OBJECTIVES:  Hereditary ATTR (hATTR) amyloidosis is a rapidly progressive, life-threatening disease caused by a mutation in the transthyretin (TTR) gene, resulting in sensory, motor and autonomic neuropathies, and cardiac dysfunction. The aggressive disease course can lead to significant morbidity, disability, and mortality. The objective of this abstract is to describe the safety and efficacy of patisiran, an investigational RNAi therapeutic inhibiting hepatic TTR protein production, from its Phase 2 open-label extension (OLE, NCT01961921) study. METHODS: Patients with hATTR amyloidosis with polyneuropathy who previously received patisiran were eligible to continue dosing (0.3mg/kg IV) every 3 weeks for two years. In addition to long-term safety, the study assessed the difference in neuropathy impairment (mNIS+7) from baseline, and other relevant measures. mNIS+7 is a 304-point composite measure of neuropathy impairment including: neurologic exam of the limbs and cranial nerves; electrophysiologic measures of nerve fiber function; quantitative sensory testing (QST); and autonomic function. RESULTS: Twenty-seven patients enrolled, median age: 64 years and 74% patients with V30M mutation, the predominant mutation in this disease. Patisiran was generally well tolerated, 6 patients experienced SAEs unrelated to study drug; flushing (25.9%) and infusion-related reactions (18.5%) were the most common related AEs (all mild) and did not result in any discontinuations. Following > 24 months of patisiran, patients experienced sustained mean serum TTR lowering of ~80% (mean maximal knockdown: 93%). Preliminary 24-month data (n=24) suggests improvement in neuropathy with a mean 6.7-point decrease in mNIS+7 driven by a mean 7.7-point change in sensation (measured by QST). Overall, 17/24 patients (71%) were noted to have no change or an improvement in mNIS+7 at 24 months compared to baseline. CONCLUSIONS: Preliminary 24-month data demonstrated long-term administration of patisiran was generally well-tolerated, and supports the therapeutic hypothesis that TTR knockdown can potentially halt or improve neuropathy progression in hATTR amyloidosis patients.