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Title: Inotersen treatment for patients with hereditary transthyretin amyloidosis
Author: Benson, Merrill D.
Waddington-Cruz, Márcia
Berk, John L.
Polydefkis, Michael
Dyck, Peter J.
Wang, Annabel K.
Planté Bordeneuve, Violaine
Barroso, Fabio A.
Merlini, Giampaolo
Obici, Laura
Scheinberg, Morton
Brannagan, Thomas H.
Litchy, William J.
Whelan, Carol
Drachman, Brian M.
Adams, David
Heitner, Stephen B.
Conceição, Isabel
Schmidt, Hartmut H.
Vita, Giuseppe
Campistol Plana, Josep M.
Gamez, Josep
Gorevic, Peter D.
Gane, Edward
Shah, Amil M.
Solomon, Scott D.
Monia, Brett P.
Hughes, Steven G.
Kwoh, T. Jesse
McEvoy, Bradley W.
Jung, Shiangtung W
Baker, Brenda F.
Ackermann, Elizabeth J.
Gertz, Morie A.
Coelho, Teresa
Keywords: Neuropaties perifèriques
Malalties del sistema nerviós
Malalties hereditàries
Peripheral neuropathies
Nervous system Diseases
Genetic diseases
Issue Date: 5-Jul-2018
Publisher: Massachusetts Medical Society
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 .).
Note: Reproducció del document publicat a:
It is part of: New England Journal of Medicine, 2018, vol. 379, num. 1, p. 22-31
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ISSN: 0028-4793
Appears in Collections:Articles publicats en revistes (Medicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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