作者: Thomas, Fabienne ; Roth, Gael ; Botté, Cyrille Y ; Millet, Arnaud ; Gharzeddine, Khaldoun ; Laverriere, Marie-Hélène ; Girard, Edouard ; Gonzalez Prieto, Cristina ; Hennot, Clara ; Malier, Marie ; Grespan, Renata ; Yamaryo-Botté, Yoshiki

BackgroundTumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, the blockade of the colony-stimulating factor 1 receptor (CSF-1R) receptor is one of the most promising ones. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor.MethodsUsing RNA sequencing and metabolomics approach, we characterize the reprogramming of human monocyte-derived macrophages under CSF-1R targeting.ResultsWe find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF-1R receptor leads to a downregulation of the expression of sterol regulatory element-binding protein 2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of extracellular signal-regulated kinase 1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of hypoxic induced factor 2 alpha in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer.ConclusionsThese results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages and its potential to reverse macrophage-mediated chemoresistance in colorectal tumors.

Journal of Neuroinflammation

Suppression of inner blood-retinal barrier breakdown and pathogenic Müller glia activation in ischemia retinopathy by myeloid cell depletion

Article

AbstractIschemic retinopathies including diabetic retinopathy are major causes of vision loss. Inner blood-retinal barrier (BRB) breakdown with retinal vascular hyperpermeability results in macular edema. Although dysfunction of the neurovascular unit including neurons, glia, and vascular cells is now understood to underlie this process, there is a need for fuller elucidation of the underlying events in BRB dysfunction in ischemic disease, including a systematic analysis of myeloid cells and exploration of cellular cross-talk. We used an approach for microglia depletion with the CSF-1R inhibitor PLX5622 (PLX) in the retinal ischemia-reperfusion (IR) model. Under non-IR conditions, PLX treatment successfully depleted microglia in the retina. PLX suppressed the microglial activation response following IR as well as infiltration of monocyte-derived macrophages. This occurred in association with reduction of retinal expression of chemokines including CCL2 and the inflammatory adhesion molecule ICAM-1. In addition, there was a marked suppression of retinal neuroinflammation with reduction in expression of IL-1b, IL-6, Ptgs2, TNF-a, and Angpt2, a protein that regulates BRB permeability. PLX treatment significantly suppressed inner BRB breakdown following IR, without an appreciable effect on neuronal dysfunction. A translatomic analysis of Müller glial-specific gene expression in vivo using the Ribotag approach demonstrated a strong suppression of Müller cell expression of multiple pro-inflammatory genes following PLX treatment. Co-culture studies of Müller cells and microglia demonstrated that activated microglia directly upregulates Müller cell-expression of these inflammatory genes, indicating Müller cells as a downstream effector of myeloid cells in retinal IR. Co-culture studies of these two cell types with endothelial cells demonstrated the ability of both activated microglia and Müller cells to compromise EC barrier function. Interestingly, quiescent Müller cells enhanced EC barrier function in this co-culture system. Together this demonstrates a pivotal role for myeloid cells in inner BRB breakdown in the setting of ischemia-associated disease and indicates that myeloid cells play a major role in iBRB dysregulation, through direct and indirect effects, while Müller glia participate in amplifying the neuroinflammatory effect of myeloid cells.

Future Oncology

MANEUVER: A Phase III study of pimicotinib to assess efficacy and safety in tenosynovial giant cell tumor patients

Article

作者: Shi, Haosong ; Gelderblom, Hans ; Zou, Qingping ; Niu, Xiaohui ; Guo, Qiuxiang ; Shan, Boyao ; Ravi, Vinod

Tenosynovial giant cell tumor (TGCT) is a rare, locally invasive soft tissue tumor arising from the synovium of joints, bursa and tendon sheaths and is associated with the overexpression of the colony-stimulating factor 1 (CSF-1) gene. Pimicotinib is an orally available, highly selective and potent small molecule CSF-1 receptor (CSF-1R) inhibitor with robust efficacy and safety profile in patients with TGCT and is under development in multiple diseases. In an open-label Phase I study in patients with TGCT not amenable to surgery, pimicotinib showed superior efficacy and safety. In this article, we elucidate the rationale and study design of the multi-region Phase III MANEUVER trial (NCT05804045), which is designed to assess the efficacy and safety of pimicotinib in patients with TGCT not amenable to surgical resection in Asia, North America and Europe.

项与 CSF-1R抑制剂(Mithra) 相关的新闻（医药）

2024-10-26

·药渡Daily

小而美Biotech，将迎来重磅催化

和誉马上面临核心管线的三期临床揭盲，股价成败在此一举。作为一家港股市值并不大的biotech，和誉目前具备非常多的加分项：有和MNC的稳定BD，有即将商业化的潜在best in class管线，后续管线也具备着充足的想象力。 ABSK021临床III期揭盲如果成功，将会使其前景大幅度明朗起来。 01 ABSK021——即将到来的核心催化 ABSK021是一条针对CSF-1R（集落刺激因子1受体）的管线。与从前所述的CD47靶点类药物类似，它在机制上也是主要针对巨噬细胞的。对于肿瘤微环境（TME）中的巨噬细胞而言，它在极端状况下有两种形态，分别是抑制肿瘤生长的M1形态，和促进肿瘤生长的M2形态。而在大多数情况下，巨噬细胞都是两种情况的中间形态，主要看复杂的靶点通路将巨噬细胞往哪个方向去诱导。因此，对于抗肿瘤疗法而言，自然希望巨噬细胞能够尽可能转化成M1形态，在肿瘤微环境中起到抑制肿瘤的作用。而CSF-1/CSF-1R，就是起到这样关键作用的靶点，它在巨噬细胞表面大量存在，可以促进肿瘤微环境中的巨噬细胞向M2型分化激活。并且巨噬细胞表面的CSF-1R与CSF-1 结合后，可使其分泌VEGF等多种细胞因子，进一步促进肿瘤的增殖、侵袭转移以及血管生成。因此，可以通过阻断该通路来抑制肿瘤微环境中的巨噬细胞向M2型去转化。而CSF-1R抑制剂或是相关抗体，起的就是该作用。目前该类药物的主要适应症方向，在腱鞘巨细胞瘤（TGCT）上。目前市场上唯一一款获批的CSF-1R小分子抑制剂是第一三共的PLX3397。但该药由于分子结构的原因，使其对靶点的特异性不是很好。特异性不佳的处理方式是增大剂量，而增大剂量的后果是毒性的增大。目前PLX3397被FDA打上了黑框警告的标签，first in class的商业化并不是很顺利，这也给后继者们留足了商业空间去拓展。而ABSK021，目前是best in class的最强竞争者。如图所示，在临床Ib期试验中，ABSK021初显峥嵘，在初步的25周随访中ORR便达到了68%，DCR直接达到了100%。而在一年后的2023年CTOS年会上，ABSK021公布了一年随访的最新数据：ORR直接达到了87.5%。（图片来源：和誉官网PPT）可以将该数据与PLX3397进行对比，PLX3397的III期临床来看，在24周的初步评估疗效中，仅有39%的患者达到了ORR（肿瘤体积至少减小30%，可以视为PR＋CR），而后续的治疗中，达到ORR的比率为53%。（图片来源：ENLIVEN study: Pexidartinib for tenosynovial giant cell tumor (TGCT)）目前PLX3397真正的强有力对手是罗氏的RG-7155（Emactuzumab），它是一款针对CSF-1R的大分子抗体。从临床Ib期的数据来看，ORR为71%（45/63），DCR为98%（62/63），与ABSK021旗鼓相当，不过一年后随访数据来看，ORR为70%，疗效持续性上不如PLX3397。此外，作为大分子抗体来说，大部分都是以静脉注射的方式给药，部分依从性好一些的剂型是皮下注射，而小分子可以采取口服方式给药，从患者便利性来说，小分子这方面占据着较大的优势。 ABSK021马上到了开盲盒的阶段。根据和誉九月份发布的临床公告，ABSK021已经在今年三月完成了三期临床的所有患者入组，而试验周期为24周，今年Q4有较大可能发布临床III期顶线数据。如果真的开出了一款best in class，那么和誉公司的价值，可能远不止如今的数字。（图片来源：和誉官网PPT，ABSK021三期临床试验设计）除此之外，ABSK021在cGvHD（慢性移植物抗宿主病）适应症上的II期临床预计也离数据揭盲并不遥远。前不久，同靶点单抗Axatilimab刚刚获FDA批准，该靶点抑制剂在cGvHD上的疗效已经能得到证实：根据AGAVE-201这项关键II期临床试验，每两周接受0.3mg/kg剂量（推荐剂量）的axatilimab治疗的患者，在治疗的前六个月内获得了75%的ORR。该适应症上，ABSK021目前并不算落后，目前需要的则是临床II期数据的验证。 02 ABSK011——肝癌潜在破局者如果说ABSK021是腱鞘巨细胞瘤适应症的潜在BIC的话，那么ABSK011就是肝癌细分领域的潜在破局者了。 ABSK011靶向FGFR4（成纤维细胞生长因子受体4），与EGFR同为酪氨酸激酶（RTKs）家族的成员，它近年来被引起广泛关注，是因为它的过表达导致的细胞癌变。FGFR4和FGF19是受体和配体的关系，FGF19和FGFR4的过表达都会导致肝癌风险的上升，因此，可以用抑制FGFR4的方式，来对FGF19亦或FGFR4过表达的患者进行治疗。（图片来源：《FGFR4:一种有望治疗肝癌的靶点》）而目前的研发管线来看，ABSK011是一条被寄予很高预期的药物。今年9月，ESMO大会上展示了ABSK011的I期临床数据。给药方面，分为每日一次给药（QD）和每日两次给药（BID）。从疗效方面来看，主要关注FGF19过表达肝癌患者的疗效数据。在40例FGF19过表达患者中，采用220mg每日两次给药进行治疗，其中38例可评估疗效，ORR达到了36.8%，DCR达到了78.9%。比较惹人注意的是，接受过ICIs（免疫检查点抑制剂，如PD-1）和mTKIs（多靶点酪氨酸激酶抑制剂，肝癌适应症药物如索拉非尼）治疗的患者应答率达到44.8%。事实上，高选择性FGFR，例如FGFR4抑制剂也是近些年来才火的方向，更早流行的是pan-FGFR（泛FGFR，不针对某种特定FGFR亚型），但FGFR4在近两年来大部分管线进入了瓶颈期。2024年10月24日去检索clinical trial网站（关键词：FGFR4），目前还在进行的FGFR4的临床试验仅仅有5个，而其中两个试验并不针对肝癌适应症，目前仅BB-102，SY-4798和和誉的ABSK011还处于临床试验正在进行的状态。并且之前两条管线都还在在临床I期（Phase I）阶段，而ABSK011临床II期已经将要完成。此前被寄予厚望的管线是BluePrint的BLU-554，该药进展较早，算是这个领域的开拓者，但在临床I期公布数据后，迟迟未有新的进展，目前查阅BluePrint官网，也已经无法看到该条管线。不知不觉间，和誉的ABSK011已经将要成为first in class。而接纳它的市场，是我国发病率第四的癌症（数据来源：J Natl Cancer Cent.2024,4(1)）。在肝癌适应症中，FGFR19过表达的比率为30%。未来，将会有三成肝癌的患者迎来它们的救命稻草——这个适应症将不再只有免疫检查点抑制剂疗法苦苦支撑。根据CSCO（中国临床肿瘤协会）诊疗指南，对于中晚期的肝细胞癌（HCC）而言，一线疗法目前为VEGF（如贝伐珠单抗）联用PD-1（信迪利单抗），而二线疗法为K药，恒瑞的PD-1或者百济的PD-1，此外，还有主要针对VEGFR的多靶点抑制剂瑞戈替尼，以及针对VEGFR2靶点的阿帕替尼。总体来说，肝细胞癌药物还是处于非常匮乏的状态，除了ADC等新一代大分子外，也急需类似于EGFR TKI之于NSCLC的靶向药去横扫这个市场。现在，这一切都成为了可能。 03 和誉——被低估的小而美按照从前筛选港股biotech的标准来看，和誉在小市值biotech里质地是非常好的。 BD方面，和誉在去年12月与默克达成了BD的协议，授予了其在大中华区对ABSK021的独家商业化权利，研发与商业化里程碑付款达到6.055亿美元，此外还有超过10%的销售分成。以默克的商业化渠道来说，将比和誉自己搭建商业化团队放量减少相当大的成本，风险也小得多，是一个比较稳健的选择。毕竟对一个还没有商业化产品上市的biotech而言，最重要的是通过第一个商业化单品“回血”，为之后更大规模的自研铺路。而更为重要的是，默克除了拿到其大中华区的商业化权利外，还拿到了未来全球其它地球商业化权利的选择权，这也是和誉的三期临床试验做的是MRCT（国际多中心临床的原因）。默克大概率会根据之后三期临床的结果，来决定是否行使该期权，将该药物推向发达国家的市场，毕竟在药物定价方面，中国和欧美是有相当大差距的。这也是这次三期临床极为关键的原因所在，如果入组人种足够复合具有多样性，那么之后直接申报FDA等并不是不可能。推向全球，在此一举。当然，BD交易方也并不止默克。2023年3月，和誉与艾力斯就当时的一条临床前小分子管线——ABK3376达成BD，合同总金额达到了1.88亿美元，该分子由和誉发现，未来和誉和艾力斯将共同推进研发。该管线则是耳熟能详的EGFR-TKI抑制剂，它的潜力在于能够针对三代TKI耐药——即C797S突变的患者，这实际上已经有了四代TKI的雏形。 ABK3376已经于今年9月进入临床阶段。（图片来源：公司官网）估值方面，和誉目前的市净率仅为1.15，市值为26.84亿港元（10月24日），距离其过往的巅峰市值接近90亿港元还有很大一段距离，这当然与和誉还没有商业化单品有关，但目前而言以和誉稳定的BD结果来看，这个市值显然是被低估的。结语：和誉目前主要的市值弹性在于ABSK021这波临床三期的催化，毕竟大概率是第一个商业化的单品，也有着best in class的潜力。但和誉公司的长期竞争力却不止于此，以目前公司的自研能力以及各大龙头与其BD的进展来看，未来成为国内小分子biotech的头部企业，并不是不可能。免责声明 “药渡Daily”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。

临床3期申请上市临床2期临床终止

2024-09-10

·PRNewswire

Lausanne Researchers Combine 10x Genomics' Chromium and Xenium for Novel Insights into Resistance and Potential Therapeutics for Brain Cancer

In the September 9 cover article of Cancer Cell, researchers integrated 10x single cell and spatial technologies to identify a mechanism of glioblastoma recurrence in mice and develop a promising potential therapeutic approach. PLEASANTON, Calif., Sept. 10, 2024 /PRNewswire/ -- 10x Genomics, Inc. (Nasdaq: TXG), a leader in single cell and spatial biology, announced today that its Chromium Single Cell Gene Expression and Xenium In Situ platforms were used in a publication – featured on the cover of Cancer Cell – that sheds light on the role of fibrotic scars in glioblastoma treatment recurrence. The study, led by researchers in the laboratory of Professor Johanna Joyce (University of Lausanne, Switzerland) and the Ludwig Institute for Cancer Research (Lausanne, Switzerland), also showcased how inhibiting both colony stimulating factor 1 receptor (CSF-1R; a therapeutic target under investigation for treating multiple cancers, including glioblastoma (GBM)) and the formation of fibrotic scars led to improved survival of mice in preclinical trials. GBM is both the most common brain cancer and the most aggressive, with a five-year survival rate of less than 5%. Even with treatment, more than 90% of patients have their tumors recur. In this study, "Fibrotic Response to Anti-CSF-1R Therapy Potentiates Glioblastoma Recurrence," Professor Joyce and her team sought to understand the mechanisms behind GBM recurrence and how to improve existing therapies. Using a mouse model of GBM as their starting point, the team first noticed that all GBM treatments they tested were associated with fibrosis – a type of scarring – in the brain. Notably, all recurrent tumors were found immediately adjacent to these fibrotic scars; high-plex protein analysis indicated these scars contained dormant tumor cells that the researchers believe act as seeds for GBM recurrence. They next used Chromium Single Cell Gene Expression to characterize cell populations in fibrotic scars at several time points post-treatment, then turned to single cell spatial transcriptomics with Xenium In Situ to reveal the location of cells within the scars. "Assessing how the glioblastoma microenvironment responded to treatment was extremely challenging, because the spatial localization of all the cell types was so important," said Dr. Spencer Watson, co-first author and postdoctoral fellow in the Joyce lab at the University of Lausanne. "We generated very rich datasets: mass-spec proteomics, HIFI digital pathology and Chromium single cell RNA-seq. But what made all these disparate data so powerful was integrating them all together with Xenium single cell spatial transcriptomics. This allowed us to analyze the biology holistically, in ways that no single technique could do on its own." Normally, T cells act to kill cancer cells. However, the data they generated using Xenium showed that while T cells interacted with GBM tumor cells throughout the tissue, the T cells inside fibrotic scars were much more likely to be exhausted (e.g. non-functional). This raised the possibility that these scars not only contained residual tumor cells but helped protect them from immune recognition, acting like a reservoir for GBM recurrence and presenting a potential therapeutic target. Combining Xenium and Chromium, the researchers found that genes associated with the formation of these scars were highest in one specific cell type: pericyte-derived fibroblast-like cells. Focusing on these cells, they identified two critical pathways linked to scar formation that spiked seven days post-treatment, but dropped back down after fourteen days, suggesting therapeutic relevance for inhibiting fibrotic scar formation. Using Chromium to narrow down potential druggable targets, the Joyce lab created a three-drug treatment regimen consisting of a CSF-1R inhibitor and two different drugs inhibiting scar formation. Over long-term preclinical trials, these drugs had little effect when administered separately. When combined, however, these treatments led to a dramatic increase in survival in mice, with only 1 in 18 mice experiencing tumor recurrence over the several-month-long trial – a vast improvement compared to conventional treatments. Professor Joyce said, "Strategies such as these to limit fibrotic scarring could significantly improve outcomes for GBM patients receiving surgical, radiation, or macrophage-targeting therapies; this is an area of active investigation in my lab." Ben Hindson, Co-Founder and Chief Scientific Officer of 10x Genomics, said, "This paper by Watson, Zomer, Joyce, and colleagues is a powerful example of how integrating Xenium single cell spatial and Chromium scRNA-seq can completely reshape our understanding of cancer dynamics. Seeing not just how cancer develops, but where and in what context, enabled these researchers to develop a potential therapy in their preclinical work by leveraging the strengths and synergies of different technologies to generate insights that simply aren't possible with a single platform. Advances like these are why we continuously drive innovation to help researchers move science forward." To learn more about the study, read the full article. About 10x Genomics 10x Genomics is a life science technology company building products to accelerate the mastery of biology and advance human health. Our integrated solutions include instruments, consumables and software for single cell and spatial biology, which help academic and translational researchers and biopharmaceutical companies understand biological systems at a resolution and scale that matches the complexity of biology. Our products are behind breakthroughs in oncology, immunology, neuroscience and more, fueling powerful discoveries that are transforming the world's understanding of health and disease. To learn more, visit 10xgenomics.com or connect with us on LinkedIn or X (Twitter). Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 as contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, which fall under the "safe harbor" provisions of those sections. All statements, other than statements of historical facts, may be forward-looking statements. Forward-looking statements generally can be identified by the use of forward-looking terminology such as "may," "might," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplate," "believe," "estimate," "predict," "potential" or "continue" or variations of them or similar terminology, but the absence of these words does not mean that a statement is not forward-looking. These forward-looking statements include statements regarding 10x Genomics, Inc.'s ("10x Genomics") product performance, configuration, capabilities and potential applications, including potential applications of findings powered by 10x Genomics products. These statements are based on management's current expectations, forecasts, beliefs, assumptions and information currently available to management, and actual outcomes and results could differ materially from these statements due to a number of factors. Other risks and uncertainties that could affect 10x Genomics' financial and operating results and cause actual results to differ materially from those indicated by the forward-looking statements made in this press release include those discussed under the captions "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" and elsewhere in the documents 10x Genomics files with the Securities and Exchange Commission (the "SEC") from time to time. Although 10x Genomics believes that the expectations reflected in the forward-looking statements are reasonable, it cannot provide any assurance that these expectations will prove to be correct nor can it guarantee that the future results, levels of activity, performance and events and circumstances reflected in the forward-looking statements will be achieved or occur. The forward-looking statements in this press release are based on information available to 10x Genomics as of the date hereof, and 10x Genomics disclaims any obligation to update any forward-looking statements provided to reflect any change in its expectations or any change in events, conditions or circumstances on which any such statement is based, except as required by law. These forward-looking statements should not be relied upon as representing 10x Genomics' views as of any date subsequent to the date of this press release. Disclosure Information 10x Genomics uses filings with the Securities and Exchange Commission, our website (), press releases, public conference calls, public webcasts and our social media accounts as means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Contacts Investors: [email protected] Media: [email protected] SOURCE 10x Genomics, Inc.

2024-09-03

·医药观澜

近三年至少6款中国新药获FDA突破性疗法认定，5款治疗癌症！来自先声药业、信达生物、翰森制药等

▎药明康德内容团队报道 9月2日晚间，先声药业宣布其合作开发的一款心脑血管治疗新药产品获得了美国FDA授予的突破性疗法认定。突破性疗法认定（breakthrough therapy designation）是FDA加速药品研发和审评的重要审评程序，主要适用于治疗严重或危及生命的疾病的突破性创新药物。获得这一认定意味着FDA对其治疗潜力的认可，有望加快研发进程。由于突破性疗法认定强调对现有疗法在临床安全性和疗效方面的突破性，需在临床数据上展现出绝对优势和突破，因此通过申请难度较大。根据即刻药数数据库，近三年来（2022~2024年至今）获得FDA突破性疗法认定的中国公司研发的新药至少有6款（不完全统计，不包括仅引进中国权益的国际新药产品）。本文将根据公开资料，梳理这6款新药的研发进展，看看它们在临床上的突破性，以及有望为哪些疾病患者带来希望。图片来源：123RF 先声药业、宁丹新药：依达拉奉右莰醇舌下片作用机制：脑细胞保护剂适应症：急性缺血性脑卒中（AIS） 2024年9月，先声药业宣布与宁丹新药合作开发的先必新®舌下片（依达拉奉右莰醇舌下片）获FDA突破性疗法认定，用于治疗急性缺血性脑卒中（AIS）。依达拉奉右莰醇舌下片是一种脑细胞保护剂，含依达拉奉和右莰醇两种活性成分，具有抗氧化、抗炎和协同增效作用，能够显著减少AIS导致的脑细胞损伤。该药还具有独特的舌下片配方，有望增加卒中治疗方式的灵活性。2023年6月，该产品在中国的上市申请已经获NMPA受理，首个适应症为用于改善AIS所致的神经症状、日常生活活动能力和功能障碍。根据先声药业新闻稿，本次突破性疗法认定是基于依达拉奉右莰醇舌下片在前期临床研究中展现的显著疗效指标改善。一项在中国进行的治疗AIS多中心3期临床研究数据显示，相较于安慰剂，该舌下片显著改善AIS患者治疗后神经功能恢复及独立生活能力，达到预期疗效终点，且安全性良好。2024年2月，《美国医学会杂志·神经病学》（JAMA Neurology）在线发表了该研究的主要结果。翰森制药、GSK：HS-20093 作用机制：B7-H3靶向抗体偶联药物（ADC）适应症：小细胞肺癌 2024年8月，翰森制药和葛兰素史克（GSK）宣布，FDA授予HS-20093 （GSK5764227）突破性疗法认定，用于治疗在含铂化疗期间或之后进展的复发或难治性广泛期小细胞肺癌（ES-SCLC）患者。HS-20093是一款B7-H3靶向抗体偶联药物（ADC），翰森制药此前与GSK订立一项超17亿美元的独家许可协议，授予GSK全球独占许可（不含中国内地、香港、澳门及台湾地区），以开发、生产及商业化该产品。根据翰森制药此前新闻稿介绍，本次FDA突破性疗法的认定得到了翰森制药正在推进的1期ARTEMIS-001首次人体临床试验的数据支持。该试验评估了HS-20093用于局部晚期或转移性实体瘤（包括复发或难治性ES-SCLC）的安全性、耐受性和初步抗肿瘤活性。根据研究者按照RECIST 1.1标准评估的结果，客观缓解率（ORR）为30.0%，疾病控制率为86.0%。在小细胞肺癌受试者中，ORR为63.6%。该产品目前已经进入针对复发性小细胞肺癌的国际多中心3期临床研究（ARTEMIS-008）。迪哲医药：舒沃替尼作用机制：EGFR-TKI 适应症：非小细胞肺癌 2024年4月，迪哲医药宣布，FDA授予其首款自主研发的新型肺癌靶向药舒沃替尼片突破性疗法认定，用于一线治疗携带表皮生长因子受体（EGFR）20号外显子插入（exon20ins）突变的晚期非小细胞肺癌（NSCLC）患者。该产品此前已于2022年获FDA授予突破性疗法认定，用于经治EGFR exon20ins突变型晚期NSCLC。舒沃替尼片是一款口服、不可逆、针对多种EGFR突变亚型的高选择性EGFR-TKI，首个适应症于2023年8月获NMPA批准上市，用于经治EGFR exon20ins突变型晚期NSCLC。舒沃替尼片针对该适应症的中国注册临床研究“悟空6”数据在国际期刊《柳叶刀· 呼吸医学》发表。经独立影像评估委员会（IRC）确认的客观缓解率（ORR）高达61%，突破现有治疗瓶颈。而舒沃替尼片单药一线治疗EGFR exon20ins突变型晚期NSCLC的2期临床研究经确认的ORR达78.6%。目前，迪哲医药正在推进“悟空28”3期国际多中心研究，旨在评估舒沃替尼对比含铂双药化疗一线治疗EGFR exon20ins NSCLC的疗效和安全性。艾力斯医药：伏美替尼作用机制：第三代EGFR-TKI 适应症：非小细胞肺癌 2023年10月，艾力斯医药宣布其合作伙伴ArriVent Biopharma获得FDA授予伏美替尼突破性疗法认定，用于一线治疗非鳞状NSCLC且伴有EGFR 20号外显子插入突变患者。伏美替尼是第三代EGFR-TKI，已在中国获批两项适应症，包括经治EGFR T790M突变阳性的NSCLC成人患者、一线治疗EGFR外显子19缺失或外显子21（L858R）置换突变的局部晚期或转移性NSCLC成人患者。根据艾力斯医药此前新闻稿，本次突破性疗法认定是基于1b期FAVOUR临床研究的中期分析结果，EGFR 20号外显子插入突变NSCLC初治患者中的确认ORR和中位缓解持续时间（mDoR）分别达到78.6%及15.2个月。目前，伏美替尼针对该一线治疗适应症的关键3期注册临床FUVENT研究正在全球积极入组。和誉医药：pimicotinib 作用机制：CSF-1R抑制剂适应症：腱鞘巨细胞瘤 2023年1月，和誉医药宣布pimicotinib（ABSK021）被FDA授予突破性疗法认定，用于治疗不可手术的腱鞘巨细胞瘤。Pimicotinib是和誉医药自主研发的一款全新的口服、高选择性、高活性CSF-1R小分子抑制剂。根据和誉医药此前新闻稿，此次突破性治疗药物认定是基于pimicotinib在治疗腱鞘巨细胞瘤患者的临床1b期试验中取得的积极研究结果。在该研究中，pimicotinib以68.0%的初步总缓解率（ORR）展现出显著的抗肿瘤疗效，而一年长期随访更新数据显示，在50 mgQD队列中，ORR达到87.5%（28/32，包括3例CR）。 Pimicotinib目前正在处于针对腱鞘巨细胞瘤（TGCT）适应症的全球多中心3期临床研究阶段。其针对腱鞘巨细胞瘤适应症还于2023年12月获得FDA授予的快速通道资格。此外，和誉医药已经与德国默克（Merck KGaA）达成独家许可协议，授予其在中国大陆、香港、澳门和台湾地区针对pimicotinib就所有适应症进行商业化的许可。信达生物/葆元医药：他雷替尼胶囊作用机制：新一代ROS1酪氨酸激酶抑制剂（TKI）适应症：非小细胞肺癌 2022年8月，葆元医药（已被Nuvation Bio公司收购）宣布在研ROS1抑制剂他雷替尼获得FDA突破性疗法认定，用于治疗既往未经ROS1-TKI治疗或既往接受过克唑替尼治疗的晚期或转移性ROS1阳性NSCLC成人患者。根据葆元医药此前新闻稿，FDA本次突破性疗法认定是基于多项1期和2期临床研究，在67名患ROS1融合阳性非小细胞肺癌且既往未经ROS1-TKI治疗的患者中，确认的客观缓解率（cORR）和疾病控制率（DCR）分别92.5%和95.5%；在38名可评估的既往经克唑替尼治疗的患者中，cORR和DCR分别为50%和78.9%。目前，信达生物与葆元医药共同负责他雷替尼在大中华区的开发和商业化。他雷替尼针对上述两项适应症上市申请均已经被NMPA纳入优先审评。根据信达生物2024半年报告介绍，该产品有望于今年下半年在中国迎来获批上市。希望这些在研新药后续研发顺利进行，早日为更多的患者带来新的治疗选择。参考资料： [1]各公司官网及公开资料本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

突破性疗法快速通道临床3期优先审批

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