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

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 (Tmax) 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 (t1/2) increasing from 1.39 to 10.20 h across doses. The mean t1/2 in PBMCs was 61.29 h and 43.80 h in the 30 mg and 60 mg dose groups, respectively, and the median Tmax 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 TRIALSThis study is registered with ClinicalTrials.gov as NCT05944848.