A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol

Sci Rep. 2017 Aug 25;7(1):9447. doi: 10.1038/s41598-017-09230-0.

Abstract

Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34-PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25 ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10 mg, 10 mg and 20 mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was >72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was -0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Cells, Cultured
  • Cholesterol / chemistry
  • Cohort Studies
  • Dogs
  • Double-Blind Method
  • Drug Evaluation, Preclinical
  • Drug Resistance, Viral / genetics
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / genetics
  • HIV Envelope Protein gp41 / therapeutic use*
  • HIV Fusion Inhibitors / chemistry
  • HIV Fusion Inhibitors / therapeutic use*
  • HIV Infections / drug therapy*
  • HIV-1 / physiology*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Mutagenesis, Site-Directed
  • Peptide Fragments / chemistry
  • Peptide Fragments / therapeutic use*
  • Placebo Effect
  • Polyethylene Glycols / chemistry
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / therapeutic use*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / virology
  • Viral Load
  • Young Adult

Substances

  • 15-amino-4,7,10,13-tetraoxapentadecanoic acid
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • peptide C34
  • Polyethylene Glycols
  • Cholesterol