更新于：2024-07-05

Vidutolimod

更新于：2024-07-05

概要

研发状态

概要

基本信息

药物类型

寡核苷酸

别名

Immunodrug CYT003-QbG10、Virus-like particle-based cancer vaccine、VLP-based cancer vaccine

+ [14]

靶点

TLR9

作用机制

TLR9激动剂(Toll样受体9激动剂)、免疫调节剂

治疗领域

肿瘤皮肤和肌肉骨骼疾病免疫系统疾病+ [1]

在研适应症

转移性黑色素瘤不可切除的黑色素瘤三阴性乳腺癌+ [4]

非在研适应症

晚期癌症晚期非小细胞肺癌过敏性哮喘+ [23]

原研机构

Cytos Biotechnology AG

在研机构

Regeneron Pharmaceuticals, Inc.

Checkmate Pharmaceuticals, Inc.

Centre Hospitalier Universitaire Vaudois

非在研机构

Kuros Biosciences Ltd.

Arbutus Biopharma Corp.Cytos Biotechnology AG

+ [3]

最高研发阶段临床2/3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

序列信息

Sequence Code 29274250

来源: *****

关联

项与 Vidutolimod 相关的临床试验

NCT05445609 / Recruiting临床2期IIT

A Single Arm Study of Vidutolimod (CMP-001) With Nivolumab in Patients With Metastatic Castration Resistant Prostate Cancer

This phase II trial tests whether vidutolimod with nivolumab works to destroy tumor cells in patients with castration resistant prostate cancer that has spread to other places in the body (metastatic). Nivolumab is an antibody working by attaching to and blocking a molecule called PD 1. PD 1 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Antibodies (proteins in the immune system which act to stop infection harming the body) that block PD 1 can potentially prevent PD 1 from shutting down the immune system, thus allowing immune cells to recognize and destroy cancer cells. Vidutolimod (CMP-001) is a Toll-like receptor 9 (TLR9) agonist, with the ability to generate tumor-targeted T cells capable of killing a tumor both locally and systemically in combination with checkpoint inhibitors (nivolumab, in this case), thus potentially improving outcomes for people whose tumors are progressing. Giving nivolumab and vidutolimod may kill more cancer cells in patients with metastatic prostate cancer.

开始日期2023-06-07

申办/合作机构

Emory University

[+2]

NCT04916002 / Suspended临床2期

A Multicenter, Open-label, Phase 2 Study of Intratumoral Vidutolimod (CMP-001) in Combination With Intravenous Cemiplimab in Subjects With Selected Types of Advanced or Metastatic Cancer

The goal of this study is to learn if giving cemiplimab and vidutolimod together could be effective in treating advanced cancer. The main questions it aims to answer are:
How many participants' cancers respond to vidutolimod together with cemiplimab?
Is vidutolimod together with cemiplimab safe and well-tolerated?
How well does vidutolimod together with cemiplimab treat participants' cancer?
Participants will receive trial treatment for up to 2 years. 30 days after stopping treatment, participants will have a follow-up visit. After that visit, the trial staff will continue to follow up with participants about every 3 months, until the trial ends.

开始日期2021-11-30

申办/合作机构

Regeneron Pharmaceuticals, Inc.

NCT04708418 / Suspended临床2期IIT

Phase II Randomized Study of Neoadjuvant Pembrolizumab Alone or in Combination With CMP-001 in Patients With Operable Melanoma: Efficacy and Biomarker Study

This phase II trial studies the effect of pembrolizumab alone or in combination with CMP-001 in treating patients with melanoma that can be treated by surgery (operable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with CMP-001 may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. The addition of CMP-001 to pembrolizumab could improve the ability of the immune system to shrink tumors and to prevent them from returning.

开始日期2021-10-01

申办/合作机构

National Cancer Institute

100 项与 Vidutolimod 相关的临床结果

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100 项与 Vidutolimod 相关的转化医学

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100 项与 Vidutolimod 相关的专利（医药）

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109

项与 Vidutolimod 相关的文献（医药）

2024-01-01·Reviews in medical virology

Virus‐like particles as powerful vaccination strategy against human viruses

Review

作者: Almalki, Mohammed A ; Hadj Hassine, Ikbel ; Ben M'hadheb, Manel ; Gharbi, Jawhar

Abstract:

Nowadays, viruses are not only seen as causative agents of viral infectious diseases but also as valuable research materials for various biomedical purposes, including recombinant protein production. When expressed in living or cell‐free expression systems, viral structural proteins self‐assemble into virus‐like particles (VLPs). Mimicking the native form and size of viruses and lacking the genetic material, VLPs are safe and highly immunogenic and thus can be exploited to develop antiviral vaccines. Some vaccines based on VLPs against various infectious pathogens have already been licenced for human use and are available in the commercial market, the latest of which is a VLP‐based vaccine to protect against the novel Coronavirus. Despite the success and popularity of VLP subunit vaccines, many more VLPs are still in different stages of design, production, and approval. There are still many challenges that require to be addressed in the future before this surface display system can be widely used as an effective vaccine strategy in combating infectious diseases. In this review, we highlight the use of structural viral proteins to produce VLPs, emphasising their intrinsic properties, structural classification, and main expression host systems. We also compiled the recent scientific literature about VLP‐based vaccines to underline the recent advances in their application as a vaccine strategy for preventing and fighting virulent human pathogens. Finally, we presented the key challenges and possible solutions for VLP‐based vaccine production.

2023-12-01·Clinical colorectal cancer

Combination Treatment of Intratumoral Vidutolimod, Radiosurgery, Nivolumab, and Ipilimumab for Microsatellite Stable Colorectal Carcinoma With Liver Metastases

Article

作者: Golan, Talia ; Berger, Raanan ; Halpern, Naama ; Mauro, David ; Appel, Sarit ; Raskin, Stephen ; Urban, Damien ; Symon, Zvi ; Ben-Ayun, Maoz ; Lieberman, Sivan ; Margalit, Ofer ; Ackerstein, Aliza ; Yarom, Nirit ; Shulman, Katerina ; Lawrence, Yaacov R ; Redinsky, Ilanit ; Krieg, Art M ; Shacham-Shmueli, Einat ; Honig, Nir ; Halparin, Sharon ; Ben-Ami, Eytan ; Semenisty, Valeriya ; Purim, Ofer ; Boursi, Ben

INTRODUCTION:

Microsatellite stable metastatic colorectal cancer (MSS mCRC) is largely refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response.

PATIENTS AND METHODS:

In this phase I single-institution study, patients with MSS mCRC were treated with a priming dose of s.c vidutolimod, 3 intratumoral injections of vidutolimod and radiosurgery, combined with nivolumab and ipilimumab. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were accrued to 4 consecutive cohorts: (1) Safety run-in without radiosurgery, (2) Radiosurgery prior to intratumoral therapy, (3) Radiosurgery prior to intratumoral therapy with a condensed timeline, and (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy.

RESULTS:

A total of 19 patients were accrued. Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2-5). None of the patients responded, aside from 1 patient, attributed to high tumor mutational burden. Grade 3 liver toxicity was reported in 0%, 0%, 75%, and 17% in cohorts 1 to 4, respectively. Systemic levels of CXCL10 and IL-10 increased, with a median of 407 versus 78 pg/mL (P = .01), and 66 versus 40 pg/mL (P = .03), respectively.

CONCLUSIONS:

The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS mCRC with liver metastases. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with high hepatic toxicity.

2023-10-19·Viruses

Nano-Sized Chimeric Human Papillomavirus-16 L1 Virus-like Particles Displaying Mycobacterium tuberculosis Antigen Ag85B Enhance Ag85B-Specific Immune Responses in Female C57BL/c Mice.

Article

作者: Zhang, Dongmei ; Zhou, Fangbin

Bacillus Calmette-Guerin (BCG), the only current vaccine against tuberculosis (TB) that is licensed in clinics, successfully protects infants and young children against several TB types, such as TB meningitis and miliary TB, but it is ineffective in protecting adolescents and adults against pulmonary TB. Thus, it is a matter of the utmost urgency to develop an improved and efficient TB vaccine. In this milieu, virus-like particles (VLPs) exhibit excellent characteristics in the field of vaccine development due to their numerous characteristics, including but not limited to their good safety without the risk of infection, their ability to mimic the size and structure of original viruses, and their ability to display foreign antigens on their surface to enhance the immune response. In this study, the HPV16 L1 capsid protein (HPV16L1) acted as a structural vaccine scaffold, and the extracellular domain of Ag85B was selected as the M. tb immunogen and inserted into the FG loop of the HPV16 L1 protein to construct chimeric HPV16L1/Ag85B VLPs. The chimeric HPV16L1/Ag85B VLPs were produced via the Pichia pastoris expression system and purified via discontinuous Optiprep density gradient centrifugation. The humoral and T cell-mediated immune response induced by the chimeric HPV16L1/Ag85B VLP was studied in female C57BL/c mice. We demonstrated that the insertion of the extracellular domain of Ag85B into the FG loop of HPV16L1 did not affect the in vitro stability and self-assembly of the chimeric HPV16L1/Ag85B VLPs. Importantly, it did not interfere with the immunogenicity of Ag85B. We observed that the chimeric HPV16L1/Ag85B VLPs induced higher Ag85B-specific antibody responses and elicited significant Ag85B-specific T cell immune responses in female C57BL/c mice compared with recombinant Ag85B. Our findings provide new insights into the development of novel chimeric HPV16L1/TB VLP-based vaccine platforms for controlling TB infection, which are urgently required in low-income and developing countries.

项与 Vidutolimod 相关的新闻（医药）

2024-04-28

·BiG生物创新社

小核酸联合疗法：千亿慢病市场的下一站

从罕见病过渡到常见病，联合疗法是小核酸疗法开发的重要方向。作为第一款在常见慢性病上市的小核酸，Inclisiran（英克司兰）联合他汀治疗高脂血症已拥有完整证据链，且证据版图仍不断扩张。近期一项发表于JACC的荟萃分析，调取了迄今为止的最大规模研究数据，再次充分论证了英克司兰联合他汀或其他口服LLTs治疗具备良好的耐受性。在我国，去年发表的《小干扰RNA 降脂药物药学专家共识》也建议：对于经他汀类药物治疗血脂不达标或由于药物不良反应他汀类药物使用受限的患者，可选择 siRNA 英克司兰作为联合治疗方案。随着人口老龄化的加剧，慢病管理及用药需求有望持续扩容和爆发。全球慢性病管理市场。仅在 2019 年，这个市场就价值 3260 亿美元。以 7.2% 的复合年增长率计算，到 2023 年它可能达到 4900 亿美元。米内网数据显示，我国慢病用药市场也在2021年超过了4000亿元人民币。目前普遍认为，通过结合通过不同作用机制发挥作用的治疗药物，在慢病管理领域可能实现更多临床获益，包括提高疗效、克服耐药性和改善不良反应，最终实现提高实现疾病完全缓解和治愈的可能性。RNAi治疗药物的独特作用机制使其成为组合治疗的理想候选者。除了已上市的Inclisiran，小核酸在癌症、乙肝、高血压等治疗领域也在积极拓展联合治疗方式。学界和工业界正在临床前模型和临床试验中探索小核酸与各种其他类型药物的组合，例如，siRNA可以与抗体或其他小分子药物联合使用，以增强治疗效果或减少药物抵抗。此外，RNAi治疗还可以与其他治疗方法如基因治疗和基因编辑相结合，为患者提供更全面的治疗方案。01癌症：小核酸联用有望攻克耐药性问题癌症本质上具有高度异质性，并且在治疗时常常会产生药物耐药的情况，包括化疗、放射治疗和光动力治疗 (PDT)等等不同的治疗方式均可能会产生耐药性。近年来，癌症各类疗法与基于RNA疗法的联合使用为癌症靶向治疗打开了新的窗口，并引起了全世界研究人员的兴趣。基于siRNA 、适体、反义寡核苷酸等已被证明与药物相结合可有效克服癌症中的多重耐药性（MDR），有效减少对健康细胞的不必要损伤；一些还能表现出协同/组合抗癌作用，调控与肿瘤细胞生长、发育、转移扩散和耐药性相关的多种机制和调节蛋白，以达到更好的治疗效果。1、与化疗药物联合寡核苷酸与化疗药物联合的限制是可能会与血浆蛋白竞争性结合，这将导致与单独化疗药物相比，联合治疗的体内疗效降低。使用水溶性聚合物偶联物、纳米粒子、树枝状聚合物和脂质体的基于载体的联合药物递送系统被开发并得到应用，使用聚合物纳米粒子联合递送化疗药物和sirna已经显示出一些成功。Prexigebersen+decitabine+venetoclaxPrexigebersen（BP1001）是一种由中性脂质体包覆、具抗核酸酶特性、靶向Grb2 mRNA分子的反义寡脱氧核苷酸疗法。Grb2是一种衔接蛋白，可将致癌酪氨酸激酶与下游激酶（如ERK和AKT）联系起来，ERK和AKT对细胞增殖和存活至关重要。2023年8月，Bio-Path公司公布其在研反义寡脱氧核苷酸疗法prexigebersen联合地西他滨（decitabine）和venetoclax治疗急性髓系白血病（AML）2期试验第二阶段的中期数据。分析显示，该疗法的耐受性良好，在两个队列中显示显著优于目前一线疗法的疗效。在新确诊的AML队列中，该组合疗法达成86%的完全缓解（CR）。siG12D LODER+多种化疗药物siG12D-LODER是一种由可生物降解的聚合物基质包裹的针对KRASG12D的siRNA，临床研究表明，EUS引导下肿瘤内植入siG12D-Loder联合化疗，12例局部晚期胰腺癌患者接受治疗后，10例病情稳定，2例部分缓解，中位总生存时间为15.1个月，4例患者出现严重不良反应，说明该聚合物能够靶向肿瘤并抑制肿瘤进展。目前，诺华正在针对siG12D-LODER进行下一步的研究，以测试siG12D-LODER与化疗药物（如吉西他滨和紫杉醇）联合治疗局部晚期胰腺癌患者的疗效。Oblimersen sodium (Genasense, G3139)+多种化疗药物Oblimersen钠(Genasense™，G3139)是一种反义寡核苷酸，与Bcl-2 mRNA开放阅读框的前六个密码子杂交，导致Bcl-2 mRNA降解并诱导细胞凋亡。oblimersen联合化疗药物如卡铂、紫杉醇、多西他赛、伊立替康等治疗实体肿瘤已开展了较多临床试验。在I/II期试验中，转移性结直肠癌患者对oblimersen和前药伊立替康的联合耐受性良好；其中，1例患者出现部分缓解，另外10例患者病情稳定，持续2.5-10个月(NCT00004870)。此外，临床试验的安全性数据进一步支持oblimersen联合细胞毒性药物临床开发的可行性。OGX-011 (custirsen)+多西他赛/强的松OGX-011 (custirsen)是第二代反义聚集蛋白抑制剂。为了确定OGX-011的临床活性，一项随机II期研究多西他赛/强的松联合用药用于治疗转移性去势抵抗性前列腺癌患者。研究结果表明OGX-011和多西他赛治疗耐受性良好，且与生存率提高有关，因为OGX011可以通过增加肿瘤细胞对多西他赛的敏感性来增强肿瘤杀伤能力。因此，OGX-011也可能是去势抵抗性前列腺癌(CRPC)患者的一种新的治疗策略。Atu027+吉西他滨Atu027是一种被包裹在脂质纳米颗粒(LNP)中的siRNA药物，可以特异性靶向致癌靶点PKN3。临床试验结果表明，Atu027在晚期或转移性胰腺腺癌患者联合标准化疗药物吉西他滨(NCT00938574)时具有良好的安全性和活性。2、与免疫检查点抑制剂联合AZD9150 (Danvatirsen, ISIS 481464)+度伐利尤单抗AZD9150 (danvatersen, ISIS 481464)， 2.5代ASO，是STAT3的特异性抑制剂。与2.0代和以前的ASOs相比，2.5代ASOs具有更高的亲和性和更强的内在效力。AZD9150可以特异性抑制STAT3并诱导多种白血病细胞系凋亡。此外，AZD9150还通过抑制内源性STAT3和STAT3靶基因，降低成神经细胞瘤细胞的致瘤性，增加细胞的化学敏感性。在两项I期临床研究(NCT01563302和NCT01839604)中，AZD9150单药治疗诱导了免疫介导的抗肿瘤反应，表明AZD9150联合免疫检查点抑制剂治疗有望增强抗肿瘤免疫效能。Danvatirsen联合Durvalumab（抗PDL1单抗）在晚期实体瘤患者中显示出临床益处（NCT02983578），在CT26小鼠结肠直肠癌模型上进行的临床前研究显示，在治疗的肿瘤中，M-MDSC和G-MDSC的比例降低，NK细胞和T细胞的数量增加，联合用药组NK细胞的颗粒酶表达增加，导致NK细胞毒性增强。在另一项临床试验中（NCT02499328），与Duravulumab单药治疗或Duravulumab和AZD5069 （CXCR2抑制剂）治疗组相比，接受Durvalumab和Danvarrsen联合治疗的患者显示出更高的疗效。BO-112+帕博利珠单抗BO-112是一种由聚乙烯亚胺配制的双链合成RNA，模拟病毒感染。直接肿瘤注射时可以通过树突状细胞的激活、CD8 T细胞浸润的增加和干扰素的诱导，产生一种免疫原性细胞死亡。在2022美国癌症研究协会（AACR）年会上的一项2期临床试验数据显示：对于接受抗PD-1治疗后出现耐药的黑色素瘤患者，将BO-112与帕博利珠单抗（K药）联用显示出良好的有效性和安全性。Vidutolimod（CMP-001）+帕博利珠单抗Vidutolimod（CMP-001）是一种CpG-a寡核苷酸，包装在由噬菌体外壳蛋白Qβ形成的病毒样颗粒内。在临床前研究中，瘤内注射Vidutolimod已证明可诱导局部肿瘤消退，并限制了非靶向毒性。在最近公布的一项1b期临床研究（NCT02680184）中，评估了肿瘤内注射Vidutolimod联合pembrolizumab的疗效和安全性，显示出克服晚期黑色素瘤患者的PD-1抑制剂耐药性的潜力。2、与光动力疗法（PDT）联合光动力疗法（PDT）是一种无创且有效的局部癌症治疗方法，可对靶组织和细胞产生选择性损伤。然而，单独的PDT不太可能完全抑制肿瘤转移和/或局部肿瘤复发。PDT联合RNAi疗法抑制相关靶点一直是研究热点，其临床效果优于单一疗法。2021年9月，北京理工大学黄渊余课题组发表在在顶级期刊《ACS Applied Materials & Interfaces》上的“ROS-Activatable siRNA-Engineered Polyplex for NIR-Triggered Synergistic Cancer Treatment”，设计了一种聚乙二醇（PEG）修饰、ROS响应的阳离子聚合物PPTC，该阳离子聚合物可高效负载抗RRM2基因的siRNA药物，形成稳定、均一的PPTC/siRRM2纳米药物体系。RRM2是一种脱氧核糖核酸酶还原亚基，与多种癌症的发生发展密切相关，沉默RRM2可促进肿瘤细胞发生凋亡。该复合物进入到细胞后，在近红外光的照射下能有效降解聚合物、产生ROS，ROS可破坏内涵体膜、促进内涵体逃逸，同时破坏细胞膜使肿瘤细胞发生凋亡。而进入胞质的siRNA抑制RRM2的表达，可有效阻止癌细胞增殖，从而从“促凋亡、抑增殖”双角度实现协同抗肿瘤治疗。研究人员首先在肝癌细胞上转染该小核酸药物体系，激光共聚焦显微镜（Confocal）结果显示，该体系可高效进入到细胞中；且相比于未光照组，经光照处理后，siRNA的内涵体逃逸效率得到有效提高。生物电镜（BioTEM）的研究证明，该体系经光照后产生的ROS，可有效提高细胞膜通透性，并对肿瘤细胞进行杀伤。PPTC/siRNA在CDX和PDX肿瘤模型中的药效研究进一步，研究人员在小鼠上分别建立了肝癌细胞系异种移植的CDX模型和肝癌患者癌组织异种移植的PDX肿瘤模型。研究表明，在这两种肿瘤模型中，PPTC/siRNA药物体系均可有效抑制肿瘤生长，促进癌细胞凋亡。值得注意的是，数据证明该药物体系表现出良好的光动力与siRNA治疗协同效应，相比于单独使用siRNA或单独进行光照处理，二者联合可显著提高RRM2的基因沉默效率，提升小鼠肿瘤生长的抑制效果。同时，该复合物在细胞和动物体内都展现出了良好的安全性。02乙肝：小核酸联用有望达到功能性治愈慢性乙型肝炎病毒（HBV）感染影响全球约2.9亿人，每年造成约90万人死亡。目前的治疗标准以长效干扰素为主（机理为免疫调节），但是只有约2-5%的病人可以诱导永久性的表面抗原消失，达到功能性治愈。如果联合、续贯核苷类小分子药物（机理为抑制病毒复制），可能将这一比例提高到10%。总体而言，现有的药物很难达到功能性治愈（定义为治疗结束6个月后，血液中的HBsAg低于0.05IU/ml）。其关键就在于慢性HBV感染的肝细胞中始终存在活性的cccDNA，导致持续的病毒抗原暴露抑制特异性免疫，造成宿主免疫衰竭。所以理论上，若能迅速将乙肝表面抗原HBsAg降低，则有利于激发先天性/适应性免疫。RNA疗法是近年来科学家们积极探索的方向，因为其作用机理可以降低HBsAg。目前进展积极的主要以siRNA为主，有罗氏的RG-6346（从Dicerna引进），Arbutus的AB-729，Vir的Vir-2218（被腾盛博药引进）；ASO药物主要包括GSK-836（从Ionis引进）。总体上，乙肝的联用治疗策略包括“抑制复制±降低抗原±刺激免疫”的不同组合方式，以实现乙肝治疗“1＋1＋1＞3”的效果。1、与抗体联合在RNAi疗法干扰肝细胞内病毒复制从而降低HBsAg水平达到平台期之后，与中和抗体的联用可以中和外周游离的病毒以及S抗原，继而被抗原呈递细胞吞噬，从而进一步降低HBsAg水平，为机体的免疫应答打开“窗口”，提高功能性治愈的人群比例。VIR-2218 +VIR-3434VIR-2218（又称 BRII-835）是一种正在研究中的 N-乙酰半乳糖胺（GalNAc）共轭 RNA 干扰（RNAi）疗法，其靶点是乙型肝炎病毒（HBV）基因组中所有 HBV 病毒RNA 转录本共有的一个区域。VIR-3434是一款正在进行研究的用于慢乙肝治疗的HBV中和性单克隆抗体，旨在阻断HBV的所有10个基因型进入肝细胞，并降低血液中病毒体和亚病毒颗粒的水平。正在进行的 Phase 2 期开放标签 MARCH 研究的 B 部分正在评估24 周和 48 周 VIR-2218 和 VIR-3434 加用或不加用 PEG-IFNα 用于治疗慢性乙型肝炎方案的安全性、耐受性和抗病毒活性。在2023年美国肝病学会年会（AASLD 2023）公布的大会摘要中，研究者报道了MARCH研究B部分24周队列EOT时的数据：当给药20~24周时，VIR-2218+VIR-3434与VIR-2218+VIR-3434+PEG-IFNα在EOT时达到了相似的HBsAg转阴率（分别为15%和14.3%），大约是既往观察到的VIR-2218+PEG-IFNα治疗24周HBsAg转阴率的3倍。这一数据支持VIR-3434具有叠加效应。HT-102+HT-101HT-101作为一款GalNAc偶联的siRNA创新药物，通过干扰乙肝病毒的mRNA，破坏其作为转录后的翻译模板功能，阻止相关病毒蛋白合成，从而抑制乙肝病毒颗粒形成。目前已在国内完成了针对健康志愿者的全部研究以及针对慢性乙肝患者的Ib期临床所有给药。初步研究数据表明HT-101在健康人群和慢性乙肝患者中具有良好的安全性及耐受性，并且可显著降低慢性乙肝患者乙肝表面抗原（HBsAg）,中高剂量组HBsAg降幅达21g以上且无明显反弹。HT-102中和抗体是由星曜坤泽与苏州博奥明赛生物制药有限公司联合开发、一款具有多种机制、针对HBV的全人源单克隆抗体，通过特异性结合并靶向小(S)包膜蛋白。据星曜坤泽称，临床前研究表明HT-102与HT-101注射液联用，显示更强更持久的抗病毒活性。2、与干扰素/免疫调节剂联合BRII-835 (VIR-2218)+ PEG-IFNα聚乙二醇干扰素α-2α（PEG-IFNα）已获批用于治疗HBV感染，但PEG-IFNα治疗48周后仅不到10%的患者可实现HBsAg清除。在2022年美国肝病研究学会年会（AASLD 2022）上，研究人员报告了VIR-2218单药或联合PEG-IFNα治疗慢性HBV感染者的安全性和疗效初步研究结果。数据表明，VIR-2218单独或与PEG-IFNα联合使用通常耐受性良好。大多数AE与已知的PEG-IFNα相关影响一致。PEG-IFNα可增强VIR-2218的抗病毒活性，从而实现HBsAg清除。同时启动VIR-2218 + PEG IFNα治疗的受试者在48周内HBsAg降幅更大，且联合治疗时间越长，HBsAg水平越低。联合治疗队列5在48周内HBsAg清除率可达30%，同时出现anti-HBs。bepirovirsen（GSK-3228836）+PEG-IFNBepirovirsen (BPV; GSK3228836)是一款靶向 HBV 前基因组 RNA 和mRNAs 中的20个保守核苷酸序列的反义寡核苷酸。B-Together研究是一项旨在评估 bepirovirsen 和长效干扰素(PegIFN)的序贯用药能否改善在 B-Clear临床研究中观察到的 bepirovirsen 效果的多中心、随机、开放标签 Phase 2b期临床研究。在2023年美国肝病学会年会（AASLD2023）上，研究人员公布了该项 B-Together 研究关于患者病毒基因型和乙肝表面抗原（HBsAg）应答情况的临床数据。结果显示，与单独BPV治疗（B-Clear）相比，BPV和PeglFN顺序治疗，可以减少BPV应答者的复发，从而提高停药后的应答率，没有发现新的令人担忧的安全性问题。Xalnesiran（RG6346，RO7445482）+Peg-IFN-αXalnesiran（RG6346，RO7445482）是Roche和Dicerna共同开发的一种靶向HBV基因组HBsAg编码区的siRNA药物，ruzotolimod（RG7854，RO7020531)是Roche开发的一种TLR-7激动剂，目前这两种药物均处于临床II期阶段。在AASLD2023大会LATE BREAKING摘要中，公布了xalnesiran联合ruzotolimod或聚乙二醇干扰素α（Peg-IFN-α）治疗的中期结果，显示xalnesiran单药、xalnesiran + ruzotolimod、xalnesiran+ Peg-IFN-α治疗48周的HBsAg清除率分别为6.7%、17.6%和30.0%，停药随访24周的HBsAg清除率分别为6.7%、11.8%和23.3%。AB-729+核苷(酸)类似物(NA)+聚乙二醇干扰素α-2a(peg-ifnα-2a)AB-729是一种RNA干扰(RNAi)疗法，专门用于降低所有HBV病毒蛋白和抗原，包括乙型肝炎表面抗原（HBsAg）。AB-729使用Arbutus Biopharma 的新型共价偶联N -乙酰半乳糖胺(GalNAc)递送技术靶向肝细胞，实现皮下递送。迄今为止产生的临床数据显示，单剂量和多剂量AB-729总体上是安全的，耐受性良好，同时还能显著降低 HBsAg 和HBV DNA。2022年12月, Arbutus Biopharma 公布了用于慢性乙型肝炎治疗的 AB-729 的 Phase 2a 期临床试验初步数据。临床试验受试者的登记已经完成，43名患者接受了至少一剂 AB-729。前15名患者达到治疗第16周，接受两剂量 AB-729 + NA治疗，平均(SE) HBsAg下降为1.51 log(0.12)，与完成的1b期临床试验AB-729-001在同一时间点观察到的下降(1.56 log(0.1))相当。随着试验的进行，患者将被随机分为不同的治疗组，包括AB-729联合治疗、NA治疗和短期干扰素治疗，疗程为12周或24周。 GSK-5637608（JNJ-3989）+ NA ± JNJ-6379序贯联合聚乙二醇干扰素α（PegIFNα） GSK-5637608（JNJ-3989）属于RNA 干扰疗法，包含特异性N-半乳糖胺缀合的siRNA 触发器和两个siRNA 分子，能够降解来自游离cccDNA和整合入宿主基因组的乙肝病毒（HBV）DNA产生的多种HBV RNA，抑制所有HBV蛋白的产生。GSK于去年年底从强生接手获得该药的全球权益，并计划从2024年开始，将JNJ-3989与bepirovirsen一起进行II 期序贯治疗试验，进一步加强GSK的后期专业药物管道。近日，公司在AASLD 2023大会分享的摘要中，公布了JNJ-3989 + NA ± JNJ-6379序贯联合聚乙二醇干扰素α（PegIFNα）治疗初治HBeAg阳性（大部分免疫耐受期）患者的最新数据，该2期REEF-IT研究纳入初治、HBeAg阳性、ALT < 2 × ULN的慢性乙肝患者，所有患者接受JNJ-3989 200 mg Q4W + NA ± JNJ-6379 250 mg QD治疗36 - 52周（诱导期），随后加用PegIFNα 180 mcg QW治疗12周（巩固期）。结果显示，治疗结束时，平均HBsAg相比基线的变化为-3.61（0.18）log10 IU/mL，平均HBV DNA相比基线的变化为-6.24（0.20）log10 IU/mL，7/48（15%）患者实现HBeAg清除；停药随访24周时，平均HBsAg相比基线的变化为-2.92（0.37）log10IU/mL，21/28（75%）的NA维持治疗患者实现HBV DNA阴转。REP2139/REP2165 + PEG IFNα HBsAg抑制剂REP2139/REP2165的REP 401 II期研究中，REP2139/REP2165 + PEG IFNα + TDF三联疗法在治疗结束时有55%-65%的患者获得 HBsAg清除，随访5.3年能较好的维持HBsAg清除。REP 301和REP301-LTF研究中REP2139-Ca + PEG IFNα治疗HBV/HDV合并感染者，随访3.5年时乙肝功能性治愈率达40%，平均随访7.4年持久率为100%。3、与疫苗联合BRII-835 + BRII-179（即VIR-2218 + VBI-2601）腾盛博药探究了BRII-835（即VIR-2218）联合治疗性疫苗BRII-179的效果。随机、开放标签的II期研究中，NA经治获病毒学抑制的患者在接受BRII-835联合BRII-179治疗的基础上加用IFNα佐剂，可以更好的诱导T细胞和B细胞，从而产生anti-HBs，以解决停药后HBsAg反弹的问题。在治疗第40周两个联合治疗组均有超过40%的受试者anti-HBs > 100 IU/L，而且治疗后 70%的受试者产生HBV特异性T细胞应答。03高血压：小核酸联用有望解决标准药物控制不佳问题尽管高血压治疗已经较为普及，但仍有大量患者血压控制不达标导致心血管事件风险升高，其中重要原因是患者对复杂的治疗方案依从性差。此外，尽管治疗达到规范化，血压的节律异常也可能会带来风险。Zilebesiran是一种皮下给药、靶向血管紧张素原（AGT）的在研RNAi治疗药物。AGT是肾素-血管紧张素-醛固酮系统（RAAS）中最上游的靶点，该级联反应已被证实在血压调节中发挥作用，其抑制具有明确的抗高血压作用。Zilebesiran抑制肝脏中AGT的合成，可能导致AGT蛋白持久减少，并最终导致血管紧张素减少。KARDIA-2研究（NCT05103332）将在奥美沙坦、氨氯地平或吲达帕胺为基础治疗控制不佳的高血压患者中，联合zilebesiran来进一步评估其降压疗效和长期安全性。日前，Alnylam Pharmaceuticals公司公布了zilebesiran在治疗高血压患者的2期临床试验KARDIA-2中获得的积极结果。数据分析显示，zilebesiran添加到标准治疗方案中，在接受治疗第3个月时，与安慰剂组相比，通过动态血压监测（ABPM）测量的24小时SBP显示出具有显著临床意义的降低。Zilebesiran与抗高血压药物联用，最高可将SBP额外降低12.1 mmHg。04眼部疾病：与VEGFR抑制剂联用提高药效PF-04523655 (PF-655)是一类合成的化学修饰后的siRNA，能够抑制Quark公司独有的靶点基因RTP801，后者为应激诱导的结构蛋白，可以抑制mTOR信号通路中TSC1/TSC2复合体上游的各项功能。PF-655的作用机制被认为与各类型的VEGF抑制剂类药物不同。在缺血、缺氧或氧化应激压力下，RTP801的表达量会迅速上调。在激光诱导的脉络膜新生血管(CNV)的临床前动物模型玻璃体腔中注射PF-655会导致RTP801表达量因RNAi过程而发生的下调，并且没有TLR信号的激活、抗血管生成和神经营养因子的诱导表达，以及随后的脉络膜新生血管体积减少、血管渗漏和炎性细胞浸润为脉络现象的缓解。对于动物模型中的脉络膜新生血管，当PF-655与VEGFR抑制剂联用时，能够提高效果并降低糖尿病小鼠视网膜中的血管渗漏。PF-655已进行了多项临床研究，包括针对糖尿病黄斑水肿(DME)的两项二期临床研究，以及用于治疗年龄相关性黄斑变性(AMD)的临床一期/二期研究。在代号为MONET用于治疗湿性年龄相关性黄斑变性的二期临床研究中，相比于前三个月，PF-655可显著改善平均视力水平；而该药物同Ranibizumab的联用效果比单独用药更佳。在代号为DEGAS用于治疗糖尿病黄斑水肿的二期临床研究中，相比于激光光凝治疗的对照组，PF-655对于患者视力的改善具有药物剂量依赖性。基于此项研究的结果，特别是视力改善与药物剂量间的相关性，一项Ⅱb期研究正在开展用以评估PF-655单独用药及与Ranibizumab联合用药对DME患者的治疗效果。资料来源：[1] https://doi-org.libproxy1.nus.edu.sg/10.1016/j.molmed.2023.10.005[2] Babu A, Munshi A, Ramesh R. Combinatorial therapeutic approaches with RNAi and anticancer drugs using nanodrug delivery systems. Drug Dev Ind Pharm. 2017 Sep;43(9):1391-1401. doi: 10.1080/03639045.2017.1313861. Epub 2017 May 19. PMID: 28523942; PMCID: PMC6101010.[3] https://doi-org.libproxy1.nus.edu.sg/10.3389/fbioe.2021.628137[4] 同写意Biotech，胰腺癌新的治疗方法：siRNA或适配体[5] https://doi-org.libproxy1.nus.edu.sg/10.1212/WNL.92.15_supplement.S58.005[6] Friedrich, M., Aigner, A. Therapeutic siRNA: State-of-the-Art and Future Perspectives. BioDrugs 36, 549–571 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1007/s40259-022-00549-3[7] RNAi Therapeutics and Novel RNA Bioengineering Technologies. Gavin M. Traber and Ai-Ming Yu. Journal of Pharmacology and Experimental Therapeutics January 1, 2023, 384 (1) 133-154; DOI: https://doi-org.libproxy1.nus.edu.sg/10.1124/jpet.122.001234[8] 药渡，RNA疗法一路“狂飙”，下一个重磅炸弹的掘金之地？[9] 北理工在光动力协同小核酸药物抗肿瘤方面取得进展[10] 雨露肝霖|肝霖君：谢青教授：慢乙肝在研新药——进展与挑战[11]https://mp.weixin.qq.com/s/44NfDXOv85r-a2Xkfe_-Xg [12] 肝脏时间|略晓薛：全球首个研究证实基因编辑技术联合RNAi 技术清除cccDNA和HDV RNA可行！ BiG 十周年预告本次BiG十周年庆典，将首次分为国内和国际篇章，以原创科学和临床需求为出发点，讨论创新技术平台和创新疗法（PROTACT/分子胶、双抗/ADC、siRNA/ASO、CGT、AI制药）的重大进展和发展前景，十年一药曙光现，大浪淘沙始见金！▼报名参会会议门票：审核制(免费)；含主论坛+分论坛，不含餐；优先biotech/Pharma、临床、院校科学家共建Biomedical创新生态圈！如何加入BiG会员？

siRNA核酸药物基因疗法寡核苷酸临床研究

2023-09-28

·BioSpace

Orange Grove Bio Subsidiary Awarded $2.05 Million SBIR Phase II Grant to Advance Development of Novel Platelet Preservation Technology

OGB Also Announces Key Appointments to Board of Senior Advisors and the Opening of New Headquarters CINCINNATI, Sept. 28, 2023 (GLOBE NEWSWIRE) -- Orange Grove Bio (OGB), a drug investment and development firm, today announced that Preservation Bio, one of the firm’s majority-owned subsidiaries, has been awarded a $2.05 million Small Business Innovation Research (SBIR) direct-to-Phase II grant by the National Heart, Lung, and Blood Institute, one of 27 institutes under the National Institutes of Health (NIH) umbrella. The funding will be used to advance Preservation Bio’s novel approach to preserving platelets, which is designed to allow donated platelets to survive at refrigeration temperatures for up to 14 days, more than doubling their shelf life. By significantly extending the amount of time that donated platelets remain viable for use in life-saving transfusions, Preservation Bio aims to address the healthcare industry’s growing platelet shortage, a major bottleneck in transfusion needs. Unlike red blood and other products, platelets are stored at room temperature because they do not tolerate refrigeration. This results in a short shelf life of five-to-seven days before expiration and up to 15% of all collected platelets are discarded. Preservation Bio seeks to transform blood banking for donated platelets with an ex vivo additive that protects platelets from the damage normally caused by refrigeration. The company is developing a small molecule, reversible RhoA inhibitor (G04) that can be added to platelet storage solution to prevent the cold stress response of irreversible protein clusters (Gplb) which typically renders refrigerated platelets non-viable in vivo. As a result, G04 has the potential to enable more than 14-day functional storage of platelets in the refrigerator, doubling the storage time of current room temperature-limited platelets and decreasing the risk of bacterial contamination in one single inventory for blood centers. The SBIR grant will help fund Preservation Bio’s continued advancement of G04 through preclinical development and toward the clinic. “We are excited to receive this grant from the NIH, along with the important validation of the award. With more than eight million platelet units donated yearly, the global platelet market is estimated to be at least $4 billion. Despite its size, this market is severely impacted by inefficiencies related to shelf life, storage, and shipping - all of which contribute to financial loss while creating challenges for health care delivery,” said Rich Ganz, chief executive officer of Preservation Bio. “We believe that by enabling safe refrigeration of donated platelets, G04 has the potential to transform the way these blood products are stored and used, offering enhanced patient care while addressing a significant and untapped commercial market. We look forward to leveraging this NIH grant funding to accelerate our ongoing development efforts for G04 as we work to move the program toward the clinic.” Orange Grove Bio Senior Advisory Board Appointments In additional corporate news, Orange Grove Bio announced the appointments of Abul Abbas, MBBS, Thomas F. Bumol, Ph.D., and James Wooldridge, M.D., to its board of senior advisors. These appointments further strengthen Orange Grove’s expanding team of advisors and support the company’s mission of developing new therapeutics for patients by harnessing the significant research potential in universities and academic medical centers across the United States. Dr. Abbas is a renowned researcher in the field of immunology, with a specific focus on the control of immune response and causes of autoimmunity. His laboratory is credited with using experimental models to analyze the generation and maintenance of regulatory T cells. Dr. Abbas has taught immunology at Harvard University and the University of California, San Francisco (UCSF), the latter at which he served as professor and chairman of the department of pathology for nearly 20 years. He has received a number of prestigious honors and awards, including being elected to the National Academy of Medicine and the American Academy of Arts and Sciences, and is credited with publishing more than two hundred peer-reviewed papers and invited reviews. Dr. Bumol, a pioneer in deep longitudinal immune profiling of the human immune system, was formerly the founding director and executive vice president of the Allen Institute for Immunology in Seattle. Before that he was the senior vice president of Eli Lilly’s biotechnology division and the immunology therapeutic area, as well as site head and president of the company’s biotechnology center in San Diego. During his more than 35 years with Lilly, his teams and collaborators discovered and engineered/optimized over one hundred clinical candidates, resulting thus far in eight commercialized therapeutics including Trulicity®, Mounjaro®, Emgality® and Taltz ®. Dr. Wooldridge is an experienced medical oncologist, drug-developer, and biotech executive, with almost 25 years in academia, large pharma, and biotech, including public and private companies. He most recently served as chief medical officer of Checkmate Pharmaceuticals, where he assisted in taking the company public and led the development of vidutolimod in registration-directed and expanded proof-of-concept studies until Regeneron acquired the company in May 2022. Earlier in his career, Dr. Wooldridge spent more than a decade at Eli Lilly, where he led the early phase development of several cancer compounds, was head of oncology U.S. medical affairs, and served as chief scientific officer for immuno-oncology clinical development. Opening of New Headquarters Orange Grove Bio has also announced the formal opening of its new corporate headquarters in the PNC Center, a 27-floor office tower located within Cincinnati’s business district. To celebrate its opening, the company hosted an open house yesterday, September 27. “2023 has been a very active time for Orange Grove Bio as we continue to build the firm’s presence in the U.S. and abroad, strengthen relationships with our growing stable of academic collaborators, and support our majority owned subsidiaries. Preservation Bio is the latest example of an Orange Grove Bio company that has achieved a key milestone in its quest to develop impactful therapeutics for patients in need and we are pleased to see the financial support provided by the NIH SBIR grant,” said Marc Appel, Orange Grove Bio’s chief executive officer. “At the same time, we are continuing to build a large and talented team of advisors with expertise that spans all aspects of the drug discovery and development business. The additions of Abul, Tom and Jim to our senior advisory board highlight the momentum we are achieving in this area and provide impressive experience that will help continue to guide the firm’s mission and activities.” Ryan Fox, Orange Grove Bio’s chief operating officer and head of the firm’s Cincinnati office added, “We are thrilled to formally move our headquarters into the prestigious PNC Center in the heart of Cincinnati’s business center. This location helps to solidify our connection and commitment to this important emerging hub of biotechnology excellence.” Orange Grove Bio’s mission is to develop new therapeutic options for patients by harnessing the significant research potential found in universities and academic medical centers across the United States and internationally. Orange Grove Bio fosters strong relationships with technology transfer offices outside of the traditional medical technology hubs of Boston and San Francisco. Collectively, Orange Grove Bio’s team possesses decades of drug development and company creation experience, allowing it to build and finance innovative programs from the research and development stage to clinical trials. About Orange Grove Bio Orange Grove Bio (OGB) is a capital allocation and asset development biotech company. OGB partners with universities, academic medical centers, and entrepreneurs to develop innovative treatments for important diseases, particularly cancer and immune disorders. Learn more at: Trulicity®, Mounjaro®, Emgality® and Taltz ® are registered trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. Contacts: Orange Grove Bio Taylor Negrete pr@orangegrovebio.com (513) 448-2499 Vida Strategic Partners (on behalf of Orange Grove Bio) Tim Brons (Media) tbrons@vidasp.com (415) 674-7402

高管变更并购

2023-07-16

·研发客

怎样的中国早期项目, 最终被Roger Perlmutter看上？| 第一现场

// 被Perlmutter及其公司Eikon收入囊中的博迪生物的TLR7/8受体激动剂，已经看到疗效且安全性良好；英派药业的高选择性PARP1选择性抑制剂，预计可在人体达到很高的暴露量和更好的安全性，应用空间广阔，即将提交IND。两家中国药企——博迪生物(Seven and Eight Biopharmaceuticals)和英派药业的在研项目，尽管尚处在早期阶段，但因为差异化特色，而吸引了行业大咖Roger Perlmutter的注意，将其收入囊中，合作推进临床开发。在制药界，Roger Perlmutter鼎鼎大名。他曾在默沙东工作12年，并担任执行副总裁和默克实验室(Merck Research Laboratories)总裁，领导了包括K药(Keytruda)在内的多款重要产品的研发。此外，他还在安进担任执行副总裁和研发主管多年。2021年，美国加州的生物技术初创公司Eikon Therapeutics宣布，Perlmutter加入该公司并担任CEO。Eikon成立于2019年，据其网站，该公司的研发平台基于联合创始人Eric Betzig所发明的超分辨率荧光显微镜，Betzig因此获得了2014年的诺贝尔化学奖。Perlmutter曾公开解释了Eikon这一前沿技术：“使用超分辨率显微镜，我们可以追踪单个分子。也就是说，我们可以在任何单个蛋白分子上放置荧光探针，计算荧光探针的位置，并且看到活细胞内部的单个蛋白，分辨率可以达到10亿分之1米。”Roger Perlmutter 图片来源|EndpointsPerlmutter表示，“Eikon的首要目标是发现和开发重要的新药”，他相信，通过超分辨率显微镜以及公司软件团队藉此所获得的海量数据，“不仅可以识别出药物靶点，还能识别出已知靶点但尚未发现的药物”。不过，截至目前，Eikon尚未公布任何在研产品的信息。刚刚过去的6月1日，Eikon宣布获得了近1.06亿C轮融资，将该公司成立以来所获得的融资总额推高至近7.75亿美元。同时，Eikon还宣布从3家公司购入资产，包括博迪生物的两款已进入临床试验阶段的TLR7/8激动剂、英派药业即将提交IND的PARP1选择性抑制剂，以及Cleave Therapeutics的临床前资产。谈及为何选择从外部购买资产，Perlmutter在接受Fierce Biotech采访时透露，今年初的JPMorgan大会上，Eikon与30多家公司举行了会议，会上有很多公司都愿意与Eikon建立合作伙伴关系。Perlmutter说，“这是一个机会窗口，因为现在人们渴望进来，但以后可能就不会，所以我们现在就做”。Eikon并未在新闻稿中透露这三笔交易的财务条款，不过Perlmutte表示，价格“在当下的环境下是公平的”。他在采访中将Eikon描述为一家具有竞争力的公司，可以从那些需要国际资源一起开发自己项目的生物技术公司手中接过接力棒。尽管融资环境更为困难，但Perlmutte认为，Eikon前期获得的资金足够支付新资产的早期临床开发费用。另一方面，药企愿意与Eikon合作的原因之一是Perlmutter及其团队的学术专业性以及卓越的临床运营能力。合作方博迪生物的CEO 刘华涛博士和英派药业的CEO 蔡遂雄博士在接受研发客采访时，都提到Perlmutter及其搭档——Eikon的CMO、前默沙东默克实验室CMO和全球临床开发负责人 Roy Baynes对项目的独到眼光和执行力。那么，博迪生物和英派药业这两家中国药企的早期项目，又是凭什么吸引了Perlmutter团队的注意呢？首款静脉给药且看到临床疗效的TLR7/8根据新闻稿，Eikon获得了博迪生物两款已经进入临床的Toll样受体(TLR)7/8激动剂BDB001和BDB018，以及尚处在临床前阶段的Toll样受体配体/抗体偶联(TLAC)产品的全球独家权益。拓展阅读Seven&Eight 八年只做一件事 | DJS刘华涛告诉研发客，在认真查看了BDB001已经完成的1期研究的每位患者数据后，Baynes主动提出了合作意向。考虑到后续的开发需要大量资金，“他们（Eikon）的决策比较快，我们希望能把这个药做成，所以选择和他们合作”。看上去Perlmutter和刘华涛的愿望一致。在接受Endpoints采访时，Perlmutter表示，“Roy (Baynes)和他的团队已经设计好了下一组临床试验。原则上，这些试验可以用于注册，但我们还需要与监管机构进行大量的讨论。”来源|博迪生物官网刘华涛介绍，TLR是一类重要的受体家族，配体与树突状细胞(DC)上的TLR结合后，可激活特定的细胞内信号级联，从而启动宿主针对病原体和肿瘤细胞的防御反应。近年来的基础科学研究已经证明，使用TLR特异性激动剂可以促进针对肿瘤的免疫结合。其中，TLR7和TLR9在浆细胞样DC(pDC)上表达，而TLR8在髓样DC(mDC)上表达。拓展阅读TLR激动剂能否重塑肿瘤免疫游戏规则｜边研PD-1耐药后TLR7/8激动剂能否带来转机 | 边研抗体-TLR激动剂偶联物与TLR激动剂的2021 | 边研之前几款针对TLR9受体的瘤内给药的候选药物，如vidutolimod(CMP-001)、SD-101和tilsotolimod(IMO-2125)在黑色素瘤的治疗上取得不错的疗效，但CpG分子瘤内给药的方式限制了这一类药物在其他实体瘤上的使用。而能同时激活两类DC的TLR7/8抑制剂，如MEDI-9197和NKTR-262都因为安全性问题而停止开发。“之前药物没有成功，以至于大家认为这类TLR7/8受体激动剂的治疗窗比较窄，多集中在瘤内注射，但激活免疫是系统性的，”刘华涛解释说，“我们研发出的BDB001是首款静脉给药且看到临床疗效的TLR7/8受体激动剂，而且不论是单药还是与抗PD-(L)1联用，都具有很好的安全性。我们在分子的选择上，剂量和给药模式的摸索上下了更多的功夫。我们认为ADC的潜力也很大。”安全性良好的高选择性PARP1抑制剂Eikon还从另一家中国药企英派药业获得了包括IMP1734在内的高选择性PARP1抑制剂中国以外的独家权益。目前已经有4款PARP抑制剂在全球成功上市。蔡遂雄介绍，这些分子均同时靶向PARP1和PARP2。然而，研究发现，这两个靶点中，PARP1抑制主要与药效相关，PARP2抑制非但与药效关系不大，还导致了血液学毒性。因此，与第一代PARP抑制剂相比，高选择性PARP1抑制剂可以在人体上达到高很多倍的暴露量且安全性良好，具有很好的应用前景。“最大的用处就是今后可以做很多联合用药，与化疗、靶向药和ADC都可以联用，有可能成为又一个类似PD-1抑制剂类的热门靶点。”蔡遂雄说道。而对于PARP抑制剂，Perlmutter和Baynes并不陌生。在默沙东时，两人即深度参与了与阿斯利康合作的PARP抑制剂奥拉帕利，以及目前由GSK/强生和再鼎一起销售的尼拉帕利的开发。此外，Perlmutter还告诉Endpoints，Eikon使用超分辨率显微镜观察了PARP1和PARP2两种蛋白之间的差异，支持了PARP2会导致毒性这个观点。“我们相信，这给了我们一些特别的见解，有助于我们设计开发计划。”Perlmutter说。蔡遂雄在接受研发客采访时同样提到了这一点。他表示，今年二季度到三季度的时候，公司将在中美提交IMP1734的IND，“在申报IND前，英派希望与国际上有实力的药企达成合作，加速临床开发”。而英派在多家公司中最后选择Eikon作为合作方的原因，一方面是由于Eikon的“高分辨率显微镜可以帮助更好地开发PARP1抑制剂”，另一方面，Perlmutter及其团队曾经深入参与过PARP抑制剂的开发也是重要的考量因素。编辑 | 姚嘉yao.jia@PharmaDJ.com总第1918期访问研发客网站可浏览更多文章www.PharmaDJ.com

临床申请并购

100 项与 Vidutolimod 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
转移性黑色素瘤	临床3期	美国	Regeneron Pharmaceuticals, Inc.	2021-02-24
不可切除的黑色素瘤	临床3期	美国	Regeneron Pharmaceuticals, Inc.	2021-02-24
晚期癌症	临床2期	美国	Regeneron Pharmaceuticals, Inc.	2021-11-30
晚期癌症	临床2期	澳大利亚	Regeneron Pharmaceuticals, Inc.	2021-11-30
基底细胞癌	临床2期	美国	Regeneron Pharmaceuticals, Inc.	2021-11-30
基底细胞癌	临床2期	澳大利亚	Regeneron Pharmaceuticals, Inc.	2021-11-30
皮肤鳞状细胞癌	临床2期	美国	Regeneron Pharmaceuticals, Inc.	2021-11-30
皮肤鳞状细胞癌	临床2期	澳大利亚	Regeneron Pharmaceuticals, Inc.	2021-11-30
梅克尔细胞癌	临床2期	美国	Regeneron Pharmaceuticals, Inc.	2021-11-30
梅克尔细胞癌	临床2期	澳大利亚	Regeneron Pharmaceuticals, Inc.	2021-11-30

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临床结果

适应症

分期

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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


NCT02680184 (AACR2023)	临床1期	转移性黑色素瘤	199	Vidutolimod + Pembrolizumab	鬱繭築簾網鏇選鑰製夢(網蓋壓範築願膚顧夢選) = 範糧膚夢積夢鬱壓憲膚鏇鹹鹽積築鹽餘構鹽窪 (鬱壓築網廠遞餘範壓積 )	-	2023-04-04
NCT03438318 (CMP-001-003, Pubmed)	临床1期	晚期非小细胞肺癌	29	Vidutolimod and Atezolizumab	糧艱鑰鑰廠窪鹹壓鬱淵(窪艱製蓋鹹鹹築淵壓遞) = 築願艱艱鹹鑰憲選襯顧憲獵鏇積遞鬱糧範願鑰 (簾淵構膚衊襯觸窪餘艱 )	-	2023-03-01
NCT03438318 (CMP-001-003, Pubmed)	临床1期	晚期非小细胞肺癌	29	Vidutolimod, Atezolizumab, and Radiation Therapy	糧艱鑰鑰廠窪鹹壓鬱淵(窪艱製蓋鹹鹹築淵壓遞) = 壓衊簾獵鹽襯鹹鑰範餘憲獵鏇積遞鬱糧範願鑰 (簾淵構膚衊襯觸窪餘艱 )	-	2023-03-01
NCT03618641 (SITC2022) 人工标引	临床2期	不可切除的黑色素瘤新辅助	30	CMP-001+Nivolumab (PP population)	積範窪鑰壓糧壓夢觸鹹(築壓艱觸醖鬱築鏇構遞) = 顧鏇獵齋構遞糧膚構鏇餘蓋夢觸醖淵壓築選簾 (網膚簾製淵襯鏇鹹鹽鏇 ) 更多	积极	2022-11-01
NCT02680184 (ESMO2022)	临床1期	难治性黑色素瘤二线	159	Vidutolimod + pembrolizumab	網窪壓範鑰繭遞構願願(壓簾壓醖窪廠餘鬱壓遞) = 醖蓋窪淵艱構齋糧鹹鑰襯顧獵遞選餘製廠積醖 (選願齋鏇繭觸簾蓋餘構, 15.5 ~ 33.1)	-	2022-09-10
NCT03983668 (ASCO2022) 人工标引	临床1/2期	淋巴瘤二线	6	pembrolizumab+vidutolimod	壓觸顧齋網醖願糧網繭(壓衊顧選窪鹽窪鏇鹽鹹) = chills, rigors, mild headache, and fatigue 積夢簾醖獵壓艱蓋獵壓 (衊衊鹽醖夢積顧築網鹹 )	积极	2022-06-02
NCT03618641 (303 \| 605, CTgov)	临床2期	黑色素瘤 \| 淋巴结炎 \| 淋巴瘤	34	CMP-001+Nivolumab	顧簾願範觸憲衊膚鏇憲(膚鹹築選觸網顧糧廠網) = 築選觸製觸衊築壓鹽餘網繭鹽選鬱壓廠範選鹹 (顧鑰淵製憲築鹽艱製鏇, 蓋憲繭範網憲襯構醖鬱 ~ 廠簾齋鏇膚廠艱膚網鑰) 更多	-	2021-09-16
NCT02680184 (AACR2021)	临床1期	难治性黑色素瘤	199	CMP-001 + pembrolizumab	積顧衊夢繭繭蓋襯繭繭(網築衊膚襯築餘廠製廠) = 選鹽蓋糧糧廠醖壓壓鬱願糧窪築築選鑰餘鏇膚 (衊淵遞獵網衊襯窪簾積 )	-	2021-07-01
NCT02680184 (AACR2021)	临床1期	难治性黑色素瘤	199	CMP-001 monotherapy	積顧衊夢繭繭蓋襯繭繭(網築衊膚襯築餘廠製廠) = 繭遞艱餘簾齋鹹遞鏇鏇願糧窪築築選鑰餘鏇膚 (衊淵遞獵網衊襯窪簾積 )	-	2021-07-01
NCT03438318 (CMP-001-003, WCLC2021) 人工标引	临床1期	非小细胞肺癌	29	CMP-001+Atezolizumab	憲廠網衊壓構窪鏇觸願(網鏇積夢淵窪蓋廠餘齋) = 鏇鏇蓋糧鬱範鏇製鬱艱淵觸獵顧鏇壓遞憲鑰鏇 (網鑰襯簾積鏇觸膚範窪 ) 更多	不佳	2021-01-28
NCT03438318 (CMP-001-003, WCLC2021) 人工标引	临床1期	非小细胞肺癌	29	Radiation Therapy+CMP-001+Atezolizumab	憲廠網衊壓構窪鏇觸願(網鏇積夢淵窪蓋廠餘齋) = 觸網遞遞構範範蓋蓋選淵觸獵顧鏇壓遞憲鑰鏇 (網鑰襯簾積鏇觸膚範窪 ) 更多	不佳	2021-01-28
NCT02680184 (GlobeNewswire) 人工标引	临床1期	难治性黑色素瘤	199	Pembrolizumab+CMP-001	鹹淵積積鬱顧夢衊艱糧(鹹鹽鹹遞襯製網構餘衊) = hypotension (5.0%) 鏇夢夢衊鏇襯獵衊壓窪 (選艱廠夢製齋範壓鑰鹽 ) 更多	积极	2020-11-09
NCT02680184 (GlobeNewswire) 人工标引	临床1期	难治性黑色素瘤	199	CMP-001		积极	2020-11-09
CMP-001-001 (AACR2018)	临床1期	黑色素瘤	68	CMP-001	鬱遞鏇觸鏇選製衊窪鬱(艱獵齋網蓋壓遞範顧齋) = 繭糧蓋艱積鏇鑰憲顧願夢網製齋糧網積遞鬱構 (窪膚廠夢壓餘壓衊積醖, 11 ~ 39)	积极	2018-07-01