This phase I/II trial tests the safety, side effects, and best dose of PLX2853 in combination with trametinib in treating patients with uveal (eye) melanoma that has spread to other places in the body (metastatic) or nearby tissues or lymph nodes (locally advanced), or that cannot be removed by surgery (unresectable). PLX2853 works by targeting and inhibiting certain activities within cells that promote tumor growth. By inhibiting these activities, PLX2853 may help to stabilize or reduce the growth of tumor cells. Trametinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving PLX2853 in combination with trametinib may help to shrink and stabilize tumor cells in patients with advanced uveal melanoma.

开始日期2023-01-13

申办/合作机构

Alliance for Clinical Trials in Oncology

EUCTR2019-000916-27-GB

/ Unknown status临床1期IIT

Investigation into the combination of PLX2853 with ruxolitinib in patients with intermediate-2 or high risk myelofibrosis not receiving an adequate response with ruxolitinib alone. - PROMise

开始日期2020-11-12

申办/合作机构

University of Birmingham

NCT04556617

/ Terminated临床1/2期

A Multicenter, Open-Label, Parallel, Phase 1b/2a Study of PLX2853 in Combination With Abiraterone Acetate and Prednisone and Phase 1b/2a Study of PLX2853 in Combination With Olaparib in Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

The purpose of this research study is to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the investigational drug PLX2853 in subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC)

开始日期2020-09-21

申办/合作机构

Opna Bio SA

100 项与 PLX-2853 相关的临床结果

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100 项与 PLX-2853 相关的转化医学

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100 项与 PLX-2853 相关的专利（医药）

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项与 PLX-2853 相关的文献（医药）

2023-09-01·JCO precision oncology

Phase IIa Study of PLX2853 in Gynecologic Cancers With Known ARID1A Mutation and Phase Ib/IIa Study of PLX2853/Carboplatin in Platinum-Resistant Epithelial Ovarian Cancer

Article

作者: Zamarin, Dmitriy ; Bollag, Gideon ; Duska, Linda R. ; Spira, Alexander ; Yeku, Oladapo O. ; Walling, Jackie ; Richardson, Debra L. ; Hamilton, Erica ; Swisher, Elizabeth M. ; Inokuchi, Kerry ; Fleming, Gini ; Oza, Amit ; Matusow, Bernice

PURPOSE:

The Bromodomain and Extra-Terminal (BET) domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small-molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all four BET family members.

METHODS:

We conducted a multicenter and open-label study with two parallel arms: a phase IIa study of PLX2853 monotherapy in patients with advanced gynecologic malignancies with an ARID1A mutation and a phase Ib/IIa combination study of PLX2853 plus carboplatin in women with platinum-resistant OC. The primary objectives were safety and tolerability for phase Ib and efficacy for both phase IIa portions. Thirty-four of 37 enrolled patients completed at least one post-baseline response assessment.

RESULTS:

Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a best overall response of partial response (PR), 5 (35.7%) had stable disease (SD), and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable patients on the combination arm, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD.

CONCLUSION:

This study confirmed the safety profile of PLX2853 and demonstrated the feasibility of combination with carboplatin. Although these results did not meet the prespecified response criteria, evidence of clinical activity highlights the rationale for further exploration of BET inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway.

2020-07-28·Blood advances2区 · 医学

BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression

2区 · 医学

Article

作者: Carter, Matthew J. ; Ma, Yan ; Turaj, Anna H. ; Cox, Kerry L. ; Packham, Graham ; English, Vikki L. ; Cragg, Mark S. ; Dunning, Lisa ; Powell, Ben ; Johnson, Peter W. M. ; Murray, Tom D. ; Fell, Rachel ; Cummin, Thomas E. C.

Abstract:

Although the MYC oncogenic network represents an attractive therapeutic target for lymphoma, MYC inhibitors have been difficult to develop. Alternatively, inhibitors of epigenetic/ transcriptional regulators, particularly the bromodomain and extraterminal (BET) family, have been used to modulate MYC. However, current benzodiazepine-derivative BET inhibitors (BETi) elicit disappointing responses and dose-limiting toxicity in relapsed/refractory lymphoma, potentially because of enrichment of high-risk molecular features and chemical backbone-associated toxicities. Consequently, novel nonbenzodiazepine BETi and improved mechanistic understanding are required. Here we characterize the responses of aggressive MYC-driven lymphomas to 2 nonbenzodiazepine BETi: PLX51107 and PLX2853. Both invoked BIM-dependent apoptosis and in vivo therapy, associated with miR-17∼92 repression, in murine Eµ-myc lymphomas, with PLX2853 exhibiting enhanced potency. Accordingly, exogenous BCL-2 expression abrogated these effects. Because high BCL-2 expression is common in diffuse large B-cell lymphoma (DLBCL), BETi were ineffective in driving apoptosis and in vivo therapy of DLBCL cell lines, mirroring clinical results. However, BETi-mediated BIM upregulation and miR-17∼92 repression remained intact. Consequently, coadministration of BETi and ABT199/venetoclax restored cell death and in vivo therapy. Collectively, these data identify BIM-dependent apoptosis as a critical mechanism of action for this class of BETi that, via coadministration of BH3 mimetics, can deliver effective tumor control in DLBCL.

Frontiers in Oncology3区 · 医学

Inhibition of Bromodomain and Extra Terminal (BET) Domain Activity Modulates the IL-23R/IL-17 Axis and Suppresses Acute Graft-Versus-Host Disease

3区 · 医学

ArticleOA

作者: Ranganathan, Parvathi ; Gao, Yandi ; Keller, Andrea ; Zitzer, Nina C ; Snyder, Katiri J ; Sell, Natalie E ; Ma, Yan ; Bollag, Gideon ; Mihaylova, Maria M ; Powell, Ben ; Sehgal, Lalit ; Singh, Satishkumar ; Devine, Steven M ; Kalyan, Sonu ; Dorrance, Adrienne M ; Neidemire-Colley, Lotus ; Choe, Hannah K ; Braunreiter, Kara M

Acute graft-versus-host disease (GVHD) is the leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Bromodomain and extra-terminal domain (BET) proteins influence inflammatory gene transcription, and therefore represent a potential target to mitigate inflammation central to acute GVHD pathogenesis. Using potent and selective BET inhibitors Plexxikon-51107 and -2853 (PLX51107 and PLX2853), we show that BET inhibition significantly improves survival and reduces disease progression in murine models of acute GVHD without sacrificing the beneficial graft-versus-leukemia response. BET inhibition reduces T cell alloreactive proliferation, decreases inflammatory cytokine production, and impairs dendritic cell maturation both in vitro and in vivo. RNA sequencing studies in human T cells revealed that BET inhibition impacts inflammatory IL-17 and IL-12 gene expression signatures, and Chromatin Immunoprecipitation (ChIP)-sequencing revealed that BRD4 binds directly to the IL-23R gene locus. BET inhibition results in decreased IL-23R expression and function as demonstrated by decreased phosphorylation of STAT3 in response to IL-23 stimulation in human T cells in vitro as well as in mouse donor T cells in vivo. Furthermore, PLX2853 significantly reduced IL-23R+ and pathogenic CD4+ IFNγ+ IL-17+ double positive T cell infiltration in gastrointestinal tissues in an acute GVHD murine model. Our findings identify a role for BET proteins in regulating the IL-23R/STAT3/IL-17 pathway. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.

项与 PLX-2853 相关的新闻（医药）

2025-02-12

·Business Wire

Opna Bio Receives Orphan Drug Designation for OPN-6602, an Oral EP300/CBP Bromodomain Inhibitor, for Multiple Myeloma

SOUTH SAN FRANCISCO, Calif.--( BUSINESS WIRE )--Opna Bio, a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics, announced today that the FDA has granted orphan drug designation (ODD) to one of its lead programs, OPN-6602, for the treatment of multiple myeloma (MM). OPN-6602 is an oral, small molecule inhibitor of the E1A binding protein (EP300) and CREB-binding protein (CBP) currently being tested in a Phase 1 trial in patients with relapsed or refractory MM. Multiple myeloma is a rare and aggressive cancer of the plasma cells in the bone marrow that often leads to serious complications such as bone damage, kidney failure and immune suppression. The disease is typically diagnosed in older adults, with limited treatment options available for patients with relapsed or refractory disease. “We are pleased to have received ODD for OPN-6602 for the treatment of multiple myeloma, a further validation of the drug’s therapeutic potential in patients with this disease who have limited treatment options once they have relapsed,” said Gideon Bollag, PhD, chief scientific officer. Orphan Drug Designation is granted by the FDA to encourage the development of therapies for rare diseases, which are defined as those affecting fewer than 200,000 people in the U.S. The designation provides several benefits, including tax credits for clinical trial costs, a waiver of certain FDA fees, and eligibility for seven years of market exclusivity upon approval. Opna recently presented data at the American Society of Hematology (ASH) meeting in December 2024 showing that in human-derived multiple myeloma models, OPN-6602 suppresses tumor growth, while downregulating key MM driving genes. Synergistic effects were observed with OPN-6602 in combination with dexamethasone, pomalidomide and mezigdomide. OPN-6602’s distinct pharmacokinetic profile allows for continuous daily dosing that potentially results in a lower incidence of toxicities and improved efficacy. The Phase 1 study in patients with relapsed or refractory multiple myeloma (NCT06433947) is taking place at multiple sites in the U.S. Opna Bio expects to complete the single agent, dose-escalation phase of the trial in 2026. Further development of OPN-6602 in combination with other standard-of-care agents in multiple myeloma is planned. About Opna Bio Opna Bio is a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics. The company’s broad portfolio targets multiple drivers of cancer, including a novel oncology discovery program focused on the fragile-X multifunctional RNA-binding protein (FMRP) and a diversified pipeline of promising oncology assets. The Opna team has a proven track record of scientific expertise and commercial value creation, having advanced multiple FDA-approved drugs to market. Opna’s lead clinical compounds include OPN-2853, a potentially best-in-class BET bromodomain inhibitor, being evaluated in patients with myelofibrosis in combination with ruxolitinib, and OPN-6602, a dual EP300/CBP inhibitor, currently being studied in a first-in-human Phase 1 clinical trial in patients with multiple myeloma. For more information, please visit opnabio.com .

临床1期孤儿药ASH会议

2024-12-09

·Business Wire

Opna Bio Announces Interim Data from Phase 1 Combination Study of OPN-2853 with Ruxolitinib in Patients with Advanced Myelofibrosis

SAN DIEGO--( BUSINESS WIRE )--Opna Bio, a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics, announced interim data from its lead clinical program, OPN-2853, in patients with advanced myelofibrosis showing encouraging levels of spleen reduction, with minimal toxicities and adverse events. Preclinical data from a second program, OPN-6602, showed significant tumor regression in multiple myeloma models as a single agent and in combination with other therapeutics. The presentations took place this weekend at the American Society of Hematology (ASH) annual meeting, December 7-10, 2024, in San Diego. OPN-2853 Shows Spleen Reduction in Patients with Advanced Myelofibrosis OPN-2853, a small molecule bromodomain and extra-terminal motif (BET) inhibitor, is being evaluated in an ongoing Phase 1 investigator-led study in patients with advanced myelofibrosis who are no longer responding to ruxolitinib alone. Myelofibrosis is a type of blood cancer that causes fibrosis in the bone marrow, anemia and enlarged spleen, amongst other symptoms. The study is testing three dose levels of OPN-2853 (20 mg, 40 mg and 80 mg), given orally once daily, in combination with ruxolitinib. As of February 2024, the cut-off date, 16 patients had been enrolled at different dose levels, across multiple sites in the United Kingdom, coordinated by the Cancer Research UK (CRUK) Clinical Trials Unit at the University of Birmingham. In 12 evaluable patients, the median spleen size was reduced from baseline with spleens no longer palpable in 50% of evaluable patients. The combination dose has been well tolerated, and the majority of patients have completed eight cycles of combination treatment. “We are very encouraged by these data to date, which demonstrate that daily dosing of OPN-2853 in combination with ruxolitinib was well tolerated, and showed spleen reduction in patients with myelofibrosis who have very limited options once they have progressed,” said principal investigator Adam Mead, PhD, MRCP, FRCP, professor of hematology at the University of Oxford and CRUK senior cancer research fellow. “We are enthusiastic about the OPN-2853 and ruxolitinib combination and expect to have a recommended Phase 2 dose in early 2025.” Opna Bio is planning further clinical development with OPN-2853. OPN-6602 Combinations Demonstrate Complete Tumor Regression in Preclinical Multiple Myeloma Models OPN-6602, an oral, small molecule inhibitor of the E1A binding protein (EP300) and CREB-binding protein (CBP), is currently being tested in a Phase 1 trial in patients with multiple myeloma (MM) . MM is a type of blood cancer derived from malignant plasma cells in the bone marrow. In MM mouse xenograft models, OPN-6602 showed 71% tumor suppression as a single agent, and 100% tumor regression when combined with dexamethasone, pomalidomide or mezigdomide with a sustained duration of response. RNA sequencing of treated tumors showed that OPN-6602 downregulated key MM driver and signature genes, and has the potential to overcome resistance mechanisms to standard-of-care regimens. “We are very encouraged by the strength of the OPN-2853 clinical and OPN-6602 preclinical data, which highlights the potential of their unique pharmacokinetic profiles and validates our ‘safety by design’ approach. Both drug candidates have a high Cmax and short half-life, which allows for continuous daily dosing and effective target engagement with rapid clearance to mitigate toxicities,” said Gideon Bollag, PhD, co-founder and chief scientific officer of Opna Bio. “This confers a significant advantage to these drugs when used as single agents and a potentially synergistic effect when used in combination with other therapies.” About Opna Bio Opna Bio is a clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology therapeutics. The company’s broad portfolio targets multiple drivers of cancer, including a novel oncology discovery program focused on the fragile-X multifunctional RNA-binding protein (FMRP) and a diversified pipeline of promising oncology assets. The Opna team has a proven track record of scientific expertise and commercial value creation, having advanced multiple FDA-approved drugs to market. Opna’s lead clinical compounds include OPN-2853, a potentially best-in-class BET bromodomain inhibitor, being evaluated in patients with myelofibrosis in combination with ruxolitinib, and OPN-6602, a dual EP300/CBP inhibitor, currently being studied in a first-in-human Phase 1 clinical trial in multiple myeloma patients. For more information, please visit opnabio.com .

临床1期临床结果ASH会议

2024-04-06

·药融圈

从老东家第一三共购买剥离资产，小分子Biotech不能停

▲5月30-31日第八届广州生物医药创新者峰会扫码立即报名注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。2022年1月12日，日本制药巨头第一三共（Daiichi Sankyo）宣布决定关闭其位于美国三藩市南部的研发子公司Plexxikon，以最大限度地将投资用于研发旗下的多种抗体偶联药物开发（当时的3ADC—ENHERTU®、Dato DXd和HER3 DXd），部分研发管线转送至总部进行开发。Plexxikon于2022年3月31日正式永久暂停运行。Plexxikon始创于2000年，是第一三共在2011年以9.35亿美元的价格收购的子公司，当时拥有两款已上市抗肿瘤药物（Zelboraf/Vemurafenib与罗氏共同开发推广；和Turalio/Pexidartinib治疗腱鞘巨细胞瘤/TGCT）和6款已经启动临床试验的药物。药融云数据www.pharnexcloud.com显示：原Plexxikon团队从公司收购了部分资产(5款)，于2022年3月份成立了新的小分子新药公司Opna Bio（Opna-IO LLC ），产品线处于临床阶段的有：OPN-2853 (此前的PLX2853), 一款BET候选新药；OPN-7486 (此前的PLX7486), 一款CSF-1R/TRK候选新药。公司临床前阶段的资产有：EP300抑制剂；CD73抑制剂；TEAD抑制剂；FMRP（Fragile X mental retardation protein，脆性 X 染色体智力迟滞蛋白）等等。2022年11月，公司完成3800万美元A轮融资，现有投资人有：Longitude Capital、Northpond Ventures、Menlo Ventures等等。笔者认为，从此类关停或者破产清算BIOTECH公司购买合适资产去开发的模式，或者适合当下的中国创业者或者药企。原来存在一些庞大公司里的资产过于复杂，开发也许并未深究。参考：NMPA/CDE；药融云数据www.pharnexcloud.com；FDA/EMA/PMDA；相关公司公开披露；opnabio.com；https://www.plexxikon.com/；https://www.biocentury.com/article/646652/opna-bio-targeting-fmrp-to-treat-cancer；https://precoro.com/blog/opna-bio-sa-case-study/；https://www.businesswire.com/news/home/20221121005179/en/;https://www.daiichisankyo.co.jp/files/news/pressrelease/pdf/202201/20220112_J.pdf；https://www.daiichisankyo.co.jp/rd/pipeline/；等等。本文仅用于向医疗卫生专业人士提供科学信息，不代表平台立场，不作任何用药推荐活动推荐 5月 • 第八届大湾区生物医药创新者峰会关键词：小分子，XDC，多肽及GLP-1热点话题，80+行业专家（点击下方图片查看详情）▼【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

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100 项与 PLX-2853 相关的药物交易

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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
转移性去势抵抗性前列腺癌	临床2期	美国	Opna Bio SA	2020-09-21
转移性去势抵抗性前列腺癌	临床2期	英国	Opna Bio SA	2020-09-21
前列腺癌	临床2期	美国	Plexxikon, Inc.	2020-09-21
前列腺癌	临床2期	英国	Plexxikon, Inc.	2020-09-21
卵巢上皮癌	临床2期	美国	Plexxikon, Inc.	2020-08-11
卵巢上皮癌	临床2期	加拿大	Plexxikon, Inc.	2020-08-11
铂耐药上皮性卵巢癌	临床2期	美国	Opna Bio SA	2020-08-11
铂耐药上皮性卵巢癌	临床2期	加拿大	Opna Bio SA	2020-08-11
弥漫性大B细胞淋巴瘤	临床2期	美国	Plexxikon, Inc.	2017-09-12
滤泡性淋巴瘤	临床2期	美国	Plexxikon, Inc.	2017-09-12

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临床结果

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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


NCT04556617 (CTgov)	临床1/2期	转移性去势抵抗性前列腺癌	19	Olaparib+PLX2853 20 mg (Phase 1b PLX2853 (20 mg) + Olaparib)	夢壓鑰遞鏇範範鬱蓋顧 = 廠網衊顧襯廠構鏇繭構廠願願淵憲壓顧遞廠鹹 (餘構蓋壓構廠膚淵構構, 鬱範鬱獵餘廠鬱觸構鹽 ~ 壓鹹夢網餘糧觸醖遞膚) 更多	-	2025-04-08
				prednisone+Abiraterone Acetate+PLX2853 40 mg (Phase 1b PLX2853 (40 mg) + Abiraterone Acetate + Prednisone)	夢壓鑰遞鏇範範鬱蓋顧 = 獵範鑰壓築鬱積鏇鹽餘廠願願淵憲壓顧遞廠鹹 (餘構蓋壓構廠膚淵構構, 衊積簾鹽製衊鹹繭淵糧 ~ 遞願壓願齋繭醖鹽廠蓋) 更多
NCT04493619 (CTgov)	临床1/2期	铂耐药上皮性卵巢癌	37	PLX2853 (PLX2853 Phase 2a Monotherapy)	構鏇齋餘鹹願襯窪壓簾 = 遞構獵繭廠顧廠獵蓋鏇選膚製糧範鹹艱獵齋鏇 (製遞繭鑰製廠鹹遞衊廠, 鬱蓋顧艱鬱襯餘鹽選蓋 ~ 鏇遞淵積鹹衊憲鹹夢選) 更多	-	2024-11-04
				Carboplatin+PLX2853 (PLX2853 + Carboplatin Phase 1b/2a Combination Therapy)	構鏇齋餘鹹願襯窪壓簾 = 窪鹹觸網鹽願鏇積繭醖選膚製糧範鹹艱獵齋鏇 (製遞繭鑰製廠鹹遞衊廠, 齋製衊構夢網積願願糧 ~ 鑰鹹窪廠憲糧獵顧餘鹹) 更多
NCT04493619 (AACR2023) 人工标引	临床1/2期	卵巢癌 ARID1A	34	PLX2853	鬱遞範糧遞繭觸獵蓋製(壓膚積壓網壓糧蓋醖顧) = 繭鏇積構顧顧蓋願製糧夢鏇窪範餘範積鏇網顧 (築齋襯選網範廠夢淵蓋 ) 更多	积极	2023-04-14
				PLX2853+carboplatin	鬱遞範糧遞繭觸獵蓋製(壓膚積壓網壓糧蓋醖顧) = 齋廠製觸醖獵齋鹹淵獵夢鏇窪範餘範積鏇網顧 (築齋襯選網範廠夢淵蓋 ) 更多
NCT03787498 (ASH 12021 \| ASH 22021) 人工标引	临床1期	复发性急性髓细胞白血病 \| 高危骨髓增生异常综合征	22	PLX 2853	醖繭壓壓齋襯構襯製餘(繭廠艱膚製鑰製鏇遞選) = fatigue =14, nausea =13, decreased appetite =13, anemia =10, diarrhea =10, vomiting =9, hypokalemia =9, international normalized ratio increased =8, hyperglycemia =8, hypophosphatemia =8, peripheral edema =7, blood bilirubin increased =7, dyspnea =7, febrile neutropenia =6, constipation =6, sepsis =6, hypoalbuminemia =6, hyponatremia =6, insomnia =6, proteinuria =6, and hypertension =6 蓋夢窪夢簾鑰製選壓襯 (積憲積窪鬱築廠鹽選膚 ) 更多	积极	2021-11-05
NCT03297424 (ASCO 12021 \| ASCO 22021) 人工标引	临床1/2期	HR阳性/HER2低表达实体瘤 \| 淋巴瘤	44	PLX2853	膚蓋簾憲醖壓鬱鏇艱齋(製鹽築獵憲衊鑰夢壓範) = 廠餘壓獵淵憲網廠餘範鹽淵願淵襯襯製遞襯壓 (艱獵齋壓選夢鹹遞網醖 ) 更多	积极	2021-05-28