Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG2000 -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.

Trial registration: ClinicalTrials.gov NCT01960348.

Keywords: exposure-response; hereditary transthyretin-mediated amyloidosis (hATTR); patisiran; pharmacodynamics (PD); pharmacokinetics (PK); small interfering ribonucleic acid (siRNA).

Conflict of interest statement

The data in this article were obtained from the APOLLO trial funded by Alnylam Pharmaceuticals Inc. Authors are employees of Alnylam Pharmaceuticals Inc.

© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean plasma concentrations of (A) ALN‐18328, (B) DLin‐MC3‐DMA, and (C) PEG2000‐C‐DMG (semilog scale) after administration of patisiran 0.3 mg/kg once every 3 weeks over 18 months in patients (PK population). The error bars represent the ± standard deviation. Note: 1‐sided error bars for ALN‐18328 and some PEG2000‐C‐DMG concentrations are presented because values are negative. ALN‐18328, patisiran drug substance (small interfering RNA); Cmax, maximum concentration observed at end of infusion; Cp(30 minutes), concentration observed 30 minutes postinfusion; Cmin, observed predose concentration; DLin‐MC3‐DMA, lipid excipient (6Z,9Z,28Z,31Z)‐heptatriaconta‐6,9,28,31‐tetraen‐19‐yl‐4‐(dimethylamino) butanoate; PEG2000‐C‐DMG, lipid excipient α‐(3′‐{[1,2‐di(myristyloxy)proponoxy]carbonylamino}propyl)‐ω‐methoxy, polyoxyethylene; PK, pharmacokinetic.

Figure 2

Mean steady‐state plasma concentrations of ALN‐18328 across patient subgroups. (A) Cmax,ss, (B) Cp,ss(30 min), and (C) Cmin,ss. The error bars represent the standard deviation. There were no statistically significant differences within subgroups after controlling for type I error. ALN‐18328, patisiran drug substance (small interfering RNA); BW, body weight; Cmax,ss, maximum concentration observed at end of infusion at steady state; Cp,ss(30 min), concentration observed 30 minutes postinfusion at steady state; Cmin,ss, predose concentration observed at steady state; HF, hepatic function; HI, hepatic impairment; RI, renal impairment; RF, renal function; TTR, transthyretin.

Figure 3

Effect of body weight on ALN‐18328 PK exposure and TTR reduction. Box plots by body‐weight quartiles for (A) Cmax,ss and Cp,ss(30min) for ALN‐18328 and (B) individual maximum TTR reduction and individual mean TTR reduction over 18 months. The lower and upper bounds of the rectangles represent the first and third quartiles, the horizontal line represents the median, the whiskers extend to the highest and lowest values within 1.5 × the the interquartile range, and data beyond the end of the whiskers are plotted as points. Body weights associated with the 4 quartiles are: Q1, 36.2‐56.6 kg; Q2, 56.9‐65.0 kg; Q3, 66.0‐79.0 kg; and Q4, 79.5‐110 kg. ALN‐18328, patisiran drug substance (small interfering RNA); Cmax,ss, maximum concentration observed at end of infusion at steady state; Cp,ss(30 min), concentration observed 30 minutes postinfusion at steady state; PK, pharmacokinetic; TTR, transthyretin.

Figure 4

Mean change from baseline over time for serum levels of (A) vitamin A and (B) retinol‐binding protein in the patisiran and placebo groups (PD population). The error bars represent the standard error of the mean. PD, pharmacodynamic.

Figure 5

Analysis by intrinsic and extrinsic factors for change from baseline to 18 months with ALN‐18328 in (A) mean serum TTR levels compared with baseline and (B) mean mNIS+7 from baseline at 18 months compared with placebo. The error bars represent the standard error of the mean. aData from Adams et al 2018.17 BW, body weight; HF, hepatic function; HI, hepatic impairment; mNIS+7, modified Neuropathy Impairment Score+7; RF, renal function; RI, renal impairment; TTR, transthyretin.

Figure 6

Effect of interpatient PK variability on (A) TTR change from baseline and (B) mNIS+7 change from baseline compared with placebo (PK/PD population). Quartile 1, 0%‐≤25%; quartile 2, >25%‐≤50%; quartile 3, >50%‐≤75%; quartile 4, >75%‐≤100%. The error bars represent the standard error of the mean. ALN‐18328, patisiran drug substance (small interfering RNA); Cmax,ss, maximum concentration observed at end of infusion at steady state; Cp,ss(30 min), concentration observed 30 minutes postinfusion at steady state; Cmin,ss, predose concentration observed at steady state; mNIS+7, modified Neuropathy Impairment Score+7; PD, pharmacodynamic; PK, pharmacokinetic; TTR, transthyretin.