Authors :
Presenting Author: Minjuan Zhu, MD – Shanghai Zhimeng Biopharam, Inc.
Matt Hudson, PhD – Monash University
Ruoling Guo, PhD – Shanghai Zhimeng Biopharam, Inc.
Zhihong Lu, PhD – Shanghai Zhimeng Biopharam, Inc.
Yanling Zhou, MD – Shanghai Zhimeng Biopharam, Inc.
Baini Li, MSN – Shanghai Zhimeng Biopharam, Inc.
Hui Wan, BS – Shanghai Zhimeng Biopharam, Inc.
Huanming Chen, PhD – Shanghai Zhimeng Biopharam, Inc.
Terence J O'Brien, MBBS MD – School of Translational Medicine, Monash University, The Alfred Centre
Rationale:
KCNQ2/3 is a promising therapeutic target for treatment of epilepsy. CB03-154 is a novel, highly selective and potent small molecular KCNQ2/3 opener. In a first-in-human Phase 1 study, CB03-154 was found to be safe and well tolerated.
Many Central Nervous System (CNS) active drugs have effects on the power of different frequency bands in the electroencephalogram (EEG). These EEG changes can be used as a biomarker of CNS penetration, effects on neuronal networks, and to assess potential adverse effects (Jobert et al., 2012).
To further explore the impact of the CB03-154 on brain electrical activity, we analyzed changes in EEG power and dominant frequencies across specific bands with Fast Fourier Transform on selected leads. This quantitative electroencephalogram (qEEG) analysis was to detect the drug's effects post dosing and following repeated daily dosing.
Methods:
qEEG analysis was conducted using MATLAB. The single ascending dose (SAD) analysis involved a total of 8 healthy subjects (6 received 30 mg CB03-154 and 2 received placebo as controls). The multiple ascending dose (MAD) analysis included a total of 10 healthy subjects (6 received 20 mg CB03-154 and 4 received placebo, two from cohort 1 or 2 respectively, once daily for 14 days). For each recording, EEG data was extracted for pre-treatment (-30min to 0 relative to dosing) and post-treatment (+30 to +60min relative to dosing).
To evaluate the immediate impact of treatment on qEEG, pre-treatment absolute power values was compared to post-treatment values for each recording. For long-term effects, pre-treatment power at different timepoints (Days 1, 8, and 14) was analyzed using relative power, calculated as the ratio of power in the frequency band of interest to total power (1-46Hz). Statistical analysis for the MAD section was conducted using two-way ANOVA in GraphPad Prism 10.1.2, while the SAD section utilized an unpaired t-test.
Results:
Statistical analysis of the qEEG results revealed no significant effect of treatment (i.e. CB03-154 vs placebo) for all frequency bands when assessing acute effects for both the MAD cohort (20mg/day) and the SAD cohort (single 30mg dose). In addition, when comparing relative power measures across consecutive sessions (Days 1, 8 and 14) in MAD cohort (20mg/daily) there was no significant effect of treatment for all frequency bands.
Conclusions:
There is no evidence from the qEEG analysis that the study drug (CB03-154) has any adverse brain effects on brain network activity, either when administered acutely or chronically over a two-week period, at the doses tested. Results suggest that CB03-154 should have minimal CNS side-effects at these doses. The lack of frequency spectrum power band effects does not imply a lack of anti-seizure effects at the doses tested, as the changes seen with the older anti-seizure medications relate to their adverse CNS effects not their anti-seizure actions.Funding:
Jobert M, Wilson FJ, Ruigt GS, Brunovsky M, Prichep LS, Drinkenburg WH. The IPEG Pharmaco-EEG Guideline Committee. Guidelines for the Recording and Evaluation of Pharmaco-EEG Data in Man: The International Pharmaco-EEG Society (IPEG). Neuropsychobiology (2012) 66 (4): 201–220.