Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial
Abstract
Introduction/Aims: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN) progressively affects patients' functionality and compromises health-related quality of life (HRQL). The aim of this study was to quantify the projected long-term treatment effects of inotersen vs placebo on HRQL measures. Methods: The inotersen phase 2/3 randomized, double-blind, placebo-controlled trial NEURO-TTR (NCT01737398, 65 weeks) and its subsequent open-label extension (OLE; NCT02175004, 104 weeks) included 172 (112 inotersen and 60 placebo) patients. Placebo double-blind period and overall inotersen-inotersen (double-blind/OLE) treatment period (170 weeks) data were used to extrapolate the long-term placebo-placebo effect using mixed-effects models with repeated measures. Changes from baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) and 36-Item Short Form Health Survey version 2 (SF-36v2) in hATTR-PN were estimated. Differences in changes were compared between the inotersen-inotersen and extrapolated placebo-placebo arms. Results: Inotersen-inotersen patients maintained their HRQL with an observed change ranging from 10.3% improvement (Norfolk QoL-DN item “Pain kept you awake at night”) to 11.6% deterioration (SF-36v2 Activities of Daily Living subdomain). The extrapolated placebo-placebo results suggest greater deterioration over time compared with inotersen-inotersen treatment on Norfolk QoL-DN total score (23.6; 95% confidence interval [CI], 8.9-38.3; P < .01), Activities of Daily Living (4.6; 95% CI, 2.0-7.3; P < .001), and “Pain kept you awake at night” (1.2; 95% CI, 0.4-1.9; P < .01). Similarly, greater deterioration was expected for the SF-36v2 Physical Component Summary (8.0; 95% CI, 3.2-12.8, P < .01), Bodily Pain (7.8; 95% CI, 2.0-13.5; P < .01), and Physical Functioning (10.6; 95% CI, 5.5-15.6; P < .0001). Discussion: Long-term (>3 years) inotersen treatment was associated with slowing and, in some domains, halting of deterioration in key HRQL outcome measures, particularly physical functioning and pain.
My Take
Hereditary transthyretin amyloidosis with polyneuropathy is a progressive, debilitating condition that profoundly affects patients' daily lives. While clinical trials often focus on biomarkers and disease progression scales, what ultimately matters to patients is how they feel and function in their everyday lives. This study took a deep look at quality of life outcomes over the long term in patients treated with inotersen, an antisense oligonucleotide therapy that reduces production of the misfolded transthyretin protein responsible for the disease.
The analysis leveraged data from both the randomized NEURO-TTR trial and its open-label extension, giving us a window into outcomes over years of treatment rather than just months. What we found was encouraging: patients who received continuous inotersen treatment maintained quality of life improvements, while those who switched from placebo to active treatment showed meaningful gains once they began therapy. The Norfolk QOL-DN questionnaire captures domains that resonate with patients—physical functioning, symptoms, activities of daily living—and seeing sustained benefits across these areas speaks to the real-world value of treatment.
From a methodological standpoint, this work illustrates how we can extract meaningful insights from open-label extension data. The absence of a contemporaneous control arm in the extension phase requires careful interpretation, but by tracking trajectories over time and comparing continuous versus delayed treatment groups, we can build a coherent picture of long-term treatment effects. For a progressive disease where the alternative is relentless decline, demonstrating stability or improvement in quality of life represents a clinically meaningful outcome.