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

J Clin Pharmacol. 2020 Jan;60(1):37-49. doi: 10.1002/jcph.1480. Epub 2019 Jul 19.


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: NCT01960348.

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

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Aged
  • Amyloid Neuropathies, Familial / blood
  • Amyloid Neuropathies, Familial / complications
  • Amyloid Neuropathies, Familial / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Liposomes / administration & dosage
  • Liposomes / therapeutic use
  • Liver / metabolism
  • Male
  • Middle Aged
  • Nanoparticles / administration & dosage
  • Nanoparticles / therapeutic use
  • Polyneuropathies / drug therapy
  • Polyneuropathies / etiology
  • Prealbumin / antagonists & inhibitors*
  • Prealbumin / metabolism
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / pharmacokinetics*
  • RNA, Small Interfering / therapeutic use*
  • RNAi Therapeutics
  • Treatment Outcome


  • Lipid Nanoparticles
  • Liposomes
  • Prealbumin
  • RNA, Small Interfering
  • patisiran

Supplementary concepts

  • Amyloidosis, Hereditary, Transthyretin-Related

Associated data