Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis

被引:1073
作者
Benson, M. D. [1 ]
Waddington-Cruz, M. [2 ]
Berk, J. L. [3 ]
Polydefkis, M. [5 ]
Dyck, P. J. [6 ]
Wang, A. K. [7 ]
Plante-Bordeneuve, V. [8 ]
Barroso, F. A. [9 ]
Merlini, G. [10 ]
Obici, L. [10 ]
Scheinberg, M. [12 ]
Brannagan, T. H., III [13 ]
Litchy, W. J. [6 ]
Whelan, C. [15 ]
Drachman, B. M. [16 ]
Adams, D. [17 ]
Heitner, S. B. [18 ]
Conceicao, I. [19 ]
Schmidt, H. H. [21 ]
Vita, G. [11 ]
Campistol, J. M. [22 ]
Gamez, J. [23 ]
Gorevic, P. D. [14 ]
Gane, E. [24 ]
Shah, A. M. [4 ]
Solomon, S. D. [4 ]
Monia, B. P. [25 ]
Hughes, S. G. [25 ]
Kwoh, T. J. [25 ]
McEvoy, B. W. [25 ]
Jung, S. W. [25 ]
Baker, B. F. [25 ]
Ackermann, E. J. [25 ]
Gertz, M. A. [6 ]
Coelho, T. [20 ]
机构
[1] Indiana Univ Sch Med, Indianapolis, IN 46202 USA
[2] Fed Univ Rio Janeiro, Univ Hosp, Ctr Estudos Paramiloidose Antonio Rodrigues de Me, Natl Amyloidosis Referral Ctr, Rio De Janeiro, Brazil
[3] Boston Univ, Sch Med, Amyloidosis Ctr, Boston, MA USA
[4] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA
[5] Johns Hopkins Univ, Baltimore, MD USA
[6] Mayo Clin, Rochester, MN USA
[7] Univ Calif Irvine, Irvine, CA USA
[8] Univ Paris Est, Hosp Henri Mondor, AP HP, Amyloid Network, Creteil, France
[9] Inst Neurol Res Raul Carrea, FLENI, Buenos Aires, DF, Argentina
[10] Univ Pavia, Amyloidosis Res & Treatment Ctr, Fdn IRCCS Policlin San Matteo, Pavia, Italy
[11] Univ Hosp, Unit Neurol, Messina, Italy
[12] Hosp AACD, Associacao Assistencia Crianca Deficiente, Sao Paulo, Brazil
[13] Columbia Univ, Med Ctr, New York, NY USA
[14] Mt Sinai Med Ctr, New York, NY 10029 USA
[15] UCL, Natl Amyloidosis Ctr, London, England
[16] Univ Penn Hlth Syst, Penn Presbyterian Med Ctr, Philadelphia, PA USA
[17] Univ Paris Sud, AP HP, Unite 1195, CHU Bicetre, Paris, France
[18] Oregon Hlth & Sci Univ, Portland, OR 97201 USA
[19] Hosp Santa Maria, Ctr Hosp Lisboa Norte, Lisbon, Portugal
[20] Ctr Hos Porto, Porto, Portugal
[21] Univ Klinikum Munster, Munster, Germany
[22] Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, Hosp Clin, Barcelona, Spain
[23] Hosp Univ Vall dHebron, Barcelona, Spain
[24] Auckland City Hosp, Auckland, New Zealand
[25] Ionis Pharmaceut, Carlsbad, CA USA
关键词
ANTISENSE OLIGONUCLEOTIDES; ATTR AMYLOIDOSIS; POLYNEUROPATHY; 2'-O-METHOXYETHYL; DIFLUNISAL; NEUROPATHY; TAFAMIDIS; DISEASE; SAFETY;
D O I
10.1056/NEJMoa1716793
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 multi-organ 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.
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收藏
页码:22 / 31
页数:10
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