Luye Pharma Group announced that the first subject has been enrolled in a Phase 1 clinical trial in China for its LY03021, which was filed through China's Class 1 pathway for innovative drugs. LY03021 is an inhibitor of the norepinephrine transporter (NET), the dopamine transporter (DAT), and a gamma-aminobutyric acid type A receptor-positive allosteric modulator (GABA_AR PAM), intended for the treatment of Major Depressive Disorder (MDD).

MDD has a high prevalence rate, a high disability rate, and a high recurrence rate. In China, the lifetime prevalence of this disease is 3.4%, and the 12-month prevalence is 2.1%.^[1] Existing antidepressants have failed to deliver satisfactory response and remission rates, their onset of action usually takes 2 to 4 weeks, ^[2] and patients taking them may have multiple residual symptoms and adverse reactions. Therefore, how to quickly and effectively control the symptoms of MDD and further improve the efficacy of antidepressants and patient prognosis is a challenge in developing such drugs today.

The onset of MDD is believed to be closely associated with imbalances in brain neurotransmitters, including serotonin (5-HT), norepinephrine (NE), dopamine (DA), and gamma-aminobutyric acid (GABA). Among them, GABA has emerged as a key therapeutic target for psychiatric disorders. A series of studies have implied critical roles of the altered GABAergic system, the major inhibitory signaling system of the central nervous system (CNS), in the pathogenesis of MDD.^[3] There is also evidence that GABAergic interneurons are involved in depression-related behaviors and rapid antidepressant responses.^[4] However, current antidepressants often excessively activate the synaptic GABA_A receptor (subtype α₁β₂γ₂), leading to adverse reactions such as excessive sedation, drowsiness, and even confusion. These side effects pose challenges such as a narrow therapeutic window and dose limitations.

Developed on Luye Pharma's New Chemical Entity/New Therapeutic Entity (NCE/NTE) platform, LY03021 acts on all of the three targets: NET, DAT, and GABA_AR, a novel mechanism of action (MoA) that makes it a potential first-in-class antidepressant. By targeting synaptic GABA_A receptor (subtype α₁β₂γ₂) and extrasynaptic GABA_A receptor (subtype α₄β₃δ) at a more appropriate binding ratio, this drug enhances the GABAergic activation of GABA_A receptors, regulates the glutamate/GABA balance in the brain, inhibits the excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis, and rapidly relieves depressive symptoms. At the same time, it also increases NE and DA levels in the brain by inhibiting NET and DAT, significantly improving core symptoms in addition to anhedonia and sexual dysfunction in MDD patients. Through the wake-promoting effects of NE and DA, it also reduces adverse reactions such as sedation, drowsiness, and loss of consciousness caused by GABA receptor activation.

Non-clinical studies showed that LY03021 significantly inhibited depressive symptoms in animal models 24 hours after administration, and continuous administration could maintain the efficacy until the end of a 21-day study. Apart from its rapid onset of action and sustained efficacy, this drug also has a good safety profile, for its NOAEL (no-observed-adverse-effect-level) is 50 times above its effective dose.

The Phase 1 clinical trial recently initiated in China 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.

There is a huge demand for CNS drugs, including those for treating MDD. However, new drug development in this area has been relatively slow. Luye Pharma has obtained marketing authorizations for a number of internationally competitive innovative drugs and formulations in China, the U.S., Japan, and other markets. Here are some examples: Erzofri^® (paliperidone palmitate) extended-release injectable suspension and Rykindo^® (risperidone) for extended-release injectable suspension, both approved for marketing in the U.S.; Rivastigmine Twice Weekly Transdermal Patch, which has been approved for marketing in multiple European countries, Japan, and China; and Ruoxinlin^® (Toludesvenlafaxine Hydrochloride Extended-Release Tablets) and Jinyouping^® (Rotigotine Microspheres for Injection), both have been approved for marketing in China. In addition, the company is also conducting clinical studies for several other investigational drugs filed through China's Class 1 pathway, such as LY03020, which targets TAAR1 and 5-HT_2CR, LY03015, which targets VMAT2 and Sigma1, and LY03017, which targets 5-HT_2AR and 5-HT_2CR.