Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis

Teresa Coelho, Aaron Yarlas, Marcia Waddington-Cruz, Michelle K White, Asia Sikora Kessler, Andrew Lovley, Michael Pollock, Spencer Guthrie, Elizabeth J Ackermann, Steven G Hughes, Chafic Karam, Sami Khella, Morie Gertz, Giampaolo Merlini, Laura Obici, Hartmut H Schmidt, Michael Polydefkis, P James B Dyck, Thomas H Brannagan Iii, Isabel Conceição, Merrill D Benson, John L Berk, Teresa Coelho, Aaron Yarlas, Marcia Waddington-Cruz, Michelle K White, Asia Sikora Kessler, Andrew Lovley, Michael Pollock, Spencer Guthrie, Elizabeth J Ackermann, Steven G Hughes, Chafic Karam, Sami Khella, Morie Gertz, Giampaolo Merlini, Laura Obici, Hartmut H Schmidt, Michael Polydefkis, P James B Dyck, Thomas H Brannagan Iii, Isabel Conceição, Merrill D Benson, John L Berk

Abstract

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo.

Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66.

Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm.

Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.

Keywords: Physical function; Polyneuropathy; Quality of life; Rare disease; Transthyretin amyloidosis.

Conflict of interest statement

Coelho, Prothena: consultancy, honoraria; Ionis: consultancy, other: investigator; Alnylam: consultancy, honoraria, other: investigator; Pfizer: consultancy, honoraria, other: investigator. Yarlas, Lovley, Sikora Kessler, and White are employees of Optum, which received payment from Akcea Therapeutics and Ionis Pharmaceuticals Inc. to conduct these analyses and develop this manuscript. Waddington Cruz: Ionis: honoraria; Genzyme/Sanofi: honoraria; Pfizer: honoraria. Pollock is an employee of and owns stock in Akcea Therapeutics. Guthrie was an employee of and owned stock in Akcea Therapeutics. Ackermann, Akcea: consultancy. Hughes is a former employee of and owns stock in Ionis Pharmaceuticals, Inc. Karam, Acceleron: consultancy; Akcea: consultancy; Alexion: consultancy; Alnylam: consultancy; Biogen: consultancy; Cytokinetics: consultancy; CSL Behring: consultancy, Sanofi Genzyme: consultancy. Khella: Akcea: consultancy; Alnylam: consultancy; Pfizer: consultancy. Gertz: Janssen: consultancy; Teva: consultancy; Spectrum: consultancy, honoraria; Alnylam: honoraria; Ionis: honoraria; Amgen: consultancy; Annexon: consultancy; Prothena: honoraria; research to practice: consultancy; Apellis: consultancy; Celgene: consultancy; Abbvie: consultancy; Medscape: consultancy; Physicians Education Resource: consultancy. Merlini: no relationships to disclose. Obici, has received speaking and consulting fees from Akcea, Pfizer and Alnylam. Schmidt, Akcea: consultancy; Alnylam: consultancy; Pfizer: consultancy. Polydefkis, Pfizer: honoraria; Alnylam: honoraria. Dyck, Ionis: consultancy; Alnylam: consultancy. Brannagan, Alnylam: honoraria, other: investigator, Speakers Bureau; Ionis: honoraria, consultancy, speaking, other: investigator. Conceição, Ionis: other: investigator; Alnylam: consultancy, honoraria, other: investigator; Pfizer: consultancy, honoraria, other: investigator. Benson, Ionis: other: investigator, research funding. Berk, Ionis: honoraria, other: investigator; Alnylam: honoraria, other: investigator; Pfizer: other: investigator.

Figures

Fig. 1
Fig. 1
Change in mean Norfolk QOL-DN Domain Scores from baseline to week 66 by treatment arm. ADL activities of daily living, PF physical functioning. Error bars represent standard errors *p < 0.05, †p < 0.01, ‡p < 0.001
Fig. 2
Fig. 2
Change in mean SF-36v2 Domain Scores from baseline to week 66 by treatment arm. Error bars represent standard errors *p < 0.05, †p < 0.01, ‡p < 0.001
Fig. 3
Fig. 3
Responder analysis: percentage of patients with better or same Norfolk QOL-DN Scores at week 66 relative to baseline by treatment arm. ADL activities of daily living, QOL Quality of Life, PF physical functioning. Better/same scores defined as less than 0.5 of a standard deviation higher at week 66 than at baseline *p < 0.05, †p < 0.01, ‡p < 0.001
Fig. 4
Fig. 4
Responder analysis: percentage of patients with better/same SF-36v2 Scores at week 66 relative to baseline by treatment arm. BP bodily pain, GH general health, MH mental health, MCS mental component summary, PCS physical component summary, PF physical functioning, RE role-emotional, RP role-physical, SF social functioning, VT vitality. Better/same scores defined as greater than the minimally important change (MIC) threshold value lower at week 66 than at baseline *p < 0.05, †p < 0.01, ‡p < 0.001

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