Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients

Alice Turner, Jan Stolk, Robert Bals, Jason Linkliter, James Hamilton, Dawn Christianson, Bruce Given, Jonathan Burdon, Rohit Loomba, James Stoller, Jeffery Teckman

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
455 Downloads (Pure)


Background & Aims: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation results in mis-folded alpha-1 antitrypsin protein (Z-AAT) leading to hepatocyte accumulation, fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of alpha-1 antitrypsin.

Methods: Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (2 placebo: 4 active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 PiZZ genotype AATD patients who received up to 4.0 mg/kg or placebo. Patients with baseline FibroScan® >11 kPa or FEV1 (forced expiratory volume in one second) < 60% were excluded. Assessments included safety, pharmacokinetics, and change in serum alpha-1 antitrypsin (AAT) concentrations.

Results: 36 healthy volunteers received ARC-AAT and 18 received placebo (Part A). Seven PiZZ individuals received ARC-AAT and 4 received placebo (Part B). A dose-response in serum AAT reduction was observed at doses ≥ 4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. Time for serum AAT return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early due to toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study.

Conclusion: PiZZ and HV responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated.

Lay Summary: Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency.
Original languageEnglish
Pages (from-to)378-384
Number of pages7
JournalJournal of Hepatology
Issue number2
Early online date21 Mar 2018
Publication statusPublished - Aug 2018


  • siRNA
  • phase 1
  • PiZZ
  • RNAi
  • therapeutic


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