SPOTLIGHT 204: A Multicenter, Phase 2b, open-label, non-randomized, clinical trial to evaluate safety, tolerability and preliminary efficacy of intra-lesional BO-112 in patients with resectable primary low and high risk basal cell carcinoma - BOT-112-204

开始日期2024-12-10

申办/合作机构-

NCT06422936

/ Recruiting临床2期

SPOTLIGHT 204: a Multicenter, Phase 2b, Open-label, Non-randomized, Clinical Trial to Evaluate Safety, Tolerability and Preliminary Efficacy of Intra-lesional BO-112 in Patients with Resectable Primary Low and High Risk Basal Cell Carcinoma

This is a multicenter, phase 2b, open-label, non-randomized, clinical trial to evaluate safety, tolerability, pharmacodynamics and preliminary efficacy of intra-lesional BO-112 in patients with resectable primary low and high risk basal cell carcinoma.
* primary endpoint is complete visual and pathological response [at surgery] on patient level assessed by central review
* secondary endpoints are
1. Occurrence of adverse events (AEs), serious adverse events (SAEs), and AEs leading to discontinuation or death on patient level.
2. Pathological response [at surgery] on patient level assessed by the investigator and central review, respectively, and visual response [during the study and at surgery] on patient level assessed by the investigator and central review, respectively.
3. Recurrence [at 12 and 24 months] after surgery on patient level assessed by the investigator.

开始日期2024-05-27

申办/合作机构

Highlight Therapeutics SL

NCT05265650

/ Unknown status临床1/2期IIT

Phase Ib/II Open-label Clinical Study of Intratumoral Administration of BO-112 in Combination With Radiotherapy and Nivolumab in Patients With Metastatic PD- 1/PD-L1 Refractory Non-small Cell Lung Cancer

This is a study of repeated IT administrations of BO-112 in combination with ablative radiotherapy (SABR) and concurrent nivolumab in patients with metastatic PD-1/PD-L1-refractory NSCLC.

开始日期2022-06-13

申办/合作机构

Clínica Universidad de Navarra

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100 项与 BO-112 相关的临床结果

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100 项与 BO-112 相关的转化医学

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100 项与 BO-112 相关的专利（医药）

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项与 BO-112 相关的文献（医药）

2024-04-01·Journal for immunotherapy of cancer

Efficacy of LCMV-based cancer immunotherapies is unleashed by intratumoral injections of polyI:C

Article

作者: Quintero, Marisol ; Russo-Cabrera, Joan Salvador ; Alvarez, Maite ; Gomar, Celia ; Ardaiz, Nuria ; Di Trani, Claudia Augusta ; Berraondo, Pedro ; Lauterbach, Henning ; Gonzalez-Gomariz, Jose ; Aranda, Fernando ; Arrizabalaga, Leire ; Bella, Angela ; Fernandez-Sendin, Myriam ; Orlinger, Klaus K ; Schippers, Timo ; Melero, Ignacio

Background:

Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored.

Methods:

We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination’s efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials.

Results:

Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8+T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8+T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included.

Conclusion:

Intratumoral injection of poly(I:C) sensitizes MHClowtumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.

2023-12-31·Oncoimmunology

Intratumoral neoadjuvant immunotherapy based on the BO-112 viral RNA mimetic

Article

作者: Glez-Vaz, Javier ; Alvarez, Maite ; Garasa, Saray ; Gomis, Gabriel ; Quintero, Marisol ; Molina, Carmen ; Olivera, Irene ; Berraondo, Pedro ; Cirella, Assunta ; Ochoa, Maria C. ; Gonzalez-Gomariz, Jose ; Bolaños, Elixabet ; azpilikueta, arantza ; luri-Rey, carlos ; Rodriguez-Ruiz, Maria E ; Melero, Ignacio ; Teijeira, Alvaro

BO-112 is a poly I:C-based viral mimetic that exerts anti-tumor efficacy when intratumorally delivered in mouse models. Intratumoral BO-112 synergizes in mice with systemic anti-PD-1 mAbs and this combination has attained efficacy in PD1-refractory melanoma patients. We sought to evaluate the anti-tumor efficacy of BO-112 pre-surgically applied in neoadjuvant settings to mouse models. We have observed that repeated intratumoral injections of BO-112 prior to surgical excision of the primary tumor significantly reduced tumor metastasis from orthotopically implanted 4T1-derived tumors and subcutaneous MC38-derived tumors in mice. Such effects were enhanced when combined with systemic anti-PD-1 mAb. The anti-tumor efficacy of this neoadjuvant immunotherapy approach depended on the presence of antigen-specific effector CD8 T cells and cDC1 antigen-presenting cells. Since BO-112 has been successful in phase-two clinical trials for metastatic melanoma, these results provide a strong rationale for translating this pre-surgical strategy into clinical settings, especially in combination with standard-of-care checkpoint inhibitors.

2023-01-01·Journal for immunotherapy of cancer

Intratumoral BO-112 in combination with radiotherapy synergizes to achieve CD8 T-cell-mediated local tumor control

Article

作者: Barrio-Alonso, Celia ; Quintero, Marisol ; Alvarez, Maite ; Sánchez-Mateos, Paloma ; Rodríguez López, Inmaculada ; Perez-Gracia, Jose Luis ; Escuin-Ordinas, Helena ; Garate-Soraluze, Eneko ; Serrano-Mendioroz, Irantzu ; Arbea Moreno, Leire ; Diaz Pascual, Victor ; Rodriguez-Ruiz, Maria E ; Sanmamed, Miguel F ; Melero, Ignacio

Background:

Radioimmunotherapy combines irradiation of tumor lesions with immunotherapy to achieve local and abscopal control of cancer. Most immunotherapy agents are given systemically, but strategies for delivering immunotherapy locally are under clinical scrutiny to maximize efficacy and avoid toxicity. Local immunotherapy, by injecting various pathogen-associated molecular patterns, has shown efficacy both preclinically and clinically. BO-112 is a viral mimetic based on nanoplexed double-stranded RNA (poly I:C) which exerts immune-mediated antitumor effects in mice and humans on intratumoral delivery. BO-112 and focal irradiation were used to make the proof-of-concept for local immunotherapy plus radiation therapy combinations.

Methods:

Murine transplantable tumor cell lines (TS/A, MC38 and B16-OVA) were used to show increased immunogenic features under irradiation, as well as in bilateral tumor models in which only one of the lesions was irradiated or/and injected with BO-112. Flow cytometry and multiplex tissue immunofluorescence were used to determine the effects on antitumor immunity. Depletions of immune cell populations and knockout mice for the IFNAR and BATF-3 genes were used to delineate the immune system requirements for efficacy.

Results:

In cultures of TS/A breast cancer cells, the combination of irradiation and BO-112 showed more prominent features of immunogenic tumor cell death in terms of calreticulin exposure. Injection of BO-112 into the tumor lesion receiving radiation achieved excellent control of the treated tumor and modest delays in contralateral tumor progression. Local effects were associated with more prominent infiltrates of antitumor cytotoxic tumor lymphocytes (CTLs). Importantly, local irradiation plus BO-112 in one of the tumor lesions that enhanced the therapeutic effects of radiotherapy on distant irradiated lesions that were not injected with BO-112. Hence, this beneficial effect of local irradiation plus BO-112 on a tumor lesion enhanced the therapeutic response to radiotherapy on distant non-injected lesions.

Conclusion:

This study demonstrates that local BO-112 immunotherapy and focal irradiation may act in synergy to achieve local tumor control. Irradiation plus BO-112 in one of the tumor lesions enhanced the therapeutic effects on distant irradiated lesions that were not injected with BO-112, suggesting strategies to treat oligometastatic patients with lesions susceptible to radiotherapy and with at least one tumor accessible for repeated BO-112 intratumoral injections.

项与 BO-112 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/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/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/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/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/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

2022-04-13

·BioSpace

Global Roundup: A CAR-T Partnership and CDR-Life Nabs $76M to Engage Solid Tumors

Australia’s Chimeric Therapeutics has partnered with WuXi ATU on two autologous CAR T-cell therapies for solid tumors. Switzerland-based CDR-Life closed a $76 million Series A. Australia’s Chimeric Therapeutics has partnered with WuXi ATU , a global contract testing and manufacturing organization focusing on the company’s two autologous CAR T-cell therapies for solid tumors. Chimeric’s first CAR-T is CHM 2101 and is in preclinical development for gastrointestinal (GI) cancers. CHM 2101 will leverage WuXi ATU’s end-to-end closed-loop CAR T process development, Good Manufacturing Practice (GMP) manufacturing and testing platform, aiming to accelerate development towards its planned first-in-human study. CHM 1101 is being evaluated in a single-site Phase I clinical trial for recurrent or progressive glioblastoma patients. CHM 1101 will also leverage WuXi ATU’s scalable manufacturing and analytical testing capacity to enable potential future expansion of the program to multiple additional clinical trial sites and additional solid tumor indications, including metastatic melanoma. This partnership is expected to enable Chimeric to accelerate clinical manufacturing readiness for new CAR T assets and scale its CAR T manufacturing in order to support multiple, simultaneous, multi-center CAR T clinical trials in the future. “We are very excited to enter into this partnership with WuXi ATU,” Jennifer Chow, chief executive officer of Chimeric Therapeutics said in a statement. “With its extensive experience in cGMP manufacturing and analytical testing, as well as its seamless platform process for CAR T-cell production, WuXi ATU is uniquely positioned to support the acceleration and expansion of the CHM 1101 and CHM 2101 development programs.” Elsewhere around the globe: Trinity Biotech : Ireland’s Trinity Biotech secured a $45 million strategic investment and partnership with Korea-based MiCo Ltd., an in vitro diagnostics company. Funds are expected to be used to repay an $81.25 million loan and reduce annual interest costs of $4 million. Trinity also hopes that this investment will facilitate its exploring lower-cost debt funding options. SciRhom Gmbh: Based in Germany, SciRhom nominated the anti-iRhom2 antibody, which will advance into clinical development. This first-in-class drug candidate has demonstrated “outstanding preclinical efficacy” in treating rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Having completed the comprehensive characterization of the molecule, SciRhom will now enter into IND-enabling activities. SciRhom’s drug candidate inhibits the cell surface-localized protein iRhom2, a critical regulator of the protease TACE. By interfering with this complex, the anti-iRhom2 antibody allows the simultaneous blockade of several pro-inflammatory signaling pathways without impairing protective functions. Captor Therapeutics: Based in Poland, Captor announced the molecular targets of one of its core pipeline projects, which focuses on developing TPD therapy for hepatocellular carcinoma (HCC). Preclinical data have shown that CT-101 induces degradation of Eukaryotic peptide chain release factor GTP-binding subunit ERF3A (GSPT1), Sal-like protein 4 (SALL4) and another undisclosed neo-substrate with an essential function in tumorigenesis. XORTX Therapeutics : Alberta, Canada-based XORTX, received a no objection letter (NOL) from Health Canada regarding the company’s upcoming XRX-OXY-101 clinical bridging pharmacokinetics study. The study will determine which formulation results in the best circulating oxypurinol concentrations and the effect of food on the formulation. The study is expected to support a New Drug Application filing in the U.S. and Europe. Revive Therapeutics : Toronto’s Revive Therapeutics announced the Data Safety and Monitoring Board will assess the current clinical and safety data of the ongoing Phase III study of Bucillamine, an oral drug with anti-inflammatory and antiviral properties, in patients with mild to moderate COVID-19 in order to advise whether or not the trial should be halted early due to efficacy. Numinus Wellness: Across Canada in Vancouver, Numinus Wellness announced plans to acquire all outstanding shares of Novamind Inc. for $26.2 million. The combined company will operate 13 wellness following the Transaction to become a leading psychedelic-assisted therapy provider in North America. Achilles Therapeutics : Based in the U.K., Achilles announced the manufacturing expansion of its facility at the Cell & Gene Therapy Catapult in Stevenage and received the go-ahead from the UK Medicines and Healthcare products Regulatory Agency. The Catapult facility is now GMP certified to produce clinical grade doses of cNeT. The approach will initially support Achilles’ proprietary VELOS manufacturing process. Separately, the company entered into a partnership agreement for clinical manufacturing with the Center for Breakthrough Medicines in Pennsylvania. Recce Pharmaceuticals: Back Down Under, Recce Pharmaceuticals announced that the Intellectual Property Department of the Hong Kong Special Administrative Region granted a patent for its “Anti-Virus Agent and Method for Treatment of Viral Infection,” which furthers marketing and manufacturing exclusivity to February 2037. MediWound : Israel-based MediWound announced data from its Phase II study of EscharEx was highlighted in a poster and oral presentation at the 35th Symposium on Advanced Wound Care (SAWC) spring conference. The poster entitled: “Results from an Ongoing Open Phase 2 Study Assessing the Safety, Efficacy and Pharmacological Effects of Bromelain-based Enzymatic Debridement on Biofilm, Microbial loads and Cytokines in patients with DFU and VLU,” featured data from an ongoing Phase II study that showed EscharEx to debride wounds and promote wound area reduction, while reducing biofilm and bacterial bioburden safely and effectively. Sotio Biotech: Sotio, which is based in Prague, announced interim safety and efficacy results from the ongoing Phase 1/1b AURELIO-03 study of SOT101, an IL-15 superagonist, in combination with Keytruda in patients with advanced/metastatic solid tumors. The data showed that the combination was well tolerated, and most patients saw a clinical benefit. Highlight Therapeutics: Based in Spain, Highlight announced positive results from a Phase II study of intratumoral administration of BO-112 with Keytruda in patients with advanced melanoma whose disease had progressed on first-line anti-PD1-based therapy. BO-112 is a dsRNA agonist targeting anti-PD1 resistance, which has demonstrated anti-cancer activity in previous Phase Ib studies. ITM Isotope: Germany-based ITM announced a global clinical supply agreement with Pennsylvania’s Molecular Targeting Technologies Inc., which provides the U.S. company with ITM’s medical radioisotope no-carrier-added lutetium-177 for the preclinical and clinical development of that MTTI’s own radiopharmaceutical candidate lubetate for cancers. CDR-Life Inc.: Switzerland-based CDR-Life closed a $76 million Series A financing round that will support the advancement of its lead program, CDR404, a first of its kind dual MAGE-A4 T cell engager which targets solid tumors across multiple indications. The finances will support the development of CDR404 through potential clinical proof-of-concept readout as well as expansion of the pipeline leveraging the company’s M-gager technology. The Series A was led by Jeito Capital and RA Capital Management. Other participants include Omega Funds.

临床2期临床1期临床结果临床3期免疫疗法

2021-03-30

·MobiHealthNews

Quibim works with Highlight Therapeutics to improve immunotherapy in melanoma with AI

Quibim, a global medical imaging analysis specialist, has joined Highlight Therapeutics, a clinical-stage company specialising in immuno-oncology, to assess the efficacy of new immunotherapy treatments in advanced melanoma skin cancer using AI in a Phase II clinical trial in Spain. The alliance will analyse the information contained in radiological scans and correlate these findings with biological changes in patients who are treated with pembrolizumab and BO-112, a synthetic double stranded RNA that is administered as intratumoral therapy in advanced melanoma. WHY IT MATTERS Assessing efficacy in terms of response rate and correlating it with tumour biomarkers will help better understand different patterns of response, a task that remains challenging in immunotherapy, especially with intratumoral treatments. The study will use Quibim’s AI-fed whole-body imaging ecosystem to correlate radiomic signatures with immunohistochemistry biomarkers to identify those patients who will benefit the most from immunotherapy. THE LARGER TREND Global incidence of melanoma has reached epidemic proportions and cases are expected to grow to almost half a million by 2040, according to the World Health Organisation. The trial will bring much needed evidence on those patients who may benefit the most from the new approach and improve treatment for melanoma, by helping overcome current pitfalls in treatment response evaluation. ON THE RECORD “We are facing the unmet medical need of treating patients who have developed progressive disease to immunotherapy,” said Dr Sonia Macia, medical director of Highlight Therapeutics. “We will try to overcome this resistance by adding BO-112 to pembrolizumab, an approved anti-PD1 drug, which is currently indicated in the treatment of several solid tumours. Confirming the biological changes in injected lesions and correlating these findings with imaging features may help us predict which patients will have a better response to therapy.” “Quibim is committed to the discovery of new imaging biomarkers that can later be applied in clinical practice,” commented Dr Ángel Alberich-Bayarri, Quibim CEO and Co-founder. “Oncology and more specifically immunotherapy are key areas where quantitative imaging plays a pivotal role. Having objective measures can help improve the evaluation of treatment response and save lives, by identifying early on who will benefit the most from a specific approach.”

免疫疗法

100 项与 BO-112 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
基底细胞癌	临床2期	以色列	Highlight Therapeutics SL	2024-05-27
基底细胞癌	临床2期	西班牙	Highlight Therapeutics SL	2024-05-27
转移性非小细胞肺癌	临床2期	西班牙	Highlight Therapeutics SL	2022-06-13
非小细胞肺癌	临床2期	西班牙	Highlight Therapeutics SL	2022-06-13
不可切除的黑色素瘤	临床2期	法国	Merck Sharp & Dohme LLC	2020-12-30
不可切除的黑色素瘤	临床2期	法国	Highlight Therapeutics SL	2020-12-30
不可切除的黑色素瘤	临床2期	西班牙	Highlight Therapeutics SL	2020-12-30
不可切除的黑色素瘤	临床2期	西班牙	Merck Sharp & Dohme LLC	2020-12-30
结直肠癌	临床2期	比利时	Highlight Therapeutics SL	2020-06-17
结直肠癌	临床2期	意大利	Highlight Therapeutics SL	2020-06-17

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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


NCT04508140 (CTgov)	临床2期	食管癌 \| 胃食管交界处癌 \| 结直肠癌	18	Hepatic Biopsy+pembrolizumab (Cohort A)	製簾構積顧範網襯衊衊 = 夢製齋範艱糧鹹窪鑰鏇壓鬱觸簾觸繭糧鏇衊鹹 (構構選觸醖艱齋願糧鹹, 鹹獵膚壓鑰鹹獵衊鏇獵 ~ 積鬱餘壓觸糧繭廠獵顧) 更多	-	2024-11-29
NCT04508140 (CTgov)	临床2期	食管癌 \| 胃食管交界处癌 \| 结直肠癌	18	Hepatic Biopsy+BO-112+pembrolizumab (Cohort B)	製簾構積顧範網襯衊衊 = 齋鑰築鏇選餘選鬱鏇艱壓鬱觸簾觸繭糧鏇衊鹹 (構構選觸醖艱齋願糧鹹, 簾糧觸觸鹽構淵鏇襯衊 ~ 衊蓋製衊遞網餘鑰壓築) 更多	-	2024-11-29
NCT04570332 (SPOTLIGHT203, AACR2022) 人工标引	临床2期	局部晚期黑色素瘤	42	Pembrolizumab+BO 112 (Global )	簾築製顧鑰網糧夢艱醖(壓淵繭積艱顧鹹憲選簾) = 繭餘築蓋醖顧淵蓋願鬱選獵廠鑰遞襯範鹽簾鹽 (膚簾衊鑰壓繭醖鑰窪觸 ) 更多	积极	2022-06-15
NCT04570332 (SPOTLIGHT203, AACR2022) 人工标引	临床2期	局部晚期黑色素瘤	42	Pembrolizumab+BO 112 (Mucosal)	簾築製顧鑰網糧夢艱醖(壓淵繭積艱顧鹹憲選簾) = 製觸夢願願衊製選顧鬱選獵廠鑰遞襯範鹽簾鹽 (膚簾衊鑰壓繭醖鑰窪觸 ) 更多	积极	2022-06-15
NCT04570332 (AACR2022)	临床2期	难治性黑色素瘤	42	BO-112 plus pembrolizumab	繭簾鬱糧艱壓築醖襯膚(選鏇顧觸糧簾簾簾鹽鑰) = 鹽糧構築淵網簾膚製選蓋顧願鹽遞鹽鬱襯鏇衊 (蓋襯膚繭構顧鹹網憲範 ) 更多	-	2022-06-15
AACR2021	临床2期	结肠癌肝转移 \| 胃食管交界处癌	69	BO-112	艱簾鬱夢壓鏇鬱鏇繭窪(糧鏇餘鏇鹹齋積積願積) = 廠鑰醖顧選艱獵遞齋憲壓網齋艱襯選鏇膚顧鹽 (選觸鏇鬱鹹糧觸積衊製 )	-	2021-07-01
NCT04570332 (AACR2021)	临床2期	黑色素瘤	40	BO-112 in combination with pembrolizumab	糧觸窪繭鬱獵廠範範簾(網範壓廠鏇憲積鏇窪繭) = 鹽鹽壓觸夢積製選醖餘遞遞築蓋獵鬱夢窪繭餘 (廠壓餘鹽襯餘襯夢糧範 ) 更多	-	2021-07-01
NCT02828098 (ESMO2018)	临床1期	实体瘤	28	BO-112 Monotherapy	鬱鏇鏇廠觸願蓋襯願簾(憲膚齋膚衊蓋廠構築餘) = 獵襯觸鏇鹹壓淵築選窪憲淵醖膚顧範壓鹹觸壓 (窪齋簾願選憲壓淵範簾 ) 更多	积极	2018-10-20
NCT02828098 (ESMO2018)	临床1期	实体瘤	28	Combination BO-112+anti PD-1	鬱鏇鏇廠觸願蓋襯願簾(憲膚齋膚衊蓋廠構築餘) = 繭顧憲選糧繭憲醖獵淵憲淵醖膚顧範壓鹹觸壓 (窪齋簾願選憲壓淵範簾 )	积极	2018-10-20