Phase I/II, Open-Label, Dose Escalation Study of the Safety, Pharmacokinetics and Pharmacodynamics of NV1205 in Pediatric Male Subjects With Childhood Cerebral Adrenoleukodystrophy (CCALD)

This is a phase I/II, open label dose escalation study of multiple dose levels of NV1205 with a long-term treatment phase.

开始日期2018-08-01

申办/合作机构

NeuroVia, Inc.

NCT01787578 / Withdrawn临床1期IIT

A Prospective Safety, Tolerance, Pharmacodynamics and Pharmacokinetics Study of Sobetirome in Male Subjects Diagnosed With X-linked Adrenoleukodystrophy (X-ALD)

The purpose of this study is to assess the safety, tolerance, pharmacokinetics, and pharmacodynamics of sobetirome, a selective thyroid hormone analog, in adult male X-ALD patients.

开始日期2013-04-01

申办/合作机构

Oregon Health & Science University

EUCTR2017-001684-21-FR / Unknown status临床1期

Phase 1, Open-Label, Dose Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of NV1205 in Pediatric Male Subjects with Childhood Cerebral Adrenoleukodystrophy (CCALD)

开始日期-

申办/合作机构

NeuroVia, Inc.

100 项与 Sobetirome 相关的临床结果

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100 项与 Sobetirome 相关的转化医学

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100 项与 Sobetirome 相关的专利（医药）

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141

项与 Sobetirome 相关的文献（医药）

2024-11-01·AQUATIC TOXICOLOGY

Testing the sensitivity of the medaka Transgenic Eleuthero-embryonic THYroid-Specific assay (TETHYS) to different mechanisms of action

Article

作者: Lemkine, Gregory F ; Pasquier, Et David Du ; Tindall, Andrew J ; Tindall, Andrew J. ; Benitez-Gonzalez, Jessica ; Pesce, Elise ; Sachs, Laurent M. ; Sachs, Laurent M ; Lemkine, Gregory F. ; Pasquier, et David Du ; Robin-Duchesne, Barbara

There are many concerns about the impacts of Endocrine-Disrupting Chemicals on both wildlife and human populations. A plethora of chemicals have been shown to interfere with the Hypothalamic-Pituitary-Thyroid (HPT) axis in vertebrates. Disruption of the HPT axis is one of main endocrine criteria considered for the regulation of chemicals, along with the estrogen axis, androgen axis and steroidogenesis (EATS). In response to these concerns, the Organization for Economic Cooperation and Development (OECD) initiated the validation of test guidelines (TGs) covering the EATS modalities. Regarding thyroid activity and/or disruption assessment, three OECD TGs are validated, all of them using amphibians. To date, no OECD TGs based on fish are available for the detection of Thyroid Active Chemicals (TACs). To fill this gap, we developed a new test for the detection of TACs, the TETHYS assay (Transgenic Eleuthero-embryonic THYroid-Specific assay). This assay uses a medaka (Oryzias latipes) transgenic line Tg(tg:eGFP) expressing Green Fluorescent Protein in the thyroid follicles, under the control of the thyroglobulin promoter. This assay is performed at eleuthero-embryonic life-stages with an exposure length of 72 h. In the present study, the following reference chemicals with known thyroid hormone system mechanism of action have been tested: methimazole, sodium perchlorate, sodium tetrafluoroborate, diclofenac, iopanoic acid, sobetirome, NH-3 and 1-850. Except for the thyroid receptor antagonists, all chemicals tested were identified as thyroid active, modifying the total fluorescence and the size of the thyroid follicles. To investigate the test specificity, we tested three chemicals presumed to be inert on the HPT axis: cefuroxime, abamectin and 17α-ethinylestradiol. All were found to be inactive in the TETHYS assay. This promising New Approach Methodology can serve as a foundation for the development of a new OECD TG in the frame of regulatory assessment of chemicals for thyroid activity.

2024-01-01·The European journal of neuroscience

Sobetirome rescues α‐synuclein‐mediated demyelination in an in vitro model of multiple system atrophy

Article

作者: Himmler, Marcus ; Arnold, Philipp ; Schubert, Dirk W ; Dörje, Frank ; Winkler, Jürgen ; Schneider, Yanni ; Mészáros, Lisa

Abstract:

Multiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α‐synuclein (α‐syn), demyelination, inflammation and neuronal loss. To date, no disease‐modifying therapy is available. Targeting α‐syn‐driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood–brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α‐syn specifically in oligodendrocytes (MBP29 mouse line), a well‐described MSA model, and non‐transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin‐specific proteins in control and α‐syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α‐syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.

2023-10-28·Journal of microbiology and biotechnology

Comprehensive Evaluation System for Post-Metabolic Activity of Potential Thyroid-Disrupting Chemicals

Article

作者: Jang, Yurim ; Lee, Hong Jin ; Moon, Ji Hyun ; Park, Ho Jin ; Jeon, Byung Kwan ; Lee, Do Yup

Endocrine-disrupting chemicals (EDCs) are compounds that disturb hormonal homeostasis by binding to receptors. EDCs are metabolized through hepatic enzymes, causing altered transcriptional activities of hormone receptors, and thus necessitating the exploration of the potential endocrine-disrupting activities of EDC-derived metabolites. Accordingly, we have developed an integrative workflow for evaluating the post-metabolic activity of potential hazardous compounds. The system facilitates the identification of metabolites that exert hormonal disruption through the integrative application of an MS/MS similarity network and predictive biotransformation based on known hepatic enzymatic reactions. As proof-of-concept, the transcriptional activities of 13 chemicals were evaluated by applying the in vitro metabolic module (S9 fraction). Identified among the tested chemicals were three thyroid hormone receptor (THR) agonistic compounds that showed increased transcriptional activities after phase I+II reactions (T3, 309.1 ± 17.3%; DITPA, 30.7 ± 1.8%; GC-1, 160.6 ± 8.6% to the corresponding parents). The metabolic profiles of these three compounds showed common biotransformation patterns, particularly in the phase II reactions (glucuronide conjugation, sulfation, GSH conjugation, and amino acid conjugation). Data-dependent exploration based on molecular network analysis of T3 profiles revealed that lipids and lipid-like molecules were the most enriched biotransformants. The subsequent subnetwork analysis proposed 14 additional features, including T4 in addition to 9 metabolized compounds that were annotated by prediction system based on possible hepatic enzymatic reaction. The other 10 THR agonistic negative compounds showed unique biotransformation patterns according to structural commonality, which corresponded to previous in vivo studies. Our evaluation system demonstrated highly predictive and accurate performance in determining the potential thyroid-disrupting activity of EDC-derived metabolites and for proposing novel biotransformants.

项与 Sobetirome 相关的新闻（医药）

2022-12-23

·药智网

股价暴涨268%！THR-β激动剂，如何打破NASH研发魔咒？

我国脂肪肝患者约1.5亿，且在不断增加，NASH（非酒精性脂肪性肝炎）是脂肪肝中比较严重的类型。据悉，有1.1亿轻度脂肪肝患者，可以通过饮食及锻炼好转，但是上千万中度重度NASH患者不能通过该方法恢复。且NASH需要终生用药，市场规模大。然而，面对如此庞大的患病人群，人类却无计可施。40年来，药企在NASH新药领域的研究几乎全军覆没，NASH的复杂性是这个时代最困难的医学挑战之一。好在，经过全球制药企业的不断努力，40年研发“坟场”终见曙光。THR-β激动剂有望首次登顶NASH“珠峰”近日，位于美国宾夕法尼亚州的Madrigal Pharmaceuticals宣布，瑞美替罗(resmetirom)达到了3期临床MAESTRO-NASH活检试验的主要终点和关键次要终点。受此消息影响，Madrigal股价暴涨268%，市值超过40亿美元，足以证明市场对NASH药物的渴望。图1 Madrigal股价上涨图片来源：百度股市通据悉，MAESTRO-NASH试验在经活检证实的非酒精性脂肪性肝炎(NASH)患者中评估了80毫克和100毫克剂量的甲状腺激素受体激动剂瑞美替罗与安慰剂的对比。NASH是脂肪肝疾病的一种晚期形式。在两种剂量水平上，与安慰剂组的个体相比，resmetirom治疗的患者在后期试验中表现出显着更高水平的NASH消退和肝纤维化改善（该研究的共同主要终点）。两种剂量的效果都轻松优于安慰剂。值得注意的是，该药物在两种剂量下都显得安全且可耐受。此外，口服药物治疗还显着改善了LDL-C胆固醇水平（“坏胆固醇”），这是该研究的一个关键次要终点。Madrigal的管理层在新闻稿中指出，在研究参与者中，resmetirom在两种剂量水平下都是安全且耐受性良好的。Madrigal的高层打算2023年上半年，向FDA申请resmetirom的加速批准，作为治疗非肝硬化NASH伴肝纤维化的药物。在服用resmetirom一年后，接受最高剂量治疗的患者中有30%在八分制量表上的症状至少改善了两分。同时，他们的纤维化没有恶化。另一项指标着眼于肝纤维化缓解，它分五个阶段进行测量。结果26%的患者表现出至少一个阶段的纤维化改善，并且他们的症状没有恶化。总体而言，56%的患者达到了临床试验研究的目标之一。2023年，该药有望成为美国市场上第一个FDA批准的NASH药物。THR-β选择性激动剂研发难点安全性一直是NASH药物开发的痛点。在众多治疗NASH的药物靶点中，THR-β选择性激动剂终于取得成功。先来看一下这个靶点的背景。众所周知，甲状腺激素(THs)对许多生理过程产生显着影响，例如生长、发育和新陈代谢。缺乏甲状腺激素会引发多种疾病。大多数TH效应由两种不同的甲状腺激素受体(THR)亚型介导，即THR-α和THR-β，已知THR-β亚型负责TH对肝脏的有益作用。因此，在过去的二十年里，人们付出了很多努力来开发能够将对肝脏（降低甘油三酯和胆固醇）和中枢神经系统（减少突胶质细胞增生）的有益作用与对心脏、肌肉和骨头有害副作用有选择性的甲状腺激素类似物。图2 甲状腺激素(T3)在细胞核中产生和作用的模型图片来源：参考资料3甲状腺素(T4)是甲状腺产生的甲状腺激素(TH)的主要形式，一旦释放，就会通过脱碘酶1和2（D1和D2）转化为T3，即TH的主要形式。脱碘酶3(D3)将T4转化为无活性的rT3。(二)甲状腺激素受体(TR)作为调节多种基因的转录因子。Unliganded TR，通常作为与视黄酸X受体(RXR)的异二聚体，与DNA上的甲状腺激素反应元件(TRE)结合，然后募集共阻遏物及其相关的组蛋白乙酰转移酶(HAT)。辅因子结合的这种改变导致聚合酶III的募集和基因转录的开始。Sobetirome(GC-1)2和随后的Eprotirome(KB2115)5是THR-β选择性激动剂的早期例子，Sobetirome与甲状腺素的结构不同，因为它没有卤素、联芳基醚氧和氨基酸侧链。尽管这两种拟甲状腺素都显示出令人鼓舞的抗高胆固醇血症、非酒精性脂肪性肝炎(NASH)和刺激肝细胞增殖的作用，但它们分别在1期和2-3期临床试验后宣告失败。图3 几款THR激动剂小分子的结构图片来源：参考资料2近年来，分子和结构生物学的进步，促进了新的选择性甲状腺激素模拟物的设计，这些模拟物表现出THR亚型选择性结合和/或肝脏和组织选择性摄取，Resmetirom(MGL-3196)和Hep-Direct前体药物VK2809(MB07811)代表了两种最有前途药物。图4 Resmetirom和Eprotirome的结构图片来源：参考资料3来看一下Madrigal公司在早期研发中，如何通过药物化学优化提高安全性：在核激素受体激动剂领域，很难预测配体结构的细微改变如何影响其生物学特征。为了鉴定更具THR-β选择性且可能更安全的化合物，基于药物代谢和安全性的考量，Madrigal公司把精力主要集中于不含富电子的苯酚环的T3类似物。在早期临床试验中，化合物5的酚环与亚硝酸盐在胃强酸性环境下通过自由基硝化形成的毒性化合物在血浆中能被检测到，从而造成药物安全性的问题。而拜耳公司一系列基于吲哚结构的THR激动剂，如化合物7，证明了T3的酚环可以被杂环取代。在Madrigal公司研究的几种缺电子杂环修饰中，由化合物8为代表的哒嗪酮类似物被证明是最有希望的，这种新型杂环为化合物提供了改进的THR-β选择性，构成了resmetirom这款药的结构基础。根据Madrigal发布的Resmetirom安全性数据（图5）所示在80mg和100mg剂量下都是安全且耐受性良好的，严重不良事件的频率在治疗组中相似因不良事件而中止研究的比率很低。这些数据与之前的临床数据一致，与安慰剂组相比，服药组最常见不良反应是治疗开始时轻度和短暂性腹泻以及轻度恶心。图5 Resmetirom安全性数据图片来源：公司官网小结NASH是生物制药中最热门的研究领域之一，正在进行300多项临床试验。此前，Intercept Pharma公司看起来很有可能赢得将NASH药物推向市场的竞赛，但在FDA于2020年拒绝其奥贝胆酸（OCA）的上市申请并被迫撤回其申请后，希望破灭。而凭借THR-β选择性激动剂3期临床的成功，行业专家判断Madrigal公司可能已经成为各大药企2023年最想并购的候选者，若收购成功，可能获得高达90亿美元的收入。未来，随着NASH药物研发进展，也会有更多脂肪肝患者收益。道阻且长，行则将至；行而不辍，未来可期。参考资料：1.Madrigal公司新闻稿宣布三期临床成功https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-announces-positive-topline-results-pivotal-phase-32.Resmetirom药物化学论文https://pubs.acs.org/doi/10.1021/jm4019299#3.THR-β药物开发综述https://www.frontiersin.org/articles/10.3389/fmed.2020.00331/full4.谢博士NASH评论文章https://ibook.antpedia.com/x/523197.html5.万字闲谈NASH新药研发https://mp.weixin.qq.com/s/4Zuutih8xsJUHONIlVzTfA声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。如对本文有异议或投诉，请联系18323856316（同微信）。责任编辑 | 八角转载开白 | 马老师 18323856316（同微信）— Tips —如果您有医药行业相关的线索或对医药政策、研发创新、资本市场、行业发展有深度观察欢迎投稿给我们马老师 18323856316（同微信）邮箱：maxuelian@yaozh.com 阅读原文，是昨天最受欢迎的文章哦

ASH会议临床3期加速审批

100 项与 Sobetirome 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09381	-	-	DB07425

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
肾上腺脑白质营养不良	临床2期	阿根廷	NeuroVia, Inc.	2018-08-01
肾上腺脑白质营养不良	临床2期	澳大利亚	NeuroVia, Inc.	2018-08-01
肾上腺脑白质营养不良	临床2期	智利	NeuroVia, Inc.	2018-08-01
肾上腺脑白质营养不良	临床2期	哥伦比亚	NeuroVia, Inc.	2018-08-01
肾上腺脑白质营养不良	临床2期	法国	NeuroVia, Inc.	2018-08-01
肾上腺脑白质营养不良	临床2期	俄罗斯	NeuroVia, Inc.	2018-08-01
肾上腺脑白质营养不良	临床2期	乌克兰	NeuroVia, Inc.	2018-08-01
肾上腺脑白质营养不良	临床2期	英国	NeuroVia, Inc.	2018-08-01
肥胖	临床1期	美国	QuatRx Pharmaceuticals Co.	2008-01-29
脂质代谢紊乱	临床1期	美国	QuatRx Pharmaceuticals Co.	-

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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


ATS2023	N/A	肺纤维化	-	GC-1	廠積觸願鹹構觸積夢鹽(衊築衊範鹽廠獵餘觸積) = decreased 簾鏇鬱鏇構鑰鹽膚鏇範 (淵願構顧網糧構艱艱鹽 ) 更多	-	2023-05-21