Luye Pharma Group has enrolled the first subject in a Phase 1 clinical trial in China for LY03021, an investigational antidepressant with a novel triple-target mechanism of action. The drug, filed through China's Class 1 pathway for innovative drugs, represents a potential first-in-class treatment for Major Depressive Disorder (MDD) by simultaneously targeting the norepinephrine transporter (NET), dopamine transporter (DAT), and serving as a gamma-aminobutyric acid type A receptor-positive allosteric modulator (GABAAR PAM).
Addressing Critical Unmet Medical Need
Major Depressive Disorder presents significant clinical challenges in China, with a lifetime prevalence of 3.4% and 12-month prevalence of 2.1%. Current antidepressants have demonstrated unsatisfactory response and remission rates, with onset of action typically requiring 2 to 4 weeks. Patients frequently experience multiple residual symptoms and adverse reactions, highlighting the urgent need for more effective therapeutic options.
The pathogenesis of MDD is closely associated with imbalances in brain neurotransmitters, including serotonin (5-HT), norepinephrine (NE), dopamine (DA), and gamma-aminobutyric acid (GABA). GABA has emerged as a key therapeutic target for psychiatric disorders, with studies indicating critical roles of the altered GABAergic system in MDD pathogenesis. GABAergic interneurons are involved in depression-related behaviors and rapid antidepressant responses.
Novel Mechanism of Action
LY03021, developed on Luye Pharma's New Chemical Entity/New Therapeutic Entity (NCE/NTE) platform, employs a distinctive approach by targeting synaptic GABAA receptor (subtype α1β2γ2) and extrasynaptic GABAA receptor (subtype α4β2δ) at a more appropriate binding ratio. This mechanism enhances GABAergic activation of GABAA receptors, regulates the glutamate/GABA balance in the brain, and inhibits excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis to rapidly relieve depressive symptoms.
The drug simultaneously increases NE and DA levels in the brain by inhibiting NET and DAT, significantly improving core symptoms including anhedonia and sexual dysfunction in MDD patients. Through the wake-promoting effects of NE and DA, LY03021 reduces adverse reactions such as sedation, drowsiness, and loss of consciousness typically caused by GABA receptor activation.
Current antidepressants often excessively activate the synaptic GABAA receptor, leading to adverse reactions including excessive sedation, drowsiness, and confusion. These side effects create challenges including narrow therapeutic windows and dose limitations.
Promising Preclinical Results
Non-clinical studies demonstrated that LY03021 significantly inhibited depressive symptoms in animal models within 24 hours after administration. Continuous administration maintained efficacy throughout a 21-day study period. The drug exhibited a favorable safety profile, with a no-observed-adverse-effect-level (NOAEL) 50 times above its effective dose.
Phase 1 Trial Design
The recently initiated Phase 1 clinical trial is a single-center, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety, tolerability, and pharmacokinetic profile of LY03021 in healthy subjects.
Company Pipeline and Market Position
Luye Pharma has established a strong presence in CNS drug development, obtaining marketing authorizations for multiple innovative drugs across international markets. The company's approved products include Erzofri® (paliperidone palmitate) and Rykindo® (risperidone) extended-release injectable suspensions approved in the U.S., and Rivastigmine Twice Weekly Transdermal Patch approved in multiple European countries, Japan, and China.
The company is conducting clinical studies for several other investigational drugs filed through China's Class 1 pathway, including LY03020 targeting TAAR1 and 5-HT2CR, LY03015 targeting VMAT2 and Sigma1, and LY03017 targeting 5-HT2AR and 5-HT2CR.
From 2021 to 2025, Luye Pharma has achieved approval for 13 new drugs across multiple countries including the U.S., European countries, Japan, and China. The company operates 8 GMP-compliant manufacturing facilities worldwide and has launched over 30 products across CNS, oncology, cardiovascular and other therapeutic areas, conducting business in over 80 countries and regions.
