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 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.

Keywords: RNAi therapeutic; amyloidosis; lipid nanoparticle; patisiran; pharmacokinetics (PK); small interfering ribonucleic acid (siRNA).

Figure 1

Mean plasma concentration‐time profiles of ALN‐18328 (A, B), DLin‐MC3‐DMA (C, D), and PEG₂₀₀₀‐C‐DMG (E, F) after the first dose (left) and second dose (right) of patisiran in patients with hATTR amyloidosis in the phase 2 MAD study. Error bar represents standard deviation. ^aContains data from Suhr et al (2015).33 ALN‐18328, patisiran drug substance (small interfering ribonucleic acid); DLin‐MC3‐DMA, (6Z,9Z,28Z,31Z)‐heptatriaconta‐6,9,28,31‐tetraen‐19‐yl‐4‐(dimethylamino)butanoate; hATTR, hereditary transthyretin‐mediated amyloidosis; MAD, multiple ascending dose; PEG₂₀₀₀‐C‐DMG, α‐(3′‐{[1,2‐di(myristyloxy)proponoxy]carbonylamino}propyl)‐ω‐methoxy, polyoxyethylene; q3w, once every 3 weeks; q4w, once every 4 weeks.

Figure 2

Plasma PK profiles for ALN‐18328 following intravenous administration of patisiran 0.3 mg/kg once every 3 weeks for 24 months of treatment in the OLE study. (A) Mean ALN‐18328 plasma concentration‐time profiles in weeks 1, 34, and 106. (B) Mean ALN‐18328 plasma C_min and C_max over time. Error bar represents standard deviation. ALN‐18328, patisiran drug substance (small interfering ribonucleic acid); C_max, maximum concentration at EOI; C_min, concentration at the end of the dosing interval; EOI, end of infusion; OLE, open‐label extension; PK, pharmacokinetic.

Figure 3

Plasma PK profiles for DLin‐MC3‐DMA following intravenous administration of patisiran 0.3 mg/kg once every 3 weeks for 24 months of treatment in the OLE study. (A) Mean DLin‐MC3‐DMA plasma concentration‐time profiles in weeks 1, 34, and 106. (B) Mean DLin‐MC3‐DMA plasma C_min and C_max over time. Error bar represents standard deviation. C_max, maximum concentration at EOI; C_min, concentration at the end of the dosing interval; DLin‐MC3‐DMA, (6Z,9Z,28Z,31Z)‐heptatriaconta‐6,9,28,31‐tetraen‐19‐yl‐4‐(dimethylamino)butanoate; EOI, end of infusion; OLE, open‐label extension; PK, pharmacokinetic.

Figure 4

Plasma PK profiles for PEG₂₀₀₀‐C‐DMG following intravenous administration of patisiran 0.3 mg/kg once every 3 weeks for 24 months of treatment in the OLE study. (A) Mean PEG₂₀₀₀‐C‐DMG plasma concentration‐time profiles in weeks 1, 34, and 106. (B) Mean PEG₂₀₀₀‐C‐DMG plasma C_min and C_max over time. Error bar represents standard deviation. C_max, maximum concentration at EOI; C_min, concentration at the end of the dosing interval; EOI, end of infusion; OLE, open‐label extension; PEG₂₀₀₀‐C‐DMG, α‐(3′‐{[1,2‐di(myristyloxy)proponoxy]carbonylamino}propyl)‐ω‐methoxy, polyoxyethylene; PK, pharmacokinetic.

Figure 5

Proposed mechanism of liver uptake of patisiran LNP and release from the liver following intravenous administration. (1) After intravenous administration of patisiran, PEG₂₀₀₀‐C‐DMG dissociates from the LNP. (2) Removal of the PEG coating allows endogenous ApoE to associate with the LNP, facilitating uptake into hepatocytes via an ApoE‐dependent process. (3) On internalization via endocytosis, the ionizable DLin‐MC3‐DMA lipid is protonated (positively charged), as the pH decreases in the endosome. (4) The positively charged DLin‐MC3‐DMA lipid interacts with the negatively charged endosomal lipid, resulting in disintegration of the LNP, destabilization of the endosome membrane, and release of ALN‐18328 into the cytoplasm. (5) ALN‐18328 binds to RISC, leading to the targeted degradation of TTR mRNA and subsequent reductions in the target protein levels. (6) A proportion of internalized LNPs undergo exocytosis egress from late endosomes/lysosomes back into the circulation. ALN‐18328, patisiran drug substance (small interfering ribonucleic acid); ApoE, apolipoprotein E; IV, intravenous; LDLR, low‐density lipoprotein receptor; LNP, lipid nanoparticle; mRNA, messenger RNA; PEG₂₀₀₀‐C‐DMG, α‐(3′‐{[1,2 di(myristyloxy)proponoxy]carbonylamino}propyl)‐ω‐methoxy, polyoxyethylene; PEG, PEG₂₀₀₀‐C‐DMG; DLin‐MC3‐DMA, (6Z,9Z,28Z,31Z)‐heptatriaconta‐6,9,28,31‐tetraen‐19‐yl‐4‐(dimethylamino)butanoate; RISC, RNA‐induced silencing complex; siRNA, small interfering ribonucleic acid; TTR, transthyretin.