based approaches estimated RDs for NIS/NIS-LL scores, with responders defined as patients who did not experience clinically meaningful neuropathic progression. Responder analyses compared the proportion of patients classified as responders for each NIS/NIS-LL score between treatment arms. Results Within each patient subgroup, mean increases in NIS/NIS-LL total and muscle weakness subscales were significantly smaller after 65 weeks of treatment with inotersen compared to placebo. Similar patterns were observed for some, but not all, subgroups on NIS/NIS-LL reflex subscale scores. Recommended RDs were 8.1 points for NIS total and 4.7 points for NIS-LL total. Patients receiving inotersen for 65 weeks were significantly less likely than those receiving placebo to exhibit clinically meaningful increases on NIS/NIS-LL total, muscle weakness, and sensation subscales. Conclusions This study supports previous evidence for efficacy of inotersen in this patient population and provides interpretation guidelines for clinically meaningful changes in NIS/NIS-LL scores.