A First-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of NS-041, a Novel KCNQ2/3 Activator, in Healthy Subjects (NS041HV101)
Abstract number :
1.553
Submission category :
2. Translational Research / 2A. Human Studies
Year :
2025
Submission ID :
1307
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Xiaolan Yong, MD – Chengdu Xinhua Hospital
Chao Zhang, PhD – NeuShen Therapeutics
Yonggang Wu, MD – Shinesta Medicine
Danqing Xu, PhD – NeuShen Therapeutics
Yangyi Qu, MS – NeuShen Therapeutics
Yonggang Zhao, PhD – NeuShen Therapeutics
Presenting Author: Joan HQ Shen, MD/PhD – NeuShen Therapeutics
Rationale: KCNQ2/3 represents a clinically validated therapeutic target for neurological disorders, including epilepsy and major depressive disorder. NS-041, a next-generation KCNQ2/3 activator, demonstrates enhanced potency, selectivity, and pharmacokinetic (PK) properties compared to first-generation agent retigabine. Critically, NS-041’s novel chemical structure eliminates the risk of pigmentation associated with retigabine, which was withdrawn from the market due to dimer formation. This study evaluated the safety, tolerability, and PK of NS-041 in healthy subjects following single and multiple ascending oral doses.
Methods: The single ascending dose (SAD) phase enrolled 40 healthy volunteers randomized (6:2) to receive NS-041 (5, 10, 20, 35, or 40 mg) or placebo. A crossover cohort (N=12) assessed food effects (FE) using a 30 mg dose. Based on SAD and FE results, the multiple ascending dose (MAD) phase evaluated 10 mg (fasted), 30 mg, and 35 mg (fed) once-daily regimens for 14 days (N=8/cohort, 6:2 randomization). Serial plasma PK samples were collected, and safety assessments included adverse event (AE) monitoring, laboratory tests, electrocardiograms (ECGs), physical exams, and ophthalmologic evaluations (with pupillary dilation at screening and follow-up).
Results: All reported AEs were mild and self-resolving. Dizziness, the most common AE, showed dose-dependent, mild and self-resolving pattern (consistent with antiepileptic drug class effects). No moderate/severe AEs or clinically significant laboratory/ECG abnormalities were observed. NS-041 exhibited a half-life of 36–45 hours at clinically relevant doses (20–45 mg), supporting once-daily dosing. PK exposure increased subproportionally with dose in SAD cohotrs (5–45 mg): Cmax 17.1 ± 4.48 to 70.8 ± 19.7 ng/mL; AUC0-inf 55.0 ± 20.6 to 556 ± 157 h·ng/mL. Moreover, fed conditions increased exposure (AUCinf: ~147%; Cmax: ~123% vs. fasted) and delayed Tmax from 0.75 to 4.00 hours. Comparable exposure between 30 mg and 35 mg MAD cohorts indicated attainment of steady-state plateau.
Conclusions: NS-041 demonstrated favorable safety and tolerability up to 45 mg (single-dose) and 35 mg (multiple-dose), with PK properties suitable for once-daily administration without titration. A Phase 2 proof-of-concept study is currently underway in patients with focal-onset seizures as adjunctive therapy.
Funding: N/A
Translational Research