Phase 1 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

Abstract

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.

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

“…Given the impracticality of intrathecal delivery, it is unlikely that intact apoE could serve as a viable therapeutic strategy in acute neurological disease. To address this issue, a series of small apoE mimetic peptides derived from its receptor-binding region have been created (Laskowitz and Vitek, 2007; Laskowitz et al, 2006; Guptill et al, 2017). These peptides retain the anti-inflammatory and neuroprotective effects of the native apoE protein yet cross blood-brain-barrier (Lynch et al, 2003; Laskowitz et al, 2001; Laskowitz et al, 2007; Laskowitz et al, 2017).…”

Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action

“…There is now overwhelming evidence from experimental studies that CARPs represent a novel class of neuroprotective agent with great potential for the treatment of neurological disorders. However, only two CARPs with neuroprotective properties (TAT-NR2B9c/NA-1 and CN-105) have so far progressed to clinical trials for a neurological condition (363)(364)(365). Further studies are required to obtain a more complete understanding of the neuroprotective mechanisms of action of CARPs in acute CNS injury and chronic neurodegenerative disease models.…”

“…Importantly, CARPs have properties that greatly enhance the likelihood of translational success at the clinical level including possessing a pluripotent mechanism of action, the capacity to enter the CNS, and the ability to exert a broad range of beneficial extracellular, intracellular and intra-organelle effects. Based on human studies with TAT-fused peptides, such as TAT-NR2B9c/NA-1 (366), the poly-arginine peptide R9/ALX40-4C (367), and argininerich peptides CN-105 (365), protamine (368) and RD2 (369), it appears this class of peptide has a favorable safety profile. Moreover, our recent experimental neuroprotection study with the poly-arginine peptide R18 in a non-human primate stroke model (26), has not disclosed any neurological or other toxic effects, which also augurs well for the translational potential of other CARPs to the clinical arena.…”

Emerging cytoprotective peptide therapies for stroke

“…Following demonstration that CN-105 was safe when administered intravenously to healthy volunteers as a single dose (14,42,140, 420 or 1,400 nmol/kg) or in repeated doses (1,400 nmol/kg 6 hourly for 72 h) [36], a phase 2 open label first-in-disease trial in intracerebral hemorrhage has recently been completed [16] and a phase 2, randomized, doubleblind, placebo-controlled study is underway [37]. The protocol involves administering CN-105 intravenously within 12 hours of symptom onset, and every 6 hours for up to a maximum of 3 days (total of 13 doses).…”