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

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 PEG₂₀₀₀ -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 PEG₂₀₀₀ -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 PEG₂₀₀₀ -C-DMG.