A 12-Month Open-label Extension Study to Evaluate the Long-term Safety, Tolerability, and Effectiveness of SEP-4199 Controlled Release (CR) for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression)

This is a clinical trial to determine the long-term safety and tolerability of an investigational drug in people with Major Depressive Episode Associated with Bipolar I Disorder (Bipolar I Depression). Participants in the study will receive the drug being studied. This study is accepting male and female participants between 18 and 65 years old who have completed Study SEP380-301. This study will be conducted in approximately 90 study centers worldwide. The treatment duration for this study is one (1) year.

开始日期2022-03-17

申办/合作机构

Sumitomo Pharma America, Inc.

NCT05169710

/ Terminated临床3期

A Multi-region, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Evaluating SEP-4199 Controlled Release (CR) for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression)

A clinical trial to study the efficacy and safety of an investigational drug in people with major depressive episodes associated with with Bipolar I disorder (bipolar I depression) Participants in the study will either receive the drug being studied or a placebo. The study will be conducted in approximately 90 sites in North America, Europe, Latin America and Japan. It will be have both male and female participants ages 18-65. Participation in the study will be approximately 10 weeks.

开始日期2021-12-21

申办/合作机构

Sumitomo Pharma America, Inc.

NCT03543410

/ Completed临床2期

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of SEP-4199 for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression)

A clinical study to test the effectiveness of an investigational drug to treat people that have major depressive episodes when they have Bipolar 1 Depression

开始日期2018-06-26

申办/合作机构

Sumitomo Pharma America, Inc.

100 项与 Aramisulpride/Esamisulpride 相关的临床结果

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100 项与 Aramisulpride/Esamisulpride 相关的转化医学

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100 项与 Aramisulpride/Esamisulpride 相关的专利（医药）

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项与 Aramisulpride/Esamisulpride 相关的文献（医药）

2024-10-01·PSYCHIATRY RESEARCH

Enrichment using speech latencies improves treatment effect size in a clinical trial of bipolar depression

Article

作者: Szabo, Steven T ; Siegel, Joshua S ; Opler, Mark ; Cohen, Alex S ; Tomioka, Sasagu ; Hopkins, Seth ; Kirkpatrick, Brian

Clinical trials in depression lack objective measures. Speech latencies are an objective measure of psychomotor slowing with face validity and empirical support. 'Turn latency' is the response time between speakers. Retrospective analysis was carried-out on the utility of turn latencies as an enrichment tool in a clinical trial of bipolar I depression. Speech data was obtained from 274 participants during 1,352 Montgomery-Åsberg Depression Rating Scale (MADRS) recordings in a randomized, placebo controlled, 6-week clinical trial of SEP-4199 (200 mg or 400 mg). Post-randomization turn latencies were compared between patients with moderate to severe depression and patients whose depression had remitted. A cutoff was determined and applied to turn latencies pre-randomization to classify individuals into two groups: Speech Latencies Slow (SL-Slow) and Speech Latencies Normal (SL-Normal). At week 6, SL-Slow (N = 172) showed significant separation in MADRS scores between placebo and treatment arms. SL-Normal (N = 102) showed larger MADRS improvements and no significant separation between placebo and treatment arms. Excluding SL-Normal increased primary outcome effect size by 52 % and 100 % for the treatment arms. Turn latencies are an objective measure available from standard clinical assessments and may assess the severity of symptoms more accurately and screen out placebo responders.

2024-10-01·Contemporary Clinical Trials

A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression

Article

作者: Szabo, Steven T ; Tomioka, Sasagu ; Hopkins, Seth C ; Koblan, Kenneth S

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials. Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710.

2024-08-01·CLINICAL PHARMACOLOGY & THERAPEUTICS

Discovery and Model‐Informed Drug Development of a Controlled‐Release Formulation of Nonracemic Amisulpride that Reduces Plasma Exposure but Achieves Pharmacodynamic Bioequivalence in the Brain

Article

作者: Tsushima, Yuki ; Lew, Robert ; Snowden, Thomas J. ; Shi, Lei ; Rabiner, Eugenii A. ; Watanabe, Takao ; Hopkins, Seth C. ; Wilding, Ian ; Koblan, Kenneth S. ; Darpo, Borje ; Searle, Graham E. ; Corriveau, Taryn J. ; Zann, Vanessa ; Galluppi, Gerald R. ; van der Graaf, Piet H. ; Asada, Takumi ; Szabo, Steven T. ; Toongsuwan, Siriporn

Nonracemic amisulpride (SEP‐4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP‐4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled‐release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24‐hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non‐human primates produced significantly greater D2R occupancies during a gradual 6‐hour administration compared with a single bolus; (iii) concentration–occupancy curves were left‐shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model‐informed drug development to continue in Phase III using the non‐bioequivalent CR formulation with diminished QT prolongation as dose‐equivalent to the immediate release (IR) formulation utilized in Phase II.

项与 Aramisulpride/Esamisulpride 相关的新闻（医药）

2025-12-22

·情绪障碍笔记

双相情感障碍药物研发进展：锂盐疗效确认75年之后

摘要双相情感障碍是一种以显著情绪波动为特征的精神疾病，与精神分裂症存在较强的遗传关联。该病多在青春期发病，对患者心理社会功能影响显著，因此需要持续且综合的干预。尽管传统心境稳定剂仍被广泛使用，但学界对更有效疗法的探索从未停止，当前研究已覆盖疾病发展的多个阶段。本研究对截至2024年4月22日处于II期和III期临床试验阶段的治疗双相情感障碍的新药进行了全面梳理。通过系统检索美国国立卫生研究院国家医学图书馆数据库，重点关注已进入后期试验阶段的药物再定位及创新药物。研究识别出数种前景良好的治疗药物，包括针对伴有自杀倾向的重度心境障碍的药物，以及旨在治疗与心境相关的神经炎症的药物。其中，能增强多巴胺稳定性的药物以及作用于5-羟色胺受体活性的药物表现突出。此外，本研究探讨了现有药物通过策略性再定位以扩大治疗用途的潜力，并评估了旨在快速控制症状的新剂型的可能性。我们的分析强调了应对双相情感障碍的两大主要策略：挖掘现有药物的新用途，以及开发具有独特作用机制的新药。这一方向体现了药物治疗的持续进步，有助于患者更好地管理病情，并应对双相情感障碍的复杂本质。 1. 引言双相情感障碍是一种以情绪波动为主要特征的精神障碍，并与精神分裂症存在显著的遗传关联。该障碍通常始于青春期，表现为不同阶段，严重影响患者的心理社会功能，需要长期且细致的综合管理（McIntyre 等人，2020）。在躁狂发作期进行有效干预对于降低患者自身及他人的风险至关重要，锂盐、丙戊酸和卡马西平等心境稳定剂以及各类抗精神病药物已被证实有效。对于抑郁期，喹硫平、鲁拉西酮和拉莫三嗪显示有效，其中锂盐被推荐为主要治疗药物，尽管其抗抑郁效果相较于抗躁狂作用较为有限（Volkmann 等人，2020）。维持治疗的主要目标是预防躁狂和抑郁发作的复发。锂盐、喹硫平和长效注射剂已被证明对此目标有效。锂盐是唯一一种对上述大部分情况都有效的药物，并且有证据表明其可有效预防双相情感障碍患者的自杀行为。迄今为止，我们尚未发现任何在疗效上显著超越锂盐的药物（Lewitzka 等人，2015）。尽管距离锂盐疗效首次被评估（Cade, 1949）已近75年，它仍然是该类中最重要的药物。在此背景下，最初为精神分裂症开发的第二代抗精神病药已逐渐被用作双相情感障碍的治疗。当前药物的耐受性和安全性已引起广泛关注，开发新药对于为患者提供长期治疗选择至关重要。双相情感障碍的治疗策略已经从心境稳定剂逐渐演变为使用第二代抗精神病药（Rhee 等人，2020）。这些药物在治疗精神分裂症方面有已证实的记录，其使用也基于其安全性和广泛应用（Kort 和 Jovinge, 2021）。本综述概述了目前处于II期和III期临床试验阶段的，针对双相情感障碍的药物再定位和创新药物研发进展。每种药物都因其独特的作用机制和应对双相情感障碍不同方面的潜力而受到研究。这些研发进展正通过持续的研究和临床试验进行监测。 2. 方法我们检索了截至2024年4月22日的美国国立卫生研究院国家医学图书馆临床试验数据库，以寻找仍处于临床试验阶段的药物。我们的检索范围限定在II期和III期研究，旨在识别具有相当潜力的药物。根据其研发阶段，这些药物被分为两类：药物再定位和创新药物。药物再定位指的是使用已获批准治疗其他疾病的药物，而创新药物则指专为治疗双相情感障碍而新开发的药物。 3. 结果我们识别出7种在研药物（表1），并将其分为两类："药物再定位"和"创新药物"。 3.1. 药物再定位 3.1.1. 依匹哌唑（中国大陆叫布瑞哌唑）依匹哌唑已获美国批准用于治疗精神分裂症、作为成人重度抑郁障碍抗抑郁药的辅助治疗，以及用于管理阿尔茨海默病痴呆相关的激越症状（FDA批准药物，REXULTI）。其作用类似于阿立哌唑，是一种多巴胺部分激动剂，但在D2受体的活性降低，对5-HT2A、5-HT1A和α-1B肾上腺素能受体的亲和力增强。这一特性或可降低静坐不能和锥体外系症状的风险（Stahl, 2016）。大冢制药正在扩大其在双相I型和II型障碍领域的研究。其在躁狂发作期双相I型患者中进行的III期试验结果已经披露。包括两项随机、双盲、安慰剂对照试验和一项评估依匹哌唑对急性躁狂发作疗效的长期开放标签研究。研究显示，在这些研究中，依匹哌唑与安慰剂在症状减轻方面无显著差异；然而，长期研究中的患者在杨氏躁狂评定量表得分上显示出逐渐改善（Vieta等人，2021）。一项针对目前处于抑郁期的双相障碍患者的初步研究，评估了为期八周、每日最高4 mg的依匹哌唑。该研究使用了蒙哥马利-阿斯伯格抑郁评定量表和自评抑郁症状量表，结果显示抑郁症状显著减轻，生活质量得到提升（Brown等人，2019）。此外，一项针对双相I型抑郁的依匹哌唑III期开放标签试验正在进行中（ClinicalTrials.gov，ID NCT0456944）。 3.1.2. BXCL501 右美托咪定于2022年4月获FDA批准用于管理精神分裂症或双相I型或II型障碍成人患者的急性激越症状（FDA批准药物，IGALMI）。BioXcel Therapeutics将该药物制成舌下膜剂给药。BXCL501含有与右美托咪定相同的活性成分，由BioXcel Therapeutics开发用于家庭使用，针对双相障碍或精神分裂症的急性激越症状。 BXCL501的作用机制涉及对中枢神经系统（包括脑干）内α2肾上腺素能受体的调节。这种激活抑制了神经递质的释放，从而减轻激越并产生镇静作用（Jones等人，2023）。一项分两阶段的III期双盲、安慰剂对照研究评估了BXCL501在此情况下的安全性和有效性（ClinicalTrials.gov ID NCT04276883）。初始阶段在临床环境中测试了60微克的BXCL501，而后续阶段则侧重于家庭给药。初始阶段的主要疗效结果显示，在给药后2小时与安慰剂相比无显著差异；然而，在4小时观察到显著改善。60微克剂量被证明是安全且耐受性良好的，未报告严重不良事件。这些发现支持了基于初始试验结果，BXCL501 60微克或更高剂量（如80微克）潜在的家庭应用（Preskorn等人，2022）。 3.1.3. 大麻二酚美国食品药品监督管理局已批准大麻二酚（商品名Epidiolex）用于治疗严重癫痫类型，具体为Dravet综合征、Lennox-Gastaut综合征以及与结节性硬化症相关的癫痫发作（FDA批准药物，EPIDIOLEX）。大麻二酚的作用机制包括间接调节内源性大麻素系统、影响T型钙通道、增强γ-氨基丁酸效应以降低神经元过度兴奋，以及通过其抗炎特性减少癫痫发作的频率和强度（Bladen等人，2015；Dearborn等人，2022；Zavala-Tecuapetla等人，2022）。近期研究表明，大麻二酚调节中枢神经系统的神经递质平衡，稳定情绪并缓解双相情感障碍的情绪波动，同时还能减轻焦虑。这种调节作用有助于在躁狂或抑郁发作的高焦虑阶段稳定情绪（Khan等人，2020；Scherma等人，2020）。此外，其抗炎和神经保护特性可能减少炎症反应并保护神经元细胞，从而可能减缓双相情感障碍中神经退行性变的进展。爵士制药公司是正在进行的研究与开发工作的领导者。不列颠哥伦比亚大学正在进行一项为期六周、双盲、平行组随机对照的III期试验，研究大麻二酚作为双相抑郁的辅助疗法。该试验评估了大麻二酚对比安慰剂，在标准治疗（如锂盐或拉莫三嗪）反应不佳的急性双相抑郁患者中的疗效、安全性和耐受性。本研究旨在阐明大麻二酚的治疗潜力及其在治疗双相抑郁中的总体安全性和有效性（ClinicalTrials.gov，ID NCT04276883）。 3.2. 创新药物 3.2.1. NRX-101 NRX-101是一种在研化合物，针对伴有自杀意念的重度双相抑郁。该口服制剂以固定剂量组合了NMDA受体调节剂D-环丝氨酸和D2受体及5-HT2A受体拮抗剂鲁拉西酮。NRx制药公司主导其开发。 D-环丝氨酸作为NMDA受体的部分激动剂，对学习、记忆和神经可塑性至关重要（Goff等人，1999）。鲁拉西酮通过阻断5-HT2A受体，在缓解情绪和焦虑症状方面具有潜力，并可能减少抗精神病药物相关的不良反应（Wang等人，2020）。经过初步稳定治疗后，NRX-101专门针对具有明显双相抑郁和自杀倾向的患者。 II期结果已披露，突出了一项多中心双盲随机试验。最初，患有双相抑郁和自杀倾向的成年人接受氯胺酮或生理盐水治疗。有反应者进入第二阶段，接受D-环丝氨酸与鲁拉西酮的固定剂量组合或单独使用鲁拉西酮。使用临床总体印象量表严重程度分量表评估整体改善情况。联合疗法在改善抑郁和减少自杀意念方面显著优于单独使用鲁拉西酮（Nierenberg等人，2023）。 2024年1月，NRx制药公司完成了NRX-101在伴有自杀意念的难治性双相抑郁中的IIb/III期试验受试者招募（ClinicalTrials.gov，ID NCT03395392）。这项为期六周的随机、前瞻性、多中心、双盲研究比较了NRX-101与鲁拉西酮。 3.2.2. JNJ 55308942 JNJ 55308942是一种P2X7拮抗剂，正在研究作为双相情感障碍及相关心境障碍的潜在疗法。近年来，已明确该化合物在中枢神经系统中的主要作用与炎症反应相关（Bhattacharya，2018）。 P2X7受体的激活会触发小胶质细胞释放白细胞介素-1β等促炎细胞因子。这些细胞因子导致神经炎症，可能加剧双相情感障碍的情绪波动和认知缺陷（Miller和Raison，2016）。此外，JNJ 55308942可中断NLRP3炎症小体的组装和激活，从而抑制caspase-1的活化和IL-1β的释放，并减少炎症（Bhattacharya等人，2018）。强生公司和杨森制药正在进行JNJ 55308942的II期开发（ClinicalTrials.gov，ID NCT05328297）。当前的II期试验评估了JNJ-55308942在减轻双相情感障碍抑郁症状方面的疗效。在这项随机、双盲、安慰剂对照研究中，参与者每天接受JNJ-55308942或安慰剂，为期六周。 3.2.3. OSU6162 OSU6162是一种多巴胺稳定剂，可降低多巴胺功能过度活跃和低下状态。在一项涉及健康受试者的研究中，研究人员正在考察其治疗一系列神经精神疾病（包括双相情感障碍、帕金森病、精神分裂症、注意缺陷多动障碍和慢性疲劳综合征）的潜力（Tolboom等人，2015）。在双相情感障碍中，OSU6162作为D2受体和5-HT2A受体的部分激动剂发挥作用，旨在平衡这些神经递质并缓解疾病症状（Burstein等人，2011；Melas等人，2021）。哥德堡大学目前正在推进OSU6162的研究，II期试验正在进行中（ClinicalTrials.gov，ID NCT05296356）。该试验是一项探索性、开放标签、单组、灵活剂量、为期八周的II期试验。重点评估OSU6162在双相抑郁患者中的有效性和安全性。本研究招募被诊断为原发双相I型或II型障碍、正处于急性抑郁期的住院患者。 3.2.4. SEP-4199 SEP-4199是氨磺必利对映体的非外消旋混合物，其特点是相对于D2受体，对5-HT7受体的活性增强，这可能增强其治疗双相抑郁的抗抑郁疗效（Hopkins等人，2021）。 II期试验结果已报告，该试验涉及来自美国、欧洲和日本的344名患者（ClinicalTrials.gov，ID NCT03543410）。参与者被随机分配接受SEP-4199，剂量为200毫克/天、400毫克/天或安慰剂。试验显示，在初步分析中，两种剂量均改善了蒙哥马利-阿斯伯格抑郁评定量表总分，SEP-4199 200毫克/天的效应值为0.31，400毫克/天的效应值也为0.29。CGI-S-双相版本量表评分的变化显示两种剂量均有显著改善，SEP-4199 200毫克/天的效应值为0.34，400毫克/天的效应值为0.31。不良事件发生率低，对体重和血脂影响极小（Loebel等人，2022）。 4. 讨论在本综述过程中发现，双相情感障碍新型疗法的研发有两个方向：针对精神分裂症和其他疾病的药物再定位，以及开发具有新作用机制的药物。依匹哌唑、NRX-101、OSU6162和SEP-4199是多巴胺D2受体的部分激动剂，并且在其他受体上也表现出活性。D2受体是多巴胺受体家族的成员，是一种G蛋白偶联受体，可结合神经递质多巴胺。该受体激活细胞内信号通路以调节神经元活动。其主要作用包括调节与大脑奖赏系统相关的认知功能和情绪、药物依赖、食欲、性欲、基底节运动的平滑协调、学习和记忆。临床上，多巴胺过度与D2受体结合被认为与精神分裂症的症状有关，抗精神病药物作为该受体的拮抗剂发挥作用。在帕金森病的治疗中，D2受体激动剂被用来模拟多巴胺的作用并增强运动功能（Tsuboi等人，2022）。双相情感障碍与D2受体的关联表明，多巴胺系统内的失衡可能是双相情感障碍病因的基础。D2受体在多巴胺信号传导中至关重要，其活性的改变可能促成双相情感障碍的情绪变化，尤其是抑郁和躁狂发作（Jones等人，2021）。双相情感障碍个体多巴胺受体功能和表达的异常被认为是该病症状产生的原因之一（Hsueh等人，2021）。依匹哌唑、NRX101和OSU6162是5-HT2A受体的部分激动剂，依匹哌唑还是5-HT1A受体的部分激动剂。5-HT2A受体主要位于中枢神经系统，对神经传递和心理功能不可或缺。它参与各种心理过程、行为和情绪调节，并且是精神科药物（包括抗抑郁药和抗精神病药）的作用焦点。此外，该受体在致幻剂的药效学中起着关键作用，LSD和裸盖菇素等药物通过与之结合诱导幻觉效应（Carhart-Harris和Nutt，2017）。 5-HT1A受体是5-羟色胺受体的一种，主要存在于大脑的特定区域。该受体作为一种具有自我抑制功能的突触前受体发挥作用，也存在于神经元的突触后侧，涉及许多神经传递过程（Rojas和Fiedler，2016）。5-HT1A受体在抗抑郁药的效果中起着重要作用。激活该受体被认为是抗抑郁药发挥作用的机制之一，而5-HT1A受体激动剂被认为具有抗抑郁作用（Smith等人，2023）。它还参与焦虑的调节，据报道激活该受体的药物具有抗焦虑作用，并被用于治疗焦虑症（Feighner和Boyer，1989）。此外，它被认为具有神经保护作用，并正在被研究作为治疗神经退行性疾病的潜在靶点（de Aguiar等人，2021）。5-HT1A受体可能在双相情感障碍的病理生理学中发挥重要作用，因为5-羟色胺系统功能障碍牵涉其中。5-HT1A受体参与情绪调节、焦虑抑制和应激反应调节，这表明针对这些受体的药物可能有效治疗双相情感障碍（Lan等人，2013）。 SEP4199与5-HT7受体相关。5-HT7受体是一种属于GPCR家族的5-羟色胺受体，被认为参与介导5-羟色胺在神经系统中的作用，并在认知、情绪、睡眠和体温调节等多种生理功能中发挥作用（Nikiforuk，2015）。5-HT7受体影响认知、情绪、睡眠和体温调节，并参与这些过程的调节。具体来说，它在记忆和学习中的作用及其潜在的抗抑郁作用已被指出（Roberts和Hedlund，2012）。此外，该受体影响消化道的运动和平滑肌的松弛，表明其在各种生理功能和病理状况中具有重要作用（Osman等人，2023）。5-HT7受体被认为参与多种大脑功能，如情绪、睡眠、学习记忆、应激、癫痫发作和昼夜节律调节。此外，特别是在患有心境障碍的人群中，5-HT7受体可能在介导认知方面发挥关键作用。鉴于这些关联，5-HT7受体可能是治疗心境和焦虑障碍的一个有前景的靶点（Gottlieb等人，2023）。 BXCL501具有独特的特征，是α-2肾上腺素能受体的部分激动剂。α-2肾上腺素能受体作为G蛋白偶联受体超家族的一部分，对肾上腺素和去甲肾上腺素表现出高亲和力，主要通过调节血压和产生镇静效果对神经系统发挥抑制作用。激活这些受体可减少神经递质在突触前神经元的释放，从而减弱中枢神经系统内的兴奋机制。它们协调一系列抑制性反应，包括血管收缩、血压调节、心率降低、镇痛和镇静。具体来说，α-2肾上腺素能受体的刺激会阻碍去甲肾上腺素的释放，从而调节神经元兴奋性（Giovannitti等人，2015）。在双相情感障碍中，这些受体被认为在神经递质释放和神经元传导中发挥调节作用（Bücheler等人，2002）。大麻二酚将成为一种与大麻素系统相关的在研药物。大麻素受体是体内内源性大麻素系统的一部分，主要包括CB1和CB2两种类型。CB1受体主要分布在大脑中，主导心理效应，而CB2受体在免疫系统和外周组织中更丰富，在炎症和疼痛调节中发挥作用。这些受体通过源自大麻植物的植物大麻素和体内产生的内源性大麻素的激活来调节各种生理过程。一些研究表明，内源性大麻素系统的失调可能与双相情感障碍相关的情绪波动有关。该系统通过大麻素受体影响与情绪调节相关的关键过程，如大脑的奖赏系统和应激反应，这可能有助于理解双相情感障碍的病理生理学和治疗策略（Arjmand等人，2019）。炎症信号已成为双相情感障碍中一个值得关注的概念（Jones等人，2021）。处理双相情感障碍中的过度炎症可能改善神经进行性改变和共病，提供治疗益处（von Mücke-Heim和Deussing，2023）。JNJ55308942是唯一一种因其独特性质而脱颖而出的P2X7拮抗剂。P2X7受体是一种由细胞外三磷酸腺苷门控的三聚体离子通道，存在于越来越多的不同细胞类型中，包括干细胞、血细胞、神经胶质细胞、神经元、眼细胞、骨细胞、牙细胞、外分泌细胞、内皮细胞、肌细胞、肾细胞和皮肤细胞（Sluyter，2017）。P2X7受体以细胞特异性方式诱导各种下游事件，如炎症分子的释放、细胞增殖和死亡、代谢事件以及对饮食的影响。P2X7受体是一种由细胞外ATP激活的离子通道型受体，在炎症反应中发挥重要作用（Di Virgilio等人，2017；Santos等人，2022）。锂盐仍然是最有证据支持的选项，有强有力的证据支持其在疾病各种状态下的有效性。然而，使用锂盐存在若干安全问题，需要谨慎监测。这些问题包括其治疗窗窄、可能导致甲状腺功能减退、药物相互作用、长期肾毒性风险以及致畸作用（McIntyre等人，2020）。近期研究强调了神经保护和神经传递等机制是锂盐对双相情感障碍患者发挥治疗作用的关键因素（Malhi和Outhred，2016）。在图1中，我们根据锂盐发挥作用的机制对潜在治疗药物进行了分类。锂盐在双相情感障碍长期治疗中最显著的治疗效果之一是其神经保护作用，锂盐作为糖原合成酶激酶-3β的直接抑制剂发挥作用（Carter，2007）。因此，预期它通过调节线粒体功能和减少细胞凋亡来降低神经毒性。然而，目前在我们所调研的在研药物中，尚未发现具有与锂盐类似明确神经保护作用的候选药物。锂盐还具有抗氧化特性，通过谷胱甘肽等抗氧化分子防止脂质过氧化，并抑制白细胞介素-6等炎症因子（Malhi和Outhred，2016）。此外，它通过cAMP反应元件结合蛋白表现出抗炎和抗氧化作用。 JNJ55308942是一种P2X7受体拮抗剂，预期会表现出抗炎作用。此外，其与大麻二酚和P2X7受体的关联近来受到关注（Akcay和Karatas，2024）。抑郁症和双相情感障碍中的炎症假说越来越得到支持，这些药物正从未来个体化治疗的角度受到重视。然而，在现有的双相情感障碍治疗药物如卡马西平和拉莫三嗪（常用作抗惊厥药）中也观察到了神经保护和抗氧化作用。然而，在现阶段，这些发现仅限于动物实验（Leng等人，2013；Onishi等人，2023；Yoshida等人，2007）。关于神经传递，许多美国食品药品监督管理局批准用于治疗双相情感障碍的药物也是针对多巴胺受体的抗精神病药（Goes，2023）。这些药物在维持期使用，但也可用于管理躁狂发作。其副作用，如静坐不能和过度镇静，可以通过调整剂量轻松控制，使其相对安全且广泛应用。锂盐抑制谷氨酸能神经传递并减少多巴胺的代谢。基于此机制，数种药物正在被考虑作为潜在的候选者，包括依匹哌唑、BXCL501、NRX101、OSU6162和SEP4199，这些药物不仅作用于多巴胺，还作用于5-羟色胺和去甲肾上腺素，为未来的发展提供了有前景的途径。此外，人们对神经营养因子、第二信使系统和生物节律的各种影响有了更好的理解（Won和Kim，2017）。随着锂盐作用机制的阐明，预计未来将开发出更安全、更便于使用的新药。图1. 基于锂作用机制的治疗药物分类目前批准及处于临床研究阶段的药物，根据锂盐作用的三种主要机制进行分类。就抗精神病药物而言，相较于抑郁或混合状态，双相情感障碍躁狂期的发作持续时间往往更短。因此，主要用于治疗躁狂发作的药物在图示中更靠右放置。 5. 结论当前用于治疗双相情感障碍的许多药物主要通过药物再定位策略引入，其研发重点在于安全性与耐受性。这与将抗癫痫药物作为传统情绪调节剂使用的趋势相符。另一方面，尽管业界期待能阐明躁郁状态病理生理机制的新药，此类药物目前仍较为稀缺。锂盐在多种临床场景中仍是一种有效药物，但其存在治疗窗狭窄等诸多问题。因此，临床亟待开发更具优势、能有效应对双相情感障碍的药物。

2024-08-26

·PRNewswire

Schizophrenia Market: RISVAN's Approval Has Sparked a Competitive Race Among Pharmaceutical Companies | DelveInsight

The recent approval of Rovi Pharmaceuticals Laboratories' OKEDI/RISVAN (risperidone ISM) has spiked the competition among the other pharmaceutical companies that are developing novel therapies to improve the treatment landscape. RISVAN has the potential to become a blockbuster drug. LAS VEGAS, Aug. 26, 2024 /PRNewswire/ -- Schizophrenia is a severe mental illness affecting about 1% of Americans, cognitive functions, emotional responses, decision-making, and social interaction. Onset typically occurs in late teens to early 20s for men and late 20s to early 30s for women. Currently, as per the WHO, the vast majority of schizophrenia patients around the world are not receiving mental health care. Approximately 50% of people in mental hospitals have a schizophrenia diagnosis, and only 31.3% of people with psychosis receive specialist mental health care. As per DelveInsight analysis, in 2023 the total diagnosed prevalent cases of schizophrenia in the 7MM were found to be approximately 4 million cases out of which the US accounted for nearly 1.5 million cases. It is anticipated that these numbers will rise by 2034 due to several factors, including population growth, improved diagnostic techniques, increased awareness, and reduced stigma around mental health issues prompting more individuals to seek diagnosis, and potentially, environmental stressors contributing to a higher occurrence of the disorder. Schizophrenia treatment involves a blend of medication, psychological counseling, and social support. However, nearly one-third of patients do not respond sufficiently to standard treatments. Relapses, characterized by psychotic symptoms and functional impairments, are significant. Schizophrenia treatment mainly consists of antipsychotic medications that target dopamine neurotransmitters. Second-generation medications are favored because they lower the risk of severe side effects. Long-acting injectable antipsychotics can enhance adherence and improve treatment outcomes. High-dose regimens of specific medications may be advantageous for patients with severe, treatment-resistant schizophrenia. Additionally, hospitalization and electroconvulsive therapy might be necessary for patients who do not respond to medication therapy or during severe episodes. First-generation antipsychotics like chlorpromazine, fluphenazine, haloperidol, and perphenazine are effective in treating positive symptoms such as hallucinations and delusions but do not alleviate negative symptoms or cognitive impairments. Second-generation antipsychotics, including REXULTI/RXULTI (brexpiprazole), CAPLYTA (lumateperone), LATUDA (lurasidone hydrochloride), SAPHRIS (asenapine), ABILIFY MYCITE (aripiprazole tablets with sensor), VRAYLAR/REAGILA (cariprazine), SECUADO (asenapine), INVEGA SUSTENNA/TRINZA/HAYFERA (paliperidone palmitate), ARISTADA/ARISTADA INITIO (aripiprazole lauroxil), PERSERIS (risperidone), FANAPT (iloperidone), and LYBALVI (olanzapine and samidorphan), were developed to address both positive and negative symptoms, as well as cognitive symptoms. Although these medications typically have fewer extrapyramidal side effects, they can cause weight gain, sexual dysfunction, and other metabolic disorders. Additionally, elderly patients using FGAs and SGAs are at an increased risk of developing pneumonia. Learn more about the FDA-approved schizophrenia drugs @ Drugs for Schizophrenia Treatment REXULTI (brexpiprazole) is an oral tablet available in strengths from 0.25 mg to 4 mg, containing various inactive ingredients. While its exact mechanism of action is not fully understood, it work as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at serotonin 5-HT2A receptors. REXULTI was first approved in the US in July 2015 for use in adults with MDD and schizophrenia. In January 2022, it received FDA approval for pediatric patients aged 13–17. The EMA approved it in July 2018, and Japan approved it in tablet form in January 2018 and as an oral-disintegrating dose in August 2021. Generic versions of REXULTI have now been approved, which may affect its market presence. Janssen Pharmaceutical's INVEGA SUSTENNA/INVEGA TRINZA/INVEGA HAFYERA (paliperidone palmitate) is an SGA agent that seems to act as a D2 partial agonist and a 5-HT-2A receptor antagonist. INVEGA SUSTENNA is administered monthly, INVEGA TRINZA every three months, and INVEGA HAFYERA twice yearly. Paliperidone is a benzisoxazole derivative. In the EU and Japan, INVEGA SUSTENNA is marketed as XEPLION. In the EU, INVEGA TRINZA is sold as TREVICTA, and in Japan as XEPLION TRI. INVEGA HAFYERA is a long-acting injectable treatment administered in the upper buttocks every six months, providing continuous treatment and symptom control over this period. Additionally, the recent approval of RISVAN (Risperidone ISM) has intensified the competition in the schizophrenia treatment space. Risperidone ISM is a long-acting injectable antipsychotic created and patented by ROVI for treating schizophrenia in adults. From the first injection, it delivers immediate and sustained plasma drug levels without the need for loading doses or additional oral risperidone. This approval is based on the positive outcomes of the pivotal PRISMA-3 study, which assessed the efficacy and safety of Risperidone ISM in patients with schizophrenia. The study's findings demonstrate that the two doses tested (75 mg and 100 mg administered once monthly) successfully met the predetermined primary and secondary efficacy endpoints for treating patients with moderate to severe schizophrenia symptoms. Furthermore, OKEDI (risperidone ISM) was launched in Germany, the UK, and Spain in 2022. The approval was based on the positive results of the pivotal PRISMA-3 study on the efficacy and safety of risperidone ISM in schizophrenia patients. As per the estimates by Delveinsight analysts, this drug has blockbuster potential in the schizophrenia market with medium-fast uptake. To know more about schizophrenia treatment options, visit @ New Treatment for Schizophrenia The schizophrenia market is crowded with so many companies working in the domain. Various potential therapies that are projected to enter during the forecast period include Boehringer Ingelheim's Iclepertin (BI-425809), Sumitomo Pharma/Otsuka's Ulotaront (SEP-363856), Reviva Pharmaceuticals' Brilaroxazine (RP5063), Minerva Neurosciences/Mitsubishi Tanabe Pharma's Roluperidone (MIN-101/MT-210), Karuna Therapeutics (Bristol Myers Squibb)/Royalty Pharma's KarXT (xanomeline-trospium), ACADIA Pharmaceuticals' NUPLAZID (pimavanserin), Teva Pharmaceutical/MedinCell/Royalty Pharma's Olanzapine LAI (mdc-TJK/TV-44749), Neurocrine Biosciences/Mitsubishi Tanabe Pharma's Valbenazine (NBI-98854), Lyndra Therapeutics' LYN-005 (long-acting oral risperidone), Newron Pharmaceuticals' Evenamide (NW-3509), Luye Pharma's LY03010 (ER paliperidone palmitate), and others. Discover which therapies are expected to grab major schizophrenia market share @ Schizophrenia Market Report Iclepertin (BI 425809) is an investigational drug and a glycine transporter 1 (GlyT1) inhibitor aimed at addressing the brain biology related to cognitive symptoms in schizophrenia (CIAS). Abnormalities in glutamatergic signaling downstream of neuronal NMDA receptors contribute to cognitive impairment in this condition. Enhancing NMDA receptor function could potentially improve synaptic plasticity and cognition. Glycine, an essential NMDA receptor co-agonist, is modulated by glycine transporters GlyT-1 and GlyT-2, which are located in presynaptic and astrocyte membranes. These transporters regulate glycine levels by taking it up into nerve terminals and adjacent glial cells, affecting synaptic cleft glycine concentration. By inhibiting these transporters, BI 425809 aims to increase glycine levels, thereby modulating NMDA receptor function. Administered orally, this potent and selective GlyT1 inhibitor is also under investigation for Alzheimer's disease. However, early 2020 Phase II trial results did not support its continued development for this indication, and the focus has now shifted to schizophrenia, with multiple Phase III trials currently underway. Since schizophrenia, patients frequently ignore certain symptoms, such as cognitive impairment. Therefore, if approved, BI-425809 will be the first approved pharmacotherapy for the treatment of CIAS. Ulotaront (SEP-363856), developed by Sumitomo Pharma and Otsuka Pharmaceuticals, is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity. It is a small-molecule oral agent that does not bind to dopamine D2 or serotonin 5-HT2A receptors. Sunovion discovered Ulotaront in collaboration with PsychoGenics using the in vivo phenotypic SmartCube platform and associated artificial intelligence algorithms. Ulotaront is currently in late-stage development for schizophrenia and generalized anxiety disorder (GAD) in Japan and as an adjunctive treatment for major depressive disorder, schizophrenia, and GAD in the US. Top-line results from Phase III DIAMOND 1 and DIAMOND 2 trials in schizophrenia have been released, but the Phase III DIAMOND 3 trial in the US has been halted. Sumitomo Pharma has also stopped a Phase III trial for schizophrenia in Japan and another Phase II/III trial in China, Japan, Taiwan, and the Philippines, citing business strategy reasons. Despite this, two Phase III trials are still ongoing. Recently, Otsuka and Sumitomo revised their licensing agreement, excluding SEP-4199 and SEP-378614. Under this revision, Otsuka gained exclusive rights from SMPA to develop, manufacture, and commercialize ulotaront worldwide. If Otsuka successfully develops and commercializes ulotaront, they will pay up to 30 million USD (approximately 4.5 billion yen) in milestones, along with royalties based on sales, without any upfront payment. Starting January 2024, Otsuka will cover the full cost of studies conducted by both Sumitomo Pharma Group and Otsuka, except for certain studies. KarXT (xanomeline–trospium) is an oral modulator targeting muscarinic receptors found in both the central nervous system (CNS) and various peripheral tissues. This proprietary product combines xanomeline, a novel muscarinic agonist, with trospium, an approved muscarinic antagonist, to preferentially stimulate muscarinic receptors in the CNS. As a dual M1/M4 muscarinic acetylcholine receptor agonist, KarXT aims to improve the positive, negative, and cognitive symptoms of schizophrenia. The US FDA has accepted Karuna Therapeutics' NDA for KarXT for adult schizophrenia treatment, with a PDUFA date of September 26, 2024. Additionally, KarXT is undergoing multiple Phase III trials as an adjunctive treatment with standard-of-care agents for schizophrenia and is being evaluated for psychosis treatment in Alzheimer's disease patients. Following Bristol Myers Squibb's acquisition of Karuna Therapeutics, Karuna is now a wholly-owned subsidiary of BMS. At the Annual Congress of the Schizophrenia International Research Society (SIRS) in April 2024 in Italy, BMS presented promising results from the latest interim analysis of the Phase III EMERGENT-4 open-label extension trial, showing KarXT's efficacy in reducing symptoms in adults with schizophrenia. BMS plans to continue discussions with the US FDA and will release more data from the EMERGENT program later this year. Discover more about drugs for schizophrenia in development @ Schizophrenia Clinical Trials The anticipated launch of these emerging therapies for schizophrenia are poised to transform the market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the schizophrenia market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. DelveInsight estimates that the market size for schizophrenia is expected to grow from USD 2.6 billion in 2023 with a significant CAGR by 2034. This growth can be attributed to the introduction of upcoming therapies and the rising prevalence of the disease. The anticipated launch of these therapies is also expected to attract new entrants to the Schizophrenia market, resulting in increased competition and innovation. DelveInsight's latest published market report titled as Schizophrenia Market Insight, Epidemiology, and Market Forecast – 2034 will help you to discover which market leader is going to capture the largest market share. The report provides comprehensive insights into the schizophrenia country-specific treatment guidelines, patient pool analysis, and epidemiology forecast to help understand the key opportunities and assess the market's underlying potential. The schizophrenia market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Prevalent Cases of Schizophrenia Total Diagnosed Prevalent Cases of Schizophrenia Gender-specific Diagnosed Prevalent Cases of Schizophrenia Severity-specific Diagnosed Prevalent Cases of Schizophrenia The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM schizophrenia market. Highlights include: 11-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this schizophrenia market report to assess the epidemiology forecasts, understand the patient journeys, know KOLs' opinions about the upcoming treatment paradigms, and determine the factors contributing to the shift in the schizophrenia market. Also, stay abreast of the mitigating factors to improve your market position in the schizophrenia therapeutic space. Related Reports Schizophrenia Pipeline Schizophrenia Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key schizophrenia companies, including Otsuka Pharmaceutical Development & Commercialization, Inc., Gedeon Richter Ltd., Lyndra Therapeutics, Neurocrine Bioscience, Takeda Pharmaceutical Company, Memory Pharmaceuticals, Hoffmann-La Roche, Neurocrine Biosciences, Boehringer Ingelheim, Meiji Seika Pharma Co., Ltd., SK Life Science, Inc., Alkermes, Inc. , Solvay Pharmaceuticals, Mitsubishi Tanabe Pharma Corporation, SyneuRx International (Taiwan) Corp, BioXcel Therapeutics Inc, Cognitive Research Corporation, Amarex Clinical Research, Forum Pharmaceuticals Inc, Amneal Pharmaceuticals, LLC, Recognify Life Sciences, Accutest Research Laboratories (I) Pvt. Ltd., Eli Lilly and Company, Johnson & Johnson Pharmaceutical Research & Development, L.L.C, Janssen, LP, Delpor, Inc., Jiangsu Hansoh Pharmaceutical, Cerevel Therapeutics, LLC, Zogenix, Inc., Luye Pharma, Reviva Pharmaceuticals, Alkermes, Inc., Karuna Therapeutics, Autifony Therapeutics, Neumora Therapeutics, Adex Therapeutics, among others. Schizophrenia Epidemiology Forecast Schizophrenia Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and schizophrenia epidemiology trends. Dementia Market Dementia Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key dementia companies, including Hoffmann-La Roche, Forest Laboratories, Inc., Janssen Pharmaceuticals, Inc., Merck and Co., Inc., Novartis, among others. Bipolar Depression Market Bipolar Depression Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key bipolar depression companies, including Intra-Cellular Therapies, Sunovion Pharmaceuticals, COMPASS Pathways, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP

临床3期临床2期临床结果上市批准引进/卖出

2024-03-27

·SYNAPSE

Sumitomo Pharma Renews Collaborative Development Agreement with Otsuka Pharmaceutical for Multiple Psychiatric Disorder Treatments

On March 15th, Sumitomo Dainippon Pharma Co., Ltd., and its U.S. subsidiary, Sumitomo Pharma America, Inc. (SMPA), announced that they have amended the global collaboration and commercialization agreement originally signed with Sumitomo Dainippon Pharma, SMPA, and Otsuka Pharmaceutical Co., Ltd., on September 30, 2021, concerning the joint development of four investigational compounds in the fields of psychiatry and neurology, including ulotaront, SEP-380135, SEP-4199, and SEP-378614 (hereinafter referred to as "the Amendment Agreement"). It is reported that SEP-4199 and SEP-378614 from the original collaboration agreement will no longer be included in the scope of this Amendment Agreement. SMPA has granted Otsuka Pharmaceutical exclusive global rights to develop, produce, and market ulotaront and SEP-380135 for all indications. SMPA is entitled to receive milestone payments of up to 30 million U.S. dollars (approximately 45 billion Japanese yen) related to the development progress of ulotaront and SEP-380135 from Otsuka Pharmaceutical, as well as royalties based on Otsuka Pharmaceutical's sales revenue. Sumitomo Pharma and SMPA have been collaborating with Otsuka Pharmaceutical in the development of novel candidate compounds including ulotaront in the priority areas of psychiatry and neurology. However, given the current situation, the likelihood of these compounds generating revenue during the Mid-Term Business Plan period for fiscal 2027 (FY2023-FY2027) poses significant challenges. In light of this, the Sumitomo Pharma Group has reassessed its priority development products and has decided to focus its efforts on the development of projects in the fields of oncology and regenerative medicine/cell therapy, which are expected to come to market during the Mid-Term Business Plan period for fiscal 2027. Consequently, Sumitomo Pharma Group has transferred the development responsibilities for the aforementioned ulotaront and SEP-380135 to Otsuka Pharmaceutical. At the same time, Sumitomo Pharma Group is evaluating further development strategies for SEP-4199 and SEP-378614. Ulotaront is an agonist associated with Trace Amine-Associated Receptor 1 (TAAR1) and exhibits agonist activity at the 5-HT1A receptor. Currently, ulotaront is in the development phase for the treatment of schizophrenia, as an adjunctive treatment for major depressive disorder (MDD), and for generalized anxiety disorder (GAD). In May 2019, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to Ulotaront for the treatment of schizophrenia, making it the first and only TAAR1 agonist to enter Phase III clinical trials for schizophrenia. Additionally, Ulotaront is the first TAAR1 agonist to progress to Phase II/III clinical trials as an adjunctive treatment for Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD). However, on July 31, 2023, Sumitomo Pharma announced on its official website that its antipsychotic clinical candidate Ulotaront (SEP-363856) failed to meet the primary endpoints in two recent Phase III clinical studies (DIAMOND 1 and DIAMOND 2). In April 2020, the team at Sunovion, the U.S. subsidiary of Sumitomo Pharmaceuticals, published the results of a Phase 2 clinical study on the oral small molecule SEP-363856 for the treatment of schizophrenia in The New England Journal of Medicine online. The study conducted a randomized controlled trial to evaluate the efficacy and safety of SEP-363856 in adult patients with an acute exacerbation of schizophrenia. Patients were randomly assigned in a 1:1 ratio to receive SEP-363856 treatment (either 50 mg or 75 mg) or placebo once daily for a duration of 4 weeks. The primary endpoint was the change in the total score on the Positive and Negative Syndrome Scale (PANSS; range 30 to 210, with higher scores indicating more severe psychotic symptoms) from baseline to week 4. A total of 120 patients were assigned to the SEP-363856 group, and 125 patients were allocated to the placebo group. At baseline, the mean total score on the Positive and Negative Syndrome Scale (PANSS) was 101.4 for the SEP-363856 group and 99.7 for the placebo group. The mean change at week 4 was -17.2 for the SEP-363856 group and -9.7 for the placebo group. The reductions in the Clinical Global Impressions - Severity (CGI-S) and the Brief Negative Symptom Scale (BNSS) scores at week 4 were consistent with the primary outcome in terms of direction of improvement. The adverse reactions of SEP-363856 include somnolence and gastrointestinal symptoms; a case of sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms in the trial group, as well as changes in blood lipid levels, glycated hemoglobin, and prolactin levels, was similar. In 2021, the Sunovion team published an article in the journal Schizophrenia, reporting on the safety and efficacy of SEP-363856 in the treatment of schizophrenia (results from a 6-month open-label extension study). According to the study report, this 26-week open-label extension study was designed to evaluate the safety and efficacy of Ulotaront (25/50/75 mg/day) in patients who completed the initial 4-week study. The results showed that after 26 weeks of extended treatment, the mean change in the observed PANSS total score compared to the open-label baseline was -22.6. The long-term treatment with the TAAR1 agonist Ulotaront had a relatively high completion rate, characterized by the absence of extrapyramidal related adverse reactions, a lower incidence of weight and metabolic adverse reactions, and no effect on prolactin levels. It is reported that the Phase III clinical trial results jointly announced by Sumitomo Pharmaceuticals and Otsuka are multicenter, randomized, double-blind, parallel-group, fixed-dose studies. The DIAMOND 1 study evaluated the efficacy, safety, and tolerability of ulotaront (50 mg/day and 75 mg/day) compared to placebo; while DIAMOND 2 assessed the efficacy, safety, and tolerability of ulotaront (75 mg/day and 100 mg/day) compared to placebo. In the DIAMOND 1 study, over time, the Positive and Negative Syndrome Scale (PANSS) total scores for all three treatment groups decreased. However, at the primary endpoint of change from baseline in PANSS total score at week 6, the ulotaront treatment groups did not show superiority to the placebo group (patients treated with ulotaront at doses of 50 mg/day and 75 mg/day had changes of -16.9 and -19.6, respectively, compared to -19.3 in the placebo group). In the DIAMOND 2 study, the 75 mg/day and 100 mg/day ulotaront treatment groups did not show statistically significant improvement over placebo at the primary endpoint. At week 6, the least squares (LS) mean changes for patients treated with 75 mg/day and 100 mg/day ulotaront were -16.4 and -18.1, respectively, compared to -14.3 for the placebo group. In both DIAMOND 1 and DIAMOND 2 studies, a substantial placebo effect was observed which may have masked the therapeutic effect of the molecule. SEP-380135 is an orally-administered small molecule drug targeting the central nervous system, jointly developed by SMPA and PsychoGenics, and is currently in Phase I clinical trials in the United States. The discovery of this drug was made possible by the in vivo phenotypic SmartCube® platform and its associated artificial intelligence algorithms. SmartCube® is a proprietary state-of-the-art automated testing platform by PsychoGenics that uses custom hardware to guide mice through a series of challenges, extracting profound behavioral and physiological insights through integrated computer vision and artificial intelligence (AI) technology. Compared to traditional behavioral testing methods, the SmartCube® system boasts the following advantages: ·High Automation: Using precise hardware devices, SmartCube® can automatically guide mice to participate in a variety of experimental challenges, reducing the errors associated with human interference and enhancing experiment efficiency and accuracy. ·Real-time Behavior Monitoring: Employing advanced computer vision technology, it captures and precisely identifies the mice's behavior in real-time, providing researchers with a wealth of behavioral data. ·AI Data Analysis: The built-in artificial intelligence algorithms are capable of deep learning and intelligent analysis on the vast amount of behavioral data collected, revealing behavioral patterns and physiological correlations that traditional methods may fail to detect. ·Multidimensional Assessment: Beyond basic behavioral parameters, SmartCube® also synchronously acquires physiological indicators, enabling comprehensive and multi-level evaluations. ·High Throughput Capacity: Compared to manual operation, SmartCube® can process large quantities of experimental samples more rapidly and efficiently, accelerating the process of drug screening and disease model research. PsychoGenics has identified thousands of active behavioral compounds through the screening of various compound libraries, which can serve as starting points for new drug discovery projects. Typically, the discovery process begins with the search for "hits" that possess desired characteristics and other specific features. For instance, a project might focus on finding compounds with antidepressant features similar to certain psychedelic compounds but without activity on the 5HT2a receptor. In preclinical studies, SEP-380135 has demonstrated a broad range of in vivo activity, preliminarily indicating its effectiveness against a variety of behavioral and psychological symptoms of dementia, including, but not limited to, agitation/aggression, psychomotor hyperactivity, and depressive symptoms. This suggests that SEP-380135 has the potential to be one of the effective medications for treating multiple complex symptoms associated with dementia, offering new possibilities for further improving the quality of life of patients with dementia. SEP-4199 is a small molecule compound that functions as a dual antagonist targeting 5-HT receptors and D2 receptors. It is currently undergoing phase 3 clinical trials for the treatment of bipolar I disorder, major depressive disorder, and severe depression. SEP-378614 is a small molecule compound jointly developed by Sumitomo and PsychoGenics, which is currently undergoing phase 1 clinical trials for the treatment of major depressive disorder.

100 项与 Aramisulpride/Esamisulpride 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
躁郁症1型	临床3期	美国	Sumitomo Pharma America, Inc.	2021-12-21
躁郁症1型	临床3期	日本	Sumitomo Pharma America, Inc.	2021-12-21
躁郁症1型	临床3期	保加利亚	Sumitomo Pharma America, Inc.	2021-12-21
躁郁症1型	临床3期	加拿大	Sumitomo Pharma America, Inc.	2021-12-21
躁郁症1型	临床3期	罗马尼亚	Sumitomo Pharma America, Inc.	2021-12-21
躁郁症1型	临床3期	斯洛伐克	Sumitomo Pharma America, Inc.	2021-12-21
重度抑郁症	临床3期	美国	Sumitomo Pharma America, Inc.	2021-12-21
重度抑郁症	临床3期	日本	Sumitomo Pharma America, Inc.	2021-12-21
重度抑郁症	临床3期	保加利亚	Sumitomo Pharma America, Inc.	2021-12-21
重度抑郁症	临床3期	加拿大	Sumitomo Pharma America, Inc.	2021-12-21

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05227209 (CTgov)	临床3期	躁郁症1型 \| 重度抑郁症	64	SEP-4199 CR	鏇築膚艱製淵鑰製製製 = 遞鹹獵鬱窪網壓製壓鹽繭壓餘鏇壓築願願鏇夢 (獵蓋簾構艱繭繭選構窪, 齋襯鹽鹽遞積艱夢鑰顧 ~ 襯衊繭網廠願遞鑰選憲) 更多	-	2025-02-21
NCT05169710 (CTgov)	临床3期	躁郁症1型 \| 重度抑郁症	83	Placebo (Placebo)	齋獵糧顧壓憲願憲艱繭(鏇築觸積繭顧網鹽膚鑰) = 遞鏇鑰製鏇觸鹽鹹膚願範鬱願獵蓋獵簾願網積 (窪襯淵獵廠淵餘艱範構, 2.004) 更多	-	2024-09-19
				SEP-4199 CR 200 mg (SEP-4199 CR 200 mg)	齋獵糧顧壓憲願憲艱繭(鏇築觸積繭顧網鹽膚鑰) = 衊網齋衊築餘鑰選蓋憲範鬱願獵蓋獵簾願網積 (窪襯淵獵廠淵餘艱範構, 2.055) 更多
NCT03543410 (CTgov)	临床2期	躁郁症1型 \| 重度抑郁症	344	SEP-4199 200 mg (SEP-4199 200 mg)	鬱憲夢構鑰憲選艱構選(襯鹽鏇顧顧廠鹽艱窪顧) = 鬱糧範糧糧齋獵網願襯艱淵繭願廠淵觸積醖鬱 (願鏇餘窪蓋鏇遞醖壓齋, 1.226) 更多	-	2023-05-18
				SEP-4199 400 mg (SEP-4199 400 mg)	鬱憲夢構鑰憲選艱構選(襯鹽鏇顧顧廠鹽艱窪顧) = 襯觸鏇膚憲齋衊蓋鏇憲艱淵繭願廠淵觸積醖鬱 (願鏇餘窪蓋鏇遞醖壓齋, 1.182) 更多