Tolerability and Pharmacokinetics of Single Escalating and Repeated Doses of CN-105 in Healthy Participants

Purpose CN-105 is an IV, apolipoprotein E–mimetic pentapeptide. Preclinical studies have reported that CN-105 effectively down-regulates neuroinflammatory responses in microglia and mitigates neuronal excitotoxicity following acute brain injury. The CN-105 Phase I and II trials that have been done in the United States have demonstrated that CN-105 was well tolerated in US participants. Thus, the main objective of the present Phase I study was to investigate the tolerability and pharmacokinetic (PK) profiles of CN-105 in healthy Chinese participants. Methods This randomized, double-blind, placebo-controlled, dose-escalation study was performed in healthy participants using sequential 30-minute IV administration of single and multiple doses of CN-105 (four times daily for 13 doses). Forty volunteers were randomly assigned, in an 8:2 ratio, to one of four dosing groups, receiving either CN-105 (0.03, 0.1, 0.3, or 1 mg/kg), or placebo. Serial blood samples were collected for the measurement of plasma concentrations of CN-105. Tolerability was also assessed. Findings After single-dose administration, the plasma CN-105 concentration rapidly reached the peak by the end of infusion. The mean elimination half-life of CN-105 ranged from 2.3 to 3.6 hours. During single- and multiple-dosing paradigms, exposure to CN-105 (AUC) exhibited linear dependency on dose. Steady state was reached by the fourth dose, with minimal accumulation. The PK properties of CN-105 with single and multiple dosing were comparable to those observed in US participants. CN-105 was generally well tolerated in Chinese participants. A total of 13 adverse events were reported in 30% of subjects (12/40) at the 0.03 mg/kg (6/8), 0.1 mg/kg (1/8), 0.3 mg/kg (2/8), 1 mg/kg (0/8) doses and with placebo (3/8). All adverse events were mild or moderate in severity and self-limited, with no dose relationship observed. Implications CN-105 was well tolerated in these healthy Chinese participants at doses of 0.1 to 1 mg/kg with single and multiple IV administrations. The PK characteristics of CN-105 were comparable among Chinese and Western subjects. A Phase II study in patients with intracranial hemorrhage is being planned in China. ClinicalTrials.gov identifiers: NCT02670824 and NCT03168581; Chinese Clinical Trial Registration identifier: CTR20202397.