Safety and pharmacokinetics of CL-197, a potent compound with low cytotoxicity against HIV-1: a randomized, double-blind, placebo-controlled, first-in-human phase 1 clinical trial

ABSTRACT HIV infection remains a critical global public health concern. A potential long-acting therapeutic agent, 4′-ethynyl-2-fluoroadenosine analog 1c (CL-197), was investigated in a first-in-human phase 1 clinical trial. This single-center, randomized, double-blind, dose-escalation, placebo-controlled study assessed the safety and pharmacokinetics (PKs) of five doses of CL-197 (1, 10, 30, 60, and 100 mg) in healthy adults aged 18–45 years. The 1 mg group was open-label ( n = 4), while the other groups were randomized 4:1 to CL-197 or placebo. The primary endpoints were safety and tolerability. The PK evaluation involved the characterization of systemic exposure parameters (based on plasma drug concentrations and peripheral blood mononuclear cell [PBMC] drug concentrations) and urinary excretion parameters. CL-197 was well tolerated at all dose levels. The most frequently reported adverse reactions were sinus arrhythmia, followed by decreased apolipoprotein B, decreased blood iron, increased triglycerides, and elevated low-density lipoprotein. Plasma PKs showed dose-proportional exposure, with a mean time to maximum plasma concentration ( T max ) of 0.50–1.00 h. As the dose increased, the elimination time was prolonged. The plasma drug concentrations were approximately dose-proportional, whereas AUC 0-t and AUC 0-∞ exhibited non-linear characteristics within the range of 1-100mg, with the mean elimination half-life ( t 1/2 ) increasing from 1.39 to 10.20 h across doses. The mean t 1/2 in PBMCs was 61.29 h and 43.80 h in the 30 mg and 60 mg dose groups, respectively, and the median T max was 12 h. In conclusion, a single administration of CL-197 demonstrated an acceptable safety profile in younger adults. The intracellular CL-197-TP in PBMCs had a long half-life, providing preliminary support for the potential use of extended dosing intervals in further development. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT05944848 .