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Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
China Medical University Hospital, Taichung, Taiwan.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
Hospital El Cruce, Buenos Aires, Argentina.
Instituto de Neurologia de Curitiba, Paraná, Curitiba, Brazil.
Boston University School of Medicine, MA, Boston, United States.
Amyloidosis Research and Treatment Centre, IRCCS, Fondazione Policlinico San Matteo, Pavia, Italy.
Neurology Department, Fleni, Buenos Aires, Argentina.
Amyloidosis Center and Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
Centro Hospitalar Universitário Lisboa-Norte, Hospital de Santa Maria, Lisbon, Portugal.
Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
Late-Stage Development Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, MD, Gaithersburg, United States.
Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
Ionis Pharmaceuticals Inc, CA, Carlsbad, United States.
OHSU, Center for Hypertrophic Cardiomyopathy and Amyloidosis, OR, Portland, United States.
Mayo Clinic, MN, Rochester, United States.
Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
National Amyloidosis Centre, University College London, London, United Kingdom.
University of Pennsylvania, School of Medicine, Philadelphia, United States.
Mayo Clinic, MN, Rochester, United States.
Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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2023 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 330, no 15, p. 1448-1458Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
American Medical Association (AMA), 2023
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-216127 (URN)10.1001/jama.2023.18688 (DOI)001077079100001 ()37768671 (PubMedID)2-s2.0-85174751577 (Scopus ID)
2023-11-062023-11-062023-11-06Bibliographically approved