Coelho, Teresa; Marques, Wilson; Dasgupta, Noel R; Chao, Chi-Chao; Parman, Yesim; França, Marcondes Cavalcante; Guo, Yuh-Cherng; ... NEURO-TTRansform Investigators; + view all Coelho, Teresa; Marques, Wilson; Dasgupta, Noel R; Chao, Chi-Chao; Parman, Yesim; França, Marcondes Cavalcante; Guo, Yuh-Cherng; Wixner, Jonas; Ro, Long-Sun; Calandra, Cristian R; Kowacs, Pedro A; Berk, John L; Obici, Laura; Barroso, Fabio A; Weiler, Markus; Conceição, Isabel; Jung, Shiangtung W; Buchele, Gustavo; Brambatti, Michela; Chen, Jersey; Hughes, Steven G; Schneider, Eugene; Viney, Nicholas J; Masri, Ahmad; Gertz, Morie R; Ando, Yukio; Gillmore, Julian D; Khella, Sami; Dyck, P James B; Waddington Cruz, Márcia; NEURO-TTRansform Investigators; - view fewer (2023) Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA: Journal of the American Medical Association , 330 (15) pp. 1448-1458. 10.1001/jama.2023.18688.

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Abstract

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.

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