更新于：2024-11-01

D2 receptor

更新于：2024-11-01

基本信息

别名

D(2) dopamine receptor、Dopamine D2 receptor、dopamine receptor D2

+ [2]

简介

Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase (PubMed:21645528). Positively regulates postnatal regression of retinal hyaloid vessels via suppression of VEGFR2/KDR activity, downstream of OPN5 (By similarity).

关联

322

项与 D2 receptor 相关的药物

Samidorphan/olanzapine

奥氮平萨米多芬

靶点

5-HT2 receptor x D1 receptor x D2 receptor x μ opioid receptor

作用机制

5-HT2 receptor拮抗剂 [+3]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2021-05-28

Lumateperone Tosylate

靶点

5-HT2A receptor x D2 receptor

作用机制

5-HT2A receptor拮抗剂 [+1]

在研机构

Intra-Cellular Therapies, Inc.

原研机构

Bristol Myers Squibb Co.

在研适应症

躁郁症 [+7]

非在研适应症

痴呆引起的激越 [+2]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2019-12-20

Aripiprazole Lauroxil

阿立哌唑十二烷酸酯

靶点

5-HT1A receptor x 5-HT2A receptor x D2 receptor

作用机制

5-HT1A receptor激动剂 [+2]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2015-10-05

4,393

项与 D2 receptor 相关的临床试验

NCT06291116 / Not yet recruiting临床2期IIT

Safety of RotigotiNe in Patients With Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease linked to mutation of the PKD1 or PKD2 genes encoding polycystins 1 and 2. Patients develop renal cysts with progressive impairment of renal function leading to renal failure. terminal renal failure for 1/3 of them. These patients also present early with high blood pressure and cardiovascular complications, notably intracerebral aneurysms. This phenotype is linked to abnormal polycystins on the cilia of renal epithelial and vascular endothelial cells which no longer ensure the mechanotransduction of shear forces linked to urinary and blood flow leading to the modification of numerous cellular functions.
Experimental results suggested that stimulation of dopamine receptor type 5 (DR5) could restore the mechanosensitivity of endothelial cells, a hypothesis supported by our first results showing that local administration of dopamine improves endothelial function in patients with ADPKD. through restoration of endothelial NO release upon increased blood flow. Similar positive results on endothelial function and hemodynamics were recently obtained in the IMPROVE-PKD study with rotigotine, a dopamine agonist administered via transdermal patches for 2 months at a low dose (4 mg/24h).
Dopaminergic stimulation could also prevent abnormalities linked to polycystin deficiency at the renal level and we therefore hypothesize that rotigotine could slow the progression of ADPKD both at the renal and cardiovascular levels.
This phase 2 study aims to ensure the good long-term tolerance of rotigotine in patients with ADPKD and to collect preliminary data on its renal impact.

开始日期2025-01-01

申办/合作机构-

CTRI/2024/08/072829 / Not yet recruitingN/A

An Open-Label, Randomized, Two-Treatment, Two-Period, Two-Sequence, Multiple-Dose, Steady-State, Fully Replicate, Crossover Bioequivalence Study of Aripiprazole 400 mg Powder and Solvent for Prolonged-Release Suspension for Injection and Abilify Maintena® 400 mg Powder and Solvent for Prolonged-Release Suspension for Injection in Adult Patients withSchizophrenia under Fasting Condition. - NIL

开始日期2024-12-02

申办/合作机构

Laboratorios Liconsa SA

[+1]

NCT06554613 / Not yet recruiting临床2期IIT

An Open-label, Two-arm, Multicenter, Phase II Randomized Controlled Trial Assessing the Impact of Olanzapine on the Efficacy of First-line Immunotherapy in Patients With Advanced EGFR Mutation-negative Non-small Cell Lung Cancer (NSCLC).

Clinical Trial
The objective of this clinical trial is to determine whether antidepressant medications, such as olanzapine, in combination with immune checkpoint inhibitors are more effective than the use of immune checkpoint inhibitors alone. The main questions it aims to answer are:
Is the combination therapy of antidepressant medication with immune checkpoint inhibitors more efficacious than the therapy with immune checkpoint inhibitors alone? What medical issues might participants encounter when treated with the combination of antidepressant medication and immune checkpoint inhibitors?
Participants will:
Take olanzapine in combination with immune checkpoint inhibitors or immune checkpoint inhibitors alone for 2 months.
Visit the clinic for check-ups and tests every two weeks, and have follow-up visits every six weeks after the treatment ends.
Keep a record of their symptoms and disease progression.

开始日期2024-12-01

申办/合作机构

南昌大学第二附属医院

100 项与 D2 receptor 相关的临床结果

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100 项与 D2 receptor 相关的转化医学

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0 项与 D2 receptor 相关的专利（医药）

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12,786

项与 D2 receptor 相关的文献（医药）

2025-01-01·Journal of Affective Disorders

Abnormal functional lateralization and cooperation in bipolar disorder are associated with neurotransmitter and cellular profiles

Article

作者: Zhang, Li ; Ji, Gong-Jun ; Tian, Weichao ; Zhao, Xiya ; Huang, Tongqing ; Xu, Wenqiang ; Sun, Jinmei ; Cao, Hai ; Wang, Kai ; Hua, Qiang

BACKGROUNDHemispheric lateralization and cooperation are essential for efficient brain function, and aberrations in both have been found in psychiatric disorders such as schizophrenia. This study investigated alterations in hemispheric lateralization and cooperation among patients with bipolar disorder (BD) and associations with neurotransmitter and cell-type density distributions to identify potential molecular and cellular pathomechanisms.METHODSSixty-seven BD patients and 127 healthy controls (HCs) were examined by resting-state functional MRI (rs-fMRI). Whole-brain maps of the autonomy index (AI) and connectivity between functionally homotopic voxels (CFH) were constructed to reveal BD-specific changes in brain functional lateralization and interhemispheric cooperation, respectively. Spatial associations of regional AI and CFH abnormalities with neurotransmitter and cell-type density distributions were examined by correlation analyses.RESULTSBipolar disorder patients exhibited higher AI values in left superior parietal gyrus, cerebellar right Crus I, and cerebellar right Crus II, and these regional abnormalities were associated with the relative densities (proportions) of oligodendrocyte precursor cells and microglia. Patients also exhibited lower CFH values in right inferior parietal gyrus, bilateral middle occipital gyrus, left postcentral gyrus, and bilateral cerebellar crus II, and these regional abnormalities were associated with the densities of serotonin 1A and dopamine D2 receptors, oligodendrocyte precursor cells, astrocytes, and neurons.CONCLUSIONSThese findings indicate that abnormal functional lateralization and cooperation in BD with potential molecular and cellular basis.

2024-12-01·Current Medicinal Chemistry

The Roles of Endogenous D2R Dopamine and μ-opioid Receptors of the Brain in Alcohol use Disorder

Review

作者: Bjørklund, Geir ; Khikhmetova, Kamila ; Semenova, Yuliya

:Alcohol use disorder (AUD) affects millions of people worldwide. It is characterized by a strong physiological and psychological craving to consume large amounts of alcohol despite adverse consequences. Alcohol use disorder carries a large health and economic burden on society. Despite its prevalence, AUD is still severely undertreated. The precise molecular mechanisms of how alcohol addiction forms are yet unknown. However, previous studies on animal models show that along with the μ-opioid receptors, the D2R dopamine receptors may also be involved in alcohol craving and reward pathways. Currently, there is a limited number of treatment strategies for alcohol use disorder, which include several medications and therapy. By understanding the limitations of current treatment options and exploring new potential targets, it could be possible to find more effective ways of treating AUD in the future.

2024-12-01·Cellular and Molecular Neurobiology

A Pharmacogenomics-Based In Silico Investigation of Opioid Prescribing in Post-operative Spine Pain Management and Personalized Therapy

Article

作者: Lewandrowski, Kai-Uwe ; Schmidt, Sergio Luis ; Blum, Kenneth ; Elfar, John ; Wetzel, Franklin Todd ; Sharafshah, Alireza

AbstractConsidering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP (https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/snp/), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein–protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene–miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein–Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, l-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein–Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.Graphical Abstract

177

项与 D2 receptor 相关的新闻（医药）

2024-10-16

·GlobeNewswire-Health Care

Neurogastrx Announces Positive Proof-of-Concept Data for Investigational Drug NG101 in Reducing Nausea and Vomiting Associated with the Administration of GLP-1 Agonist Medication

NG101 Significantly Reduced Incidence of Nausea by 40% and Frequency of Vomiting by 56% without Changing the Safety Profile of the GLP-1 AgonistWOBURN, Mass., Oct. 16, 2024 (GLOBE NEWSWIRE) -- Neurogastrx, Inc. today announced positive topline results from a new study of NG101 (metopimazine mesylate) showing significant reduction of nausea and vomiting side effects caused by a glucagon-like peptide 1 (GLP-1) agonist medication. NG101 is an oral, peripherally restricted dopamine D2 receptor antagonist. “The randomized, double-blind, placebo-controlled proof-of-concept (POC) safety and efficacy study showed positive effects of NG101 in participants who received double the starting dose of the GLP-1 agonist semaglutide,” said Cyril De Colle, Ph.D., Chief Scientific Officer, Neurogastrx. “Findings from this study suggest NG101 could be an important addition to GLP-1 agonist therapy, helping more patients adhere to treatment as they transition to the higher doses needed to reach weight loss and broader health goals.” Key efficacy endpoints showed NG101 significantly: Reduced the incidence of nausea by 40% (p=0.0343)Reduced the frequency of vomiting by 56% (p=0.0412) NG101 also significantly reduced both the duration of nausea (p=0.0101) and the participant-reported severity of nausea (p=0.0225). The addition of NG101 to semaglutide dosing was not associated with any new safety findings, including the incidence of other common adverse events (AEs) such as diarrhea or constipation. There were no serious AEs and no discontinuations due to treatment emergent adverse events (TEAEs) in the study. Gastrointestinal (GI) adverse events, especially nausea and vomiting, are the primary challenge to titration and adherence of GLP-1 therapy. A recent real-world adherence study utilizing an IQVIA database followed over 160,000 new semaglutide weight loss patients and showed a 50% discontinuation rate at six months and 70% at one year. “Our POC study offers hope to patients who cannot tolerate these medicines long enough to realize their benefits,” said James O’Mara, President and Chief Executive Officer, Neurogastrx. “We look forward to discussions with the FDA to initiate a larger Phase 2/3 study in 2025, with the goal to bring this product to patients.” Study Design A total of 90 participants aged 18-55 received a single subcutaneous dose of semaglutide (0.5 mg) along with five days of NG101 20 mg twice per day (BID) or placebo. The study evaluated the efficacy of NG101 in reducing the incidence, duration and severity of nausea and vomiting. Efficacy endpoints included: Number of days with TEAEs of nausea and/or vomiting within four days (96 hours) following a single subcutaneous GLP-1 agonist injection.Moderate and/or severe TEAEs of nausea and/or vomiting within four days (96 hours) following a single subcutaneous GLP-1 agonist injection (as graded by the principal investigator or designee).TEAEs of nausea and/or vomiting within four days (96 hours) following a single subcutaneous GLP-1 agonist injection. The study also evaluated the safety of NG101 (20 mg BID) in participants receiving a single subcutaneous injection of the GLP-1 agonist. Primary safety endpoints included incidence and severity of TEAEs (other than nausea and vomiting), and standard laboratory assessments. For more details, go to www.clinicaltrials.gov, NCT006500429. About Neurogastrx, Inc. Neurogastrx, Inc. is a privately held specialty pharmaceutical company developing transformative therapies to advance the treatment of GI disorders for which meaningful therapeutic innovation is required to satisfy unmet patient need and disease burden. Media ContactAmanda BreedingScient PRamanda@scientpr.com

临床结果

2024-10-10

·医药观澜

针对精神分裂症，超15款在研新药正在中国开展临床研究丨世界精神卫生日

▎药明康德内容团队报道今日（10月10日）是世界精神卫生日。精神分裂症作为一种常见的严重精神疾病，再次引起广泛的关注。根据世界卫生组织（WHO）数据[1]，全球范围内约有2400万人正遭受着精神分裂症的折磨，即每300人中就有1人患有精神分裂症（0.32%）。尽管当下一些疗法可以有效控制某些症状，但仍有很大一部分患者对现有疗法无效，或出现不可接受的副作用。精神分裂症新药开发难度大，失败率高，研发界一直期待能够在这一领域有新的突破。好消息是，随着科学研究的进展，这一领域已经迎来了诸多有希望的进展。本文将根据公开资料，整理当前在中国正在研发的部分精神分裂症产品管线，仅供读者参阅。（注：本文为不完全统计，仅盘点部分在中国正在开展临床研究的精神分裂症在研管线。）图片来源：123RF 再鼎医药/百时美施贵宝：KarXT 作用机制：M1/M4毒蕈碱乙酰胆碱受体激动剂中国研发阶段：3期临床 KarXT（xanomeline-trospium）是一种毒蕈碱类抗精神病药物。该产品于今年9月27日获美国FDA批准，用于治疗成人精神分裂症。彼时FDA新闻稿指出，这是靶向胆碱能受体的首个抗精神病药物，也标志着数十年来首个治疗精神分裂症的新机制药物。KarXT在中枢神经系统中充当M1/M4毒蕈碱乙酰胆碱受体激动剂，被认为可以改善精神分裂症的阳性、阴性和认知症状。且与现有疗法不同，KarXT不会直接阻断多巴胺受体。在中国，再鼎医药拥有KarXT在大中华区的权益。再鼎医药正在开展一项评估KarXT用于精神分裂症的3期桥接注册研究。勃林格殷格翰：lclepertin（BI 425809）作用机制：Gly-T1抑制剂中国研发阶段：3期临床 Iclepertin是勃林格殷格翰（Boehringer Ingelheim）管线中一款新型甘氨酸转运蛋白1（Gly-T1）抑制剂，通过抑制Gly-T1，改善N-甲基-D-天冬氨酸（NMDA）受体的功能减退起到治疗作用。NMDA受体功能低下导致的谷氨酸能途径异常是精神分裂症发病的病理原因之一。目前该产品正在开展针对精神分裂症的全球3期临床，中国同步参与其中。2021年5月，FDA 基于一项2期临床试验的积极结果，授予lclepertin治疗精神分裂症的突破性疗法认定。同年6月，该产品在中国被CDE纳入突破性治疗品种，用于治疗与精神分裂症相关的认知障碍（CIAS）。中泽医药：ZZ6398 作用机制：D2/D3/5-HT1A/5-HT2A受体泛拮抗剂中国研发阶段：2期临床 ZZ6398是一款D2、D3、5-HT1A和5-HT2A四个受体泛拮抗剂，可通过合理D2/D3选择性和5-HT1A拮抗作用，来同时改善精神分裂阳性、阴性和认知症状。目前，中泽医药正在开展该产品针对精神分裂症患者的一项1b/2a期临床研究。翰森制药：HS-10380片作用机制：多靶点激动剂中国研发阶段：2期临床 HS-10380是翰森制药神经系统疾病领域的研发项目之一，为一款D2、D3受体和5-HT1A部分受体多靶点激动剂，对5-HT2A受体具显著拮抗作用，有望改善精神疾病患者的症状。根据药物临床试验登记与信息公示平台，翰森制药正在开展HS-10380片治疗急性期精神分裂症的一项2期临床研究，以及一项针对中国成年精神分裂症患者的1b/2期临床研究。灵北制药/恩华药业：Lu AF35700/NHL35700 作用机制：小分子靶向药中国研发阶段：2期临床 Lu AF35700是灵北公司（Lundbeck）开发的一款口服小分子药物，拟治疗难治性精神分裂症。公开资料显示，该产品可靶向多巴胺受体、血清素受体和肾上腺素受体，对多巴胺D1受体的亲和力高于D2受体，其药理学机制有望减少锥体外系反应、高泌乳素血症等副作用的发生率。2021年11月，恩华药业与灵北达成合作，获得Lu AF35700在大中华区的独家权益。根据中国药物临床试验登记与信息公示平台，一项评价NHL35700治疗精神分裂症的2期临床试验正在进行中。京新药业：JX11502MA片作用机制：多巴胺D3/D2受体部分拮抗/激动剂中国研发阶段：2期临床公开资料显示，JX11502MA为京新药业在研的一款多巴胺D3/D2受体部分拮抗/激动剂，它同时对5-HT1A和5-HT2A受体具有拮抗作用，可以改善精神分裂症患者的情感淡漠。根据药物临床试验登记与信息公示平台，京新药业正在开展一项2b期和一项2c期临床研究，评估JX11502MA针对成人急性期精神分裂症的有效性和安全性。绿叶制药：LY03020 作用机制：TAAR1/5-HT2CR双靶点激动剂中国研发阶段：1期临床 LPM787000048马来酸盐缓释片（LY03020）为绿叶制药开发的一款痕量胺相关受体1（TAAR1）和5-羟色胺2C受体（5-HT2CR）双靶点激动剂。目前，该产品针对精神分裂症和阿尔茨海默病精神病性障碍的1期临床研究均已启动。据公开资料，不同于已上市抗精分药物抑制突触后膜D2和5-HT2A受体的机制，新一代抗精分药物以激动突触前膜为特征。TAAR1和5-HT2CR双靶点作用机制可起到提高疗效，减少不良反应的作用，有望减少锥体外系反应（EPS）和代谢综合征等不良反应，并可显著改善精神分裂症阴性症状和认知症状等。礼来/索元生物：DB103（pomaglumetad methionil）作用机制：强效mGlu2/3受体激动剂中国研发阶段：1期临床 DB103是索元生物从礼来公司（Eli Lilly and Company）引入的一款新药，是一种强效mGlu2/3受体 (mGlu2/3R)激动剂 (LY404039) 的甲硫氨酸前体药物，计划开发用于治疗精神分裂症。据索元生物官网介绍，LY404039的临床前特征显示了潜在的临床疗效，但在人体胃肠道中的生物利用度非常差。向LY404039添加氨基酸甲硫氨酸，可通过经由人肽转运蛋白（hPepT1）的主动转运作用，而提高口服生物利用度。根据中国药物临床试验登记与信息公示平台，一项DB103在早期精神分裂患者中的1b期研究已经完成。恩华药业：NH300231肠溶片作用机制：5-HT2A受体拮抗剂和多巴胺受体调节剂中国研发阶段：1期临床 NH300231是恩华药业研发的1类新药，为新一代非典型抗精神分裂症药物。它是一种5-HT2A受体拮抗剂和多巴胺受体调节剂，且对5-HT2A受体的拮抗活性明显高于多巴胺D2受体，同时能够抑制五羟色胺转运体活性。根据中国药物临床试验登记与信息公示平台官网，恩华药业正在开展一项1期临床研究，评估单次口服NH300231的安全性、耐受性和药代动力学特征。旺山旺水生物医药/中国科学院上海药物研究所：TPN672 作用机制：双向调节多巴胺受体中国研发阶段：1期临床 TPN672是一款在研抗精神分裂症药物，由中国科学院上海药物研究所和旺山旺水生物医药共同开发。公开信息显示，TPN672对多巴胺受体具有双向调节作用，并同时作用于5-羟色胺受体和5-羟色胺转运体，从而起到平衡调节中枢神经系统功能的作用。它在临床前研究中表现出改善精神分裂症阴性症状和认知功能的作用。根据中国药物临床试验登记与信息公示平台，该产品已经完成两项1期临床，还有一项评价TPN672片在精神分裂症患者的1b期临床研究目前状态为主动暂停。默沙东（MSD）：MK-8189 作用机制：PDE10A选择性抑制剂中国研发阶段：1期临床 MK-8189是一款磷酸二酯酶10A（PDE10A）的选择性抑制剂。PDE10A在人脑纹状体中大量表达，而在其他组织中没有。纹状体的异常输出与精神分裂症阳性症状有关，包括精神病、幻觉和妄想。临床前研究表明，PDE10A抑制剂有可能缓解多巴胺能和谷氨酸能功能障碍，表明MK-8189除了精神病症状外，还可能对认知障碍具广谱活性。MK-8189已在精神分裂症患者中完成多项1期试验，在全球正在进行2期临床。根据中国药物临床试验登记与信息公示平台，一项评价MK-8189在健康中国受试者中的安全性、耐受性和药代动力学行为的多次给药临床研究已经完成。旺山旺水生物：VV119胶囊中国研发阶段：1期 VV119胶囊为一款化药1类新药，于2023年在中国获批IND。根据中国药物临床试验登记与信息公示平台官网，旺山旺水生物正在开展两项1期临床研究，分别评估单次和多次口服VV119胶囊，在中国成年健康受试者和精神分裂症患者中的安全性、耐受性和药代动力学特征。翰森制药：HS-10509片中国研发阶段：1期 HS-10509片为翰森制药在研的一款1类化药新药，目前正在开展针对中国精神分裂症成人患者的1期临床研究。绿叶制药：LPM526000133富马酸盐胶囊（LY03017）中国研发阶段：1期绿叶嘉奥制药申报的LPM526000133富马酸盐胶囊已在中国获批临床，拟开发治疗精神分裂症阴性症状（NSS）、帕金森病精神病性障碍（PDP）相关的幻觉和妄想、阿尔茨海默病精神病性障碍（ADP）相关的幻觉和妄想。根据中国药物临床试验登记与信息公示平台，绿叶制药已针对该产品开展三项1期临床研究，评估其安全性、耐受性和药代动力学。恩华药业：CY150112 中国研发阶段：1期临床 CY150112片是恩华药业正在研发的一款小分子药物（尚未披露靶点机制），于2020年在中国获批临床，开展精神分裂症的临床试验。根据中国药物临床试验登记与信息公示平台，一项评价CY150112片在成人健康受试者中滴定给药及多次给药的1b期临床研究正在招募中。纽欧申医药：NS-136 作用机制：毒蕈碱型乙酰胆碱M4受体正向变构调节剂中国研发阶段：获批临床 NS-136片是纽欧申医药研发的一款新型选择性毒蕈碱型乙酰胆碱M4受体正向变构调节剂（M4 PAM）。纽欧申医药此前新闻稿介绍，对M4受体进行正向调节是治疗精神分裂症的新作用机制，尤其是对阴性症状和认知功能损伤的改善被认为是精神分裂症治疗重要的进步。NS-136片此前已在澳大利亚启动1期临床研究。今年7月，该产品在中国获批IND，适应症为精神分裂症。参考资料： [1]各公司官网及公开新闻稿 [2]中国药物临床试验登记与信息公示平台官网. From http://www.chinadrugtrials.org.cn/index.html [3]WHO官网. From https://www-who-int.libproxy1.nus.edu.sg/news-room/fact-sheets/detail/schizophrenia 本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

突破性疗法临床2期临床3期临床1期

2024-09-27

·医药魔方

全球首批！创新机制疗法获FDA批准，再鼎医药这款新药的潜力有多大？

2024年9月26日，百时美施贵宝（BMS）同类首创新药Cobenfy (xanomeline和trospium chloride复方，KarXT）顺利获得FDA批准上市，用于治疗成人精神分裂症，成为数十年来首个获批的全新机制的精神分裂症治疗药物，也是首款获批治疗精神分裂症的毒蕈碱乙酰胆碱受体激动剂。 KarXT最初由Karuna Therapeutics开发，2021年11月，再鼎获得了这款产品在大中华区的权益，并正在参与其多个全球临床研究。根据再鼎医药此前发布的信息，目前这款药物在中国开展的用于精神分裂症的注册性临床正在进行中，患者入组已全部完成，未来如果其在中国获批上市，也将会给中国精神分裂症患者治疗带来重大变革。据Evaluate发布的最新报告，其预测的2030年前十大最有价值的管线中，KarXT位列第九，年销售额有望达到31亿美元。制药巨头BMS也是看到了这款药物的潜力，于2023年底以140亿美元价格收购Karuna，获得了这款药物。精神分裂症：巨大未满足需求亟待解决据统计，2023年全球销售额达到30亿美元以上的创新药有51款，其中不乏多款上市多年的重磅药物。KarXT还未上市就被预测也能到达这一水准，背后最首要原因就是精神分裂症的巨大临床需求。精神分裂症是一种病因未明的严重慢性精神疾病，临床症状表现多样，涉及感觉、思维、情感、意志行为、认知功能等多方面，比较典型的阳性症状包括幻觉、妄想、躁狂、易怒、言语行为紊乱等，比较典型的阴性症状包括情感迟钝冷漠、意志贫乏、认知障碍等，而且精神分裂症患者临床症状的个体差异很大。这种疾病影响了全球大约2400万人口，美国大约有280万患者[1]。中国有超过800万精神分裂症患者。目前批准的抗精神病药物主要通过阻断多巴胺D2受体作为拮抗剂或部分激动剂起作用，对于控制患者的阳性症状具有较好的效果，但是对阴性症状和认知症状的改善几乎无能为力。另外，经典抗精神病药由于对多巴胺其他受体亚型（D1,D3,D4,D5）和D2受体位置的选择性不高，通常会带来药源性阴性症状和锥体外系副作用。一些针对5-HT2的非典型精神病药能够降低锥体外系副作用，但是对阴性症状的改善依然充满争议[2]。从药物疗效和安全性上看，目前至少1/3的精神分裂症患者对现有的治疗药物无法产生应答，另外50%患者的症状只有部分改善或出现不可接受的副作用[1]，75%的患者会在治疗18月后会因严重副作用停止治疗[3]，新的精神分裂症药物是远未得到满足的需求。但是受限于精神分裂症这种疾病本身的特殊性，病因的复杂性，动物模型建造的难度，创新药的开发几乎跟阿尔茨海默症一样是整个制药行业的重灾区。由医药魔方全球新药数据库NextPharma可以发现，针对多巴胺D2、5-HT受体之外靶点的精神分裂症新药开发除了此次获批的KarXT外，在近几十年来无成功案例。注：虽图表中有涉及α-肾上腺素受体、MALT1、μ阿片受体药物，不过为多靶点新药，其中也包含多巴胺D2、5-HT受体，例如：硫利达嗪，同时靶向MALT1、多巴胺D2、5-HT2A受体； KarXT：为精神分裂症患者带来新希望近50年来，精神分裂症药物的开发屡屡受挫，鲜有新靶点/新机制疗法获得积极的临床数据，而KarXT一路走来，从2019年积极II期数据披露到III期注册性临床大获成功再到近日获得FDA批准，实属不易。 KarXT是由呫诺美林和曲司氯胺组成的毒蕈碱受体（mAChR）的口服调节剂。其中，呫诺美林是中枢毒蕈碱受体M1和M4双激动剂；而曲司氯胺则是临床上使用多年的外周毒蕈碱受体拮抗剂。所以这个精神分裂症复方算是“老药新用”。 KarXT的两种成分由于经不同的肝药酶代谢，并且半衰期不同，所以在搭配使用的机制上就显得比较巧妙。比如，精神分裂症患者的阳性症状（如躁狂、易怒）容易控制，但阴性症状（如冷漠、意志贫乏）较难改善，呫诺美林可以刺激中枢毒蕈碱受体，用于可以缓解精神分裂症患者的阴性症状。曲司氯胺不能透过血脑屏障，无法进入中枢，不会影响呫诺美林的作用，同时可以凭借较长的半衰期持续抑制呫诺美林的外周毒蕈碱受体激动副作用[4]。其有别于现有多巴胺D2受体阻断剂的新型作用机制也就意味着患者有了更多的治疗选择。 KarXT两种成分发挥互补作用疗效方面，KarXT的批准得到了EMERGENT系列研究有效性与长期安全性的数据支持，EMERGENT系列研究包括三项已完成的、对比安慰剂的EMERGENT-1、EMERGENT-2和EMERGENT-3研究，这三项研究均取得阳性的有效性和安全性结果，以及评估KarXT长期安全性的EMERGENT-4和EMERGENT-5研究。所有三项安慰剂对照研究中，KarXT都达到了主要终点，与安慰剂相比，KarXT组阳性和阴性综合征量表 (PANSS) 总分具有统计学意义和临床意义的降低。研究还证明，通过PANSS阳性、PANSS阴性和PANSS阴性Marder因子分量表（研究的次要终点）测量，受试者精神分裂症的阳性和阴性症状均有所减轻。 EMERGENT-3研究中mITT人群KarXT组和安慰剂组PANSS和临床总体改善-严重程度(CGI-S)评分变化（参考资料[5]）今年4月披露的EMERGENT-4试验长期数据中期分析结果显示[1]，52周时，KarXT能显著改善精神分裂症患者所有症状的疗效指标。根据PANSS评分，在开放标签延长期结束时，超过75%的患者症状改善超过30%，与基线（98.4分）相比平均减少33.3分。此外，受试者的临床整体印象-严重程度（CGI-S）评分与基线（5.2分）相比平均改善了1.7分，从基线时的"明显不适"转变为一年后的"中度不适"或"轻度不适"。在长期试验中，KarXT的耐受性普遍良好，其副作用与之前针对精神分裂症患者进行的KarXT试验一致。在52周的治疗过程中，KarXT不会导致泌乳素发生显著变化，也不会导致运动障碍量表评分发生有临床意义的变化。当然，KarXT的潜力还不止于此，其还可作为联合疗法使用，一项代号为ARISE的III期研究正在评估KarXT作为辅助治疗，用于对目前的非典型抗精神病药物治疗反应不足的精神分裂症患者的疗效和安全性。与此同时，KarXT还在开展治疗阿尔茨海默病相关的精神行为症状的注册性临床研究。 KarXT能为中国患者带来什么？ KarXT在美国的获批无疑是数百万美国精神分裂症患者的福音。而中国患者对新型精神分裂症治疗药物的需求也十分迫切。中国目前有超过800万精神分裂症患者，占全球患者总数的1/3[3]，但接受治疗的患者不足一半，从目前的抗精神病药物治疗中获得足够症状改善的人更少。与全球患者类似，中国精神分裂症患者迫切需要更有效的、安全性更高的治疗方法。遗憾的是，目前中国在研的新型精神分裂症药物也十分稀少，根据医药魔方NextPharma数据库，中国目前进入临床试验阶段在研精神分裂症新药仅16款，且大多依然是多巴胺受体以及5-HT受体靶向药物。而KarXT在中国的开发进度也十分领先，已进展至III期临床阶段，有望成为下一款在中国获批上市的精神分裂症新药。中国进入临床阶段的在研精神分裂症新药根据医药魔方TrialCube数据库，目前再鼎医药正在中国开展一项桥接研究（ZL-2701-001），旨在评价KarXT在中国急性精神病成年住院受试者的有效性和安全性。该项III期研究为多中心、两阶段研究，包括5周的双盲阶段（随机、平行分组、安慰剂对照）以及后续的12周开放扩展阶段。研究的主要终点为第5周时PANSS总评分较基线的变化。今年8月12日，再鼎医药宣布已完成所有中国内地患者的入组。据再鼎医药2024年半年报披露，公司预计未来12个月内将向NMPA提交KarXT的上市申请。 KarXT能在中国迅速开展临床研究，正是得益于再鼎医药“自主研发+外部合作”双轮驱动模式。其借助于自身善于市场洞察和BD的优势，率先发现了中国精神分裂症领域巨大未满足临床需求，并早于BMS两年的时间从Karuna Therapeutics手中获得了在大中华区（包括中国内地、香港、澳门和台湾地区）开发、生产及商业化KarXT的独家许可协议，这足以看出再鼎医药的独到眼光和高效执行力。 KarXT也是再鼎医药中枢神经系统疾病领域布局的一款重磅药物，除了被开发用于精神分裂症外，其用于精神分裂症辅助治疗、阿尔茨海默病引起的精神障碍的适应症也正在中国开展III期临床研究。来源：再鼎医药官网总的来说，KarXT作为再鼎医药管线中一项重要资产，再鼎医药必将加快推进其在中国的开发进程，KarXT凭借独特的作用机制和优异的临床治疗效果，很有机会能得到临床医生和患者的青睐，有望在中国市场打开新的天地，为再鼎未来营收增长带来重要助力。总结未来精神分裂症患病人数还将进一步增加，患者对新型药物的需求十分迫切，KarXT的上市将满足这一临床需求，其市场潜力也将得到充分释放。期待这款药物也能尽快在中国上市。 - 上下滑动查看参考资料 - [1]https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-New-Interim-Long-Term-Efficacy-Data-from-the-EMERGENT-4-Trial-Evaluating-KarXT-in-Schizophrenia-at-the-2024-Annual-Congress-of-the-Schizophrenia-International-Research-Society/default.aspx [2]https://www.msdmanuals.cn/professional/psychiatric-disorders/schizophrenia-and-related-disorders/antipsychotic-drugs [3]https://mp.weixin.qq.com/s/EIU0FB1dN2d5bXPZBftI1A [4]Karuna Therapeutics 2019 Wedbush PacGrow Healthcare Conference Presentation— Karuna Therapeutics [5]Kaul I, Sawchak S. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024 Aug 1;81(8):749-756. doi: 10.1001/jamapsychiatry.2024.0785. Erratum in: JAMA Psychiatry. 2024 Aug 1;81(8):846. Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

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