Phase I randomized double-blind placebo controlled study to determine the safety tolerability and pharmacokinetics of a single escalating dose and repeated doses of CN-105 in healthy adult subjects

摘要

Spontaneous intracranial hemorrhage (ICH) remains a devastating stroke subtype, affecting as many as 80,000 people annually in the United States and associated with extremely high mortality. In the absence of any pharmacological interventions demonstrated to improve outcome, care for patients with ICH remains largely supportive. Thus, despite advances in the understanding of ICH and brain injury, there remains an unmet need for interventions that improve neurologic recovery and outcomes. Recent research suggesting inflammation and APOE genotype play a role in modifying neurologic outcome after brain injury has led to the development of an APOE-derived peptide agent (CN-105). Preclinical studies have demonstrated that CN-105 effectively down regulates the inflammatory response in acute brain injury, including ICH. Following Investigational New Drug (IND) enabling studies in murine models, this first in-human single escalating dose and multiple dose placebo-controlled clinical trial was performed to define the safety and pharmacokinetics (PK) of CN-105. A total of 48 subjects (12 control, 36 active) were randomized in this study; all subjects completed the study. No significant safety issues were identified with both dosing regimens, and PK analysis revealed linearity without significant drug accumulation. The median half-life in the terminal elimination phase of CN-105 following a single or repeated dosing regimen did not change (approximately 3.6 hr). With the PK and preliminary safety of CN-105 established, the drug is now poised to begin first in disease phase 2 clinical trials in patients with ICH who urgently need new therapeutic options.