Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR

Abstract

Introduction: Patients with hereditary transthyretin amyloidosis associated with polyneuropathy (ATTRv-PN) experience deterioration in health-related quality of life (HRQOL) as the disease progresses. Findings from the randomized placebo-controlled phase III NEURO-TTR study showed treatment benefit of inotersen, an antisense oligonucleotide, for preserving or improving HRQOL after 65 weeks of treatment. The current analysis examines longitudinal trends in specific aspects of HRQOL, including polyneuropathy symptoms, daily activities, and physical, role, and social functioning in patients with ATTRv-PN receiving long-term treatment in a follow-up open-label extension (OLE) study.

Methods: One-hundred thirty-five patients with ATTRv-PN were enrolled in an ongoing 5-year OLE study following completion of NEURO-TTR. Eighty-five patients received continuous weekly treatment with inotersen in both studies (inotersen-inotersen group), while 50 patients switched from placebo to inotersen at OLE study baseline (placebo-inotersen group). Descriptive analyses of changes in domain scores and item responses through week 104 of the OLE study were conducted for measures of neuropathy-related and generic HRQOL: Norfolk QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2), respectively.

Results: For both inotersen-inotersen and placebo-inotersen groups, all Norfolk QOL-DN and most SF-36v2 domain scores remained stable from OLE baseline through week 104. Differences in HRQOL between the two groups at OLE baseline were sustained through week 104. Analysis of item responses from NEURO-TTR baseline to OLE study week 104 (170 weeks) for the inotersen-inotersen group found no notable increases in the proportion of patients reporting substantial impairments across a wide variety of symptoms, daily activities, and functioning.

Conclusion: Long-term treatment with inotersen preserved HRQOL for patients with ATTRv-PN for periods of up to 3 years. The gap in HRQOL between those who had previously received inotersen or placebo in NEURO-TTR did not close by week 104 of the OLE phase, indicating the importance of early treatment for maintaining HRQOL in these patients.

Trial registration: ClinicalTrials.gov Identifiers NCT01737398 for NEURO-TTR study; NCT02175004 for OLE study INFOGRAPHIC.

Keywords: Clinical trial; Hereditary transthyretin amyloidosis; Inotersen; Open-label extension trial; Physical function; Polyneuropathy; Quality of life; Rare disease.

© 2021. The Author(s).

Figures

Fig. 1

Mean change in Norfolk QOL-DN domain scores from NEURO-TTR baseline through week 104 of the open-label extension study. i. Activities of daily living domain. ii. Autonomic neuropathy domain. iii. Large fiber neuropathy/physical functioning domain. iv. Small fiber neuropathy domain. v. Neuropathic symptoms domain. OLE open-label extension, SE standard error

Fig. 2

Mean change in SF-36v2 domain scores from NEURO-TTR baseline through week 104 of the open-label extension study. i. Physical functioning domain. ii. Role-physical domain. iii. Bodily pain domain. iv. General health domain. v. Vitality domain. vi. Social functioning domain. vii. Role-emotional domain. viii. Mental health domain. OLE open-label extension, SE standard error

Fig. 3

Percentage of patients in the inotersen-inotersen group showing substantial impairment on Norfolk QOL-DN items from NEURO-TTR baseline through week 104 of the Open-Label Extension Study. i. Items from the activities of daily living domain. ii. Items from the large fiber neuropathy/physical functioning domain. iii. Items from the small fiber neuropathy domain. iv. Items from the autonomic neuropathy and neuropathic symptoms domains. OLE, open-label extension; SE, standard error

Fig. 4

Percentage of patients in the inotersen-inotersen group showing substantial impairment on SF-36v2 items from NEURO-TTR baseline through week 104 of the Open-Label Extension Study. i. Items on walking/climbing from the physical functioning domain. ii. Items on daily activities from the physical functioning domain. iii. Items from the role-physical domain. iv. Items from the bodily pain and social functioning domains. OLE open-label extension, SE standard error