Efficacy, Safety, and Tolerability of Ansofaxine (LY03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Phase 2 Clinical Trial

Mi, Weifeng; Yang, Fang; Li, Huafang; Xu, Xiufeng; Li, Lehua; Tan, Qihua; Wang, Guoqiang; Zhang, Kerang; Tian, Feng; Luo, Jiong; Xia, Jielai; Yuan, Kai; Lü, Lin; Deng, Jiahui; Tian, Jingwei; Zhang, Hongyan

doi:10.1093/ijnp/pyab074

Cited by 15 publications

(26 citation statements)

References 35 publications

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“…In several preclinical models including the forced swimming test, the chronic unpredictable mild stress model and the olfactory bulbectomized model, LPM570065 demonstrated significant antidepressant-like effects ( Zhang et al, 2014 ; Zhu et al, 2021 ). In a phase II clinical study, LPM570065 extended-release tablet was safe, well-tolerated, and effective in improving depression symptoms in MDD patients ( Mi et al, 2021 ), suggesting that LPM570065 could be a useful treatment option for MDD patients.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice

Meng

Duan

et al. 2022

Front. Pharmacol.

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Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a “two-hit” stress mouse model. The “two-hit” stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the “two-hit” stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.

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Section: Introductionmentioning

confidence: 99%

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice

Meng

Duan

et al. 2022

Front. Pharmacol.

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“…Significant differences were found in the mean HAMD-17 total score changes at week 6 in all the active intervention groups vs placebo, and the overall tolerability of the drug was good ( Mi et al, 2021 ). Treatment-related adverse events occurred in 141 patients, with an incidence of 52, 65.4, 56.8, 62.7, and 38.7% in the 40, 80, 120, 160 mg and placebo groups, respectively ( Mi et al, 2021 ).…”

Section: Investigational Drugs With Monoaminergic Mechanism Of Actionmentioning

confidence: 98%

“…Ansofaxine (LY03005) is a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine, orally administered as an extended-release tablet ( Mi et al, 2021 ). A multicenter, randomized, double-blind, placebo-controlled, dose-finding, phase II clinical trial, conducted in China, enrolled adult MDD patients ( N = 255) who were randomly assigned to receive fixed dose of ansofaxine (40, 80, 120, or 160 mg/day) or placebo for 6 weeks ( Mi et al, 2021 ). Significant differences were found in the mean HAMD-17 total score changes at week 6 in all the active intervention groups vs placebo, and the overall tolerability of the drug was good ( Mi et al, 2021 ).…”

Section: Investigational Drugs With Monoaminergic Mechanism Of Actionmentioning

confidence: 99%

“…A multicenter, randomized, double-blind, placebo-controlled, dose-finding, phase II clinical trial, conducted in China, enrolled adult MDD patients ( N = 255) who were randomly assigned to receive fixed dose of ansofaxine (40, 80, 120, or 160 mg/day) or placebo for 6 weeks ( Mi et al, 2021 ). Significant differences were found in the mean HAMD-17 total score changes at week 6 in all the active intervention groups vs placebo, and the overall tolerability of the drug was good ( Mi et al, 2021 ). Treatment-related adverse events occurred in 141 patients, with an incidence of 52, 65.4, 56.8, 62.7, and 38.7% in the 40, 80, 120, 160 mg and placebo groups, respectively ( Mi et al, 2021 ).…”

Section: Investigational Drugs With Monoaminergic Mechanism Of Actionmentioning

confidence: 99%

“…A new generation of monoaminergic agents has been studied, e.g. new triple monoaminergic inhibitors and new atypical antipsychotics ( Fava et al, 2019 ; Mi et al, 2021 ). Old drugs have been repurposed as antidepressants or adjuvants to current antidepressant treatment, in the hope of finding new ways to mitigate residual symptoms or to increase the chance of reaching a response/remission in treatment-resistant MDD patients ( Vasiliu et al, 2017 ; Kalmoe et al, 2020 ; Papakostas et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Investigational Drugs for the Treatment of Depression (Part 1): Monoaminergic, Orexinergic, GABA-Ergic, and Anti-Inflammatory Agents

Vasiliu¹

2022

Front. Pharmacol.

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Therapeutic management of depression has currently important limitations, and its low efficacy is reflected in high rates of non-response even after multiple trials of antidepressants. Almost two-thirds of the patients diagnosed with major depression who received a 4–6 weeks trial of antidepressant could not reach remission, and more than 30% of these patients are considered treatment-resistant. In bipolar depression, the situation is also discouraging if we analyze the high suicide rate, the risk for the treatment-emergent affective switch when antidepressants are added, the high rate of treatment resistance (up to 25%), and the severe functional impairments associated with these episodes. Therefore, new therapeutic agents are needed, as well as new pathogenetic models for depression. The vast majority of the currently approved antidepressants are based on the monoamine hypothesis, although new drugs exploiting different neurotransmitter pathways have been recently approved by FDA. Brexanolone, an allopregnanolone analog, is an example of such new antidepressants, and its approval for post-partum depression inspired the search for a new generation of neurosteroids and GABA-ergic modulators, with an easier way of administration and superior tolerability profile. Orexin receptors antagonists are also extensively studied for different psychiatric disorders, depression included, in phase II trials. Antiinflammatory drugs, both cyclo-oxygenase 2 inhibitors and biological therapy, are investigated in patients with depressive disorders based on the proven correlation between inflammation and mood disorders in preclinical and clinical studies. Also, a new generation of monoamine-based investigational drugs is explored, ranging from triple reuptake inhibitors to atypical antipsychotics, in patients with major depression. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost seven decades, that new pathogenetic pathways should be targeted to increase these patients’ response rate.

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Uncovering the Elusive Structures and Mechanisms of Prevalent Antidepressants

Lin,

Bu,

Unge

et al. 2024

Advanced Therapeutics

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Most treatments to alleviate major depression work by either inhibiting human monoamine transporters, vital for the reuptake of monoamine neurotransmitters, or by inhibiting monoamine oxidases, which are vital for their degradation. The analysis of the experimental 3D structures of those antidepressants in their drug formulation state is key to precision drug design and development. In this study, microcrystal electron diffraction (MicroED) is applied to reveal the atomic 3D structures for the first time of five of the most prevalent antidepressants (reboxetine, pipofezine, ansofaxine, phenelzine, and bifemelane) directly from the commercially available powder of the active ingredients. Their modes of binding are investigated by molecular docking, revealing the essential contacts and conformational changes into the biologically active state. This study underscores the combined use of MicroED and molecular docking to uncover elusive drug structures and mechanisms to aid in further drug development pipelines.

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Efficacy, Safety, and Tolerability of Ansofaxine (LY03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Phase 2 Clinical Trial

Cited by 15 publications

References 35 publications

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice

Investigational Drugs for the Treatment of Depression (Part 1): Monoaminergic, Orexinergic, GABA-Ergic, and Anti-Inflammatory Agents

Uncovering the Elusive Structures and Mechanisms of Prevalent Antidepressants

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