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Abstracts

Preclinical Overview of CB03 (KCNQ2/3 Channel Opener) for Epilepsy

Abstract number : 1.52
Submission category : 1. Basic Mechanisms / 1E. Models
Year : 2024
Submission ID : 1521
Source : www.aesnet.org
Presentation date : 12/7/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Xiuxiu Liu, PhD – Shanghai Zhimeng Biopharma Inc.

Bo Hua, Master – Shanghai Zhimeng Biopharma Inc.
Bo Liang, PhD – Shanghai Zhimeng Biopharma Inc.
Author: Ruoling Guo, PhD – Shanghai Zhimeng Biopharam, Inc.

Gang Liu, PhD – Shanghai Zhimeng Biopharma Inc.
Chao Song, BS – Shanghai Zhimeng Biopharma Inc.
Jinhui Dou, PhD – Shanghai Zhimeng Biopharma Inc.
Zhihong Lu, PhD – Shanghai Zhimeng Biopharam, Inc.
Huanming Chen, PhD – Shanghai Zhimeng Biopharam, Inc.

Rationale: Shanghai Zhimeng Biopharma, Inc. is developing CB03, a potent and highly selective voltage-gated potassium channel-2/3 (Kv7.2/Kv7.3) opener for the treatment of patients with refractory epilepsy and other neuropsychiatric disorders. Kv7 (or KCNQ) channels are known to function importantly in controlling membrane excitability. The well-known first-generation KCNQ (or Kv7) opener, Retigabine/Ezogabine (RTG/EZG), was approved by the FDA in 2011 as an anticonvulsant used as adjunctive therapy for partial epilepsies. RTG/EZG acts as a positive allosteric modulator of K+ channels leading to an inhibition of high-frequency action potential firing at the axon initial segment due to increased hyperpolarization. Unfortunately, RTG/EZG was withdrawn from the market in 2017 due to its side effects of causing bluish skin pigmentation as well as potential retinal toxicity. Compared to RTG/EZG, CB03 has shown encouraging efficacy in animal models of epilepsy, with better metabolic and chemical stability, better BBB (blood-brain barrier) penetration, a much-improved safety profile, and better selectivity between KCNQ2/3 and 4/5. CB03 is a promising anti-epileptic drug.

Methods: Multiple cellular and animal studies have been performed to evaluate the efficacy of CB03 in epilepsy.

Results: Preclinical data from in vitro and in vivo studies demonstrated CB03 had anti-epilepsy effects with the following characteristics: (1) CB03 acted as an opener of KCNQ channels and showed high potency on and selectivity for KCNQ2/3, while had no obvious effect on the KCNQ1 channel. (2) CB03 exhibited weak inhibitory effects on voltage-gated sodium channels (Nav1.1- Nav1.8), voltage-gated calcium channels (Cav1.2, Cav2.1, Cav2.2, and Cav3.2), and inward rectifying potassium channels (Kir2.1, Kir3.1/3.4). (3) CB03 exhibited weak inhibitory effects on NMDA, GABAA and AMPA receptors. (4) CB03 decreased the number of action potentials at the concentrations of 0.1 µM, 1 µM and 10 µM in neonatal rat hippocampus. (5) CB03 prevented MES-induced seizure behaviors in ICR mice and 6-Hz induced seizures in C57BL/6 mice in a dose-dependent manner. (6) CB03 had Protective Index (PI) values of 4.23 and 3.77 for male and female ICR mice, respectively, which is expressed as the ratio of its TD50 determined in the rotarod test and its ED50 determined in the MES test (TD50/ED50).

Conclusions: Preclinical data showed that CB03 was highly selective for KCNQ2/3, inhibited neuronal firing, and was effective in preventing seizures in epileptic animals.  CB03 is a potential drug for treating epilepsy.

Funding: NA

Basic Mechanisms