Inotersen treatment for patients with Hereditary transthyretin amyloidosis

Merrill D. 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 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

    156 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. D., 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 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; 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, MD, 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, S, 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 MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK et al. Inotersen treatment for patients with Hereditary transthyretin amyloidosis. New England Journal of Medicine. 2018 Jul 5;379(1):22-31. https://doi.org/10.1056/NEJMoa1716793
    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 ; 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 = "Benson, {Merrill D.} 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 Stephen Heitner 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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    TY - JOUR

    T1 - Inotersen treatment for patients with Hereditary transthyretin amyloidosis

    AU - Benson, Merrill D.

    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

    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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