OBJECTIVES: hATTR is a rare, progressive, fatal disease caused by systemic accumulation of transthyretin (TTR) amyloid, which causes significant morbidity and progressive decline in quality of life (QOL). Here we report safety and efficacy of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, in patients with hATTR polyneuropathy.

METHODS: NEURO-TTR (NCT01737398) is a global, randomized, double-blind, placebo-controlled phase 3 study. Adults (n=172) with Stage 1 or 2 hATTR polyneuropathy were randomized (2:1) and treated with 300-mg weekly subcutaneous inotersen or placebo for 15 months. The primary end points were change from baseline to week 66 in the Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QOL-DN) total score and modified Neuropathy Impairment Score+7 (mNIS+7). The SF-36v2 Health Survey (SF-36v2) score was an exploratory outcome.

RESULTS: At baseline, 69% of patients were male; mean age was 59 years. Inotersen treatment compared with placebo resulted in significant improvement in both primary end points based on the difference in mean change from baseline to week 66 [95% CI] in mNIS+7 (–19.73 [–26.43 to –13.03], P<0.0001) and Norfolk QOL-DN (–11.68 [–18.29 to –5.06], P=0.0006) total score. Significant improvement in favor of inotersen compared with placebo was also observed at week 66 in the SF-36v2 Physical Component Summary score. Fifty percent and 36.5% of inotersen-treated patients improved from baseline to week 66 in Norfolk QOL-DN total score and mNIS+7, respectively. Most adverse events were mild or moderate. Key safety findings of thrombocytopenia and renal events were easily managed and monitored with routine testing. Eighty percent of patients completed the 15-month treatment period, and >95% of patients who completed treatment entered the open-label extension study.

CONCLUSIONS: Inotersen demonstrated highly significant benefits in QOL and prevention of neurological disease progression in patients with hATTR polyneuropathy.