Depression (MDD) is a common mental disorder characterized by high incidence, high recurrence and high disability. It is the leading cause of disability worldwide and a major contributor to the global burden of disease. According to statistics, about 350 million people in the world suffer from MDD. Among them, 1/3 to 50% of MDD patients have limited improvement in symptoms and develop treatment-resistant depression (TRD) after adequate treatment with two or more different antidepressants.
However, the etiology and pathogenesis of MDD are still unclear. It is believed that the risk factors of MDD include gender, age, race, socioeconomic status, personality characteristics, social environment, body fixation, psychoactive substance abuse and dependence, and drug factors.
At present, drug therapy is an important treatment for MDD. The commonly used anti-MDD drugs in clinical practice include selective 5-light tryptamine reuptake inhibitors (SSRIs, such as escitalopram, sertraline, fluoxetine), serotonin and norepinephrine reuptake inhibitors (SNRIs, Such as gramracine, duloxetine), norepinephrine, specific serotonergic antidepressants (NaSSAs), tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors (MAOLs), agoguantine, etc. Among them, SSRIs and SNRIs are the mainstream anti-MDD drugs. However, there are many defects such as slow onset, low efficiency, sexual dysfunction and cognitive impairment.
The size of China's antidepressant market exceeds 20 billion yuan
According to public data, there are a large number of MDD patients in China. According to WHO data, the number of MDD patients in China reached 54 million in 2021.
At present, the structure of anti-MDD clinical drugs is gradually improved in China, which is mainly composed of six categories: SSRIs, SNRI, norepinephrine and specific 5-hydroxytrypsin antidepressants (NaSSA), 5-HT receptor antagonism and reuptake inhibitors (SARIs), selective 5-HTIA receptor agonists and other drugs.
With more and more MDD patients seeking treatment, the market size of MDD drugs in China is expected to exceed 20 billion yuan by 2030. It is reported that the TOP5 anti-MDD drugs in China's sample hospitals in the first half of 2022 are escitalopram, agomelatine, sertraline, venlafaxine and mirtazapine. Three of the top five SSRI/SNRI inhibitors were escitalopram (1), sertraline (3), and venlafaxine (4). Agomelatine moved up to No. 2, and mirtazapine broke into the top 5 for the first time.
It is worth mentioning that at present, many pharmaceutical companies in China are actively layout the MDD new drug market, such as Enhua Pharmaceutical, widely Pharmaceutical, Suoyuan Biological. Moreover, there are several proprietary Chinese medicines developed to treat MDD in China, such as Chaijin Jieyu Anshen Tablet from Hunan University of Chinese Medicine and Zhile Capsule from Zhejiang Shiqiang Pharmaceutical Co., LTD.
In addition, around the development of MDD new drugs, Chinese pharmaceutical enterprises have reached cooperation with many enterprises in recent years. For example, in September 2021, Jingxin Pharmaceutical and Jingtai Technology, an artificial intelligence drug R&D company, reached project cooperation to jointly promote the research and development of small molecule anti-depression drugs. In July 2022, Soyuan Biologics entered into a partnership with NuroseneHealth to leverage the latter's NetraAI AI technology for DB104 development.
On September 26, Tengshengbo announced top-line results for its phase 1 trial of BRII-296 for postpartum depression (PPD); The findings suggest that BRI-296 has the potential to provide a novel and effective one-time injection treatment option for patients with postpartum depression (PPD) that can be administered in the outpatient setting. In addition, Teng Shengbo has identified the optimal dosing regimen for BRII-296 in a phase 2 study expected to be conducted by the end of 2022.
In fact, many anti-MDD drugs have made encouraging progress in the world this year.
Several anti-MDD drugs have been approved for sale
More than 10 new drugs are under research
In fact, in the face of huge clinical drug demand, as well as enrich the drug choice of patients. Antidepressant drugs are being developed around the world.
According to incomplete statistics, several new anti-MDD drugs have been approved by global regulators in recent years, such as Axsome's Auvelity, Johnson & Johnson's Spravato (esketamine, Esketamine hydrochloride nasal spray), Intra-CellularTherapies' Caplyta (lumateperone), SageTherapeutics' Zulresso (brexanolone), Takeda/Reibi's Trintellix/Brint ellix (vortioxetine, votioxetine), AbbVie's Vraylar (cariprazine, carbimizine), and Rexulti (brexpiprazole) from Linbuk/Otsuka.
Auvelity (AXS-05) is a novel, orally fast-acting N-methyl-D-aspartate (NMDA) receptor antagonist that utilizes proprietary formulations and dosing of dextromethorphan and bupropion, as well as Axsome's metabolic suppression technology to modulate the delivery of drug components. The drug was approved by the FDA in August to treat major depression in adults.
Spravato, an NMDA receptor antagonist and the first antidepressant with a novel mechanism of action approved by the FDA in nearly 30 years, was approved in March 2019 in combination with oral antidepressants for the treatment of adults with major depression who are resistant to existing therapies. In 2020, it was approved by the FDA for adults with depression who have acute suicidal thoughts or behaviors.
Caplyta is a first-of-its-kind small-molecule drug that selectively and simultaneously modulates serotonin, dopamine, and glutamate, three neurotransmitter pathways involved in severe mental illness. Caplyta was approved by the FDA in December 2019 for the treatment of adult patients with schizophrenia. In December 2021, the drug was approved by the FDA as a monotherapy and as an adjunctive therapy to lithium or valproate for the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) in adult patients.
Zulresso, an allosteric modulator that acts on both synaptic and extrapsynaptic GABAA receptors, was approved by the FDA in March 2019 for the treatment of postpartum depression.
Trintellix/Brintellix, which has serotonin reuptake inhibitor and serotonin receptor modulatory effects, was approved for the treatment of depression and depressive states in the United States in 2013.
Vraylar, a partial agonist for oral dopamine D3/D2 receptors, was approved by the FDA in September 2015 for the treatment of schizophrenia and manic depression in adults.
Rexulti was approved by the FDA in July 2015 as an adjunctive drug for the treatment of major depression in adults, as well as for the treatment of schizophrenia in adults.
In addition, there are currently a number of new drugs in development against MDD worldwide (see the table below for details). Two of the products have entered clinical phase 3; Two products are in application for marketing, Luye Pharma's LY03005 and Biogen/Sage's zuranolone.
LY03005 is a novel molecular entity therapy drug with a novel mechanism of action. It has completed phase I to phase III clinical trials in the treatment of depression in China and is in the market review stage. It is also under marketing review in the United States and has completed phase I clinical trials in Japan for the treatment of depression.
Zuranolone is a once-daily forward allosteric regulator of the γ-aminobutyric acid (GABAA) receptor for two weeks. COMP360 is the only psilocybin candidate currently clinically available for the treatment of MDD, selectively activating the 5-HT receptor. pimavanserin is a selective serotonin reverse agonist that preferentially targets the 5-HT2A receptor.
This year, zuranolone has made several groundbreaking clinical advances. It showed a rapid improvement in depressive symptoms in CORAL, a phase 3 study of major depressive disorder, and a greater effect than placebo was observed on day 3 of a 2-week course of treatment. In addition, SKYLARK, the Phase 3 study of zuranolone for postpartum depression, had positive results -- the 50mgzuranolone treatment group showed a statistically and clinically significant improvement in depressive symptoms at day 15 compared with placebo. Biogen/Sage has a rolling new drug application (NDA) for zuranolone for the treatment of major depression and plans to submit an NDA for the treatment of postpartum depression early next year.
conclusion
According to WHO, MDD is currently the fourth largest disease burden in the world and one of the leading causes of functional disability. With the approval of new drugs on the market, and the change of the public's understanding of MDD and the concept of medical treatment, the global MDD market has been expanding. So far, scientists are still exploring the field of MDD. It is expected that with the approval of fast-acting and new MDD drugs, the treatment status of MDD patients will be effectively improved.
