Phase 2 open-label extension study of patisiran, an investigational RNAi therapeutic for the treatment of familial amyloid polyneuropathy (S9.003)

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 FAP patients showed >80[percnt] sustained knockdown of serum TTR with a generally favorable safety profile. Methods: The Phase 2 open-label extension (OLE) study of patisiran in FAP patients was initiated in 2013. The primary objective is to evaluate the safety of intravenous patisiran 0.3 mg/kg administered q3w. Secondary objectives include assessment of TTR levels, mNIS+7 neurologic impairment score, and quality of life (QOL). Results: Twenty-seven patients were enrolled; the mean duration of treatment was 7 months (range 3-12), with 282 doses administered (median of 11 doses/patient). Chronic dosing has been generally well tolerated. Two patients experienced serious adverse events regarded as being unrelated to study drug. Mild infusion-related reactions that did not cause discontinuation were observed in 14.8[percnt] of the patients. No clinically significant changes in liver function, renal function or hematological parameters were observed. Sustained TTR lowering of at least 80[percnt] for over 9 months was achieved, with nadir of up to 89.6[percnt] between doses. Neurologic impairment was stable after 6 months of patisiran in patients with or without concurrent TTR tetramer stabilizers. A mean decrease from baseline in mNIS+7 of 0.95 points (N=19) observed in this study compared favorably to the estimated increase of 7-10 points in mNIS+7 at 6 months from prior studies. Stabilization of QOL, neurologic and cardiac assessments was also observed. Conclusion: The 6-month data from the ongoing patisiran Phase 2 OLE study show preliminary evidence of safety and disease stabilization in FAP patients. Dosing continues and 12-month data will be presented. This study is supported by Alnylam Pharmaceuticals. Disclosure: Dr. Coelho has nothing to disclose. Dr. Suhr has nothing to disclose. Dr. Conceicao has received personal compensation for activities with GLG Councils. Dr. Waddington Cruz has nothing to disclose. Dr. Schmidt has nothing to disclose. Dr. Juan has nothing to disclose. Dr. Campistol has received personal compensation for activities with Wyeth Pharmaceuticals, Astellas Pharma, Roche, and Novartis as a consultant. Dr. Pouget has nothing to disclose. Dr. Berk has received personal compensation for activities with Banyu Pharmaceutical Co, Ltd. as a lecturer. Dr. Falzone has nothing to disclose. Dr. White has nothing to disclose. Dr. Bettencourt has nothing to disclose. Dr. Cehelsky holds stock and/or stock options. Dr. Nochur holds stock and/or stock options. Dr. Vaishnaw has nothing to disclose. Dr. Gollob has nothing to disclose. Dr. Adams has received personal compensation for activities with Pfizer and ALNYLAM as a speaker and/or a consultant.