This research study is studying a combination of two targeted therapies as a possible treatment for acute myeloid leukemia (AML) that has relapsed after initial treatment or did not fully respond.
The name of the study interventions involved in this study are:
* Merestinib
* LY2874455

开始日期2017-08-10

申办/合作机构

Dana-Farber Cancer Institute, Inc.

[+1]

NCT03027284

/ Completed临床1期

A Phase I Study of Merestinib Monotherapy or in Combination With Other Anti-Cancer Agents in Japanese Patients With Advanced and/or Metastatic Cancer

The main purpose of this study is to evaluate tolerability of merestinib monotherapy or in combination with other anti-cancer agents in Japanese participants with advanced and/or metastatic cancer.

开始日期2017-02-03

申办/合作机构

Eli Lilly & Co.

100 项与 Merestinib 相关的临床结果

登录后查看更多信息

100 项与 Merestinib 相关的转化医学

登录后查看更多信息

100 项与 Merestinib 相关的专利（医药）

登录后查看更多信息

项与 Merestinib 相关的文献（医药）

2025-12-31·CANCER BIOLOGY & THERAPY

Cooperative CCL2/CCR2 and HGF/MET signaling enhances breast cancer growth and invasion associated with metabolic reprogramming

Article

作者: Acevedo, Diana S ; Gorrepati, Haasini S ; Cote, Paige ; Brownfield, Audrey ; Arviso, Nizhoni ; Espinoza, Ashley ; Brodine, Rebecca ; Fang, Wei ; Gerdes, Zachary ; Thompson, Alala ; Kozai, Yuuka ; Bergeron, Nick ; Cheng, Nikki

With over 60,000 cases diagnosed in women annually, ductal carcinoma in situ (DCIS) is the most common form of pre-invasive breast cancer in the US. Despite standardized therapy, under-treatment and over-treatment are prevailing concerns. By understanding the mechanisms regulating DCIS progression, we may develop tailored strategies to improve treatment. CCL2/CCR2 and HGF/MET signaling pathways are upregulated in breast cancers. Our studies indicate that these pathways cooperate to promote DCIS progression and metabolism. DCIS and IDC tissues were immunostained for CCL2 and HGF expression. DCIS.com and HCC1937 cells were analyzed for cell proliferation through PCNA immunostaining, apoptosis through cleaved caspase-3 immunostaining, and invasion through Matrigel transwell assays. AKT, AMPK, p42/44MAPK and PKC activities were analyzed in vitro through immunoblot and pharmacologic inhibition. CCL2 and HGF-mediated metabolism were analyzed by LC-MS. Glucose uptake and lactate production were measured biochemically. CCR2 and MET were targeted in breast xenografts through CCR2 knockout and treatment with Merestinib. Significant associations between CCL2 and HGF were detected in DCIS and IDC tissues. CCL2 and HGF co-treatment enhanced breast cancer cell growth, survival, and invasiveness over individual CCL2 or HGF treatment. These CCL2/HGF-mediated phenotypes were associated with metabolic changes including glycolysis and increased AKT, AMPK, p42/44MAPK and PKC signaling. CCL2/HGF-mediated glycolysis was reduced with AKT, AMPK and p42/44MAPK inhibition. CCR2 knockout combined with Merestinib treatment inhibited growth, survival, and stromal reactivity of breast xenografts more than CCR2 or MET targeting alone. CCL2/CCR2 and HGF/MET cooperate to enhance breast cancer progression and metabolic reprogramming.

2025-03-01·FREE RADICAL BIOLOGY AND MEDICINE

Merestinib inhibits cuproptosis by targeting NRF2 to alleviate acute liver injury

Article

作者: Luo, Yingli ; Luo, Xianyu ; Ma, Yinchu ; Liu, Didi ; Huang, Yi ; Zhou, Xinru ; Linghu, Maoyuan ; Huang, Qian ; Ji, Shurong ; Ru, Yi

The emergence of cuproptosis, a novel form of regulated cell death, is induced by an excess of copper ions and has been associated with the progression of multiple diseases, including liver injury, cardiovascular disease, and neurodegenerative disorders. However, there are currently no inhibitors available for targeting specific cuproptosis-related pathways in therapy. Here, the compound merestinib (MTB) has been identified as a strong inhibitor of cuproptosis through screening of a kinase inhibitor library. The results show that MTB effectively blocks elesclomol-CuCl₂ (ES-Cu) induced cuproptosis by preventing the aggregation of lipoylated proteins and the destabilization of Fe-S cluster proteins, thereby preventing proteotoxic stress and ultimately cell death. Mechanistically, MTB decreases oxidative stress levels by binding directly to NRF2. Additionally, it boosts the efficiency of the copper homeostasis and facilitates the exocytosis and transportation of copper ions, ultimately inhibiting cuproptosis. Furthermore, our research showed that MTB has the ability to alleviate cuproptosis-driven acute liver injury in mice. These findings suggest that MTB is a specific inhibitor of cuproptosis, presenting a hopeful option for therapeutic approaches in cuproptosis-related diseases.

2025-01-01·Current research in microbial sciences

Gut microbial metabolite, sphingosine-1-phosphate (S1P), drives mesangial cell phenotypic transformation and accelerates progression of IgA nephropathy via CCL2-MET-FAK pathway

Article

作者: Sun, Wei-Qian ; Xie, Ting ; Huang, Lu-Sheng ; Xu, Xu-Dong ; He, Hai-Dong ; Jin, Mei-Ping ; Liu, Ping ; Zhang, Dong-Liang ; Wu, Jia-Jun ; Hu, Ping ; Tang, Yu-Yan

Introduction:

IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis subtype, affects many patients worldwide. To identify new therapeutic targets for IgAN, this study aimed to investigate the role and mechanisms of gut microbiota metabolites in mesangial cell proliferation.

Methods:

Building on our prior finding of elevated serum sphingosine-1-phosphate (S1P) in IgAN patients versus healthy controls,we established complementary in vivo and in vitro models.Using humanized-gut microbiota mice and IgA1-stimulated mesangial cells, we examined S1P effects via receptor modulation and Chemokine ligand 2(CCL2)-Mesenchymal to epithelial transition factor(MET)-Focal Adhesion Kinase(FAK) pathway analysis, validated in renal biopsies.

Results:

Treatment of human mesangial cells with aggregated IgA1 (aIgA1) successfully induced an IgAN phenotype, characterized by increased proliferation, reduced apoptosis, and significant intracellular IgA accumulation. This model demonstrated upregulated CCL2 expression, along with increased proportions of cells in S and G2 phases. Western blot analysis further revealed significant upregulation of MET, phosphorylated MET (Tyr1234/1235 and Tyr1349), Proliferating Cell Nuclear Antigen(PCNA), cyclin D1, S1PR1, and S1PR3 protein expression. Targeted intervention using CCL2 siRNA, the CCL2 inhibitor NOX-E36, and the MET inhibitor LY2801653 decreased IgA deposition, p-Met protein expression, and cell proliferation. Furthermore, S1P intervention in IgAN mesangial cell models significantly increased S1PR1, S1PR3, CCL2, and MET protein expression, promoting mesangial cell proliferation. Importantly, the CCL2-MET-FAK signaling pathway was activated in both the mice with an IgAN-like phenotype and IgAN patients.

Conclusions:

Disruption of the gut microbiota in IgAN increases CCL2 expression in renal mesangial cells, driven by the metabolite S1P. This, activates the MET/FAK signaling pathway, promoting mesangial cell proliferation and contributing to IgAN progression.Our findings support targeting S1P as a therapeutic strategy for IgAN.

项与 Merestinib 相关的新闻（医药）

2025-12-03

·Business Wire

Taiho Oncology Europe announces the launch of Lytgobi ® (futibatinib) in the United Kingdom for eligible adult patients with a previously treated subtype of locally advanced or metastatic cholangiocarcinoma 1

BAAR, Switzerland--(BUSINESS WIRE)--For United Kingdom (UK) Trade and Medical Media Only Taiho Oncology Europe GmbH announced today the UK launch of Lytgobi® (futibatinib), an irreversibly binding fibroblast growth factor receptor (FGFR) inhibitor.1,3 This development follows the conditional marketing authorisation (4 September 2024) and subsequent National Institute for Health and Care Excellence (NICE) recommendation (11 September 2024) for futibatinib monotherapy as an option for the treatment of eligible adult patients with locally advanced or metastatic cholangiocarcinoma (CCA) with a FGFR2 fusion or rearrangement that have progressed after at least one prior line of systemic therapy.1,4 CCA is an aggressive cancer of the bile ducts that carry bile inside the liver and from the liver and gallbladder to the small intestine. In England, approximately 3,110 people were diagnosed with CCA in 2023,5,6 and the disease is growing in incidence worldwide.7 CCA is usually diagnosed at an advanced stage, with a very poor prognosis with less than one in five patients surviving five years, and there is an unmet need for additional treatment options such as futibatinib.7,8 “Patients with CCA are mostly identified at a late stage of disease and consequently have a poor prognosis. The launch of futibatinib in the UK and positive NICE recommendation for treating locally advanced or metastatic CCA with a FGFR2 fusion or rearrangement that has progressed after at least one prior line of systemic treatment in adults represents a much needed additional treatment option for eligible patients with this aggressive cancer,” said Professor John Bridgewater, Clinical Researcher and Medical Oncologist at University College London Cancer Institute and University College London Hospitals NHS Foundation Trust. Lytgobi monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or rearrangement that have progressed after at least one prior line of systemic therapy.1 The medicine is taken orally, once daily, on a continuous basis (treatment should be continued until disease progression or unacceptable toxicity).1 The conditional marketing authorisation*, where UK approval is granted for medicines that fulfil an unmet medical need while regulatory data review is ongoing,9 is based on findings from the pivotal Phase 2 FOENIX-CCA2‡ global open-label, single-arm trial evaluating 103 patients with unresectable, locally advanced or metastatic CCA with a FGFR2 fusion or rearrangement.1,10 The trial showed that futibatinib provided a clinically meaningful benefit, meeting its primary endpoint of objective response (partial or complete response as assessed by independent central review) with a rate of 42% (95% CI, 32–52), and a median duration of response of 9.7 months (95% CI, 7.6–17.0).10,11 Among the secondary endpoints, the 12-month overall survival rate was 72% (95% CI, 62–80).10 The most common (≥20%) adverse reactions were hyperphosphatemia (89.7%), nail disorders (44.1%), constipation (37.2%), alopecia (35.2%), diarrhoea (33.8%), dry mouth (31.0%), fatigue (31.0%), nausea (28.3%), dry skin (27.6%), increased AST (26.9%), abdominal pain (24.8%), stomatitis (24.8%), vomiting (23.4%), palmar-plantar erythrodysaesthesia syndrome (22.8%), arthralgia (21.4%), and decreased appetite (20.0%).1 The results of the FOENIX-CCA2 trial were published in The New England Journal of Medicine in 2023.10 Within Europe, eligible patients were enrolled in this trial from France, Germany, Italy, the Netherlands, Spain and the United Kingdom.10 “The launch of futibatinib in the UK is the culmination of extensive and productive collaboration among researchers, healthcare professionals, and patients, all united in their commitment to advance care in cholangiocarcinoma and to improve the lives of eligible patients,” said Dr. Peter Foertig, General Manager of Taiho Oncology Europe. “This marks the first medicine Taiho Oncology has introduced in the UK on our own, signifying our intention to establish a strong presence and reinforcing our ongoing commitment to bringing innovative oral therapies to patients with cancer.” Futibatinib was developed by Taiho Oncology Europe’s parent company, Taiho Pharmaceutical Co., Ltd., Tokyo. The larger Taiho family of companies continues to investigate its potential in other tumours.12 ▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. * A conditional marketing authorisation is granted for medicines that fulfil an unmet medical need to treat serious diseases, and the benefits of having them available earlier outweigh any risks associated with using the medicines while waiting for further evidence. As part of this authorisation there will be ongoing review of data to ensure the benefit-risk balance remains positive.9 ‡ The FOENIX-CCA2 trial is a Phase 1 / 2 Study of TAS-120 in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: FGFR Oral SElective Novel Inhibitor X [across] tumors. About Lytgobi (futibatinib) Futibatinib is an oral, potent, selective, and irreversible tyrosine kinase inhibitor of FGFR1, 2, 3 and 4. Futibatinib irreversibly binds to the adenosine triphosphate-binding pocket of FGFR1–4 resulting in the inhibition of FGFR-mediated signal transduction pathways, reduced tumour-cell proliferation and increased tumour-cell death in tumours with FGFR1–4 genetic aberrations.1,3 About Taiho Oncology Europe The mission of Taiho Oncology Europe is to improve the lives of patients with cancer, their families, and their caregivers. The company specialises in orally administered anti-cancer agents and has a growing pipeline of selectively targeted anti-cancer agents. Taiho Oncology Europe GmbH (Baar, Switzerland) is the European subsidiary of Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan). For more information, visit www.taihooncology.eu. Lytgobi is a registered trademark of Taiho Pharmaceutical Co., Ltd. References: Lytgobi ® (futibatinib): Summary of Product Characteristics. Available at https://www.medicines.org.uk/emc/product/100700/smpc#gref Last accessed: November 2025. Taiho Oncology Europe. Futibatinib in Italy for the treatment of cholangiocarcinoma. Published 12 February 2025. Available at Taiho Oncology Europe Announces Availability of Lytgobi® (futibatinib) in Italy for the Treatment of Cholangiocarcinoma Last accessed: November 2025. Sootome H, Fujita H, Ito K, et al. Futibatinib is a novel irreversible FGFR 1–4 inhibitor that shows selective anti-tumor activity against FGFR-deregulated tumors. Cancer Res. 2020;80:4986-4997. Available at: https://aacrjournals.org/cancerres/article/80/22/4986/645861/Futibatinib-Is-a-Novel-Irreversible-FGFR-1-4 Last accessed: November 2025. NICE. Futibatinib for previously treated advanced cholangiocarcinoma with FGFR2 fusion or rearrangement. Published: 11 September 2024. Available at https://www.nice.org.uk/guidance/ta1005 Last accessed: November 2025. Tataru D, Khan SA, Hill R, et al. Cholangiocarcinoma across England: temporal changes in incidence, survival and routes to diagnosis by region and level of socioeconomic deprivation. JHEP Reports. 2023;6(3):100983. Available at: https://www.jhep-reports.eu/article/S2589-5559(23)00314-2/fulltext Last accessed: November 2025. Office for National Statistics. Population estimates for the UK, England, Wales, Scotland and Northern Ireland: mid-2023. Available at: Population estimates for the UK, England, Wales, Scotland and Northern Ireland - Office for National Statistics Last accessed: November 2025. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-588. Available at: https://www.nature.com/articles/s41575-020-0310-z#:~:text=CCA%20is%20a%20rare%20cancer,in%20the%20past%20few%20decades Last accessed: November 2025. Valle JW, Bai LY, Orlova R, et al. Ramucirumab (RAM) or merestinib (MER) or placebo (PL) plus gemcitabine (GEM) and cisplatin (CIS) as first-line treatment for advanced or metastatic biliary tract cancer (BTC): a randomized, double-blind, phase II study. J Clinical Oncol . 2020;38(4):Abstract 477. Available at: https://ascopubs.org/doi/10.1200/JCO.2020.38.4_suppl.477 Last accessed: November 2025. GOV.UK. Conditional marketing authorisations, exceptional circumstances MAs, scientific advice. Available at: https://www.gov.uk/guidance/conditional-marketing-authorisations-exceptional-circumstances-marketing-authorisations-and-national-scientific-advice Last accessed: November 2025. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med . 2023 Jan 19;388(3):228-239. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2206834 Last accessed: November 2025. National Library of Medicine. A study of TAS-120 in patients with advanced solid tumors. Available at: https://clinicaltrials.gov/study/NCT02052778 Last accessed: November 2025 National Library of Medicine. Futibatinib search results. Available at: https://clinicaltrials.gov/search?term=Futibatinib%20 Last accessed: November 2025 LYT-PM-UK-0011

临床结果上市批准临床2期

2025-06-11

·药时空

原料药生产中应用连续流动化学的质量考量

连续流动化学是一项很有前景的新兴制药技术，具有可缩短生产周期、自动化程度较高、环境友好、节能减排等优点，尤其有利于批次模式难以进行的反应，是原料药(即活性药物成分，API) 技术革新的趋势。但由于质量控制和监管的原因，长期以来连续流技术在制药行业推广缓慢。ICH 指导原则《Q13 ：原料药和制剂的连续制造》的颁布，提出了原料药工艺开发要点和控制策略，监管期望逐渐明晰。该文结合新颁布的ICH Q13，综述连续流动化学的特点、应用场景和质量考量，通过文献案例分享，进一步说明连续流动化学开发要点和控制策略，以期推动连续流动化学在国内制药企业的应用，提升行业制造水平，努力实现国家的“双碳”目标。原料药[即活性药物成分(active pharmaceutical ingredient，API)] 供应是确保广大患者药品可及性的前提，在集采背景下尤为重要。随着国家“双碳”目标的制定，国家发展和改革委员会、工业和信息化部于2021年11月初颁布了关于推动原料药产业高质量发展实施方案的通知，原料药生产技术的创新升级朝着绿色化、低碳化转型已是必然的趋势[1]。连续流动化学是一种化工过程强化技术，应用微通道反应、固定床、连续搅拌釜等微反应器实现连续生产，具有本质安全、可迅速扩大产能的特点，是工信部、生态环境部、国家卫健委、国家药监局等四部委重点推荐的绿色制药技术[2]，也是保证原料药供应链安全的关键技术。连续流技术在大化工领域已大规模使用，体现出许多明显的优势，但该技术在原料药生产中的应用进展缓慢，尤其是多步整合连续生产的原料药品种更少，近年来只有1 个品种在FDA 获批[3]。FDA 药品评价和研究中心原主任WOODCOCK 认为连续制造技术应用的主要障碍是进入的成本较高和审评周期长[4]。为了帮助制药公司了解连续制造的监管考虑和设施检查、增强投资信心，FDA于2019 年发布了《工业连续制造的质量考量》草案[5]，并征求意见，但该指南只针对小分子药物的口服制剂。2021年，人用药品技术要求国际协调理事会(The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use，ICH) 终于发布了首个涉及原料药连续制造的监管文件Q13[6]，即《原料药和制剂的连续制造》，囊括了原料药和制剂的连续制造，为连续制造提供了研究指南。ICH Q13 草案对连续制造及其批次进行了定义，指导控制策略建立，讨论了工艺确证和工艺变更的研究方法。该指南草案结合实际提出了对连续制造产品的监管考量，并且在附件中以案例的形式帮助申请者理解，撰写水平较高且不教条。本研究梳理了Q13 草案和相关文献，并结合课题组近年在连续流合成工艺方面的研究体会作一综述，以期将这一技术应用于中间体和原料药的生产，降低制造成本和节能减排，以推动这一先进制备技术在化学原料药生产上的应用。福利 | 连续流系列白皮书领取扫码登记信息并留言“连续流白皮书系列”，即可获取由药石科技提供的下列技术资料（工作人员会通过登记的邮箱发送，请务必填写正确信息）：《Techwhitepaper-flowchemsitry_diazotizationreaction》《连续光催化技术的研究》《连续流技术手册》《药石科技2024年环境、社会及公司治理报告》......1连续流技术的特点连续流技术给原料药生产带来的最明显优势就是可以显著缩短生产周期，尤其是多步整合连续生产的模式。与传统批次生产不同，不间断的连续生产一般要求采用过程分析技术( process analysis technology，PAT) 和设备对质量进行在线监测，由于无需等每步中间体检测合格后才能进入下一步，可减少大量等待时间。其他的一些特点具体如下：①自动化程度高，全程涉及生产人员较少，可降低人为错误风险，保障产品质量[7]。②连续流反应器持液量小，传热、传质快，可安全地使用在釜式反应中需要避免的工艺条件，如高温(高压) 下的反应和超快速放热反应。此外，连续流反应中还可以安全使用危险性较大、不适于釜式反应的试剂，如一些高毒和高活试剂[8]。③微反应器的流体基本是平推流[9]，“三传一反”调控容易，放大效应小，从实验室开发到生产放大周期短，可快速形成产能，尤其适合那些服务创新药公司的合同定制研发生产机构及合同定制生产机构，缩短工艺开发和供样周期[10]。④连续流设施占地面积小，可减少宝贵的药品生产质量管理规范(Good Manufacturing Practice of Medical Products，GMP) 设施空间，大大减少工厂固定资产投入和运营成本。美国CONTINUUS Pharmaceuticals 公司的案例显示，采用集成的连续制造，固定资产投入可减少90％，API 生产运营成本降低33.6％，片剂生产降低29.4％ [11]。2连续流技术的应用对于医药行业，应用新的制造技术的目的是期望加强药品供应链稳定性，使其更加高效和适应性更强，最终为患者带来好处。将连续流技术应用于原料药生产不仅要考虑具体品种情况，如工艺是否适合、是否要求专线、创新药还是仿制药等因素，还要平衡产能与市场需求，不是简单地在批次生产和连续生产之间做“二元”选择。一般认为，连续流技术更适合批量小的特色原料药或者需求很大的基础原料药[12]。3连续流生产的质量考量3.1批量范围传统间歇式生产工艺的注册批量与起始原料的投料量相关，根据注册批的投料量和收率范围确定商业化批量，批量范围一般较窄。而Q13 草案对连续制造的批量要求相对灵活，不仅可以根据输入物料量和输出物料量制定，还可以规定运行时间(限定质量流量)，通过定义最小和最大运行时间来确定批量范围。甚至还允许其他基于连续制造工艺特征的科学合理的方法来定义批量，批量的范围将更加灵活，更有利于制造商根据需求安排产能，减少仓储成本。3.2设备的设计和整合生产设备情况是原料药申报资料里需要提供的内容。传统间歇釜只需提供每个设备型号及技术参数，但是连续流设备大多是定制化设备，需要提供更多的内容。ICH Q13 草案中要求对设备设计或配置以及系统整合的任何方面都要进行详细描述，其附件Ⅰ提供了原料药连续生产的示例，包括了由2步连续反应和1步批次反应组成的混合工艺连续生产案例。该示例从控制策略、工艺稳健性、长期性能、工艺验证和监管考虑几个方面进行了详细描述和讨论，易于理解，此处不再赘述，但需要指出的是，质量保证(quality assurance，QA) 部门应建立适合连续流设备性能和稳定性的验收标准(例如包括参数差异和偏移，以及瞬时干扰的发生)，以支持连续生产工艺的开发和运行。连续生产方式需要通过长时间运行来达到预定批量大小，因此设备的稳健性对质量的影响至关重要。3.3工艺过程控制连续流技术是一个动态的过程，在过程的每个时点，微通道的前后各个位点料液的组分比例均不同，对于多步整合的连续流反应，不同位点的组分可能都不同。前一个位点的反应程度如果由于干扰发生变化，必将影响下一个位点的质量，经过连续叠加，将导致终产品质量产生较大偏差，因此在连续流反应中，轻微的扰动就可能导致产品质量发生较大偏差。Q13 草案中明确要求建立工艺监测和维持受控状态的稳健方法，在附件中进行了重点描述，要求增加多个PAT 装置，精确控制进料的浓度和流速，监测每一步的质量，根据上一步中间体的质量水平，反馈控制下一步物料添加流速，达到控制反应、维持受控状态的目的。对于扰动的管理是不同于传统批次工艺的重要内容。Q13 草案要求基于设备的停留时间分布(remain time distribution，RTD) 开发合适的扰动检测、纠正措施以及物料分流策略。对干扰的研究一般处于工艺开发的后期，通过动态模拟的方法，了解反应过程动力学与输入物料属性、工艺参数和设备参数的关系，这些知识可以帮助识别和评估风险。Q13 草案的附件Ⅴ提供的案例可供参考，通过一系列基于RTD 的干扰幅度和持续时间的分析，采用漏斗图工具，评估工艺对扰动的大小或持续时间的容忍度，再根据评估结果制定物料分流点和分流决策，还给出了物料分流决策树。这方面研究结果是注册资料中工艺开发章节须重点提供的内容。3.4清洁验证现有GMP 体系带来最大的挑战之一是连续流设备的清洁验证。连续流动化学应用最多的是微通道反应器，反应模块通道直径为毫米级；为了保持密封性，一般都采用一体成型，通道无法打开清洗。商业化的微通道反应器往往会根据工艺的混合要求，定制特殊设计的通道，这使得反应器里可能残留的组分种类更多，尤其是多步连续的设施内组分更加复杂，如何清洗、如何取样都给生产商和监管机构带来了困惑。Q13 草案中没有提供清洁方法开发指南，建议申请人可以参考FDA 于2019 年发布的“连续制造的质量考量征求意见稿”[13]。该指南建议首先应从开发和工艺放大(例如增加生产运行时间)研究中获得的知识来开发和定义清洁方法，然后定期验证以确认持续的有效性。清洁程序应基于在操作期间和拆卸后密切监控物料的结果而建立，方案的制定应考虑以下几点：①检查物料在设备、管道、过滤器和仪器上的滞留和积聚，包括在线分析仪和传感器；②在运行过程中关注生产线上的物料降解、形成的化学膜和微生物生长；③清洁验证期间的评估条件应考虑在预期最差条件( 例如延长生产时间)下的潜在故障模式( 例如结垢和磨损)。3.5质量标准制定对于多步整合连续生产的品种，过程中不分离中间体，连续反应时需要制定过程中监测或控制的可接受标准和采样计划，成品的实时检测放行的方法和标准，这些方法和标准的建立不同于传统生产方式，需要基于PAT 设备进行全新开发。如应用在线液相色谱法对中间体质量进行监控，检测结果用于前馈和反馈控制。在线液相色谱的方法开发不同于传统离线液相色谱的方法开发，首先要求结果尽快响应，其次除了要开发液相色谱方法以外还需要开发样品在线处理方法，如样品淬灭、稀释、过滤方法，并通过方法学验证，这些工作给质量分析人员提出了新的挑战。总之，连续流生产的质量控制策略的制定对于国内制造商和监管机构都是新的挑战，需要双方加强沟通，共同努力，逐渐完善法规和指南。4原料药连续生产案例连续流技术应用于原料药生产的优势和挑战并存。连续制造目前在国内尚处于起步状态，国外虽然发展多年，但目前获批上市的连续制造产品主要是制剂产品[14]，公开报道的只有葛兰素公司的丙酸氟替卡松作为连续制造的原料药获批[15]。为了进一步理解连续流工艺的开发和质量考量，本研究介绍2个GMP 阶段的原料药文献典型案例，供同仁参考。4.1单步连续流生产[16]Vaborbactam 是美国Rempex公司开发的一种环硼酸β-内酰胺酶抑制剂。2017 年FDA 批准vaborbactam 与美罗培南合用，用于治疗复杂的尿路感染和肾盂肾炎，商品名为Vabomere。Vaborbactam 的制备工艺见图1。图1 Vaborbactam 的制备工艺其中关键中间体α- 氯代烷基硼酸酯(4)的制备需要在超低温(–100 ～ –95 ℃ ) 条件下进行，商业化生产很困难，制造商决定将该步反应由批次反应变更为连续生产，小试反应设备流程图见图2。采用连续化生产，收率可由75％提高到90％，但是在放大过程中发现氯化锌淬灭反应时会产生固体，堵塞通道，而且放热明显，导致非对映异构体含量增加。制造商重新设计了淬灭工序的设备，改成连续循环淬灭设备，见图3。图2 Vaborbactam 中间体4的小试连续反应流程图图3 Vaborbactam 中间体4的连续生产流程图优化后的连续反应设备经过长时间运行，证明了装置的稳健性，转化率超过90％，选择性超过95％，产能达到百公斤级。随后制造商又定制一套相同设备，将中间体4 的cGMP 商业化产能提高到吨级，这些连续化生产设施于2017年通过了FDA的审核。4.2多步连续流生产[17]Merestinib 由美国礼来公司开发，用于治疗晚期实体瘤，目前将进入Ⅲ期临床试验。Ⅲ期临床试验前样品由礼来公司采用连续流技术制备，为了降低成本、缩短周期，Ⅲ期临床试验样品转移给合同加工外包公司合全药业负责，在cGMP 条件下生产183 kg 产品的生产周期为25 d，工艺路线见图4。图4 Merestinib 的合成工艺路线Ⅲ期临床试验前，礼来公司采用全连续的方式制备样品，而制备Ⅲ期临床试验样品时为了适应cGMP的生产和进度要求，变更为批次和连续混合工艺，具体变化见表1。表1 Ⅲ期临床试验前后的工艺变化由表1可见，虽然该产品的最初工艺是全连续制造工艺，但到了cGMP 生产阶段，为了满足监管要求且考虑到时间成本，最终只是将步骤3和步骤4进行了连续生产(反应设备流程图见图5)，其他都改成传统批次生产，可见采用连续流方式进行原料药的合规生产还存在较大挑战。为了研究连续反应过程，对于杂质的产生和清除情况，礼来公司在步骤3应用了在线HPLC 监控反应，每30 min 检测1次，根据结果反馈调整工艺操作，包括：①继续反应；②调整原料5和6的进料比；③如超出标准范围，切换阀门，进入废液管线排走。经过连续17 d 的连续运行监控，结果显示，未转化的中间体5控制在0.05％，产物中间体7的纯度不小于99％，剩余杂质是中间体6 和8，均在可接受范围内。步骤4可能产生2个基因毒性杂质5和15(结构见图6)，cGMP 生产过程采用LC-MS 离线检测，每8 h检测放行，连续运行17 d，粗品中2个基因毒性杂质均不超过80×10–6，精制后不超过10×10–6(Ⅱ期临床样品控制70×10–6)，确保了成品质量。图5 Merestinib 合成过程中步骤3和步骤4的连续生产流程图图6 Merestinib 杂质5和15的结构式5结语连续流技术是制药工业很有前景的新技术，可以减少药品的质量问题，降低生产成本，提高患者对优质药品的可及性[18]。在明确的监管指南发布以前，连续流工艺开发和监管要点对于申请人和监管者都是全新的挑战，采用连续制造工艺申请注册获批上市的投入可能会超过获益。ICH Q13 草案的颁布，为行业和监管机构在制药中应用连续生产技术提供了指导，但是该文件目前还只能作为一个纲领性指导，还需要各国药品监管机构针对本国国情制定操作性更强的指导原则。作为原料药研究人员，笔者建议国内的药品监管机构也成立类似美国FDA的新技术小组，加大ICH Q13 草案的宣传，组织学术界和业界专家制定细则，指导工艺开发工作，实施过程监控方法和标准的建立以及监管考量，制定实时检测放行标准等。在生产体系方面应明确那些与传统批次生产差别较大的文件和规范的制定原则和监管期望，如连续设备确认和维护、干扰管理和清洁验证等，并且在实践中不断更新和完善。希望有更多原料药生产企业应用连续流技术，共同推动该技术的发展，提升行业制造水平，尽早实现国家的“双碳”目标。参考文献[1] 国家发展和改革委员会．关于推动原料药产业高质量发展实施方案的通知[EB/OL]．[2022-04-21].[2] 工业和信息化部, 生态环境部, 国家卫生健康委, 等．关于印发《推动原料药产业绿色发展的指导意见》的通知[EB/OL]．[2022-04-21]．https://wap．miit．gov．cn/jgsj/xfpgys/wjfb/art/2020/art_95a430a0a0bf40ab82dca23e84efc185.html．[3] FDA．2020 OPQ Annual Report [EB/OL]．[2022-04-21]．https://www．fda．gov/media/145830/download．[4] FDA．August 2018: FDA's comprehensive effort to advance new innovations: initiatives to modernize for innovation[EB/OL]．(2015-04-30)[2022-04-21]．https://www．outsourcing-pharma．com/Article/2015/05/01/FDA-callson-manufacturers-to-begin-switch-from-batch-to-continuousproduction．[5] FDA．FDA statement on FDA’s modern approach toadvanced pharmaceutical manufacturing [EB/OL]．(2015-04-30)[2022-04-21]．https://www．fda．gov/news-events/press-announcements/fda-statement-fdas-modern-approachadvanced-pharmaceutical-manufacturing．[6] 国家药品监督管理局药品审评中心．关于公开征求ICH指导原则《Q13: 原料药和制剂的连续制造》意见的通知[EB/OL]．(2021-10-18)[2022-0421]https://www.cde.org cn/main/news/viewInfoCommon/d30747763265e07fae058d565519070．[7] FDA．Advancement of emerging technology applications for pharmaceutical innovation and modernization: guidance for industry [EB/OL]．[2022-04-21]．https://www．fda．gov/regulatory-information/search-fda-guidancedocuments/advancement-emerging-technology-applicationspharmaceuticalinnovation-and-modernization-guidance．[8] DALLINGER D, GUTMANN B, KAPPE C O．The concept of chemical generators: on-site on-demand production of hazardous reagents in continuous flow [J]．Acc Chem Res,2020, 53(7): 1330-1341．[9] 骆广生, 王凯．微反应器研究最新进展[J]．现代化工,2009, 29(5): 27-31．[10] REIZMAN B J, COLE K P, HESS M, et al．Smallvolume continuous manufacturing of merestinib． Part 2．Technology transfer and cGMP manufacturing [J]．Org Process Res Dev, 2019, 23(5): 870-881．[11] TESTA C J, HU C, SHVEDOVAE K, et al．Design and commercialization of an end-to-end continuous pharmaceutical production process: a pilot plant case study [J]．Org Process Res Dev, 2020, 24(12): 2874-2889．[12] SRAI J S, SETTANNI E, AULAKH P K．Evaluating the business case for continuous manufacturing of pharmaceuticals: a supply network perspective, in continuous pharmaceutical processing [M]．Berlin: Springer International Publishing, 2020: 477-512．[13] FDA．Quality considerations for continuous manufacturing[EB/OL]．[2022-04-21]．https://www．fda．gov/regulatory-information/search-fda-guidance-documents/quality-considerations-continuous-manufacturing．[14] 曹辉, 丁力承．国外已上市连续制造药品的注册审评情况及其启示[J]．中国药事, 2022, 36(4): 377-383．[15] BERRY M B．Filing a multistage continuous process for API [J/OL]．(2020-03-24)[2022-04-21]．https://www．americanpharmaceuticalreview．com/Featured-Articles/562258-Filing-a-Multistage-Continuous-Processfor-API/．[16] STUECKLER C, HERMSEN P, RITZEN B, et al．Development of a continuous flow process for a Matteson reaction: from lab scale to full-scale production of a pharmaceutical intermediate [J]．Org Process Res Dev,2019, 23(5): 1069-1077．[17] REIZMAN B J, COLE K P, HESS M, et al．Smallvolume continuous manufacturing of merestinib．Part 2．Technology transfer and cGMP manufacturing [J]．Org Process Res Dev, 2019, 23(5): 870-881．[18] 曹萌, 丁力承, 胡延臣, 等．药品连续制造全球监管发展现状与思考[J]．中国药事, 2022, 36(4): 364-376．识别微信二维码，可添加药时空小编请注明：姓名+研究方向！

医药出海

100 项与 Merestinib 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D11763	Merestinib	-	DB12381

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
非小细胞肺癌	临床2期	美国	Eli Lilly & Co.	2016-11-11
晚期胆道癌	临床2期	美国	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	阿根廷	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	澳大利亚	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	奥地利	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	比利时	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	捷克	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	丹麦	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	法国	Eli Lilly & Co.	2016-05-19
晚期胆道癌	临床2期	德国	Eli Lilly & Co.	2016-05-19

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


NCT02920996 (CTgov)	临床2期	非小细胞肺癌	12	Merestinib (NSCLC (Met Exon 14 Mutation))	製糧壓蓋鑰鑰糧齋鑰積 = 憲醖願製憲願糧餘繭窪積積簾蓋艱鏇憲選積餘 (鬱襯壓齋廠醖構構鬱願, 構鬱顧鹹糧顧繭衊衊構 ~ 顧淵淵鹽觸遞鏇選蓋醖) 更多	-	2024-04-11
				Merestinib (Solid Tumor (NTRK1,2,3 Rearrangement))	夢廠壓襯簾蓋襯鏇夢廠(蓋膚繭襯齋簾觸齋窪遞) = 襯窪築蓋醖壓顧鑰選夢簾蓋鹹艱糧鏇膚網鏇廠 (膚壓膚積醖壓襯願鹹選, 衊願鏇觸淵衊繭顧蓋製 ~ 構鹹夢遞廠網糧鏇鹽膚) 更多
NCT03027284 (Pubmed) 人工标引	临床1期	转移性肿瘤	18	merestinib (Part A)	簾膚壓廠鹽範網網壓醖(廠餘鏇獵餘糧鹽獵夢鏇) = 襯網壓鬱簾夢糧艱製積築鹽範壓鏇憲範範簾艱 (顧糧鹽製艱憲願衊鏇衊 ) 更多	积极	2021-10-01
				Cisplatin+gemcitabine+merestinib (Part B)	願繭築衊鹹憲鏇鏇構膚(憲鏇鏇鹽構觸衊夢鏇壓) = 衊觸糧構膚積蓋網簾築鏇築窪觸衊衊選艱夢膚 (範獵獵鹹觸壓網積艱壓 ) 更多
NCT02711553 (CTgov)	临床2期	转移性肿瘤 \| 晚期胆道癌 \| 晚期癌症	309	Gemcitabine+cisplatin+Ramucirumab (8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine)	選鏇顧簾願淵鏇願鏇選(淵衊夢糧膚醖衊糧淵鏇) = 網鬱積糧築糧築夢遞範鑰襯遞淵鹽襯繭網網鹹 (獵顧憲鑰範淵艱簾糧網, 鑰憲廠壓觸構獵淵壓憲 ~ 壓獵顧鏇鬱鏇鏇窪觸鹽) 更多	-	2021-02-26
				Gemcitabine+cisplatin+Merestinib (80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine)	選鏇顧簾願淵鏇願鏇選(淵衊夢糧膚醖衊糧淵鏇) = 淵簾網鹽鏇齋窪網簾網鑰襯遞淵鹽襯繭網網鹹 (獵顧憲鑰範淵艱簾糧網, 夢餘顧醖鑰糧積餘衊壓 ~ 艱製膚觸艱醖壓範顧範) 更多
NCT02745769 (AACR2017)	临床1期	套细胞淋巴瘤 \| 结直肠癌 \| 晚期癌症	23	Merestinib (LY2801653)	淵積顧簾鬱築壓觸醖築(夢鹽壓製蓋襯遞襯廠獵) = 淵醖簾壓膚鹹構顧窪膚鏇淵糧願窪壓構壓廠鹽 (艱餘觸憲夢顧蓋襯鏇壓 )	-	2017-07-01
				DC101	淵積顧簾鬱築壓觸醖築(夢鹽壓製蓋襯遞襯廠獵) = 艱範衊網糧鹽鹹製艱廠鏇淵糧願窪壓構壓廠鹽 (艱餘觸憲夢顧蓋襯鏇壓 )