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Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis., Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy., Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group., Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60)., Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights., Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group., Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

This clinical practice guideline for the treatment of familial amyloid polyneuropathy is based on the best available evidence of clinical effectiveness. A list of questions was generated with a PICO format focused on the effectiveness and safety of the treatment of familial amyloid polyneuropathy. The search was carried out in PubMed, Cochrane and Epistemonikos. The levels of evidence and grades of recommendation were based on the GRADE system. Recommendations were graded according to their direction and their strength and were evaluated with the GLIA tool for their implementation. In patients with familial amyloid polyneuropathy and stage I and II neuropathy, it is suggested: inotersen 300 mg subcutaneous weekly or patisirán 0.3 mg/kg intravenously once every 3 weeks, since they probably stabilize or slow the progression of neuropathy and worsening quality of life (moderate quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and stage I neuropathy, treatment with tafamidis 20 mg orally, once a day, is suggested, as it could slow the progression of neuropathy and worsen quality of life (low quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and symptomatic neuropathy and in the absence of other treatments with approved efficacy, treatment with oral diflunisal 250 mg twice daily is suggested, as it could prevent the progression of neuropathy (quality evidence low; strength of recommendation weak).