主要目的为确定INCB000928在抑制FOP受试者发生新异位骨化的疗效。关键次要目的为评估INCB000928在减少疾病发作和改善疾病发作相关性症状的疗效。次要目的包括评估INCB000928用于治疗FOP受试者的安全性及耐受性；在第 48 周时，确认INCB000928在双盲期内被随机到安慰剂组的受试者的疗效；表征分析INCB000928的PK；进一步评估INCB000928对FOP受试者的疗效。

开始日期2023-04-11

申办/合作机构

因塞特医药科技（上海）有限公司

[+2]

NCT05090891 / Recruiting临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva

This Phase 2, Randomized, Double-Blind, Placebo-Controlled Study is intended to evaluate the Efficacy, Safety, and Tolerability and PK of INCB000928 administered to participants with a clinical diagnosis of fibrodysplasia ossificans progressiva (FOP).

开始日期2022-05-05

申办/合作机构

Incyte Corp.

NCT05099445 / Completed临床1期

A Phase 1 Study to Evaluate the Pharmacokinetics, Safety, and Pharmacodynamics of INCB000928 in Participants With Impaired Renal Function and Hemodialysis

This is a multicenter, open-label parallel-group to evaluate single oral doses of INCB000928 in participants with varying level of renal function or impairment.

开始日期2021-12-14

申办/合作机构

Incyte Corp.

100 项与 Zilurgisertib 相关的临床结果

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100 项与 Zilurgisertib 相关的转化医学

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100 项与 Zilurgisertib 相关的专利（医药）

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项与 Zilurgisertib 相关的文献（医药）

2022-10-01·Bioanalysis

Bioanalysis of INCB000928 in hemodialysate: prevention of nonspecific binding and validation of surrogate matrices

Article

作者: Wang, Phillip ; McGee, Ryan ; Xun, Zhiyin

Aim: To develop and validate a bioanalytical method for the quantification of INCB000928 in hemodialysate. Materials & methods: Blank dialysate and phosphate-buffered saline were compared with hemodialysate for surrogate matrix selection. Direct addition of internal standard without analyte extraction and a high-performance LC-MS/MS were used for analysis. Results & conclusion: INCB000928 in hemodialysate exhibited strong nonspecific binding to polypropylene containers. In the presence of 10% isopropyl alcohol, the loss of INCB000928 was fully recovered, regardless of pre- or post-addition of the solvent. Blank dialysate and phosphate-buffered saline were determined to be appropriate surrogate matrices by using a three-way cross-comparison and were subsequently validated in the quantitative analysis of INCB000928 in hemodialysate.

EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS

Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults

Article

作者: Gong, Xiaohua ; Wang, Phillip ; Yang, Yan-Ou ; Rockich, Kevin ; Getsy, Jay ; Sheng, Jennifer ; Liu, Xiang ; Chen, Xuejun

BACKGROUND AND OBJECTIVES:

The oral, potent, and highly selective activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (INCB000928) is in development as a treatment for fibrodysplasia ossificans progressiva (FOP), and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma. Saliva is an attractive alternative to blood for drug monitoring and pharmacokinetic analysis, as it is non-invasive to retrieve. This is beneficial for patients, such as those with FOP, for whom blood draws can be challenging due to soft tissue damage susceptibility that can cause progressive heterotopic ossification, and for whom tourniquet time and blood draws must be minimized. The objectives of these studies were to evaluate zilurgisertib pharmacokinetics, safety, tolerability, and the effect of food in healthy participants from phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) studies.

METHODS:

Both the SAD and MAD studies were double-blind, randomized, placebo-controlled dose escalation studies. In the SAD study, healthy participants received a single oral dose of zilurgisertib (10, 25, 50, 100, 175, 250, or 500 mg) or placebo in the fasted state. A further group of healthy participants were enrolled into an additional "food effect" cohort and randomized to receive a single oral dose of zilurgisertib (100 mg) after either an overnight fast or a high-fat meal in a 2-way crossover manner. In the MAD study, healthy participants received oral zilurgisertib at 50, 100, 150, 200, or 400 mg once daily or 300 mg twice daily in the fasted state. Blood, saliva, and urine samples were collected for zilurgisertib pharmacokinetic analysis. Safety was assessed throughout both studies.

RESULTS:

Overall, 91 participants (70 active, 21 placebo) were enrolled and randomized to the SAD study and 79 participants (59 active, 20 placebo) were enrolled and randomized to the MAD study. Zilurgisertib was generally well tolerated, and adverse events were generally of mild-to-moderate severity. Zilurgisertib was rapidly absorbed, with median time to maximum plasma drug concentration (C_max) of 2.0-4.1 h post-dose. Zilurgisertib exposure was more than dose proportional after single and multiple doses over the dose range tested, suggesting non-linear pharmacokinetics. Plasma half-life values ranged from 22.8 to 31.4 h, supporting once-daily dosing. There was a strong correlation between zilurgisertib concentrations in saliva and plasma. No food effect was observed on zilurgisertib pharmacokinetics, with geometric mean ratio (90% confidence interval) C_max and area under the plasma concentration-time curve values of 0.98 (0.91 to1.06) and 1.03 (0.97 to 1.10). Renal excretion under fasted conditions was 16% and 27% of total drug clearance with single and multiple doses, respectively; therefore, it was not the predominant pathway for zilurgisertib elimination.

CONCLUSIONS:

Zilurgisertib exhibited a favorable pharmacokinetic profile amenable to once-daily dosing that can be administered without regard to food. Study results support further clinical development of zilurgisertib in patients.

项与 Zilurgisertib 相关的新闻（医药）

2024-12-21

·佰傲谷BioValley

几款失败的肿瘤管线

由于减肥、自免等疾病领域的兴起，正在转移药企们的兴趣，肿瘤药物的开发似乎有所萎缩。而上周四，更是一连三家药企，因为临床的数据不佳，而宣布停止开发各自的肿瘤候选药物。 Incyte放弃ALK2抑制剂在上周四的投资者电话会议中，Incyte透露，将不再推进ALK2抑制剂zilurgisertib的开发。 Zilurgisertib是一种小分子药物，旨在抑制ALK2蛋白，ALK2蛋白的升高会导致血液中功能性缺铁，从而引发贫血。Zilurgisertib的作用机制为，通过与ALK2结合，阻断其下游信号下调hepcidin表达，恢复运铁蛋白缓解功能性缺铁，动员铁促进红细胞生成，从而改善因骨髓纤维化（MF）和其他血液恶性肿瘤导致的贫血。目前，Zilurgisertib正在进行骨髓纤维化相关贫血和进行性骨化纤维发育不良的研究。但在Incyte所披露的Zilurgisertib数据更新中显示，Zilurgisertib未能改善MF患者的贫血。正是因为1期研究显示出的“疗效有限”，Incyte决定放弃Zilurgisertib的开发，目前尚不清楚Incyte是否会在其他疾病领域继续开发zilurgisertib。事实上，Zilurgisertib的失败并不令人感到惊讶。因为早在10月时发布的第三季度财报中，Incyte就曾表示，“zilurgisertib的剂量需要高于最初的预期，才能看到更有希望的疗效。”这可能表明zilurgisertib的整体活性偏疲弱。最近，Incyte的失败信号有些多。上个月，由于MRGPRX4抑制剂INCB000547的II期数据低于预期，Incyte决定停止对其的开发；以及MRGPRX24抑制剂INCB000262在临床前体内毒理研究中观察到的毒理学信号，暂停了其针对慢性自发性荨麻疹（CSU）的II期临床。 iTeos放弃A2AR抑制剂上周四，iTeos Therapeutics宣布，将取消肿瘤候选药物A2AR抑制剂Inupadenant的优先级，将资源集中在其他项目上。做出这一决定的原因是，Inupadenant+卡铂/培美曲塞治疗非鳞状NSCLC的II期试验A2A-005中，Inupadenant未能达到足够的临床活性水平。 iTeos公司在ESMO 2024年会上更新的A2A-005的中期数据显示：在所有可评估患者中的总体缓解率（ORR）为63.9%，中位PFS为7.7个月；推荐2期剂量（RP2D）的Inupadenant 80mg+卡铂/培美曲塞队列中的ORR为73.3%，mPFS未达到，64.6%的患者达到具有里程碑意义的6个月PFS；40mg队列的ORR为53.3%，mPFS为5.6月；60mg队列的ORR为66.7%，mPFS为6.6月。探索性生物标志物CXCL13观察到在化疗耗竭后被inupadenant恢复，在PFS＞6个月的患者中具有快速恢复的动力学特征。截至数据截止日期，仍有8名患者在接受治疗（40mg队列1名，60mg队列1名，80mg队列6名）。安全性方面，Inupadenant+卡铂/培美曲塞的安全性可控，耐受性良好，无剂量限制性毒性。尽管Inupadenant显示出具有较高的缓解率，iTeos还是决定降低Inupadenant的优先级。iTeos的总裁兼首席执行官Michel Detheux在一份声明中表示：“虽然与单独的化疗相比，A2A-005试验中，RP2D的Inupadenant初始信号令人鼓舞并支持其差异化、不可逾越的特征，但我们以及我们的科学和临床顾问委员会认为，它没有达到足够的临床活性水平，需要进一步的投资。” iTeos取消了对Inupadenant的优先级，将资源集中其他管线上。目前，尚不清楚该公司将专注于哪些候选药物。iTeos公司将在2025年提供更多管线细节。第一个失败的ecDNA疗法 12月12日，Boundless Bio宣布，不再推进BBI-825的临床开发。 BBI-825是一款口服选择性核苷酸还原酶（RNR）抑制剂。RNR是dNTP生产的限速酶，而dNTP是ecDNA组装和修复所需的DNA组分，抑制RNR对ecDNA激活的癌细胞具有合成致死作用。BBI-825目前正在对耐药基因扩增的实体瘤患者（包括结直肠癌）进行首次人体1/2期临床试验。 BBI-825试验第一部分的初步药代动力学数据显示，缺乏剂量比例暴露；以及不断发展的BRAF V600E和KRASG12C突变的癌症治疗前景、开发的复杂性、成本增加，Boundless已经做出战略决策，不再继续BBI-825的第1部分剂量递增和STARMAP试验的第2部分。今年3月，Boundless以全球首家染色体外DNA（ecDNA）疗法的名头亮相纳斯达克。然而8个月后的现在，第一个ecDNA管线就失败了，以及首席医疗官（CMO） Klaus Wagner和首席商务官（CBO） Neil Abdollahian同时离职。这使得Boundless股价大跌。此外，令人担忧的是，Boundless的核心管线BBI-355的临床招募出现了问题，根据Boundless Bio公司的说法，BBI-355增强试验的联合队列中登记的患者数量比最初预计的要低。这可能和入组标准和排除标准有关，ecDNA是和肿瘤基因扩增相关的，因此这一标准可以体现在患者入组和排除标准里。延伸阅读：首个ecDNA公司，上市5个月，现在裁员小结另外，在12月16日默沙东宣布终止了TIGIT抗体Vibostolimab和LAG-3抗体Favezelimab的开发。原因也是因为临床试验的失败。参考资料： 1.https://investor.incyte.com/static-files/ef7f51e8-2419-4958-914f-35c5af6f8e03 2.https://investors.iteostherapeutics.com/news-releases/news-release-details/iteos-therapeutics-presents-interim-a2a-005-clinical-trial-data 本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

财报临床2期临床1期临床结果临床终止

2024-12-16

·Endpoints

Candid inks three T cell engager deals; PepGen trial put on hold

Plus, news about Foghorn Therapeutics, Incyte, BioNTech, Galderma, Basilea, Innovia, Pharming, bit.bio, Promise Bio, Outlook Therapeutics and Trevi Therapeutics: Candid Therapeutics’ trio of T cell engager deals: The company is paying up to $320 million in upfront and milestones to Nona Biosciences to develop next-generation T cell engagers. It’s also partnering with Ab Studio to discover T cell engagers that treat autoimmune diseases. No terms were disclosed. And, in its third announcement, Candid also said Monday that it will spend up to $1 billion in a deal with EpimAb Biotherapeutics that also aims to develop T cell engagers in the autoimmune category. — Jaimy Lee PepGen’s Duchenne trial put on hold: The biotech said the FDA put its CONNECT2-EDO51 study on hold. It’s a Phase 2 trial assessing multiple ascending doses in patients with Duchenne muscular dystrophy. Its stock $PEPG sank 28% on Monday morning. — Jaimy Lee Foghorn to drop AML candidate: The company is stopping work on an experimental drug for acute myeloid leukemia called FHD-286, and it’s seeking a potential partner for the drug. Foghorn said that it saw responses to the drug in a Phase 1 study, but “the observed response rate did not meet the company’s threshold to continue development by Foghorn alone.” — Lei Lei Wu Incyte stops developing anemia drug for patients with myelofibrosis: During an investor day last week, the company said zilurgisertib “does not significantly improve anemia in patients with myelofibrosis,” and it had halted work on the drug. — Katherine Lewin BioNTech, OncoC4’s partial clinical hold is lifted: The FDA gave the go-ahead to the partners to continue a Phase 3 lung cancer trial of an anti-CTLA-4 antibody called gotistobart, but only in a subset of patients, BioNTech disclosed Friday. In October, the study was put on partial clinical hold due to a “a possible variance in results between the squamous and non-squamous NSCLC patient populations.” The study will now only enroll squamous NSCLC patients. — Lei Lei Wu FDA approves Galderma’s Nemluvio in moderate-to-severe atopic dermatitis: The drug is now approved to treat patients 12 years and older. Nemluvio is also approved for prurigo nodularis, another chronic skin condition. According to Galderma, Nemluvio is the first approved monoclonal antibody that specifically targets the cytokine IL-31, which causes the itching and inflammation associated with the disease. Its Swiss-listed shares $GALD were up about 7% on Monday. — Katherine Lewin Basilea inks deal with Innoviva to market antibiotic: Innoviva is paying Basilea $4 million upfront and up to $223 million in sales milestones, plus royalties, to commercialize Zevtera in the US. The anti-MRSA antibiotic received FDA approval in April. — Jaimy Lee Pharming’s $66M offer to buy Abliva: Pharming wants to buy the Swedish company, which is developing a treatment for mitochondrial disease. The lead asset is currently in a pivotal trial. — Jaimy Lee Bit.bio raises $30M for cell therapy pipeline: The biotech plans to use the proceeds to invest in new tools for drug discovery and research. The fundraise was led by M&G Investments, with support from backers including ARCH Venture Partners and Milky Way. The company unveiled its lead program , which is designed to regenerate the liver, a year ago. — Ayisha Sharma Israeli biotech secures $8.3M in seed funding: Promise Bio expects to use the cash to develop a computational platform powered by AI and epiproteomics that could help predict patient responses to treatment. The round was led by Awz Ventures. AION Labs also invested. — Ayisha Sharma Outlook to cut 23% of its workforce: The company underwent a strategic review as it aims to shore up funds to support the launch of its new wet AMD treatment, which was approved in Europe and the UK this year. The company plans to submit its formulation of bevacizumab to the FDA in the first three months of next year after receiving a complete response letter last year. Outlook had 24 full-time employees, as of September 2023.— Jaimy Lee Trevi is selling 12.5 million shares at $4.00 apiece to raise $50 million. — Jaimy Lee

临床2期上市批准细胞疗法临床1期临床3期

2024-08-03

·药事纵横

大跌28%！一款B7H3 ADC二期临床暂停给药

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。为了保持竞争力，尤其是在LAG-3市场上的竞争力，Incyte公司砍掉了五条管线，其中包括：两款口服小分子PD-L1抑制剂（INCB99280、INCB99318）、一款LAG-3单克隆抗体（INCAGN2385）、一款TIM-3单克隆抗体（INCAGN2390）和一款LAG-3xPD-1双特异性抗体（INCA32459）。根据clinicaltrials.gov的资料，除LAG-3抗体处于2期试验尚未开始招募外，其他药物均处于早期试验阶段。终止原因 Incyte公司研发主管Pablo Cagnoni表示研发管线的变化是 “基于现有数据、不断变化的治疗格局和内部研发管线”的演变。终止LAG-3项目的决定是基于 “竞争态势”，公司将决定在合适的时间披露部分项目的数据。主要原因是该公司管线进展已远远落后于竞争对手：一款LAG-3与PD-1的组合疗法已经得到证实。2022年，FDA已批准百时美施贵宝的Opdualag™ （纳武利尤单抗与relatlimab复方制剂-rmbw）用于不可切除或转移性黑色素瘤的成人和12岁以上儿童患者。Opdualag是LAG-3阻断抗体relatlimab和 PD-L阻断抗体纳武利尤单抗联合的固定剂量复方制剂。至少有一款双特异性LAG-3在随机试验中已经远远领先于Incyte。前不久，Immutep也宣布其LAG-3融合蛋白疗法eftilagimod alpha（efti）与默沙东的PD-1抑制剂Keytruda联用的TACTI-003（KEYNOTE-PNC-34）临床2b期试验B队列的积极结果，在PD-L1表达阴性的复发或转移性头颈部鳞状细胞癌（HNSCC）患者中客观缓解率（ORR）达35.5%，具有相对显著的优势。未来管线规划 Incyte 宣布对其管线进行战略审查，专注于皮肤病、炎症和自身免疫领域的资产，更加关注具有高潜在影响的项目，包括但不限于： IAI/Dermatology：今年4月斥资7.5亿美元收购Escient Pharmaceuticals时获得的povorcitinib以及MRGPRX2和MRGPRX4。两项povorcitinib针对哮喘和慢性自发性荨麻疹的2期临床试验正在招募患者，数据预计于2025年公布。 MPN/GVHD：mCALR、JAK2V617Fi、BETi和ALK2i。预计BETi将于今年下半年进入3期研究阶段。zilurgisertib的临床概念验证预计将于2024 年下半年完成。评估mCALR和JAK2V617Fi的1期研究正在进行中并招募患者。这两项研究的初步数据预计将于2025年公布。肿瘤学：CDK2i、KRASG12Di和TGFβR2×PD-1。CDK2i的1期数据将于第三季度公布，2025年将启动3期试验。 Cantor分析师在周二的一份报告中将产品线变化描述为“另一项股东友好型举措”和“朝着正确方向迈出的又一步”，并指出他们对Incyte的几个项目持乐观态度，包括用于治疗白癜风的povorcitinib、Escient的MRGPR拮抗剂和用于卵巢癌的 CDK2i。财务状况：研发投入大增184% 2024年上半年，公司总收入19.25亿美元，同比增长9%；净产品收入16.36亿美元，同比增长8%。其中2024 Q2，公司总收入10.44亿美元，同比增长9%；净产品收入9.07亿美元，同比增长10%。上半年研发费用15.68亿美元，同比增长94%；2024 Q2研发费用11.38亿美元，大增184%，主要与Escient收购中获得的资产相关的费用为6.794亿美元以及对后期开发资产的持续投资有关。分析师们也对Incyte公司在管线上的支出表示担忧，对Incyte能否为其大部分研发投资带来有利回报持怀疑态度。该公司还将今年的预计研发支出从17.2亿美元到17.6亿美元之间提高到了17.55亿美元到18亿美元之间。总结根据药融云数据库，全球约有50余款LAG-3在研管线。纵观全球，国际制药巨头BMS、默沙东、再生元LAG-3赛道领跑。国内研发企业包括维立志博、九章生物、康方生物、信达生物、药明生物、时迈药业、复宏汉霖、岸迈生物、恒瑞医药、泽璟生物、科伦博泰等。全球在研LAG-3靶向疗法一览参考资料：https://investor.incyte.com/static-files/580a675f-e3b1-4833-8819-ccdc7888d5f2

临床2期临床3期临床结果并购临床成功

100 项与 Zilurgisertib 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
骨化性肌炎	临床2期	美国	Incyte Corp.	2022-01-31
骨化性肌炎	临床2期	美国	因塞特医药科技（上海）有限公司	2022-01-31
骨化性肌炎	临床2期	澳大利亚	因塞特医药科技（上海）有限公司	2022-01-31
骨化性肌炎	临床2期	澳大利亚	Incyte Corp.	2022-01-31
骨化性肌炎	临床2期	巴西	Incyte Corp.	2022-01-31
骨化性肌炎	临床2期	巴西	因塞特医药科技（上海）有限公司	2022-01-31
骨化性肌炎	临床2期	加拿大	Incyte Corp.	2022-01-31
骨化性肌炎	临床2期	加拿大	因塞特医药科技（上海）有限公司	2022-01-31
骨化性肌炎	临床2期	智利	Incyte Corp.	2022-01-31
骨化性肌炎	临床2期	智利	因塞特医药科技（上海）有限公司	2022-01-31

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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


NCT04455841 (INCB 00928-104, EHA2024) 人工标引	临床1/2期	贫血 \| 骨髓纤维化 hepcidin	45	Zilurgisertibb alone	-	积极	2024-05-14
				Zilurgisertibb wRuxolitinibinib	醖廠憲衊窪築繭艱蓋鬱(窪鑰鏇鏇遞壓壓襯鹽簾) = 鹹網鑰鹽淵憲糧憲遞艱願艱衊鹹淵簾製鑰構遞 (鬱鏇獵襯憲鹽餘蓋製簾 ) 更多
NCT04455841 (INCB 00928-104, ASH2023) 人工标引	临床1/2期	贫血	36	zilurgisertib (TGA)	遞淵構顧遞廠簾構壓構(獵製選觸範獵選餘鹽襯) = No DLTs occurred in either treatment group. 製淵餘廠網鑰選糧顧獵 (鹽襯艱艱簾淵顧築簾蓋 ) 更多	积极	2023-12-10
				zilurgisertib+ruxolitinib (TGB)
NCT04455841 (ASCO 12023 \| ASCO 22023) 人工标引	临床1/2期	原发性骨髓纤维化	31	zilurgisertib (TGA)	蓋窪簾積選鏇襯築遞製(選願窪鏇築夢選窪夢製) = No dose-limiting toxicities (DLTs) or study drug-related serious adverse events (AEs) occurred in either treatment group. 齋網簾壓遞選遞窪餘餘 (繭蓋窪製壓衊艱築窪鬱 ) 更多	积极	2023-05-31
				ruxolitinib+zilurgisertib (TGB)
NCT04455841 (INCB 00928-104, ASH 12022 \| ASH 22022) 人工标引	临床1/2期	原发性骨髓纤维化	15	INCB000928	鏇壓醖願鏇蓋廠繭簾製(蓋網襯衊艱簾製網蓋觸) = 窪願淵憲窪蓋鹽鹽壓範鏇選鹹襯繭餘糧構醖窪 (鑰廠獵鏇蓋範鏇餘鏇鹽 ) 更多	积极	2022-11-15
				INCB000928+Ruxolitinib	鏇壓醖願鏇蓋廠繭簾製(蓋網襯衊艱簾製網蓋觸) = 膚繭夢餘餘糧願憲艱觸鏇選鹹襯繭餘糧構醖窪 (鑰廠獵鏇蓋範鏇餘鏇鹽 ) 更多