Inotersen treatment for patients with Hereditary transthyretin amyloidosis

Merrill Benson, Márcia Waddington-Cruz, John L. Berk, Michael Polydefkis, Peter J. Dyck, Annabel K. Wang, Violaine Planté-Bordeneuve, Fabio A. Barroso, Giampaolo Merlini, Laura Obici, Morton Scheinberg, Thomas H. Brannagan, William J. Litchy, Carol Whelan, Brian M. Drachman, David Adams, Stephen B. Heitner, Isabel Conceição, Hartmut H. Schmidt, Giuseppe VitaJosep M. Campistol, Josep Gamez, Peter D. Gorevic, Edward Gane, Amil M. Shah, Scott D. Solomon, Brett P. Monia, Steven G. Hughes, T. Jesse Kwoh, Bradley W. McEvoy, Shiangtung W. Jung, Brenda F. Baker, Elizabeth J. Ackermann, Morie A. Gertz, Teresa Coelho

Research output: Contribution to journalArticle

142 Citations (Scopus)

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 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. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398).

Original languageEnglish (US)
Pages (from-to)22-31
Number of pages10
JournalNew England Journal of Medicine
Volume379
Issue number1
DOIs
StatePublished - Jul 5 2018

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Familial Amyloidosis
Prealbumin
Placebos
Quality of Life
Therapeutics
Diabetic Neuropathies
Glomerulonephritis
Amyloid
Confidence Intervals
Amyloidosis, Hereditary, Transthyretin-Related
Polyneuropathies
Antisense Oligonucleotides
Subcutaneous Injections
Nervous System Diseases
Least-Squares Analysis
Cardiomyopathies
Thrombocytopenia
Nucleotides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Benson, M., Waddington-Cruz, M., Berk, J. L., Polydefkis, M., Dyck, P. J., Wang, A. K., ... Coelho, T. (2018). Inotersen treatment for patients with Hereditary transthyretin amyloidosis. New England Journal of Medicine, 379(1), 22-31. https://doi.org/10.1056/NEJMoa1716793

Inotersen treatment for patients with Hereditary transthyretin amyloidosis. / Benson, Merrill; 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, Josep M.; Gamez, Josep; Gorevic, Peter D.; Gane, Edward; Shah, Amil M.; Solomon, Scott D.; Monia, Brett P.; Hughes, Steven G.; Jesse Kwoh, T.; McEvoy, Bradley W.; Jung, Shiangtung W.; Baker, Brenda F.; Ackermann, Elizabeth J.; Gertz, Morie A.; Coelho, Teresa.

In: New England Journal of Medicine, Vol. 379, No. 1, 05.07.2018, p. 22-31.

Research output: Contribution to journalArticle

Benson, M, Waddington-Cruz, M, Berk, JL, Polydefkis, M, Dyck, PJ, Wang, AK, Planté-Bordeneuve, V, Barroso, FA, Merlini, G, Obici, L, Scheinberg, M, Brannagan, TH, Litchy, WJ, Whelan, C, Drachman, BM, Adams, D, Heitner, SB, Conceição, I, Schmidt, HH, Vita, G, Campistol, JM, Gamez, J, Gorevic, PD, Gane, E, Shah, AM, Solomon, SD, Monia, BP, Hughes, SG, Jesse Kwoh, T, McEvoy, BW, Jung, SW, Baker, BF, Ackermann, EJ, Gertz, MA & Coelho, T 2018, 'Inotersen treatment for patients with Hereditary transthyretin amyloidosis', New England Journal of Medicine, vol. 379, no. 1, pp. 22-31. https://doi.org/10.1056/NEJMoa1716793
Benson, Merrill ; 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, Josep M. ; Gamez, Josep ; Gorevic, Peter D. ; Gane, Edward ; Shah, Amil M. ; Solomon, Scott D. ; Monia, Brett P. ; Hughes, Steven G. ; Jesse Kwoh, T. ; McEvoy, Bradley W. ; Jung, Shiangtung W. ; Baker, Brenda F. ; Ackermann, Elizabeth J. ; Gertz, Morie A. ; Coelho, Teresa. / Inotersen treatment for patients with Hereditary transthyretin amyloidosis. In: New England Journal of Medicine. 2018 ; Vol. 379, No. 1. pp. 22-31.
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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 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. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398).",
author = "Merrill Benson and M{\'a}rcia Waddington-Cruz and Berk, {John L.} and Michael Polydefkis and Dyck, {Peter J.} and Wang, {Annabel K.} and Violaine Plant{\'e}-Bordeneuve and Barroso, {Fabio A.} and Giampaolo Merlini and Laura Obici and Morton Scheinberg and Brannagan, {Thomas H.} and Litchy, {William J.} and Carol Whelan and Drachman, {Brian M.} and David Adams and Heitner, {Stephen B.} and Isabel Concei{\cc}{\~a}o and Schmidt, {Hartmut H.} and Giuseppe Vita and Campistol, {Josep M.} and Josep Gamez and Gorevic, {Peter D.} and Edward Gane and Shah, {Amil M.} and Solomon, {Scott D.} and Monia, {Brett P.} and Hughes, {Steven G.} and {Jesse Kwoh}, T. and McEvoy, {Bradley W.} and Jung, {Shiangtung W.} and Baker, {Brenda F.} and Ackermann, {Elizabeth J.} and Gertz, {Morie A.} and Teresa Coelho",
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T1 - Inotersen treatment for patients with Hereditary transthyretin amyloidosis

AU - Benson, Merrill

AU - Waddington-Cruz, Márcia

AU - Berk, John L.

AU - Polydefkis, Michael

AU - Dyck, Peter J.

AU - Wang, Annabel K.

AU - Planté-Bordeneuve, Violaine

AU - Barroso, Fabio A.

AU - Merlini, Giampaolo

AU - Obici, Laura

AU - Scheinberg, Morton

AU - Brannagan, Thomas H.

AU - Litchy, William J.

AU - Whelan, Carol

AU - Drachman, Brian M.

AU - Adams, David

AU - Heitner, Stephen B.

AU - Conceição, Isabel

AU - Schmidt, Hartmut H.

AU - Vita, Giuseppe

AU - Campistol, Josep M.

AU - Gamez, Josep

AU - Gorevic, Peter D.

AU - Gane, Edward

AU - Shah, Amil M.

AU - Solomon, Scott D.

AU - Monia, Brett P.

AU - Hughes, Steven G.

AU - Jesse Kwoh, T.

AU - McEvoy, Bradley W.

AU - Jung, Shiangtung W.

AU - Baker, Brenda F.

AU - Ackermann, Elizabeth J.

AU - Gertz, Morie A.

AU - Coelho, Teresa

PY - 2018/7/5

Y1 - 2018/7/5

N2 - 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. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398).

AB - 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. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398).

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