Pre‐clinical and Clinical Safety Studies of CMX‐2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury

Abstract CMX ‐2043 is an α‐lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury ( IRI ). It has been shown to be effective in a rat model of cardiac IRI . The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI . Safety and tolerability were tested in standard pre‐clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX ‐2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary ( CHO ) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14‐day repeat intravenous doses and in dogs (single intravenous dose) with a 2‐week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo‐controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre‐clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX ‐2043 in a human efficacy trial.