Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis

Nucleic Acid Ther. 2020 Feb;30(1):33-49. doi: 10.1089/nat.2019.0796. Epub 2019 Dec 10.

Abstract

Revusiran is a 1st-generation short interfering RNA targeting transthyretin conjugated to an N-acetylgalactosamine ligand to facilitate delivery to hepatocytes via uptake by the asialoglycoprotein receptors. Revusiran, in development for the treatment of hereditary transthyretin-mediated amyloidosis, was discontinued after an imbalance in deaths in the "ENDEAVOUR" phase 3 clinical trial. Nonclinical safety assessments included safety pharmacology, acute and repeat-dose toxicity, genotoxicity, and carcinogenicity. There were no effects on cardiovascular or respiratory function in monkeys after single doses of up to 100 mg/kg. No neurological effects were noted in monkeys in repeat-dose studies up to 300 mg/kg. Revusiran was well tolerated in repeat-dose mouse (weekly doses) and rat and monkey (five daily doses followed by weekly doses) toxicity studies. The no observed adverse effect level (NOAEL) in rats was 30 mg/kg based on reversible microscopic changes in liver that were accompanied by correlating elevations in clinical chemistry at higher doses. Dose-limiting toxicity was absent in monkeys, and the NOAEL was 200 mg/kg. There was no evidence of genotoxicity in vitro or in vivo at limit doses or carcinogenicity in a 2-year study in rats at doses up to 100 mg/kg. Overall, these results demonstrate that revusiran had a favorable nonclinical safety profile.

Keywords: hATTR amyloidosis; revusiran; short interfering RNA; siRNA; toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylgalactosamine / chemistry
  • Acetylgalactosamine / genetics
  • Acetylgalactosamine / pharmacology*
  • Amyloid Neuropathies, Familial / drug therapy*
  • Amyloid Neuropathies, Familial / genetics
  • Amyloid Neuropathies, Familial / pathology
  • Animals
  • Carcinogenicity Tests
  • Disease Models, Animal
  • Haplorhini
  • Hepatocytes / drug effects
  • Humans
  • Mice
  • Mutagenicity Tests
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology*

Substances

  • RNA, Small Interfering
  • Acetylgalactosamine
  • revusiran

Supplementary concepts

  • Amyloidosis, Hereditary, Transthyretin-Related