A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center Phase 2 Study to Evaluate the Efficacy, Safety, and Tolerability of Once-Weekly CT-388 Administered Subcutaneously for 48 Weeks to Participants Who Are Overweight or Obese with Type 2 Diabetes Mellitus

This is a multi-center, randomized, double-blind, placebo-controlled, parallel group dose-finding study to evaluate the efficacy and safety of CT-388 at low, middle, and high doses in participants who are overweight or obese with Type 2 diabetes mellitus (T2DM).

开始日期2024-10-30

申办/合作机构

Carmot Therapeutics, Inc.

[+1]

ISRCTN90651766 / Recruiting临床1期

Phase I trial: Quotient code QSC301813

开始日期2024-09-16

申办/合作机构

Carmot Therapeutics, Inc.

NCT06525935 / Recruiting临床2期

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Phase 2 Study to Evaluate the Efficacy, Safety, and Tolerability of Once-Weekly CT-388 Administered for 48 Weeks to Participants with Obesity or Overweight with At Least One Weight-Related Comorbidity

This is a multi-center, randomized, double-blind, placebo-controlled, parallel group dose-finding study to evaluate the efficacy and safety of CT-388 at low, middle, and high doses in participants with obesity or who are overweight with at least one weight-related comorbidity.

开始日期2024-08-16

申办/合作机构

Carmot Therapeutics, Inc.

[+1]

100 项与 Carmot Therapeutics, Inc. 相关的临床结果

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0 项与 Carmot Therapeutics, Inc. 相关的专利（医药）

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项与 Carmot Therapeutics, Inc. 相关的文献（医药）

2019-01-01·Cell chemical biology1区 · 生物学

Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

1区 · 生物学

Review

作者: Erlanson, Daniel A ; Jahnke, Wolfgang ; Davis, Ben J

Fragment-based drug discovery typically requires an interplay between screening methods, structural methods, and medicinal chemistry. X-ray crystallography is generally the method of choice to obtain three-dimensional structures of the bound ligand/protein complex, but this can sometimes be difficult, particularly for early, low-affinity fragment hits. In this Perspective, we discuss strategies to advance and evolve fragments in the absence of crystal structures of protein-fragment complexes, although the structure of the unliganded protein may be available. The strategies can involve other structural techniques, such as NMR spectroscopy, molecular modeling, or a variety of chemical approaches. Often, these strategies are aimed at guiding evolution of initial fragment hits to a stage where crystal structures can be obtained for further structure-based optimization.

2018-01-01·The Journal of biological chemistry2区 · 生物学

Co(II) and Ni(II) binding of the Escherichia coli transcriptional repressor RcnR orders its N terminus, alters helix dynamics, and reduces DNA affinity

2区 · 生物学

Article

作者: Bobst, Cedric E ; Maroney, Michael J ; Iwig, Jeffrey S ; Huang, Hsin-Ting ; Kaltashov, Igor A ; Chivers, Peter T

RcnR, a transcriptional regulator in Escherichia coli, derepresses the expression of the export proteins RcnAB upon binding Ni(II) or Co(II). Lack of structural information has precluded elucidation of the allosteric basis for the decreased DNA affinity in RcnR's metal-bound states. Here, using hydrogen-deuterium exchange coupled with MS (HDX-MS), we probed the RcnR structure in the presence of DNA, the cognate metal ions Ni(II) and Co(II), or the noncognate metal ion Zn(II). We found that cognate metal binding altered flexibility from the N terminus through helix 1 and modulated the RcnR-DNA interaction. Apo-RcnR and RcnR-DNA complexes and the Zn(II)-RcnR complex exhibited similar ²H uptake kinetics, with fast-exchanging segments located in the N terminus, in helix 1 (residues 14-24), and at the C terminus. The largest difference in ²H incorporation between apo- and Ni(II)- and Co(II)-bound RcnR was observed in helix 1, which contains the N terminus and His-3, and has been associated with cognate metal binding. ²H uptake in helix 1 was suppressed in the Ni(II)- and Co(II)-bound RcnR complexes, in particular in the peptide corresponding to residues 14-24, containing Arg-14 and Lys-17. Substitution of these two residues drastically affected DNA-binding affinity, resulting in rcnA expression in the absence of metal. Our results suggest that cognate metal binding to RcnR orders its N terminus, decreases helix 1 flexibility, and induces conformational changes that restrict DNA interactions with the positively charged residues Arg-14 and Lys-17. These metal-induced alterations decrease RcnR-DNA binding affinity, leading to rcnAB expression.

2011-01-01·Topics in current chemistry

Introduction to Fragment-Based Drug Discovery

Review

作者: Erlanson, Daniel A

Fragment-based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads. The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs. These fragments are then expanded or linked together to generate drug leads. Although the origins of the technique date back some 30 years, it was only in the mid-1990s that experimental techniques became sufficiently sensitive and rapid for the concept to be become practical. Since that time, the field has exploded: FBDD has played a role in discovery of at least 18 drugs that have entered the clinic, and practitioners of FBDD can be found throughout the world in both academia and industry. Literally dozens of reviews have been published on various aspects of FBDD or on the field as a whole, as have three books (Jahnke and Erlanson, Fragment-based approaches in drug discovery, 2006; Zartler and Shapiro, Fragment-based drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011). However, this chapter will assume that the reader is approaching the field with little prior knowledge. It will introduce some of the key concepts, set the stage for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement.

205

项与 Carmot Therapeutics, Inc. 相关的新闻（医药）

2024-10-23

·EndPoints

Allowing Novo-Catalent deal to close would be ‘wrong decision’ by antitrust authorities, Roche CEO says

Antitrust regulators shouldn’t clear Novo Holdings’ planned acquisition of Catalent, Roche CEO Thomas Schinecker said Wednesday, adding to the pressure that industry competitors appear to be trying to generate against the takeover. The deal would boost Novo Nordisk’s manufacturing capacity as it tries to meet huge demand for its obesity drugs. But Roche — which is developing its own obesity drugs — and Novo’s main rival Eli Lilly have now opposed it. While Roche was quick to highlight that it wouldn’t be directly affected by the Novo-Catalent deal, Schinecker said “it would be a wrong decision” for authorities to allow a transaction that could limit competition from a broader industry perspective. “It could be a problem for other smaller players if there is a restriction in how many [manufacturers] are available,” Schinecker said during a call with reporters on Wednesday. Lilly has made similar comments, raising concerns that a competitor would own a major supplier relied on by much of the industry. In February, Novo Holdings announced the $16.5 billion plan to buy Catalent, with Novo Nordisk set to buy three sites from Novo Holdings for $11 billion. A few weeks later, Eli Lilly CEO David Ricks said the deal was “unusual” and called for a broad inquiry into the transaction. And in August, he said Lilly had been using Catalent for manufacturing of its GLP-1 drug. Other pharma companies and smaller biotechs developing obesity drugs largely declined to comment when reached by Endpoints News on Wednesday. In the US, the Federal Trade Commission continues to review the deal, and people familiar with the situation say they’re not yet near a decision about whether to block it or ask for some sort of concession. Consumer and union groups called on the FTC to challenge the takeover, alleging it will impact competition for weight loss drugs and cell and gene therapies. Sen. Elizabeth Warren (D-MA) urged the FTC to thoroughly scrutinize the deal and its compliance with antitrust laws. Over the course of the year, Novo and Catalent have reiterated that, despite several delays , the deal is still scheduled to be completed by year’s end. And on Monday, Catalent penned an open letter to customers reassuring them that it would operate as a fully independent CDMO after deal completion. On Wednesday’s call, Roche pharma chief Teresa Graham underscored that “Roche has one of the largest and most diverse manufacturing footprints in the industry,” and so “we are not at all concerned that we will need additional CMO capacity,” she added. The company has several next-generation weight loss assets in the clinic that it obtained as part of its acquisition of Carmot Therapeutics .

并购

2024-10-23

·Endpoints

Life sciences investor Dimension seeks to raise $500M second fund

A venture capital firm that seeks to digitize the life sciences ecosystem has plans for a $500 million follow-up fund, according to a Tuesday SEC filing. The firm, Dimension Capital, debuted in January 2023 with a $350 million inaugural fund , and invests in startups from young entrepreneurs, academics and engineers, according to its website. Representatives for the investor didn’t immediately respond to questions about the new $500 million fund. Dimension’s portfolio includes startups like plant chemistry-inspired Enveda Biosciences , AI foundation model-based Chai Discovery and others, including the next bet from the founder of obesity biotech Carmot Therapeutics . There have been signs that young venture firms have struggled to raise new money for second funds. Across the VC ecosystem, about 37% of first-time VCs cannot raise a second fund, according to a PitchBook report from February. Dimension’s leaders have a track record behind them, however. It was founded by ex-Lux investors Adam Goulburn and Zavain Dar , as well as former Obvious venture partner Nan Li. “I suspect most will look at our strategy today as niche (and frankly I want them to continue to do so for as long as possible),” Dar said in a Slack interview with Endpoints News in February. “In 10 years, though, this will be the primary strategy for value creation and capture in the ecosystem.” At the time of its launch, Goulburn told Endpoints that Dimension aimed to be a “lighthouse firm for the digitization of the life sciences industry.” The firm said then it sees biologists, chemists and computer scientists coming together to lead the next generation of companies in the life sciences field. “That siloing is just so outdated,” Li said in January 2023, noting Dimension wanted to be a “one-stop shop” for nascent entrepreneurs. Dimension was among a crop of new life science investment firms to emerge in early 2023, including Curie.Bio (which disclosed another fund in June ), NYBC Ventures and Cure Ventures. If successful, Dimension’s proposed raise would add to a growing list of life sciences investors who have recently laid out additional funds, including at Flagship, Bain, ARCH and Forbion. Some smaller firms are also pulling in capital, including KdT Ventures, Asabys Partners and others.

2024-10-22

·微信

近半千亿药企入局，GLP-1是否市值驱动器？ | 行业观察

// · 市值超过1,000亿美元的15家大药企中，7家拥有新一代的减重产品资产； · 基于已发布的减重临床试验数据，12周、24周和48周的减重最好的药物分别是：安进的MariTide、罗氏的CT-388和礼来的retatrutide； · 口服小分子药物更适合作为快速减重后的长期维持治疗，正在成为各大药企角逐的又一个战场； · 该领域未来有可能催生大量交易。随着GLP-1药物的热度不断攀升，越来越多的公司进入这场减肥大战的同时，推高了相关药企在公开市场的市值。两款重磅GLP-1类减重产品的开发商——礼来和诺和诺德的股价也不断走高，超越强生，成为全球市值最高的两家药企。礼来和诺和诺德在公开市场上的优异表现，在医药行业掀起了一场减重产品大战，大量资本和药企冲进这一领域。据Stifel，2024 年至 2019 年间，针对减重产品的风险投资额增长了 10 倍，今年预计将超过10亿美元。而当前正在开发和已经获批的减重产品有264个。来源|CompaniesMarketcap.com，Bernstein，研发客分析，截至9月13日收盘基于9月13日的收盘价，市值超过1,000亿美元的15家大药企中，7家已经通过自研或者交易拥有了新一代的减重产品（见上图），并寄希望于这些产品能帮助公司进一步推高市值。关于交易及合作的讨论，欢迎关注第八届研发客临床年会(左右滑动查看讨论主题)。更好的激动剂出现？去年，诺和诺德的GLP-1明星产品司美格鲁肽销售额达到了212亿美元，成为全球最畅销的药物之一。公司股价也一路走高，超过100美元。五年后，礼来GLP-1/GIP受体双重激动剂替尔泊肽上市，并报告了更为强劲的减重数据。今年二季度，替尔泊肽的销售额大幅增长至43亿美元。得益于这款药物的强劲表现，礼来今年两次提高了全年的销售预期，年初至今股价上涨超过50%，成为全球市值最高的药企。患者接受GLP-1类药物治疗后一年半内的平均体重减轻情况来源|Epic Research 相比而言，诺和诺德的司美格鲁肽在二季度的销售额仅有59亿美元，其中减重品牌Wegovy销售额比市场预期低了14%，因此引发股价暴跌。尽管如此，凭借这款重磅减重产品，诺和诺德目前仍然稳居药企市值第二位。据FactSet，分析师预期到2026年，替尔泊肽的销售额将达到300亿美元，司美格鲁肽将超过400亿美元。为了获得销售持续的增长，两家公司正在投入巨资加快生产，解决供应问题。利润如此丰厚的市场，吸引了更多大玩家进入。罗氏在9月30日的Roche Pharma Day上，提到了对这个潜在价值高达1,000亿美元的大市场的兴趣。去年，罗氏以27亿美元收购Carmot Therapeutics获得了三款G蛋白偏向的GLP-1受体激动剂——CT-868、CT-388和CT-996。来源|Roche 当GLP-1和GIP受体激活剂与相关受体结合后，环磷酸腺苷 (cAMP) 信号通路被激活，但同时ß-arrestin也会被募集到受体上，然后部分通过受体运输减弱 G 蛋白信号传导，导致受体内化（receptor internalization）和脱敏（desensitization），削弱了药物疗效。为了最大限度扩大GLP-1和GIP受体激活剂的治疗窗口，Carmot 将产品设计成具有信号传导偏向性，以优先激活 cAMP，同时很少甚至没有 ß-arrestin募集，从而减少受体内化和脱敏，以延长药理活性。 5月16日，罗氏披露了CT-388（GLP-1/GIP受体双重激动剂）的1期临床研究数据。结果显示，24周时最高剂量组安慰剂调整后的体重减轻达到18.8%，当天公司股价上涨超过4%。这一数据也超过了6月恒瑞ADA上发布的同类药物HRS9531的2期24周减重数据（16.7%），以及已上市产品替尔泊肽（11.9%）和司美格鲁肽（8.0%），成为已发布24周数据中减重最多的产品。未来的市场领导者在新竞品出现的同时，减重市场领军公司也对正在研发的下一代GLP-1产品寄予厚望。在3月的资本市场日上，诺和诺德透露，在研新药CagriSema正在开展的3期减重研究包括五个子研究，计划招募1.3万名参与者，今年晚些时候将报告第一个研究的数据。此前发布的 20 周的 1 期减重试验结果显示，CagriSema可减重 17.1%，超过了司美格鲁肽的 9.8%。 CagriSema是cagrilintide（胰淀素和降钙素双重受体激动剂）和已上市药物司美格鲁肽的组合制剂。诺和诺德希望胰淀素（amylin）类似物和 GLP-1 受体激动剂的互补的机制能增强食欲抑制，实现更好的减重效果。礼来同样在做加法。去年的ADA（美国糖尿病协会）年会上，礼来发布了同时靶向GLP-1、GIP和GCG（glucagon）的新药retatrutide的2期减重研究结果。最高剂量下，48周安慰剂调整后减重22.1%，是已发布48周数据中减重最大的药物。此外，24周的安慰剂调整后减重也达到16%。安进的高管及其投资者对他们的减重药物MariTide（maridebart cafraglutide，AMG133）寄予厚望，期望MariTide能挑战两巨头的霸主地位。在5月的一季度业绩会上，公司CEO Bob Bradway暗示2期数据很好，“我们对 MariTide 这款差异化产品很有信心”。随后股价飙升了15%。在已发布12周减重数据的药物中， MariTide减重幅度最大，最高剂量组达到了16%，优于在2a期研究中表现出色的GLP-1/GIP受体双重激动剂VK2735的13周数据（13.1%）。安进目前正在开展MariTide针对超重和肥胖人群的2期研究，预计年底将发布结果。 MariTide拥有独特的机制，是一款同时靶向两个靶点的抗体-肽共轭物，抗体部分抑制GIP受体，而与抗体结合的两个GLP-1类似物可激活GLP-1受体。来源|Véniant, M.M., et al. Nat Metab 6, 290–303 (2024). 安进的机制研究表明，MariTide 能同时与 GIP 和 GLP-1的受体结合，从而触发 GLP-1受体的早期受体内化（receptor internalization），增强 GLP-1 特异性血浆和胞内体膜 cAMP 的生成，从而导致快速、显著和持续的体重减轻，且不易出现体重反弹。口服制剂：又一个战场尽管减重效果不如肽类注射剂，但口服小分子制剂生产成本低，且使用方便，更适合作为快速减重后的长期维持治疗，因此成为各大药企角逐的又一个战场。诺和诺德已经成功完成了司美格鲁肽的口服制剂的减重3期研究，但该公司更在意的是新的候选药物。其中，GLP-1/amylin受体双重激动剂amycretin（NN6487）的口服制剂。3月发布的1期研究初步结果显示，用药12周后，安慰剂调整后减重12.0%，诺和诺德股价应声大涨9%。年初，礼来的CEO David Ricks在投资者会议上提到了口服非肽类GLP-1受体激动剂orforglipron。根据去年ADA上发布的2期数据，最高剂量组下26周和36周安慰剂调整后减重分别可达到10.6%和12.4%。辉瑞的口服GLP-1受体激动剂danuglipron（PF-06882961）则命运多舛。在放弃开发代谢功能障碍相关性脂肪肝（MASH）适应症后，去年底又因为退出率超过50%而放弃了每日两次的剂型。不过，今年7月辉瑞表示，将继续开发剂量优化后的danuglipron每日一次的剂型。然而，此前每日两次剂型的2b期研究中，最高剂量组32周安慰剂调整后减重10%，相对于礼来的orforglipron并无优势。罗氏从Carmot获得的CT-996是一款小分子的GLP-1受体激动剂，根据7月发布的初步结果，这款每日一次的药物能在四周内达到安慰剂调整后6.1%。受此消息影响，罗氏股价一度上涨7%，竞争对手诺和诺德和礼来的股价则分别下跌了5%和近4%。阿斯利康同样选择从外部购入口服资产。去年11月，该公司花费1.85亿美元首付款从中国公司诚益生物获得了每日一次口服GLP-1受体激动剂ECC5004（AZD5004），目前正在开展2期研究，尚未公布数据。潜在买家有哪些为了尽快获得具有竞争力的产品，除了自主开发以外，大药企还积极开展交易。前文提到的罗氏和阿斯利康都是通过外部购买获得了减重候选药物。不过，仍有不少大药企迄今为止尚无新一代的减重产品，如强生、艾伯维、诺华、赛诺菲和BMS等。此外，默沙东的GLP-1和GCG受体双重抑制剂efinopegdutide（MK-6024）当前仅进行MASH适应症的开发，这些公司不可能放弃减重领域这个大市场，未来很可能会通过购买有竞争力的资产进入该领域。而已有资产的公司也不会停止交易。 9月初，礼来与Haya Therapeutics达成多年期合作，探索使用Haya的专有技术平台，寻找暗基因组中的长链非编码RNA（lncRNA）靶点，开发减重和代谢新药物。去年该公司还斥资19.3亿美元收购了Versanis，获得myostatin单抗bimagrumab，开发减重适应症。诺和诺德在今年1月以2.35亿欧元获得了EraCal的临床前食欲抑制剂Era-379等多款口服创新机制的口服小分子减重药物。去年8月，该公司11亿美元收购Inversago，获得的大麻素1型受体（CB1）逆激动剂monlunabant（INV-202）。另一方面，一些拥有不错数据的在研减重药物及其开发商很有可能是大药企未来的收购目标。例如，Viking的GLP-1/GIP受体双重激动剂VK2735，以及Altimmune 的 GLP-1/GCG受体双重抑制剂pemvidutide等。可喜的是，多家中国公司在今年的ADA等会议上发布的减重在研产品数据也相当不错，如甘李药业的GZR-18、恒瑞的HRS9531、先为达的伊诺格鲁肽（Ecnoglutide，XW003）等，受到海外关注。未来，或许会有大药企与中国药企的减重资产交易出现。编辑 | 姚嘉 yao.jia@PharmaDJ.com 总第2228期访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

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药物(靶点)	适应症	全球最高研发状态

CT-868 ( GIPR x GLP-1R )	肥胖更多	临床2期
CT-388 ( GIPR x GLP-1R )	肥胖更多	临床2期
CT-966 ( GLP-1R )	肥胖更多	临床1期
CT-859 ( GIPR x GLP-1R )	肝细胞癌更多	临床前
SNS-229 ( PDPK1 )	实体瘤更多	临床前