Responsiveness of Neuropathy Symptom and Change (NSC) score components in inotersen treatment of hereditary transthyretin amyloidosis polyneuropathy

Objective: To report the impact of inotersen, a transthyretin-directed antisense oligonucleotide indicated for treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis, on neuropathy symptoms and change (NSC) scores in patients with hATTR amyloidosis as an exploratory outcome in a global, randomized, double-blind, placebo-controlled phase 3 study (NEURO-TTR, NCT01737398). Background: hATTR amyloidosis is a rare, progressive, fatal disease that manifests with a buildup of transthyretin (TTR) protein in major organ systems, resulting in organ failure. Inotersen demonstrated significant benefit in the NEURO-TTR co-primary end points: modified Neuropathy Impairment Score +7 (mNIS+7) and the Norfolk Quality of Life–Diabetic Neuropathy questionnaire (Norfolk QoL-DN). The NSC score is a standardized measure of motor, sensory, and autonomic symptoms in generalized polyneuropathy useful for the conduct of clinical practice, epidemiology surveys, and therapeutic trials. The NSC is used to quantitate and assess the distribution and severity of muscle weakness, sensory symptoms, pain symptoms, and autonomic symptoms. Design/Methods: Adults with stage 1/2 hATTR amyloidosis were randomized (2:1) and received 300 mg weekly subcutaneous doses of inotersen or placebo for 15 months. The NSC score (total and individual domains) was assessed in tandem with the primary study end points at 9 and 15 months. Results: A total of 172 patients were evaluated. Compared with placebo, inotersen-treated patients experienced significant improvement in NSC total score from baseline to 9 months (least-square mean [LSM] difference, −3.28; 95% CI, −5.70 to −0.86; P = 0.008) and 15 months (LSM difference, −6.33; 95% CI, −9.12 to −3.55; P Conclusions: Inotersen improved neuropathic symptoms in patients with hATTR amyloidosis. Results are consistent with previously reported benefits in neuropathy composite score (mNIS+7) and in patient-reported neuropathy quality of life (Norfolk QoL-DN). Disclosure: Dr. Dyck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Coelho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam and Biogen. Dr. Coelho has received research support from Pfizer, Ionis and Alnylam. Dr. Waddington Cruz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc., Genzyme/Sanofi, and Pfizer. Dr. Brannagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols, Ionis, Alnylam, and CSL Behring. Dr. Brannagan has received research support from Ionis, Alnyalm, Viromed, Catalyst, Pharnext, Novartis, Grifols. Dr. Khella has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics and Alnylam Pharmaceuticals. Dr. Khella has received research support from Akcea Therapeutics. Dr. Karam has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea, Alexion, Alnyalm, Biogen, CSL Behring, Cytokinetics, Genzyme, Guidepoint, GLG. Dr. Karam has received research support from Genzyme. Dr. Berk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea, Alnylam. Dr. Polydefkis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis, Alnylam, Vertex, Chromocell. Dr. Polydefkis has received compensation for serving on the Board of Directors of Travel-Ionis and Pfizer. Dr. Polydefkis has received research support from Pfizer, Ionis, and Alnylam . Dr. Kincaid has received research support from Ionis Pharmaceuticals. Dr. Wiesman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Wiesman has received research support from Ionis and Alnylam. Dr. Litchy has received research support from Alnylum and IONIS. Dr. Mauermann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with IONIS and Ackea. Dr. Mauermann has received research support from IONIS and Alnylam. Dr. Ackermann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis, Akcea, Myotonic Dystrophy Foundation. Dr. Baker has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. Dr. Jung, PhD has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Guthrie has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Pollock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. Dr. Dyck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam and Ionis.