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Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis
Open accessAbstract
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 ClinicalTrials.gov number, NCT01737398 .).
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Cites
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., Tournev, I., Schmidt, H. H., Coelho, T., Berk, J. L., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716153 · Cited by 3,047
Self-citationMolecular Mechanisms of Amyloidosis
Merlini, G., & Bellotti, V. (2003) · New England Journal of Medicine · doi:10.1056/nejmra023144 · Cited by 1,920
Self-citationTafamidis for transthyretin familial amyloid polyneuropathy: A randomized, controlled trial
Coelho, T., Maia, L. F., Martins da Silva, A., Waddington Cruz, M., Planté-Bordeneuve, V., Lozeron, P., Suhr, O. B., Campistol, J. M., Conceição, I. M., Schmidt, H. H.-J., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e3182661eb1 · Cited by 816
Self-citationGuideline of transthyretin-related hereditary amyloidosis for clinicians
Ando, Y., Coelho, T., Berk, J. L., Cruz, M. W., Ericzon, B.-G., Ikeda, S.-I., Lewis, W. D., Obici, L., Planté-Bordeneuve, V., Rapezzi, C., et al. (2013) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-8-31 · Cited by 719
Self-citationRepurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial
Berk, J. L., Suhr, O. B., Obici, L., Sekijima, Y., Zeldenrust, S. R., Yamashita, T., Heneghan, M. A., Gorevic, P. D., Litchy, W. J., Wiesman, J. F., et al. (2013) · JAMA · doi:10.1001/jama.2013.283815 · Cited by 708
Self-citationFamilial amyloid polyneuropathy
Planté-Bordeneuve, V., & Said, G. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70246-0 · Cited by 645
Self-citationTransthyretin-related amyloidoses and the heart: a clinical overview
Rapezzi, C., Quarta, C. C., Riva, L., Longhi, S., Gallelli, I., Lorenzini, M., Ciliberti, P., Biagini, E., Salvi, F., & Branzi, A. (2010) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2010.67 · Cited by 350
Sekijima, Y. (2015) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2014-308724 · Cited by 332
Dyck, P. J., Kratz, K. M., Lehman, K. A., Karnes, J. L., Melton, L. J., O'Brien, P. C., Litchy, W. J., Windebank, A. J., Smith, B. E., Low, P. A., et al. (1991) · Neurology · doi:10.1212/wnl.41.6.799 · Cited by 315
Self-citationEriczon, B.-G., Wilczek, H. E., Larsson, M., Wijayatunga, P., Stangou, A., Pena, J. R., Furtado, E., Barroso, E., Daniel, J., Samuel, D., et al. (2015) · Transplantation · doi:10.1097/tp.0000000000000574 · Cited by 314
Cited by
Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., Deswal, A., Drazner, M. H., Dunlay, S. M., Evers, L. R., et al. (2022) · Circulation · doi:10.1161/cir.0000000000001063 · Cited by 4,922
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., Tournev, I., Schmidt, H. H., Coelho, T., Berk, J. L., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716153 · Cited by 3,047
Self-citation2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure
Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., Deswal, A., Drazner, M. H., Dunlay, S. M., Evers, L. R., et al. (2022) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.12.012 · Cited by 2,862
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
Gillmore, J. D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M. L., Seitzer, J., O’Connell, D., Walsh, K. R., Wood, K., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2107454 · Cited by 1,801
Self-citationFeldman, E. L., Callaghan, B. C., Pop-Busui, R., Zochodne, D. W., Wright, D. E., Bennett, D. L., Bril, V., Russell, J. W., & Viswanathan, V. (2019) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0092-1 · Cited by 1,697
Metadata
- Authors
- Benson, M. D., Waddington-Cruz, M., Berk, J. L., Polydefkis, M., Dyck, P. J., Wang, A. K., Planté-Bordeneuve, V., Barroso, F. A., Merlini, G., Obici, L., Scheinberg, M., Brannagan, T. H., Litchy, W. J., Whelan, C., Drachman, B. M., Adams, D., Heitner, S. B., Conceição, I., Schmidt, H. H., Vita, G., Campistol, J. M., Gamez, J., Gorevic, P. D., Gane, E., Shah, A. M., Solomon, S. D., Monia, B. P., Hughes, S. G., Kwoh, T. J., McEvoy, B. W., Jung, S. W., Baker, B. F., Ackermann, E. J., Gertz, M. A., & Coelho, T.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-07-05
- Volume
- 379
- Issue
- 1
- Pages
- 22-31
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2809989268
- Cited by
- 1,452
- References
- 26
- FWCI
- 50.77
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Benson, M. D., Waddington-Cruz, M., Berk, J. L., Polydefkis, M., Dyck, P. J., Wang, A. K., Planté-Bordeneuve, V., Barroso, F. A., Merlini, G., Obici, L., Scheinberg, M., Brannagan, T. H., Litchy, W. J., Whelan, C., Drachman, B. M., Adams, D., Heitner, S. B., Conceição, I., Schmidt, H. H., . . . Coelho, T. (2018). Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. New England Journal of Medicine. https://doi.org/10.1056/nejmoa1716793
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