NAUTILUS: a Phase 1b/2 Study of OKI-179 Plus Binimetinib in Patients with Advanced Solid Tumors and Activating Mutations in the RAS Pathway (Phase 1b) and in Patients with Advanced NRAS-Mutated Melanoma (Phase 2)

The NAUTILUS study is a Phase 1b/2, multi-center, open-label study in which patients with activating mutations in the RAS pathway (Phase 1b) and patients with NRAS-mutated Melanoma (Phase 2) will be treated with a combination of oral OKI-179 combined with the MEK inhibitor binimetinib.

开始日期2022-05-11

申办/合作机构

OnKure, Inc.

NCT03931681

/ Completed临床1期

A Phase 1 Study of OKI-179 as a Single Agent in Patients With Advanced Solid Tumors

This study is a Phase 1, single center, open-label study, assessing single agent dose escalation of OKI-179.

开始日期2019-05-08

申办/合作机构

OnKure, Inc.

[+1]

100 项与 Bocodepsin 相关的临床结果

登录后查看更多信息

100 项与 Bocodepsin 相关的转化医学

登录后查看更多信息

100 项与 Bocodepsin 相关的专利（医药）

登录后查看更多信息

项与 Bocodepsin 相关的文献（医药）

2022-03-01·Molecular cancer therapeutics2区 · 医学

Preclinical Development of the Class-I–Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors

2区 · 医学

Article

作者: Hartman, Sarah J. ; Schiemann, William P. ; Wendt, Michael K. ; Newton, Timothy P. ; Zhang, Gan ; Pitts, Todd M. ; Tentler, John J. ; Yacob, Betelehem W. ; Diamond, Jennifer R. ; Bagby, Stacey M. ; Gittleman, Brian ; Winkler, James D. ; Pafford, Jessica ; Piscopio, Anthony D. ; Liu, Xuedong ; DeMattei, John A. ; Phillips, Andrew J. ; Ungermannova, Dana ; Nasveschuk, Christopher G. ; Eckhardt, S. Gail

Abstract:

Histone deacetylases (HDACs) play critical roles in epigenomic regulation, and histone acetylation is dysregulated in many human cancers. Although HDAC inhibitors are active in T-cell lymphomas, poor isoform selectivity, narrow therapeutic indices, and a deficiency of reliable biomarkers may contribute to the lack of efficacy in solid tumors. In this article, we report the discovery and preclinical development of the novel, orally bioavailable, class-I–selective HDAC inhibitor, OKI-179. OKI-179 and its cell active predecessor OKI-005 are thioester prodrugs of the active metabolite OKI-006, a unique congener of the natural product HDAC inhibitor largazole. OKI-006, OKI-005, and subsequently OKI-179, were developed through a lead candidate optimization program designed to enhance physiochemical properties without eroding potency and selectivity relative to largazole. OKI-005 displays antiproliferative activity in vitro with induction of apoptosis and increased histone acetylation, consistent with target engagement. OKI-179 showed antitumor activity in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. Based on its potency, desirable class I HDAC inhibition profile, oral bioavailability, and efficacy against a broad range of solid tumors, OKI-179 is currently being evaluated in a first-in-human phase I clinical trial with plans for continued clinical development in solid tumor and hematologic malignancies.

2019-08-01·Cancer immunology research1区 · 医学

Histone Deacetylase Inhibition Sensitizes PD1 Blockade–Resistant B-cell Lymphomas

1区 · 医学

Article

作者: Wang, Jing H. ; Waschke, Brittany C. ; Liu, Xuedong ; Zhang, Gan ; Piscopio, Anthony D. ; Woolaver, Rachel A. ; Wang, Xiaoguang ; Chen, Zhangguo

Abstract:

PD1 blockade is effective in a subset of patients with B-cell lymphoma (e.g., classical-Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To study PD1 resistance, we used an isoform-selective histone deacetylase inhibitor (HDACi; OKI-179), and a mouse mature B-cell lymphoma, G1XP lymphoma, immunosuppressive features of which resemble those of human B-cell lymphomas, including downregulation of MHC class I and II, exhaustion of CD8+ and CD4+ tumor-infiltrating lymphocytes (TIL), and PD1-blockade resistance. Using two lymphoma models, we show that treatment of B-cell lymphomas refractory to PD1 blockade with both OKI-179 and anti-PD1 inhibited growth; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated with MHC class II expression level. We conclude that OKI-179 sensitizes lymphomas to PD1-blockade by enhancing tumor immunogenicity. In addition, we found that different HDACis exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas. Our study highlights the immunologic effects of HDACis on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and the individual profiles of HDACi.

Frontiers in immunology

Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy

Article

作者: Triplett, Todd A ; Duchow, Mark ; Diamond, Jennifer ; Piscopio, Anthony D ; Rios, Joshua ; Capasso, Anna ; Holay, Nisha ; Eckhardt, S Gail ; Van Den Berg, Carla ; Giri, Uma ; Kottapalli, Srividya ; Schreiber, Anna ; Soleimani, Milad ; Somma, Alexander

Histone deacetylase inhibitors (HDACi) are currently being explored for the treatment of both solid and hematological malignancies. Although originally thought to exert cytotoxic responses through tumor-intrinsic mechanisms by increasing expression of tumor suppressor genes, several studies have demonstrated that therapeutic responses depend on an intact adaptive immune system: particularly CD8 T cells. It is therefore critical to understand how HDACi directly affects T cells in order to rationally design regimens for combining with immunotherapy. In this study, we evaluated T cell responses to a novel class-selective HDACi (OKI-179, bocodepsin) by assessing histone acetylation levels, which revealed rapid responsiveness accompanied by an increase in CD4 and CD8 T cell frequencies in the blood. However, these rapid responses were transient, as histone acetylation and frequencies waned within 24 hours. This contrasts with in vitro models where high acetylation was sustained and continuous exposure to HDACi suppressed cytokine production. In vivo comparisons demonstrated that stopping OKI-179 treatment during PD-1 blockade was superior to continuous treatment. These findings provide novel insight into the direct effects of HDAC inhibitors on T cells and that treatment schedules that take into account acute T cell effects should be considered when combined with immunotherapies in order to fully harness the tumor-specific T cell responses in patients.

项与 Bocodepsin 相关的新闻（医药）

2023-06-19

·动脉网

OnKure:表观遗传疗法治疗癌症，两年内获融资1.09亿美元

肿瘤一直以来都是医疗领域的难题，尽管随着医疗技术的发展，出现各种治疗癌症的先进技术方法，但是癌症仍是全球的主要死因。据2023年世界卫生组织的数据显示，全球每年约有125万人民死于癌症，并预估2023年将会增加到130万人。针对肿瘤精准药物的发现和开发，一直是医药创新领域的热门话题近期，精准肿瘤公司OnKure,Inc.（简称OnKure）于2023年5月23日宣布完成5400万美元C轮融资，用于OnKure下一代精准药物差异化管线的持续开发，并且将其先导发现项目OKI-219（一种选择性P13K α H1047R抑制剂）推进临床。包含本轮融资在内，OnKure成立至今一共完成了8轮，共计约1.198亿美元的融资。 OnKure为什么受到投资人的持续追捧，动脉网对其进行了研究。 Array领导团队再掌舵，创建新型肿瘤药物管道 OnKure总部位于美国科罗拉多州博尔德市，成立于2011年。OnKure的候选药物旨在以表观遗传疗法，延迟对其他靶向治疗的耐药性和利用合成致死性来治疗患者。 Tony Piscopio是OnKure的联合创始人，自2011年以来一直担任公司的首席执行官兼总裁。Piscopio博士最近在全球药物发现机构Chemizon公司担任董事会主席和首席执行官，在此之前Piscopio与他人共同创建了Array生物制药公司。他是一位连续创业者，在生命科学行业有超过20年的行政领导经验。 Jim Winkler是OnKure的首席科学官。在加入OnKure之前，Jim Winkler博士曾在强生、葛兰素史克、Array、Arvinas等公司工作过。在Arvinas公司工作期间，他帮助这家公司专注于一项新技术，验证和进一步推进，并建立一个临床前管道，使Arvinas公司得以上市。往昔丰富的工作经历，使得Jim Winkler博士具有丰富的团队领导经验。 OnKure的领导团队曾为著名的小分子药物发现公司Array BioPharma的成功做出重大贡献，该公司于2019年被辉瑞收购。截至今日，OnKure基于表观遗传调控、延迟耐药性和合成致死性等技术研发的产品管道已经逐具规模，包括口服选择性I类HDAC（组蛋白去乙酰化酶）抑制剂、选择性P13K α H1047R抑制剂、致癌激酶抑制剂。 OKI-179的发现与开发，是OnKure发展历程中的重要节点。 OKI-179打破HDAC抑制剂历史局限性组蛋白是与DNA结合的蛋白质，在基因调控和DNA复制中起重要作用。组蛋白去乙酰化酶（HDAC），是一类从组蛋白和细胞质蛋白中去除缩醛基团以分别调节基因转录和蛋白质活性的酶。与正常细胞不同，癌细胞可能缺乏多种表观遗传调控机制。因此，当HDAC被抑制时，会导致肿瘤细胞周期停滞，分化和凋亡，所以HDAC抑制剂在临床前模型中显示出巨大的前景。然而由于耐受性差，不适当的给药方案，不合理的组合，以及缺乏分层的生物标志物等原因，HDAC抑制剂在治疗实体肿瘤方面几乎没有成功。目前罗米地辛是FDA批准的最有效的I类组蛋白去乙酰化酶抑制剂，通过持续输注给药。而Bocodepsin besylate (OKI-179)是口服给药，并且在临床前研究中显示出安全性。 OKI-179是被设计为具有更好的效力，选择性，耐受性以及易于组合的口服选择性I类HDAC抑制剂，用于治疗多种实体瘤和血液系统恶性肿瘤，如三阴性乳腺癌、黑色素、结直肠癌等。 ■ 1. OKI-179的人体单药试验表现出选择性和耐受性 2019年5月6日，OnKure宣布OKI-179已经通过了IND申请，可以开始I期试验。2019年6月11日，OnKure和科罗拉多大学癌症中心(University of Colorado Cancer Center)合作推进的新型HDAC抑制剂OKI-179首次人体 I期临床试验招募了第一名患者。 2021年12月14日，OKI-179 I期FIH（首次人体单药试验）单药试验已完成。此次研究表明，OKI-179作为一种单药，采用4天/3天或5天/2天的间歇性给药方案，为期21天，是安全的，而且耐受性良好。最常见的不良事件是恶心、疲劳和贫血。目前OKI-179的2期首次人体单药试验已完成。研究结果表明OKI-179会引起组蛋白过度乙酰化，进而激活转录并翻译已下调的蛋白质的产生。这些再次增多的蛋白质会被免疫系统识别并降解，进而被癌细胞用来逃避抗癌治疗。因此，OKI-179与靶向治疗相结合预计比单药使用更有效。 2022年4月8日，OnKure在AACR的最新突破性会议上宣布RAS 突变肿瘤模型中 OKI-179 的临床前数据。此数据表明OKI-179 在 RAS 通路突变癌症模型中与 MEK 和 BRAF 抑制剂联合使用时表现出化学合成致死性。基于OKI-179人体单药试验的有利结果，OnKure 于2022年4月25日宣布在博尔德开设一个研究实验室，并扩大其当地行业领导者团队，推进临床开发战略，计划启动与辉瑞合作的OKI-179 的 Nautilus 1b / 2 期试验。 ■ 2. OKI-179联合binimetinib治疗NRAS突变型黑色素瘤激活性NRAS突变发生在大约20%的黑色素瘤中，是黑色素瘤中仅次于BRAF突变的第二大最常见的致癌驱动突变。目前，对于NRAS突变的转移性患者，靶向治疗未满足医疗需求。 Binimetinib是一种丝裂原活化蛋白激酶（MEK）抑制剂，已被批准与encorafenib联合用于治疗BRAF V600E或V600K突变的不可切除或转移性黑色素瘤患者。 2022年6月2日，OKI-179联合Binimetinib治疗晚期NRAS突变黑色素瘤患者的1b/2期Nautilus试验完成首例患者给药，此项试验目前还在进行中。近期《Cancer Discovery》杂志报道了Maertens等人的一项研究，以及OnKure进行的临床前联合研究表明，合理联合使用这两种药物可能会增强抑制MAPK治疗NRAS黑色素瘤的临床获益。并且，Keith T. Flaherty博士（麻省总医院癌症中心临床研究主任）表明他与哈佛大学的合作者的转化研究同样表明了添加HDAC抑制剂可以进一步增强NRAS黑色素瘤患者的binimetinib活性这一结果。 ■ 3. OKI-179创新肿瘤治疗模式为确定OKI-179联合 binimetinib 治疗NRAS突变黑色素瘤患者的安全性和有效性，OnKure与辉瑞合作开展1b / 2 期 Nautilus 研究试验。 RAS通路激活突变患者(1b期)将接受OKI-179联合MEK抑制剂binimetinib的联合治疗。1b期试验旨在确定OKI-179 和 binimetinib 在 RAS 通路突变实体瘤患者中的最大耐受剂量、剂量限制毒性和推荐的 2 期剂量。 1b期试验的数据表明OKI-179 和 RAS 通路药物的合成致死组合在治疗 RAS 突变肿瘤中的潜力。在细胞系衍生的异种移植模型中，OKI-179、binimetinib 作为单一药物显示肿瘤生长延迟，但很少消退。但是，在NRAS突变的黑色素瘤中联合binimetinib和OKI-179或者在BRAF 突变的结直肠异种移植中联合 binimetinib + encorafenib，在给药一段时间后都显示出比任一单一药物显著增加的消退。 OKI-179一流的选择性、耐受性、更好的效力以及易于组合的特性，使得它打破了其他HDAC抑制剂的历史局限性，创新出肿瘤治疗的新模式，即HDAC抑制剂与靶向治疗相结合。创建候选药物管道，精准疗癌 OnKure自2011年成立以来，一直低调进行着肿瘤精准小分子药物的发现和开发，多年的砥砺前行，终究迎来曙光。 2018年5月2日，OnKure获得700万美元的A轮融资。OKI-179的发现，使得OnKure首次获得超百万美元的融资。这一年OnKure 在推进其首个临床候选药物 OKI-179进入第一阶段取得了重大进展。可以说OKI-179的发现和开发是OnKure发展历程中的重要节点。此后OKI-179临床试验顺利进行，目前已完成临床试验2期阶段。OnKure的另一个药物OKI-219（一种选择性 PI3K α H1047R 抑制剂）预计将在2023年完成IND提交，于2024年初将其推进临床开发。OKI-DISC-1和OKI-DISC-2两类激酶致癌抑制剂尚未公开信息。目前OnKure仍在进行下一代精准药物差异化管线的持续开发，公司药物发现资深团队正在探索一系列旨在实现最佳耐受性和疗效的新型致癌基因靶向项目，为创建候选药物管道迈步前进。内容来源于网络，如有侵权，请联系删除。

并购

2022-06-21

·BioSpace

OnKure Therapeutics Appoints Kevin S. Litwiler, Ph.D., as Senior Vice President of DMPK and Clinical Pharmacology

BOULDER, Colo., June 21, 2022 (GLOBE NEWSWIRE) -- OnKure, Inc., a clinical-stage biopharmaceutical company discovering and developing the next generation of oncology precision medicines, today announced the appointment of Kevin S. Litwiler, Ph.D., as Senior Vice President of DMPK and Clinical Pharmacology. Dr. Litwiler brings over three decades of diverse biopharmaceutical experience in clinical pharmacology, bioanalytical, drug metabolism and pharmacometrics spanning a variety of drug targets and therapeutic areas. “We are delighted to welcome Kevin to OnKure. His strong history of building innovative teams that successfully advance novel candidates from concept to market will be extremely valuable as we develop our pipeline of precision medicines,” said Tony Piscopio, Ph.D., Co-Founder, President and Chief Executive Officer of OnKure. “Kevin is well versed in our proven structure-based drug design approach and will add immediate value to our growing clinical division. We look forward to working closely with him to efficiently deliver novel oncology therapeutics to patients.” Prior to joining OnKure, Dr. Litwiler served as Executive Director, Clinical Pharmacology Global Product Development, Oncology at Pfizer Inc., where he was responsible for the late-stage advancement of Boulder-based assets, including two commercialized products. Prior to joining Pfizer, he served as Executive Director and head of Clinical Pharmacology at Array BioPharma Inc. During his tenure at Array, he oversaw strategy, productivity, compliance and budget for the department. Dr. Litwiler also contributed to INDs for 23 Array candidates and the design and conduct of over 40 clinical trials. He started his career at DuPont Biotechnology, where he held numerous research roles of increasing responsibility. Dr. Litwiler received his Ph.D. in Analytical Chemistry from the State University of New York at Buffalo and B.S. in Chemistry from Clarion University of Pennsylvania. “This opportunity to join OnKure is truly exciting. The Company’s scientific approach has immense potential, and I look forward to helping drive its clinical success,” said Dr. Litwiler. “Together with the OnKure team, I am confident in our ability to repeat past accomplishments and discover best-in-class oncology candidates that address significant unmet medical needs.” About OnKure Therapeutics OnKure, Inc. is a clinical-stage biopharmaceutical company focused on the discovery and development of best-in-class precision medicines that target biologically validated drivers of cancer. Using its proven structure-based drug design approach, the Company is building a robust pipeline of tumor-agnostic candidates that are designed to achieve optimal tolerability and efficacy. OnKure is currently developing its lead clinical candidate, OKI-179, an oral, selective Class I HDAC inhibitor, for the treatment of both hematological and solid tumors. To learn more, please visit onkuretherapeutics.com and follow us on Twitter and LinkedIn. Contacts Media Contact: Julia Deutsch Solebury Trout jdeutsch@soleburytrout.com

2021-11-09

·BioSpace

OnKure Therapeutics Appoints Mark L. Boys, Ph.D., as Vice President of Discovery Chemistry

Nov. 9, 2021 12:00 UTC BOULDER, Colo.--(BUSINESS WIRE)-- OnKure, Inc., a clinical-stage biopharmaceutical company discovering and developing the next generation of oncology precision medicines, today announced the appointment of Mark L. Boys, Ph.D., as Vice President of Discovery Chemistry. Dr. Boys is a seasoned pharmaceutical professional with more than 25 years of research and managerial expertise within large and small life science companies. “Mark is an accomplished scientific researcher and leader in the biopharmaceutical industry, with extensive experience working at the interface of medicinal and process chemistry,” said Tony Piscopio, Ph.D., Co-Founder, President and Chief Executive Officer of OnKure. “Having successfully discovered multiple candidates for clinical development, including in the oncology setting, we are looking forward to leveraging Mark’s knowledge as we continue to advance and expand our discovery pipeline of preclinical oncology programs.” Previously, Dr. Boys worked at Pfizer Inc. as a Senior Director of Medicinal Chemistry and was responsible for more than 75 (internal and CRO) medicinal, synthetic and development chemists. While at Pfizer, his teams successfully delivered preclinical and clinical candidates, including an ALK5 inhibitor for treatment of dermal scarring and he formed a Synthesis Development Group to facilitate the smooth transition of projects and compounds from research into process development. Prior to Pfizer, he worked at Array BioPharma, Inc. and lead a team that discovered a CSF1R inhibitor (ARRY-382) as part of a collaboration with Celgene Corporation, which has been undergoing clinical trials in the oncology setting. Dr. Boys also worked at G.D. Searle, LLC and successfully delivered chemical processes to the pilot plant for multi-Kg production. Earlier in his career, he worked at Glaxo plc and Pharmacia Corporation and has been involved with numerous other programs that have delivered preclinical and clinical candidates. Dr. Boys received his BSc from University of York (UK) and his Ph.D. in Synthetic Organic Chemistry from Colorado State University. “With its team of proven drug discovery and development scientists, OnKure is uniquely positioned to create a robust portfolio of novel oncology candidates designed to achieve optimal tolerability and efficacy," said Dr. Boys. “I am delighted to be working with such an experienced team and honored to lead OnKure’s discovery efforts as we continue to select and explore biologically validated drivers of cancer to grow our pipeline.” About OnKure Therapeutics OnKure, Inc. is a clinical-stage biopharmaceutical company focused on the discovery and development of best-in-class precision medicines that target biologically validated drivers of cancer. Using its proven structure-based drug design approach, the Company is building a robust pipeline of tumor-agnostic candidates that are designed to achieve optimal tolerability and efficacy. OnKure is currently developing its lead clinical candidate, OKI-179, an oral, selective Class 1 HDAC inhibitor, for the treatment of both hematological and solid tumors, with plans to initiate a Phase 2 combination trial with binimetinib in NRAS melanoma in 2022. For more information about OnKure, please visit .

100 项与 Bocodepsin 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D12552	-	-	-

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床2期	美国	OnKure, Inc.	2022-05-11
NRAS突变黑色素瘤	临床2期	美国	OnKure, Inc.	2022-05-11

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05340621 (Nautilus, ASCO2025)	临床1/2期	NRAS突变黑色素瘤 NRAS-mutated	36	Bocodepsin 300 mg daily	糧繭餘製製夢網糧鑰簾(衊築醖選壓築構選齋網) = 餘製艱廠鹹積壓糧窪壓膚構積範蓋襯簾衊廠繭 (鑰積壓顧艱鬱艱淵餘鹽 ) 更多	积极	2025-05-30
NCT05340621 (Nautilus, ENA2023)	临床1/2期	NRAS突变黑色素瘤 \| RAS突变阳性实体瘤 RAS-pathway mutated	14	Bocodepsin 300 mg + Binimetinib (NRAS-mutated melanoma)	窪選憲齋憲壓築壓衊築(蓋衊齋築築醖遞築遞艱) = Bocodepsin 300 mg + Binimetinib 45 mg 選觸廠繭築壓淵願築廠 (壓蓋壓衊願糧襯鑰繭顧 ) 更多	积极	2023-12-01
NCT03931681 (ASCO 12021 \| ASCO 22021) 人工标引	临床1期	晚期恶性实体瘤	26	OKI-179	淵積鏇壓積廠構積築憲(築顧窪願壓艱鹽膚鑰蓋) = 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing 製製餘範積壓齋鹽廠膚 (襯範積顧蓋窪鬱鹹觸簾 ) 更多	积极	2021-05-28
NCT03931681 (ENA2020)	临床1期	晚期恶性实体瘤	14	OKI-179	壓積糧醖壓窪膚壓網襯(醖淵選築壓淵齋壓壓衊) = 窪蓋網鹹夢簾鏇網簾窪衊窪顧簾鬱襯艱壓網膚 (鏇範鑰顧選衊選糧鹽鏇 ) 更多	积极	2020-10-24