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N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793.

Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.

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From the Indiana University School of Medicine, Indianapolis (M.D.B.); Centro de Estudos em Paramiloidose Antônio Rodrigues de Mello, National Amyloidosis Referral Center, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro (M.W.-C.); Amyloidosis Center, Boston University School of Medicine (J.L.B.) and Brigham and Women's Hospital, Harvard Medical School (A.M.S., S.D.S.), Boston; Johns Hopkins University, Baltimore (M.P.); Mayo Clinic, Rochester, MN (P.J.D., W.J.L., M.A.G.); University of California, Irvine, Irvine (A.K.W.); Amyloid Network-Hospital Henri Mondor-Assistance Publique-Hôpitaux de Paris (AP-HP)-Université Paris Est, Créteil, France (V.P.-B.); Institute for Neurologic Research Raúl Carrea, FLENI, Buenos Aires (F.A.B.); Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia (G.M., L.O.), and Unit of Neurology, University Hospital, Messina (G.V.) - both in Italy; Hospital AACD (Associação de Assistência à Criança Deficiente), São Paulo (M.S.); Columbia University Medical Center (T.H.B.) and Mount Sinai Medical Center (P.D.G.), New York; University College London-National Amyloidosis Centre, London (C.W.); Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia (B.M.D.); Centre Hospitaliere Universitaire Bicêtre, AP-HP, Unité 1195, INSERM, Université Paris-Sud, Paris (D.A.); Oregon Health and Science University, Portland (S.B.H.); Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Lisbon (I.C.), and Centro Hospitalar do Porto, Porto (T.C.) - both in Portugal; Universitätsklinikum Münster, Münster, Germany (H.H.S.); Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (J.M.C.), and Hospital Universitari Vall d'Hebron (J.G.), Barcelona; Auckland City Hospital, Auckland, New Zealand (E.G.); and Ionis Pharmaceuticals, Carlsbad, CA (B.P.M., S.G.H., T.J.K., B.W.M., S.W.J., B.F.B., E.J.A.).



Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin.


We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement.


A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring.


Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR number, NCT01737398 .).

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