An Open Label, Randomised Phase 2 Study to Evaluate the Safety and Efficacy of MTL-CEBPA Administered in Combination With Sorafenib or Sorafenib Alone in TKI naïve Participants With Previously Treated Advanced Hepatocellular Carcinoma (HCC) and Hepatitis B or Hepatitis C Virus (OUTREACH2)

This is a Phase II study in patients with advanced liver cancer (hepatocellular carcinoma) as a result of hepatitis B and/or C infection. Participants will be dosed with either MTL-CEBPA (an experimental treatment) and sorafenib or sorafenib alone. The MTL-CEBPA is administered once every 3 weeks via intravenous infusion. Sorafenib is taken orally from Day 8 for the combination group or Day 1 for the sorafenib alone group at a dose of 400 mg twice a day. Participants will receive 3 week cycles of treatment until disease progression, unacceptable toxicity, withdrawal of consent or death occurs. The combination of MTL-CEBA and sorafenib combination of treatment was tested in a previous Phase I study (OUTREACH) which showed anti-tumour activity along with a good safety and toxicity profile.

开始日期2022-01-01

申办/合作机构

Mina Alpha Limited

NCT05097911 / Recruiting临床1期

A Phase 1 Study of RNA Oligonucleotide, MTL-CEBPA, Atezolizumab and Bevacizumab in Patients With Advanced Hepatocellular Carcinoma Without Previous Systemic Therapy.

This is a single-center, phase 1, open label, dose-escalation study of MTL-CEBPA co-administered with atezolizumab and bevacizumab to assess the PK, PD, and potential toxicities of the drug combination in advanced HCC patients, and to determine the MTD, OBD or RP2D. The sample size employed is a minimally modified standard 3+3 cohort model commonly used in Phase I oncology studies. Once determined, the MTD/OBD/RP2D will be administered to an Expansion Cohort (Phase Ib) of 10 additional patients with advanced HCC.

开始日期2021-08-02

申办/合作机构

National University Hospital

NCT04105335 / Active, not recruiting临床1期

An Open Label Phase 1a/b Study of MTL-CEBPA in Combination With a PD-1 Inhibitor (Pembrolizumab) in Adult Patients With Advanced Solid Tumours

This is an open label Phase 1a/1b study in patients who have advanced solid cancer tumours. Patients will receive MTL-CEBPA (an experimental drug) in combination with pembrolizumab (a drug which has been given approval for use for some tumour types).
The Phase 1a dose escalation part of the study is designed to establish which doses of MTL-CEBPA are safe and well-tolerated when combined with the standard dose of pembrolizumab. Patients recruited to this part of the study will be those whose cancer progressed on standard treatment(s) or for whom no treatments are available.
Phase 1b the dose expansion part of the study will further explore how safe and well-tolerated these two drugs are when combined and will assess if the combination of drugs could potentially reduce the size of tumours. Participants in this part of the study will receive the experimental drug (MTL-CEBPA) at a dose which is considered safe and well-tolerated based on data from the first part of the study (Phase 1a). Participants will remain in the study taking study drugs until either death, or they choose to withdraw from the study.

开始日期2019-11-13

申办/合作机构

Mina Alpha Limited

100 项与 MTL-CEBPA 相关的临床结果

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100 项与 MTL-CEBPA 相关的转化医学

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100 项与 MTL-CEBPA 相关的专利（医药）

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项与 MTL-CEBPA 相关的文献（医药）

2021-11-01·Clinical Cancer Research1区 · 医学

Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer

1区 · 医学

Article

作者: Pinato, David J. ; Raulf, Nina ; Sarker, Debashis ; Palmer, Daniel ; Elasri, Naouel ; Sanseviero, Emilio ; Kossenkov, Andrew ; Meyer, Tim ; Habib, Nagy A. ; Cobbold, Mark ; Ma, Yuk-Ting ; Rossi, John J. ; Pai, Madhava ; Sharma, Rohini ; Reebye, Vikash ; Andrikakou, Pinelopi ; Huang, Kai-Wen ; Evans, Jeff ; Sodergren, Mikael H. ; Martirosyan, Anna ; Khan, Shahid ; Gabrilovich, Dmitry I. ; Spalding, Duncan ; Chee, Cheng E. ; Vasara, Jenni ; Jarvis, Sheba ; Habib, Robert ; Reynaud, Adeline ; Hashimoto, Ayumi ; Basu, Bristi ; Plummer, Ruth

AbstractPurpose:To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models.Experimental Design:We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38).Results:MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC–targeted immunotherapy.Conclusions:This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

2020-08-01·Clinical Cancer Research1区 · 医学

MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial

1区 · 医学

Article

作者: Dorman, Stephanie ; Huber, Hans E. ; Glenny, Helen ; Rossi, John J. ; Lloyd, Peter ; Evans, T.R. Jeff ; Andrikakou, Pinelopi ; Pai, Madhava ; Meyer, Tim ; Habib, Nagy ; Voutila, Jon ; Sarker, Debashis ; Sodergren, Mikael H. ; Huang, Kai-Wen ; Habib, Robert ; Saetrom, Pal ; Vasara, Jenni ; Wood, Chris ; Basu, Bristi ; Sharma, Rohini ; Palmer, Daniel H. ; Spalding, Duncan R.C. ; Nicholls, Joanna P. ; Ma, Yuk Ting ; Hunter, Sarah ; Nutbrown, Robert ; Kwatra, Vineet ; Felstead, Steve ; Chee, Cheng Ean ; Blakey, David C. ; Fairbairn, Sonia ; Collin, David ; Pinato, David J. ; Spicer, James ; Plummer, Ruth ; Reebye, Vikash

AbstractPurpose:Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α.Patients and Methods:We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design).Results:Thirty-eight participants have been treated across six dose levels (28–160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment–related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD.Conclusions:MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

2019-05-01·Molecular Therapy1区 · 医学

Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice

1区 · 医学

Article

作者: Reebye, Vikash ; Littman, Bruce H ; Pollock, Nicolette ; Li, Haitang ; Habib, Robert ; Sodergren, Mikael H ; Xia, Xin ; Huang, Kai-Wen ; Dorman, Stephanie ; Doogan, Declan ; Blakey, David ; Zhou, Jiehua ; Rossi, John J ; Habib, Nagy A ; Herrera, Alberto

Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines, and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli-derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance.

项与 MTL-CEBPA 相关的新闻（医药）

2024-04-19

·药智网

小核酸药物「再次出发」

小核酸药物，是近年来新药研发的重要类型之一。虽然，其分支ASO、siRNA正处于高产出阶段，但仍存在一些技术问题无法解决。有研究者将目光聚焦到激活机制的saRNA，以期寻求技术与领域的突破，并已有产品进入到临床开发。小核酸药物「再次出发」。01saRNA发现历史&技术特点最早提出激活RNA的概念，可追溯到上世纪60年代，有研究者认为存在一类只分布于细胞核的RNA，可与受体基因结合，形成序列特异性复合物并诱导相关基因转录对应的RNA。但在当时并未引起足够的重视。2006年，科学研究发现在p21、VEGF等多个基因的一定距离的转录起始点启动子区域设计短双链RNA（dsRNA），可上调相应靶基因的表达，并将这种具有靶向激活靶基因的短核苷酸双链命名为saRNA。saRNA，作为一类非编码RNA，结构类似于siRNA，但生物学功能完全相反。siRNA可以分别与AGO1、AGO2、AGO3和AGO4四种蛋白结合以获得活性，而saRNA只能被特异性地加载到AGO2蛋白行使功能。目前接受程度较高的RNAa基因调控模型为：1）外源性saRNA被加载到细胞质中的AGO2蛋白上；2）AGO2蛋白通过切割和丢弃其中一条RNA链，形成一个活性的AGO2-RNA复合物，并进入细胞核；3）AGO2-RNA复合物将结合到基因组DNA序列或DNA相连的反义转录本序列，进一步形成RNA诱导的转录激活复合物；4）该复合物与hnRNPs、RNAPⅡ和各种转录因子结合，诱导靶基因表达。图1 saRNA结构与作用机制图片来源：Molecular Therapy:Nucleic Acids Vol.31 March 202302saRNA药物设计相较于siRNA，saRNA技术的开发投入远不如siRNA广泛及具商业化特点的积累，目前有研究者提出如下序列设计原则：1）目标序列从靶基因的正义链序列上筛选；2）saRNA靶点选择在正义链转录起始位点上游-1200～-200 bp的区域；3）每个靶点长度的碱基数相对固定；4）靶点碱基的GC含量在40%～65%范围内；5）不能够出现连续4个以上相同的核苷酸；6）第19个碱基是A；第18个碱基是A或T，最好是A；第七个碱基最好是T；第20-23个碱基最好是A或T；7）选择目标序列时避开易受DNA甲基化影响的位点。类似于siRNA，saRNA同样可能引发脱靶效应，即以序列特异性或非序列特异性的方式诱发非预期的基因活性。为了避免序列特异性脱靶反应，所设计的序列还应该进行序列BLAST以避免与人类基因组其他核苷酸序列有显著同源性。另外，saRNA结构的修饰被证明可以阻断脱靶效应，这部分的工作进行的相对广泛。图2 特异性上调抑癌基因表达的saRNA序列图片来源：DOI:10.3781/j.issn.1000-7431.2019.55.49503saRNA抗肿瘤特点及主要品种saRNA，通过作用于基因调控序列的特异位点，诱导基因转录，这已经得到学者们的普遍认同，并成为新的肿瘤研究热点。这一点不同于早期的siRNA，以及ASO类药物。目前，技术较成熟的小核酸领域药物当属ASO和siRNA，但上述二者的获批适应症主要集中于遗传疾病、罕见病领域，众多已上市品种中，无肿瘤适应症获批。而saRNA开发的起点，即以肿瘤领域为主，这大不相同于“传统”小核酸药物，这也是其受关注的重点原因之一。如p21、p53等肿瘤领域著名靶基因及靶点，均为saRNA开发的方向内容。图3 激活寡核苷酸靶向肿瘤抑癌基因图片来源：Molecular Therapy:Nucleic Acids Vol.31 March 2023但由于saRNA药物开发仍处于早期阶段，目前进入临床的品种并不多。最具代表性的saRNA产品当属MTL-CEBPA，临床用于肝癌的治疗，目前最高临床阶段为II期。据文献报道，CEBPA是一种转录因子，可调节肝脏稳态，CEBPA表达下调与多种致癌过程有关。研究者将小鼠结肠癌细胞系CT26注射到对抗PD-1治疗敏感的小鼠中用以构建小鼠结直肠癌模型，然后注射MTL-CEBPA和PD-1抑制剂。MTL-CEBPA或PD-1抑制剂单独处理的动物肿瘤体积差异并无统计学意义，而同时注射PD-1抑制剂和MTL-CEBPA组的肿瘤体积明显小于对照组，说明MTL-CEBPA和PD-1抑制剂具有协同作用，且同时注射PD-1抑制剂和MTL-CEBPA的肿瘤组织CEBPA mRNA表达量更高（8.69倍，P＜0.0001）。另，同样可重点关注的品种还有我国国内开发的RAG-01，处于临床I期，是一款首创作用机制的特异性靶向激活肿瘤抑制基因p21的双链saRNA药物，通过RNAa机制激活p21基因的表达，以抑制肿瘤细胞增殖、诱导细胞凋亡和衰老。临床前药效研究表明，通过开发公司的小核酸递送系统，RAG-01的治疗能够显著抑制动物模型中膀胱癌肿瘤的生长，并展示充分的安全性。图4 全球范围开发的saRNA相关肿瘤靶点进展（文献举例）图片来源：Molecular Therapy:Nucleic Acids Vol.31 March 202304saRNA技术布局公司当前，基于saRNA技术进入临床的产品极少，从而对应的开发公司也相对不多。如上所述的MTL-CEBPA，原研单位为The University of Texas Southwestern Medical Center，其在药物研发领域的布局较广，技术类型涉及小分子化药、aav产品、RNA产品等，疾病领域集中于肿瘤和神经系统。另，MiNA Therapeutics公司的pipeline对MTL-CEBPA相关信息进行了重点介绍，具体如该品种的AACR年会公开信息、临床Ib期对实体瘤的联合治疗、单药用于肝癌治疗的I期临床等。图5 MiNA Therapeutics聚焦的疾病领域与开发项目图片来源：https://minatx.com/pipeline/#section_three值得一提的是，RAG-01的开发公司中美瑞康，其技术重点布局于saRNA，在国内以及国外均处于领先地位。其研发管线聚焦于目前尚无靶向治疗药物的疾病，包括单基因遗传病（例如基因突变导致的单倍体剂量不足）。对于这些疾病，RNA激活通过增强转录来补偿或消除基因活性的损失。借助于全球领先的SCAD™，LiCO™，和GLORY™递送平台技术，中美瑞康布局了多样化的管线项目，涵盖中枢神经系统、神经肌肉、眼科、肝脏和肿瘤等疾病治疗领域。图6 中美瑞康-pipeline图片来源：https://cn.ractigen.com/pipeline/05结语新技术的开发与推进，是新药领域前进的要素之一，saRNA无疑满足这一点，尤其是从基因治疗的角度来看。RNA激活技术在存在较大潜力的同时，同样存在着诸多问题，如不成熟的激活序列筛选、稳定性较差的人工合成saRNA、目标基因的激活效果不佳、不同细胞调控方式的差异性、很难满足肿瘤组织长周期的抑制作用等等。但上述存在的技术问题很难阻止saRNA的开发与发展，且已有显著的研究成果产生，并获得资本方的认可。未来几年，该领域很大可能会快速产出部分产品，但更期待的无疑是最终的临床数据。参考资料：1.中国血液流变学杂志.2022;32(1).doi:10.3969/j.issn.1009-881X.2022.01.0352.Molecular Therapy:Nucleic Acids Vol.31 March 2023.doi.org/10.1016/j.omtn.2022.12.016.3.TUMOR Vol.39,January 2019.DOI:10.3781/j.issn.1000-7431.2019.55.4954.Journal of Chinese Oncology,2019,Vol.25,No.9.doi：10.11735/j.issn.1671-170X.2019.09.B0125.https://cn.ractigen.com/about-us/6.https://cn.ractigen.com/pipeline/7.https://minatx.com/声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 金银花转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

siRNA寡核苷酸核酸药物

2024-01-24

·BioSpace

MiNA Therapeutics Presents New Data for its HbF Program at the Keystone Symposia’s Delivery of Nucleic Acid Therapeutics Conference

Pre-clinical studies confirm in vivo delivery of small activating RNA therapeutics to erythroid progenitor cells at clinically meaningful levels Compelling pre-clinical data supports advancement of MiNA’s HbF program for development in sickle cell disease and beta thalassemia LONDON--(BUSINESS WIRE)-- MiNA Therapeutics Limited, the pioneer in small activating RNA (RNAa) therapeutics, announced today that it will present new pre-clinical data for its lead RNA activation program targeting fetal hemoglobin (HbF) at the Keystone Symposia’s Delivery of Nucleic Acid Therapeutics Conference in Banff, Alberta, Canada. Pre-clinical studies confirmed in vivo delivery of MiNA’s RNAa therapeutics to erythroid progenitor cells in bone marrow at levels that are clinically meaningful for the treatment of beta-hemoglobinopathies. The data will be presented on January 24, 2024, at 7:30 pm MST during a poster presentation. MiNA’s HbF program is designed to increase transcription of the gamma globin (HBG) gene, enabling patients with beta-hemoglobinopathies to produce enhanced levels of HbF. HbF is a compensatory form of hemoglobin which has the potential to achieve a functional cure in patients with severe inherited blood disorders such as sickle cell disease and beta thalassemia. “These results demonstrate for the first time efficient in vivo delivery of RNAa therapeutics to erythroid progenitor cells with a delivery technology that is well-suited for safe and effective treatment in the clinic,” said Robert Habib, CEO of MiNA Therapeutics. “We are excited by this compelling evidence, which strongly supports advancement of our lead program for the treatment of sickle cell disease and beta thalassemia, which together affect more than five million people around the world.” MiNA’s HbF program uses a liposomal delivery technology, NOV340, which efficiently delivers RNAa therapeutics in vivo without the need for harmful pre-conditioning or complex cell engineering. NOV340 formulations have established safety and pharmacodynamic activity in clinical trials involving more than 290 patients, including 130 patients treated with MiNA’s first RNAa development candidate, MTL-CEBPA. MiNA anticipates advancing its HbF program, the first program to emerge from its genetic medicine portfolio, into pre-clinical development in 2024. In the presentation, entitled “NOV340 Liposome Encapsulating Nucleic Acid Payload Achieves Efficient Biodistribution to Erythroid Progenitor Cells,” data from animal models confirmed in vivo delivery to erythroid progenitor cells at levels that met accepted benchmarks for impactful treatment of beta-hemoglobinopathies. In non-human primates, intravenous administration of encapsulated liposomes resulted in delivery of MiNA’s RNAa compound to over 60% of committed colony-forming unit erythroid (CFU-E) cells and pro-erythroblasts (Pro-E) in bone marrow. Equivalent levels of delivery efficiency were observed in peripheral blood monocytes, a cell type in which pharmacodynamic activity of NOV340-formulated RNAa therapeutics has previously been shown in clinical studies. Following the symposia, the poster detailing full study results will be available on the MiNA website: . MiNA has previously achieved clinical proof of concept for its RNAa therapeutics platform with MTL-CEBPA. MiNA is exploring out-licensing opportunities for MTL-CEBPA and its immuno-oncology portfolio, which uniquely combines the capability to specifically restore or boost any dysregulated gene target with clinically validated in vivo delivery to myeloid immune cells. About MiNA Therapeutics MiNA Therapeutics is the global leader in small activating RNA therapeutics or RNAa. Harnessing innate mechanisms of gene activation, RNAa therapeutics are a revolutionary new class of medicines that can restore or boost normal function of genes and thereby protein-modulated pathways in cells. We are advancing a proprietary pipeline of new medicines with an initial focus on genetic medicine, while collaborating with leading pharmaceutical companies to apply our technology platform across a broad range of other therapeutic areas. Based on our unique know-how in RNA activation, we are expanding the possibilities of RNA-based medicine. .

siRNA

2023-11-05

·E药经理人

企业家、科学家、投资家共议核酸药物创新方向：适应证局限如何突破？关键在递送？

有数据统计，国内共有20 款小核酸药物研发进入临床研究阶段，但这些药物多集中在早期，并且适应证仍然是罕见病类适应证。国内企业如何突破适应证局限？突破的关键在哪？还有哪些领域可以拓展？中国药企的核酸药物研发如何构建成功的专利递送技术？由中国医药企业管理协会、中国医药生物技术协会、杭州市投资促进局、杭州市临平区商务局主办，E药经理人、中国医疗健康产业投资50人论坛承办的2023’第十五届中国医药企业家科学家投资家大会于11月1日到3日在杭州隆重召开。11月3日，在Cytiva思拓凡支持的核酸药物创新论坛上，由启辰生生物首席医学官王立峰主持，建银国际医疗成长基金总经理林雷、北京大学医学部药学院教授杨振军、Cytiva中国核酸工艺流程经理阮乾坤、头豹研究院咨询总监曹梦云、中美瑞康首席战略官谢文凯、瑞博生物高级副总经理兼CSO高山围绕核酸药物技术创新、产业化、国际化以及未来发展等话题进行了主题展示，并与在场嘉宾进行了交流与讨论。启辰生生物首席医学官王立峰建银国际医疗成长基金总经理林雷发表《核酸药物的产业形势与投资机会》主题报告北京大学医学部药学院教授杨振军发表《抗肝癌核酸药物新型制剂研发》主题报告Cytiva思拓凡核酸工艺流程经理阮乾坤发表小核酸药物产业化挑战以及解决方案头豹研究院咨询总监曹梦云讲了《核酸药物的技术突破与行业趋势》中美瑞康首席战略官谢文凯讲了《基于化学缀合的小核酸肝外递送技术》瑞博生物高级副总经理兼CSO高山讲基于RIBO-GalSTARTM平台的RNAi药物开发左右滑动查看更多中国药企突破新方向前不久，辉瑞发布了2023年三季度财报，其中对于新冠疫苗的全年销售额下调了约20%，这让业内产生了一个怀疑，mRNA疫苗所带来的核酸领域的辉煌是否只是“昙花一现”，毕竟，除了新冠疫苗外，截至今年上半年，全球16款获批上市的核酸类产品中仅有2016年上市的诺西那生钠突破了十亿美元大关，核酸类产品的市场前景到底如何？核酸类药物主要分为小核酸药物和mRNA药物两大类，公开信息显示，全球目前共有16款小核酸类药物获批上市（3款已退市），包括10款ASO药物、5款siRNA药物和1款核酸适配体药物。不过，目前罕见病仍然是小核酸药物的主要“战场”，据统计，遗传病作为适应证的核酸药物在全球已获批上市核酸药物中占比高达54.5%，其余适应证主要为眼科类疾病、传染性疾病和心血管疾病。一位与会嘉宾认为，核酸类药物相较于细胞治疗、基因治疗等新兴疗法是最具前景的药物研发领域。一方面因为细胞与基因治疗由于制备成本与产能限制，目前仍无法突破价格高昂的难题；另一方面，相较于后者，核酸类药物的安全性也更高，目前核酸药物主要使用的LNP（脂质纳米颗粒）递送系统帮助核酸药物实现靶向性，同时提升药物的安全性。不过无论是已经有10款产品上市、探索较为成熟的ASO药物，还是仍在探索过程中的siRNA药物、mRNA类药物，都存在尚未突破的技术难题。例如小核酸药物在mRNA水平上实现对疾病的治疗，具有多重优势，但同时存在较严重的脱靶效应；而mRNA类mRNA药物可应用于多个治疗领域，优势显著，但mRNA分子存在稳定性差、易被降解的问题。与会嘉宾介绍，ASO药物安全性好、成药性好，技术稳定，可延展性强，但半衰期较短，在药效上有很大提升空间；siRN A药物活性高于ASO，但安全性、脱靶效应等问题不如ASO成熟，并且很依赖好的递送系统 (Galnac)。值得注意的是，一位与会嘉宾介绍，与siRNA作用机制“相反”的小激活RNA（saRNA）类药物称为核酸类药物探索的新方向，在序列选择和递送方式上，与siRNA类似，都是通过与目标核酸的结合而发挥作用，但作用机制却恰恰相反，saRNA最终会激活基因表达，同时saRNA具有结构小，递送更简单的优势。目前全球进展较快的saRNA仍然在临床阶段，国外公司MiNA的MTL-CEBPA用于治疗晚期肝癌。此外，来自中国的biotech中美瑞康也是全球为数不多的研发saRNA药物的公司，RNA 激活（RNAa）机制就是由该公司的创始人李龙承及其团队首次发现并命名。核酸药物开发的“最后一公里”不过，核酸药物整体的难题仍然是药物递送，一位与会嘉宾将药物递送难题称为核酸药物开发的“最后一公里”。这也是目前核酸药物的适应证局限在肿瘤和遗传病的原因，据统计，小核酸药物针对的遗传病大多为一些罕见病，如遗传性血管性水肿、亨廷顿病、先天性厚甲症等。一位嘉宾直言，“递送取得怎样的突破，核酸药物研发就会取得什么样的突破。”在技术层面，对于小核酸药物来说，按照研发工序，小核酸药物的核心技术分为RNA设计、化学修饰、递送、合成及制剂技术，其中，最关键的核心技术是小核酸药物递送技术，主要利用载体提高核酸药物生物学活性，改善体内分布，提高靶组织药物浓度和生物利用度。主要分为脂质类纳米递送系统、聚合物递送系统、核酸偶联递送系统、外泌体递送系统等。与会嘉宾解释，递送技术需通过优化合成设计以解决递送系统自身毒性及易聚集和泄露等问题。而对于mRNA药物来说，其核心技术是成功的序列修饰和递送系统组装，选择合适的递送系统以提升合成mRNA的稳定性及其递送效率是该领域研究的热点问题。此外，小核酸药物生产对配套设备、工艺放大、符合GMP等生产环境的要求也非常高，对于大多数小核酸药物管线而言，高效、快速的合成生产是难以避开的挑战。一位嘉宾介绍，生命科学技术服务的作用也非常关键，小核酸药物研发公司需要生命科学技术服务商提供的从上游合成到制剂罐装更快速、高质量的多种解决方案。最后，上述多位嘉宾围绕“核酸药物持续创新的未来之路” 进行了圆桌讨论。核酸药物的突破不能从某一方面单独考量，在产业全链条上还有很长的路要走，例如修饰技术和递送技术的关系，“再好的修饰也是基于好的体内递送系统。”此外，与会嘉宾们还表达了对行业的信心，未来五年，中国的核酸行业会有多款药物获批，迎来飞跃式发展。预告2024年第十六届中国医药企业家科学家投资家大会开启合作预约联系人：尹老师电话：13716707405登记邮箱信息订阅E药经理人信息服务扫描二维码精彩推荐CM10 | 集采 | 国谈 | 医保动态 | 药审 | 人才 | 薪资 | 榜单 | CAR-T | PD-1 | mRNA | 单抗 | 商业化 | 国际化｜猎药人系列专题启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 医药界·E药经理人 | 中国医药手册创新100强榜单 | 恒瑞 | 中国生物制药 | 百济 | 石药 | 信达 | 君实 | 复宏汉霖｜翰森 | 康方生物 | 上海医药 | 和黄医药 | 东阳光药 | 荣昌 | 亚盛医药 | 齐鲁制药 | 康宁杰瑞 | 贝达药业 | 微芯生物 | 复星医药｜再鼎医药｜亚虹医药跨国药企50强榜单 | 辉瑞 | 艾伯维 | 诺华 | 强生 | 罗氏 | BMS | 默克 | 赛诺菲 | AZ | GSK | 武田 | 吉利德科学 | 礼来 | 安进 | 诺和诺德 | 拜耳 | 莫德纳 | BI | 晖致 | 再生元

核酸药物上市批准疫苗信使RNA财报

100 项与 MTL-CEBPA 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
结直肠癌	临床3期	英国	MiNA Therapeutics Ltd.	2019-09-20
乙型肝炎	临床1期	-	Mina Alpha Limited	2021-05-01
丙型肝炎	临床1期	-	Mina Alpha Limited	2021-05-01
肝细胞癌	临床1期	-	Mina Alpha Limited	2021-05-01
肝癌	临床1期	-	The University of Texas Southwestern Medical Center	-
肝癌	临床1期	-	Adhera Therapeutics, Inc.	-
肝癌	临床1期	-	The University of California, San Francisco	-
肝病	药物发现	英国	MiNA Therapeutics Ltd.	2018-02-21

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临床结果

适应症

分期

评价

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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


NCT02716012 (ASCO2018)	临床1期	肝癌	19	MTL-CEBPA	(範夢膚觸壓糧鹽膚艱顧) = one patient having an ongoing PR for 18 months associated with 73% decrease in tumour volume and reduction in IL-6, NF-κB and IFN-γ 襯醖廠鹽繭積壓繭齋鹽 (製築構鹽艱淵遞壓襯構 ) 更多	积极	2018-06-01
NCT04105335 (SITC2021) 人工标引	临床1期	实体瘤	10	MTL-CEBPA+pembrolizumab	(顧壓簾淵淵蓋鑰夢憲鹽) = 2AEs in 1 pt only were grade 3 (ALT and AST increases) 膚餘憲範壓鹹選衊鹽繭 (願鹽獵壓積淵齋鹽築夢 ) 更多	积极	2021-11-11
NCT02716012 (OUTREACH, Pubmed \| Clin Cancer Res) 人工标引	临床1期	肝癌	38	MTL-CEBPA	(膚夢製廠簾鬱醖衊鏇築) = 鹽鹹齋鏇顧構廠壓鏇膚艱網夢襯繭餘淵願膚壓 (壓艱鬱範襯製願襯鬱鏇 ) 更多	积极	2020-08-01
NCT04105335 (TIMEPOINT, Corporate Publications) 人工标引	临床1期	实体瘤 \| 肿瘤	50	pembrolizumab+MTL-CEBPA (dose escalation)	(醖鏇醖蓋選鑰構糧願積) = 膚襯淵簾鬱築夢繭醖遞觸夢簾鏇夢願鑰製繭窪 (鹽憲構遞選鬱衊壓糧鹽 ) 更多	积极	2022-11-12
NCT04105335 (TIMEPOINT, Corporate Publications) 人工标引	临床1期	实体瘤 \| 肿瘤	50	pembrolizumab+MTL-CEBPA (dose expansion)	(醖鏇醖蓋選鑰構糧願積) = 鏇淵膚鬱醖鏇鹽繭艱衊觸夢簾鏇夢願鑰製繭窪 (鹽憲構遞選鬱衊壓糧鹽 ) 更多	积极	2022-11-12