Highlights
- •CN-105 is an intravenous, apolipoprotein E (APOE) -mimetic pentapeptide, which have been demonstrated the effect of downregulates neuroinflammatory responses in microglia and mitigates neuronal excitotoxicity following acute brain injury.
- •CN-105 was safe and well tolerated in Western populations.
- •This phase I study demostrated that CN-105 was safe and well tolerated in healthy Chinese participants in the range of 0.1 mg/kg to 1 mg/kg of single and multiple intravenous administrations.
- •The PK characteristics of CN-105 were comparable among Chinese and western subjects.
Abstract
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.
Key words
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Article info
Publication history
Published online: May 10, 2022
Accepted:
March 10,
2022
Identification
Copyright
© 2022 Elsevier Inc.
