Impact of Inotersen on Subgroups of Patients with Hereditary TTR Amyloidosis: Results from a Double-Blind Placebo-Controlled Trial

Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, systemic, progressive, and fatal condition in which misfolded proteins, mainly produced in the liver, deposit in muscle and organ tissues leading to symptoms of peripheral neuropathy, and possible cardiomyopathy and autonomic neuropathy. Primary results from the NEUTO-TTR trial indicated that patients with hATTR amyloidosis who received 65 weeks of treatment with inotersen had better preservation of quality of life (QOL), as measured by the Norfolk QOL-Diabetic Neuropathy (DN) Questionnaire total score and the physical component summary score of the SF-36v2® Health Survey (SF-36v2), than did patients who received placebo. Whether the benefits of inotersen on domains of QOL differ across subgroups of patients has not been previously addressed.

Objective: To examine the efficacy of inotersen for preserving QOL in subgroups of patients with hATTR amyloidosis, defined by time of disease onset (early or late) and ambulatory stage (Stage 1 or Stage 2).

Methods: Data come from the NEURO-TTR trial, a multicenter, multinational, double-blind trial (NCT01737398) of 172 adults with hATTR amyloidosis with polyneuropathy who received 65 weeks of treatment with either the investigational drug inotersen, which is an antisense oligonucleotide, or matching placebo. The Norfolk QOL-DN and SF-36v2 were administered to patients at baseline, week 35, and week 66. The Norfolk QOL-DN is a 35-item measure which captures neuropathic-related QOL, representing five domains: activities of daily living, autonomic neuropathy, large fiber neuropathy/physical functioning, small fiber neuropathy, and neuropathic symptoms. The SF-36v2 is a 36-item measure which captures generic health-related QOL, representing eight domains: physical functioning, role limitations due to physical health (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional health (role-emotional), and mental health. Patient subgroups were defined by: (1) patients' time of symptom onset: whether symptoms first occurred early (at or before age 50) or late (after age 50) in life; and (2) patients' disease severity, as defined by ambulatory disability - Stage 1 (walking without assistance) or Stage 2 (walking with assistance, such as a cane or walker). Mixed-effects repeated-measures models tested treatment differences (inotersen vs. placebo) in changes of mean Norfolk QOL-DN and SF-36v2 domain scores from baseline to week 66 for each patient subgroup.

Results: Inotersen was more effective than placebo for preserving QOL in patients with early onset of symptoms: treatment differences in scores were statistically significant (p<0.05) for four of the five Norfolk QOL-DN domains (all except small fiber neuropathy) and for all eight SF-36v2 domains. In patients with late onset of symptoms: statistically significant treatment differences in scores were observed for no Norfolk QOL-DN domains and only one of eight SF-36v2 domains (physical functioning). Inotersen was more effective than placebo for preserving QOL in patients with Stage 1 severity, treatment differences were statistically significant for three of the five Norfolk QOL-DN domains (all except autonomic neuropathy and small fiber neuropathy) and for five of eight SF-36v2 domains (all except general health, vitality, and mental health). In patients with Stage 2 severity, significant treatment differences in scores were observed for only one Norfolk QOL-DN domain (activities of daily living) and no SF-36v2 domains.

Conclusion: Following 66 weeks of treatment, inotersen was more effective than placebo for preserving QOL in patients with hATTR amyloidosis who had early onset of symptoms or who were in Stage 1 of disease severity. Preserving QOL in patients with early onset is critical, as many of these patients are likely to be in the work force, raising children, and leading active lives. The benefits seen for patients in Stage 1 disease severity point to the crucial importance of early diagnosis and treatment, as there may be a window in which treatment can preserve QOL in patients with hATTR amyloidosis prior to the late progressive stages.