A first-in-human study of the novel HIV-fusion inhibitor C34-PEG<sub>4</sub>-Chol

Quinn, Killian, Traboni, Cinzia, Penchala, Sujan Dily, Bouliotis, Georgios, Doyle, Nicki, Libri, Vincenzo, Khoo, Saye ORCID: 0000-0002-2769-0967, Ashby, Deborah, Weber, Jonathan, Nicosia, Alfredo
et al (show 3 more authors) (2017) A first-in-human study of the novel HIV-fusion inhibitor C34-PEG<sub>4</sub>-Chol. SCIENTIFIC REPORTS, 7 (1). 9447-.

Access the full-text of this item by clicking on the Open Access link.


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-PEG<sub>4</sub>-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG<sub>4</sub>-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG<sub>4</sub>-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.

Item Type: Article
Uncontrolled Keywords: T-Lymphocytes, Cells, Cultured, Animals, Dogs, Humans, Mice, HIV-1, HIV Infections, Polyethylene Glycols, Cholesterol, Peptide Fragments, Recombinant Fusion Proteins, HIV Envelope Protein gp41, HIV Fusion Inhibitors, Viral Load, Cohort Studies, Double-Blind Method, Drug Evaluation, Preclinical, Mutagenesis, Site-Directed, Placebo Effect, Drug Resistance, Viral, Adolescent, Adult, Middle Aged, Male, Young Adult
Depositing User: Symplectic Admin
Date Deposited: 04 Jan 2019 15:21
Last Modified: 14 Oct 2023 09:26
DOI: 10.1038/s41598-017-09230-0
Open Access URL: https://www.nature.com/articles/s41598-017-09230-0
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3030759