Long-Term Efficacy and Safety of Inotersen for Hereditary Transthyretin Amyloidosis: NEURO-TTR Open-Label Extension 2-Year Update (S27.008)

Objective: To provide an update on the long-term efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of transthyretin protein production, in patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy. Background: Patients with hATTR, a rare protein misfolding disorder, experience progressive and debilitating polyneuropathy. A randomized, controlled phase 3 trial (NEURO-TTR; NCT01737398) demonstrated efficacy and safety of inotersen treatment in patients with hATTR polyneuropathy (Benson 2018 NEJM). Design/Methods: Patients who completed NEURO-TTR were eligible to enroll in the ongoing open-label extension (OLE) study (NCT02175004). Assessments included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7), Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN), and adverse events. Results: Of 139 patients who completed NEURO-TTR, 135 (97.1%) enrolled in the OLE. As of 9/15/17, 134 patients had received ≥1 dose of inotersen. Patients were predominantly white (93.3%) and male (69.4%), and 88/134 (65.7%) had both polyneuropathy and cardiac involvement. At OLE baseline, 83/134 (61.9%) patients were ambulatory without assistance, 47/134 (35.1%) required walking aid(s), and 4/134 (3.0%) were unable to walk. Patients who initiated inotersen in the OLE demonstrated slowing of neurologic disease progression by mNIS+7 and Norfolk QoL-DN within 6 months, and patients who had received inotersen for 27 months (15 months in NEURO-TTR + 12 months in the OLE) continued to show benefit. Greater benefit in mNIS+7 and Norfolk QoL-DN was observed in patients treated earlier with inotersen. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure, and no new safety concerns have been identified. This presentation will be updated with data from 2 years of follow-up in the OLE. Conclusions: In the OLE, inotersen treatment slowed hATTR polyneuropathy progression, with greater stabilization observed in patients who initiated inotersen earlier. Disclosure: 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. 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. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. 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. Dyck has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam and Ionis. 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. Plante-Bordeneuve has nothing to disclose. Dr. Berk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea, Alnylam. Dr. Barroso has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Barroso has received research support from Alnylam. Dr. Merlini has nothing to disclose. Dr. Conceicao has nothing to disclose. Dr. Hughes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals Inc. Dr. Kwoh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea Therapeutics. 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. Benson has nothing to disclose. Dr. Gertz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc., Alnylam Pharmaceuticals, and Prothena. 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.