Pharmacokinetics of Patisiran, the First Approved RNA Interference Therapy in Patients With Hereditary Transthyretin‐Mediated Amyloidosis

Abstract Hereditary transthyretin‐mediated (hATTR) amyloidosis is a rare, inherited, progressively debilitating, and often fatal disease caused by deposition of mutated transthyretin (TTR) protein. Patisiran is an RNA interference therapeutic comprising a novel small interfering ribonucleic acid (ALN‐18328) formulated with 2 novel lipid excipients, DLin‐MC3‐DMA and PEG 2000 ‐C‐DMG, in a lipid nanoparticle targeted to inhibit hepatic TTR synthesis. Here we report the pharmacokinetics (PK) of ALN‐18328, DLin‐MC3‐DMA, and PEG 2000 ‐C‐DMG from a phase 2 multiple‐ascending‐dose study and its open‐label extension (OLE) in patients with hATTR amyloidosis. Twenty‐nine patients received 2 intravenous infusions of patisiran of 0.01, 0.05, 0.15, or 0.3 mg/kg at 3‐ or 4‐week intervals; of these, 27 patients received 0.3 mg/kg once every 3 weeks over 24 months in the OLE study. Plasma PK profiles of ALN‐18328 and DLin‐MC3‐DMA exhibited 2 phases, the first characterized by a short distribution half‐life and the second by a minor peak and relatively long terminal elimination half‐life. PK exposures to 3 analytes increased proportionally across the dose range of 0.01 to 0.3 mg/kg. For ALN‐18328, mean terminal elimination half‐life was 3.2 days, mean total clearance was 3.0 mL/h/kg, and urinary excretion was negligible. All 3 analytes exhibited stable PK profiles with chronic dosing over 2 years. The 2‐ to 3‐fold plasma accumulation (AUC τ ) of ALN‐18328 at steady state is attributable to the association of ALN‐18328 with the cationic lipid DLin‐MC3‐DMA. There was no appreciable accumulation of PEG 2000 ‐C‐DMG.