Phase 2 Open-Label Extension Study (OLE) of Patisiran, an Investigational RNAi Therapeutic for Familial Amyloid Polyneuropathy (FAP) (S38.003)

Background:Familial amyloid polyneuropathy (FAP) is a progressive, fatal disease caused by deposition of transthyretin (TTR). Patisiran is an investigational systemically administered lipid nanoparticle formulation of a small interfering RNA (siRNA) targeting wild-type and mutant TTR. A Phase 2 trial of patisiran in patients with FAP showed u003e80[percnt] sustained knockdown of serum TTR with a generally favorable safety profile. Methods: The Phase 2 open-label extension (OLE; NCT01961921) study of patisiran in patients with FAP was initiated in 2013. The primary objective is to evaluate the safety of intravenous patisiran 0.3 mg/kg administered q3w for 2 years. Secondary objectives evaluated every 6 months include assessment of TTR levels, mNIS+7 neurologic impairment score, and quality of life (QOL).Results: Twenty-seven patients were enrolled; median age 64 years (range: 29-77 years). Chronic dosing with patisiran has been generally well tolerated out to 21 months. Five patients experienced serious adverse events unrelated to study drug. Flushing and infusion-related reactions were observed in 22.2[percnt] and 18.5[percnt] of the patients, respectively; these were mild in severity, and did not result in any discontinuations. Sustained mean serum TTR lowering of approximately 80[percnt] for over 18 months was achieved, with mean maximal knockdown of 91[percnt]. Neurologic impairment scores were stable at 12 months with a mean change in mNIS+7 and NIS of -3.1 and 0.2 points, respectively; this compares favorably to the 10-18 point increase in neurologic impairment scores estimated at 12 months from prior FAP studies in a patient population with similar baseline NIS. Additional clinical measures, including EQ-5D QOL, remained unchanged at 12 months.Conclusion: Twelve-month data from this patisiran Phase 2 OLE study are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression. As of Oct 2015, dosing continues in 26 patients; 18 -month results will be presented. Disclosure: Dr. Adams has received research support from Alnylam Pharmaceuticals. Dr. Coelho has received research support from Alnylam Pharmaceuticals. Dr. Conceicao has received research support from Alnylam Pharmaceuticals. Dr. Waddington Cruz has received research support from Alnylam Pharmaceuticals. Dr. Schmidt has received research support from Alnylam Pharmaceuticals. Dr. Juan has received research support from Alnylam Pharmaceuticals. Dr. Josep Campistol has received research support from Alnylam Pharmaceuticals. Dr. Pouget has nothing to disclose. Dr. Berk has received research support from Alnylam Pharmaceuticals. Dr. Falzone has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. White has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Bettencourt has received personal compensation for activities with Alnylam Pharmaceuticals as an employee. Dr. Jeff Cehelsky has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Nochur has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Vaishnaw has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Gruis has received personal compensation from Alnylam Pharmaceuticals. Dr. Goolob has received personal compensation for activities with Alnylam Pharmaceuticals. Dr. Suhr has received research support from Alnylam Pharmaceuticals.