A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 24-Week, Phase 2 Study of Two Doses of EVP-6124 Hydrochloride or Placebo in Subjects With Mild to Moderate Alzheimer's Disease Currently Receiving Memantine Medication With or Without Additional Acetylcholinesterase Inhibitor Co-Medication

The purpose of this study is to evaluate the safety of 2 fixed doses of EVP-6124 hydrochloride (HCl) compared to placebo for 24 weeks in subjects with mild to moderate Alzheimer's disease who are concurrently receiving stable treatment with memantine and currently receiving stable treatment or previously treated with an acetylcholinesterase inhibitor.

开始日期2015-07-01

申办/合作机构

FORUM Pharmaceuticals, Inc.

[+1]

NCT02327182 / Terminated临床3期

A Long-Term Safety Study of MT-4666 in Patients With Mild to Moderate Alzheimer's Disease (AD)

The objective of this study is to evaluate the safety and efficacy of 2 fixed dose of MT-4666 administered once daily for 52 weeks with or without receiving a concomitant acetylcholinesterase inhibitors (AChEIs), in patients with mild to moderate Alzheimer's Disease (AD).

开始日期2014-12-01

申办/合作机构

Mitsubishi Tanabe Pharma Corp.

NCT02004392 / Terminated临床3期

A 26-Week Extension Study of the Safety and Clinical Effects of EVP-6124 in Subjects With Alzheimer's Disease Currently or Previously Receiving an Acetylcholinesterase Inhibitor Medication

This is a 26-week, randomized extension of the Phase 3 double-blind placebo-controlled studies, EVP-6124-024 and EVP-6124-025. In this extension study, subjects who complete study EVP-6124-024 or EVP-6124-025 and fulfill all entry criteria will be randomized to receive EVP-6124 for an additional 26 weeks.

开始日期2014-06-01

申办/合作机构

FORUM Pharmaceuticals, Inc.

100 项与 Encenicline Hydrochloride 相关的临床结果

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100 项与 Encenicline Hydrochloride 相关的转化医学

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100 项与 Encenicline Hydrochloride 相关的专利（医药）

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337

项与 Encenicline Hydrochloride 相关的文献（医药）

2024-09-01·PHARMACOPSYCHIATRY

Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments

Review

作者: Hori, Satoko ; Hart, Xenia ; Takahashi, Yuna ; Komatsu, Yuki ; Takehara, Moe ; Ueno, Fumihiko ; Uchida, Hiroyuki

Abstract:

Introduction Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents. Methods A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases. Results Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function. Discussion Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia.

2024-05-01·The journal of pain

Alpha-7 Nicotinic Acetylcholine Receptor Activation Inhibits Trauma Induced Pronociceptive Autoimmune Responses

Article

作者: Shi, Xiao-You ; Guo, Tian-Zhi ; Kingery, Wade S ; Clark, John David ; Wei, Tzuping ; Li, Wen-Wu

Both autonomic nervous system dysfunction and immune system activation are characteristic of chronic pain after limb injuries. Cholinergic agonists reduce immune system activation in many settings. We hypothesized, therefore, that alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist administration would reduce nociceptive and immune changes after tibia fracture and cast immobilization in mice. Fracture mice were treated with either vehicle, a low (.2 mg/kg) dose, or a high (1 mg/kg) dose of the selective α7nAChR agonist PNU-282987 for 4 weeks. We assessed hindpaw allodynia and weight bearing as behavioral outcomes. The assessment of adaptive immune responses included regional lymph node hypertrophy, germinal center formation, α7nAChR expression, and IgM deposition. Assessment of innate immune system activation focused on IL-1β and IL-6 generation in fractured hindlimb skin. We observed that mechanical allodynia and unweighting were alleviated by PNU-282987 treatment. Drug treatment also reduced popliteal lymph node hypertrophy and germinal center formation. Immunohistochemical studies localized α7nAChR to germinal center B lymphocytes, and this expression increased after fracture. Analysis of fracture limb hindpaw skin demonstrated increased inflammatory mediator (IL-1β and IL-6) levels and IgM deposition, which were abrogated by PNU-282987. Serum analyses demonstrated fracture-induced IgM reactivity against keratin 16, histone 3.2, GFAP, and NMDAR-2B. Administration of PNU-282987 reduced the enhancement of IgM reactivity. Collectively, these data suggest that the α7nAChR is involved in regulating posttraumatic innate and adaptive immune responses and the associated nociceptive sensitization. PERSPECTIVE: These studies evaluate the effects of a selective α7nAChR agonist in a tibial fracture/cast immobilization model of limb pain. Administration of the drug reduced nociceptive and functional changes 4 weeks after injury. These novel findings suggest that well-tolerated α7nAChR agonists may be viable analgesics for chronic pain after limb injuries.

2024-05-01·Cell Chemical Biology

Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity

Article

作者: Xu, Chenqi ; Li, Hua ; Lou, Jizhong ; Wang, Kun ; Ren, Zhengxu ; Wang, Haopeng ; Zhu, Yiming ; Zhang, Yong ; Chen, Hui

T cell receptor (TCR) plays a fundamental role in adaptive immunity, and TCR-T cell therapy holds great promise for treating solid tumors and other diseases. However, there is a noticeable absence of chemical tools tuning TCR activity. In our study, we screened natural sterols for their regulatory effects on T cell function and identified 7-alpha-hydroxycholesterol (7a-HC) as a potent inhibitor of TCR signaling. Mechanistically, 7a-HC promoted membrane binding of CD3ε cytoplasmic domain, a crucial signaling component of the TCR-CD3 complex, through alterations in membrane physicochemical properties. Enhanced CD3ε membrane binding impeded the condensation between CD3ε and the key kinase Lck, thereby inhibiting Lck-mediated TCR phosphorylation. Transient treatments of TCR-T cells with 7a-HC resulted in reduced signaling strength, increased memory cell populations, and superior long-term antitumor functions. This study unveils a chemical regulation of TCR signaling, which can be exploited to enhance the long-term efficacy of TCR-T cell therapy.

项与 Encenicline Hydrochloride 相关的新闻（医药）

2024-06-12

·CPHI制药在线

礼来AD新药全票通过背后，Aβ假说遭质疑

关注并星标CPHI制药在线 6月10日，FDA外周和中枢神经系统药物咨询委员会（PCNS）就礼来的Donanemab用于治疗早期症状性阿尔茨海默病（AD）的生物制品许可申请（BLA）召开的会议结果出炉。委员会以11:0的票数一致赞同Donanemab的有效性，且一致认为其获益大于风险，并认可试验数据显示的Donanemab对早期记忆丧失的患者有效。穿过荆棘，Donanemab迎来胜利曙光 Donanemab是礼来研发的一款新一代Aβ单抗，可与β淀粉样蛋白亚型N3pG结合，从而促进患者大脑中淀粉样蛋白斑块的清除。此次PCNS的讨论，主要基于礼来 III 期TRAILBLAZER-ALZ 2研究的结论。这是一项随机、双盲、安慰剂对照III期临床研究，旨在评估Donanemab在早期症状性AD患者中的有效性和安全性。结果显示，在主要分析人群（低/中tau蛋白水平，n=1182，tau蛋白即AD进展的生物标志物）中，Donanemab组患者的iADRS评分(评估患者的认知能力和生活自理能力)和CDR-SB评分（临床痴呆评定量表，评估患者的认知能力）的下降速度分别减缓了35%和36%；并且近一半受试者（47%）在1年内没有疾病进展（定义为CDR-SB评分没有下降），而安慰剂组这一比例为29%。在总体人群（n=1736）中，与安慰剂组相比，Donanemab组患者的iADRS评分和CDR-SB评分的下降速度分别减缓了22%和29%。安全性方面，Ddonanemab组有24%患者出现淀粉样蛋白相关影像学异常-水肿（ARIA-E），6%患者出现有症状的ARIA-E；Donanemab组有31.4%患者出现脑微出血和浅表铁质沉积（ARIA-H），安慰剂组为13.6%。值得一提的是，无论ARIA-E和ARIA-H有无临床症状，均有致命风险。因此，对于ARIA高危人群，比如具有APOE4遗传标记的人，礼来建议进行更密切的监测。但是对于一般的AD患者来说，委员会认为，donanemab治疗的益处大于风险。一致性的投票结果，增加了donanemab获批上市的可能性。FDA通常在咨询委员会召开后1-2个月做出监管决定，如果获得批准，donanemab将成为美国市场上第二种治疗AD的药物（第一种为渤健/卫材的Leqembi）。值得一提的是，donanemab一路走来十分坎坷。2021年10月，礼来曾基于II 期临床试验 TRAILBLAZER-ALZ的结果，向FDA递交donanemab用于早期阿尔茨海默病加速批准的上市申请，该试验评估了donanemab 在早期症状性AD患者中的安全性、耐受性和有效性。不过2023 年 1 月，FDA 以患者数量不足的原因，发出了CRL。FDA称提交临床试验中提供的至少 12 个月药物暴露数据的患者数量有限，要求礼来公司提供至少100名接受了至少 12 个月的持续donanemab治疗的患者的数据。在礼来完成了III 期临床试验 TRAILBLAZER-ALZ 2后，于2023年5月再次递交上市申请，FDA原计划在今年第一季度对该上市申请做出决定，然而由于需要深入讨论 donanemab的几个核心问题，FDA决定召开专门委员会会议。此次一致性投票结果，是donanemab取得的又一大重磅进展，意味着donanemab 在将来的上市审批或许会有较好的前景，FDA 将于今年晚些时候做出决定。 Donanemab柳暗花明背后，Aβ蛋白假说遭质疑 AD作为一种难治的中枢神经系统疾病，已是目前照护成本最高昂、负担最重的疾病之一。由于AD致病机理复杂，多年来，这一领域药物研发折戟者众多。如辉瑞的Bapineuzumab、Mitsubishi Tanabe Pharma的Encenicline、TauRx的TRx0237、默沙东的Verubecestat等产品均折戟于此。直到2021年，渤健的Aducanumab被FDA加速批准上市，但后因有效性及安全性相关问题商业化失败。2023年1月，渤健/卫材的Lecanemab（仑卡奈单抗，商品名：Leqembi）获FDA加速批准上市，打破了AD领域长达十几年的沉寂。未来，若Donanemab顺利获得批准，其将与Lecanemab形成直接的市场竞争态势。值得一提的是，两款产品均属于Aβ（β-淀粉样蛋白）假说流派，这是目前AD领域的主流理论，其认为AD的形成过程为：淀粉样前体蛋白（APP）经酶异常切割形成Aβ，Aβ过量产生或清除不足，则聚集形成寡聚体，寡聚体进一步发展为原纤维，最终形成淀粉样斑块，该斑块具有一定毒性，影响神经细胞正常功能，最终致使AD形成。 Aβ假说虽是AD领域的主流理论，但也一直遭受质疑。就在6月5日，Science 发布重磅新闻：阿尔兹海默病发病机制领域的奠基性研究涉嫌图像造假。这一调查经历两年后，论文通讯作者终于承认论文图像涉嫌造假，并同意撤稿，目前该研究已被引用近 2500 次，是目前撤稿前被引用最高的论文，可以说这篇奠基性论文将大部分AD的研究引向这一方向。具体来说，论文中介绍了一种可以溶解在体液中的 Aβ 亚型：Aβ*56，与其他寡聚物相比，Aβ*56的分子量相对较大。研究人员分离了Aβ*56并将其注射到健康小鼠体内，之后，健康小鼠回忆简单、以前学过的信息的能力急剧下降。这一发现让科学界沸腾不已，这是首次将Aβ蛋白中的某项物质直接与AD联系起来。然而不少业界大咖在尝试在人体中寻找Aβ*56时，大都失败了。反复的失败，让科学家开始质疑这篇论文的真实性。2022年7月，science杂志发表了一篇调查报告，直指该研究涉嫌造假。报告提及，研究者在论文中发现了明显被修改或重复的图像。然而直到今年，该研究通讯作者才承认论文图片造假事实。多年来，它究竟影响了多少人相信和投入 β 淀粉样蛋白斑块研究，不得而知。不过也有人指出，Aβ*56只是Aβ蛋白中的一种，不能因Aβ*56研究造假而全盘否定Aβ假说。而且两款Aβ机制药物的临床试验成功起码部分地支持了Aβ假说。据世界卫生组织《2023年世界社会报告》数据显示，截至2018年全球约3310万人患有阿尔茨海默症，2050年这一数字将增至2.42亿。然而1998-2017 年，AD药物的研发成功率仅有2.7%。强劲的临床需求与"贫瘠"的获批药物形成强烈反差，因此不少药企在这一大蓝海赛道前赴后继。聚焦国内，先声药业、恒瑞医药、喜鹊医药、康缘药业等均有布局，未来谁将研发出开创性的药物，阿尔茨海默病市场在等一个答案。参考来源： 1.https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-public-participation-information-june-10-2024-meeting-peripheral-and-central-nervous-system#event-materials. 2.AAIC 2023 - Acumen's new amyloid approach impresses，Evaluate Vantage AAIC 2023 News Highlights，AAIC. 【企业推荐】【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床3期临床2期临床结果上市批准临床成功

2010-05-11

·BioSpace

EnVivo Pharmaceuticals, Inc. Initiates Phase IIb Alzheimer's Disease Trial For EVP-6124

WATERTOWN, Mass., May 11 /PRNewswire/ -- EnVivo Pharmaceuticals today announced the initiation and dosing of patients in a Phase IIb study of its EVP-6124 compound, a selective alpha-7 nicotinic agonist in patients with mild to moderate Alzheimer's disease. The multi-center, dose ranging, placebo controlled, six-month study taking place in the U.S. and Europe is designed to determine the safety and efficacy of EVP-6124 in producing procognitive effects and improving the clinical condition of Alzheimer's disease patients. "Patients with Alzheimer's disease have a number of symptomatic therapies available to them. However, the effects of the available medications are modest. Even if significant progress is made in slowing disease progression, more effective therapies that sustainably improve the cognition of the patients are clearly needed," said Kees Been, EnVivo president and CEO. "There is growing consensus that alpha-7 nicotinic agonists can potentially improve the cognitive function in Alzheimer's disease patients as evidenced by the number of large pharmaceutical companies advancing similar drugs through development. The potential upside for patients is considerable and we look forward to completing our Alzheimer's disease study by the middle of next year." The Phase IIb study will enroll mild to moderate Alzheimer's disease patients who will be randomized to three separate doses of EVP-6124 or placebo over six months. Efficacy will primarily be determined by the ADAS-Cog scale, a commonly used and accepted measure of cognition in patients with Alzheimer's disease. Secondary assessments will include other cognitive and clinical measures. EVP-6124 also is being tested in patients with schizophrenia in a separate Phase IIb study that started in late 2009. Two previous studies with EVP-6124 in Alzheimer's disease patients demonstrated that it was well tolerated and produced significant effects on a variety of cognitive measures of brain function such as attention, memory and executive function (complex thinking tasks). EVP-6124 had procognitive effects in two separate clinical trials: one study conducted in Alzheimer's disease patients already treated with Acetyl Choline Esterase Inhibitors (AChEI) and one in Alzheimer's disease patients not on AChEI therapy (naive patients). EVP-6124 is a selective agonist for the alpha-7 subtype of the nicotinic acetylcholine receptor and is being developed by EnVivo for potential cognitive enhancement in both schizophrenia and Alzheimer's patients. It has been shown to have excellent CNS penetration, oral bioavailability, pharmacokinetics and metabolic profile. About EnVivo Pharmaceuticals EnVivo Pharmaceuticals, located in Watertown, Mass., is a biopharmaceutical company dedicated to discovering and developing small molecule therapeutics for disorders of the central nervous system, with a current focus on Alzheimer's disease, cognitive disorders and schizophrenia. The company's lead product is an alpha-7 nicotinic acetylcholine receptor agonist and has been tested in Phase IIa clinical trials for cognition disorders in Alzheimer's disease and schizophrenia. The company's other programs include an epigenetics program based on Histone Deacetylase inhibition (HDACi) with EVP-0334 as the lead molecule for cognition in Alzheimer's disease which has completed Phase I studies, and several preclinical programs such as a Gamma Secretase Modulator (for Alzheimer's disease) and a PDE10 inhibitor program (for schizophrenia). For more information about EnVivo, visit . SOURCE EnVivo Pharmaceuticals

小分子药物

100 项与 Encenicline Hydrochloride 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D10702	Encenicline Hydrochloride	-	DB11726

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床3期	美国	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	阿根廷	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	澳大利亚	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	比利时	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	加拿大	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	捷克	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	法国	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	德国	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	意大利	FORUM Pharmaceuticals, Inc.	2013-10-01
阿尔茨海默症	临床3期	墨西哥	FORUM Pharmaceuticals, Inc.	2013-10-01

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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


NCT01480232 (CTgov)	临床2期	尼古丁成瘾 \| 尼古丁依赖	345	Brief Supportive+EVP-6124 (EVP-6124 + NRT Patch (Placebo))	繭醖鑰構膚廠積獵觸鑰(壓憲範齋顧廠窪醖選繭) = 醖醖鹽襯醖憲醖網觸範憲獵襯鏇鑰遞遞壓選鏇 (蓋繭鹹鑰淵壓製衊簾窪, 築遞醖鬱艱繭醖鬱鑰餘 ~ 夢膚齋獵夢醖願顧觸繭) 更多	-	2017-04-06
				Brief Supportive (Placebo + NRT Patch (Placebo))	繭醖鑰構膚廠積獵觸鑰(壓憲範齋顧廠窪醖選繭) = 襯鬱鹹淵膚壓構淵廠廠憲獵襯鏇鑰遞遞壓選鏇 (蓋繭鹹鑰淵壓製衊簾窪, 壓壓蓋製餘鏇艱齋範餘 ~ 觸選網繭選選艱構糧壓) 更多
P7.100 (AAN2015)	临床2期	阿尔茨海默症追加	409	Encenicline 0.27mg	膚繭蓋醖鬱齋廠願廠觸(顧衊範願製範構鹽壓廠) = 構餘壓膚齋襯鏇願鏇衊鹹衊蓋蓋蓋鏇壓襯糧鬱 (醖獵襯繭範鬱網夢鑰積 )	积极	2015-04-06
				Encenicline 0.9mg	膚繭蓋醖鬱齋廠願廠觸(顧衊範願製範構鹽壓廠) = 製艱鑰鹽顧繭衊範觸鬱鹹衊蓋蓋蓋鏇壓襯糧鬱 (醖獵襯繭範鬱網夢鑰積 )
NCT01556763 (CTgov)	临床1期	中枢神经系统疾病 \| 分裂情感性障碍 \| 精神分裂症	21	Placebo+Antipsychotic therapy (Placebo)	夢淵淵構簾糧膚壓網糧(築獵鹽構願糧衊網淵蓋) = 夢壓範憲壓艱衊衊齋選積積顧顧積膚餘醖築簾 (願餘糧願衊窪遞鬱構膚, 範鏇願製顧淵廠壓顧鹹 ~ 選積網鏇齋遞艱艱鑰範) 更多	-	2012-06-21
				EVP-6124 (1.0 mg/day)+Antipsychotic therapy (EVP-6124 (1.0 mg/Day))	夢淵淵構簾糧膚壓網糧(築獵鹽構願糧衊網淵蓋) = 廠鹽糧鹽網糧鹽網窪窪積積顧顧積膚餘醖築簾 (願餘糧願衊窪遞鬱構膚, 窪願餘廠夢獵選窪糧廠 ~ 選廠遞簾獵鑰顧衊製願) 更多
NCT00766363 (CTgov)	临床1期	阿尔茨海默症	49	EVP-6124 (0.1 mg/day)+Rivastigmine+Donepezil (EVP-6124 (0.1 mg/Day))	醖製鹹顧選積網網廠餘(蓋齋糧顧襯選淵襯壓構) = 艱窪淵觸鑰窪醖鑰觸鑰鑰築壓壓壓選構餘餘廠 (顧襯鑰鬱鑰簾積膚廠衊, 遞觸構選顧艱範襯範築 ~ 製鏇醖繭窪艱鏇觸網鑰) 更多	-	2011-07-14
				EVP-6124 (0.3 mg/day)+Rivastigmine+Donepezil (EVP-6124 (0.3 mg/Day))	醖製鹹顧選積網網廠餘(蓋齋糧顧襯選淵襯壓構) = 願襯鹽蓋糧範膚選繭膚鑰築壓壓壓選構餘餘廠 (顧襯鑰鬱鑰簾積膚廠衊, 淵構願鑰膚憲膚鹽壓積 ~ 遞膚獵顧網糧鑰選鏇鏇) 更多