A Phase 1, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Cyclin A/B-RxL Inhibitor CID-078 in Patients With Advanced Solid Tumor Malignancies

This is a first-in-human, multicenter, open-label, phase 1 study to evaluate safety, tolerability, and efficacy of CID-078, a Cyclin A/B-RxL inhibitor, in patients with advanced solid tumors.

开始日期2024-08-14

申办/合作机构

Circle Pharma, Inc.

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项与 Circle Pharma, Inc. 相关的文献（医药）

2023-12-01·Molecular Cancer Therapeutics

Abstract LB_C04: Novel orally bioavailable macrocycles that target cyclin A and B elicit antitumor activity in breast cancer patient-derived xenograft models

作者: Molina, Cristina ; Dias, Mariana Paes ; Wang, Evelyn W. ; Levin, Bernard ; Liu, Li-Fen ; Serra, Violeta ; Guzmán, Marta ; Rodríguez, Olga

AbstractBackground: Cyclin/cyclin-dependent kinase (CDK) complexes regulate the activity of RB1 and E2F to drive cell cycle progression while ensuring fidelity of DNA replication. The interaction between cyclins and a critical subset of their substrates, including RB1 and E2F, is mediated by a conserved short linear RxL motif. RxL peptides have been shown to inhibit substrate phosphorylation by CDK2/cyclin A (AACR 2022 poster #5379). Previously, we have shown that macrocycles that selectively inhibit RxL-mediated binding to cyclins A and B (RxL inhibitors) lead to growth inhibitory activity in multiple cancer cell lines, and result in tumor regression in small cell lung cancer (SCLC) and ovarian cancer xenograft models (AACR 2023 poster #1560). Here, we test the antitumor activity of CID-016 in patient-derived xenograft (PDX) models from breast cancer.Methods: Bioinformatic analyses using RNA sequencing (RNAseq) and whole exome sequencing (WES) data from 39 breast cancer cell lines was employed to identify biomarker profiles that associate with sensitivity to CID-016. The antiproliferative activity of CID-016 was assessed by GI50 after 4-8 days of treatment. Hallmark pathway scores were calculated by Gene Set Variation Analysis (GSVA) method using MSigDb Hallmark collection from cell lines and existing PDX models. Based on the calculated hallmark pathway score, triple negative breast cancer (TNBC) PDX models were selected to test the anti-tumor activity of CID-016. In vivo, NMRI-Foxn1nu/nu mice were implanted with tumor fragments in the lower flank and treated with vehicle or CID-016 oral formulation of 50-100 mg/kg BID or 100 mg/kg QD, respectively for at least 28 days. Tumor volume and body weight were measured biweekly. Pharmacodynamic (PD) analyses will be conducted after treatment with CID-016.Results: Treatment of the breast cancer cell line panel with CID-016 demonstrated greater potency by GI50 in TNBC compared to other breast cancer cell lines (p=0.009). Gene expression levels of CCNB1, CCNA2, CCNE1 as well as target hallmark scores for “E2F targets”, “G2M checkpoint” and “Mitotic spindle” were significantly higher in TNBC vs other breast cancer cell lines. Oral treatment with CID-016 resulted in tumor regression in at least one triple-negative breast cancer PDX model and was well tolerated with no significant body weight changes. In vivo PD analyses will be assessed after 5 days of treatment with CID-016.Conclusions: The selective cyclin A/B RxL inhibitor CID-016 exhibits potent antitumor activity in TNBC preclinical models, consistent with the proposed mechanism of RB1/E2F pathway dysregulation. Given their compelling characteristics, orally bioavailable RxL inhibitors are advancing as the only first-in-class orally bioavailable dual inhibitors of cyclins A and B into clinical development.Citation Format: Mariana Paes Dias, Li-Fen Liu, Bernard Levin, Cristina Molina, Marta Guzmán, Olga Rodríguez, Evelyn W. Wang, Violeta Serra. Novel orally bioavailable macrocycles that target cyclin A and B elicit antitumor activity in breast cancer patient-derived xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C04.

2023-04-04·Cancer Research

Abstract 1560: Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types

作者: Bambal, Ramesh ; Nosrati, Meisam ; Sala, Roberta ; Liu, Li-Fen ; Wang, Evelyn W. ; Aggen, James ; Hamkins-Indik, Frances ; Bhatt, Chinmay ; DeMart, Megan ; Dupper, Nathan ; Metobo, Sammy ; He, Daphne ; Singh, Rajinder ; Kreatsoulas, Constantine ; Garcia, Pablo D. ; Shapiro, Justin ; Levin, Bernard ; Earp, David J. ; Yang, Kai ; Cremin, Peadar ; Leung, Siegfried ; Fraga, Breena ; Situ, Gavin ; Odeh, Ranya ; Bockus, Andrew T. ; Gleason, Catherine E.

AbstractRB and E2F genes are frequently altered in cancer. Cyclin/Cdk (cyclin-dependent kinase) complexes regulate the activity of RB and E2F to drive cell cycle progression and ensure fidelity of DNA replication. A critical subset of their substrates (Rb, E2F, Cdc6, etc.) requires a short linear motif (RxL) that interacts with the hydrophobic patch on cyclins. Peptides that disrupt the cyclin/RxL interaction were found to be synthetically lethal in cancer cell lines displaying Rb-E2F dysregulation (Chen, 1999). Using structure-guided design, cell-permeable macrocycles were synthesized that selectively inhibit RxL-mediated binding to cyclins A and B. Preclinical studies with an orally bioavailable cyclin A/B RxL inhibitor show activity in cell lines with Rb-E2F pathway dysregulation, and inhibition of tumor growth and regression in xenograft models of small cell lung carcinoma (SCLC).RB-null mutations occur with high frequency in SCLC tumors (Febres-Aldana 2022). Previously we reported (AACR April 2022 Abs.#5379) sensitivity of a large proportion of SCLC cell lines to cyclin RxL inhibitors. Further studies have shown that such compounds have growth inhibitory activity in cell lines representing multiple types of solid tumors and hematological malignancies. Sensitivity of the cell lines to these macrocyclic inhibitors is associated with increased expression of genes involved in the E2F pathway, consistent with the proposed Rb/cyclin/E2F pathway synthetic lethality mechanism.Disruption of RxL binding to both cyclin A and B is required for sensitivity. Cyclin A/B RxL inhibitors disrupt the interactions of E2F and Cdc6 with cyclin A/Cdk complexes in co-immunoprecipitation studies and have EC50 values consistent with biochemical and cellular activity. Cyclin A/B RxL inhibition results in accumulation of cells in the G2/M phase of the cell cycle which leads to apoptosis both in vitro and in vivo. A separate study (Singh et al. AACR 2023) utilizing a CRISPR screen identified that genes of the spindle assembly checkpoint (SAC) are required for the synthetic lethality induced by the cyclin A/B RxL inhibitors. The inhibitors assessed in vitro for off-target activity showed negligible activity in a panel of 468 kinases and in safety panels that include GPCRs, ion channels, and transporters. In a 14-day tolerability study, neither neutropenia nor significant effects in other blood cell counts were noted. Cyclin A/B RxL inhibitors cause significant tumor regression via oral administration in SCLC xenograft models.Given their compelling characteristics, we are progressing the development of these orally bioavailable macrocyclic cyclin A/B RxL inhibitors to the clinic.Citation Format: Catherine E. Gleason, Pablo D. Garcia, Ranya Odeh, Frances Hamkins-Indik, Daphne He, Meisam Nosrati, Gavin Situ, Roberta Sala, Bernard Levin, Li-Fen Liu, Evelyn W. Wang, Siegfried Leung, Breena Fraga, Andrew T. Bockus, Justin Shapiro, Nathan Dupper, Chinmay Bhatt, Kai Yang, Megan DeMart, Sammy Metobo, James Aggen, Peadar Cremin, Ramesh Bambal, Constantine Kreatsoulas, David J. Earp, Rajinder Singh. Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1560.

2023-04-04·Cancer Research

Abstract 1559: Mechanisms responsible for hypersensitivity of small cell lung cancers to novel cyclin A and B RxL macrocyclic peptide inhibitors

作者: Singh, Shilpa ; Gleason, Catherine E. ; Singh, Rajinder ; Garcia, Pablo D. ; Earp, David J. ; Wang, Evelyn W. ; Oser, Matthew G. ; Durmaz, Yavuz T.

AbstractMost cancer-directed targeted therapies are developed using small molecule inhibitors that require a druggable binding pocket on the target of interest. Macrocyclic peptides can selectively block protein-protein interactions required for function and hence can be used to target previously undruggable proteins. Using a structure-guided approach, Circle Pharma developed cell-permeable macrocyclic peptides that block the ability of Cyclin A and/or Cyclin B, to bind RxL motifs on their substrates thereby inhibiting Cyclin activity. A separate study (Gleason et al. AACR 2023) revealed that cancer cell lines with RB/E2F dysregulation were highly sensitive dual Cyclin A/B peptides, which includes most small cell lung cancer (SCLC) cell lines with RB1 and TP53 inactivation. Importantly, some cancer cell lines and all non-transformed cell lines examined were insensitive to Cyclin A/B inhibitors suggesting high potential for a therapeutic window. We found that dual Cyclin A/B inhibitors blocked cellular proliferation, caused accumulation of cells in mitosis, and robustly induced apoptosis in SCLC cell lines. In contrast, selective Cyclin A or Cyclin B inhibitors had significantly lower activity than dual Cyclin A/B inhibitors demonstrating that inhibition of both Cyclin A and Cyclin B is required to induce apoptosis in sensitive cells. Using these Cyclin A/B RxL inhibitors, we performed genome-wide CRISPR/Cas9 positive selection resistance screens and subsequent rigorous validation in SCLC cells. Our screen identified Cyclin B and CDK2 as the targets of Cyclin A/B inhibitors. Our screen also showed that MAD1 and the ROD-Zwilch-Zw10 (RZZ) complex of the mitotic spindle assembly checkpoint (SAC), which is regulated by the kinase Mps1, is required for Cyclin A/B inhibitors to induce apoptosis. In line with this, chemical inhibition of Mps1 caused resistance demonstrating that SAC activation by Mps1 is required for the ability of Cyclin A/B inhibitors to induce apoptosis. Interestingly, Cyclin A/B inhibitors selectively induced DNA damage measured by phospho-H2AX accumulation and SAC activation measured by Mps1 activity in highly sensitive RB1- and TP53-deficient SCLC cell lines while having no effect on DNA damage and SAC activation in resistant RB1- and TP53-proficient cell lines. Moreover, Cyclin A/B inhibitors also significantly induced phospho-H2AX accumulation in RB1- and TP53-proficient normal RPE1 cells and A549 cells only after dual CRISPR inactivation of RB1 and TP53. In summary, we found that novel cell-permeable dual Cyclin A/B RxL macrocyclic peptides selectively induce apoptosis in RB1/TP53-deficient cancer cell lines involving a mechanism where DNA damage induces SAC activation leading to apoptosis. Our data suggests that Cyclin A/B RxL peptide inhibitors should be further explored as a therapeutic strategy in RB1/TP53-deficient cancers such as SCLC.Citation Format: Shilpa Singh, Yavuz T. Durmaz, Catherine E. Gleason, Evelyn W. Wang, Rajinder Singh, David J. Earp, Pablo D. Garcia, Matthew G. Oser. Mechanisms responsible for hypersensitivity of small cell lung cancers to novel cyclin A and B RxL macrocyclic peptide inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1559.

项与 Circle Pharma, Inc. 相关的新闻（医药）

2024-10-30

·医药观澜

总金额约170亿美元！辉瑞、罗氏、诺华等最近引进了哪些在研新药？

▎药明康德内容团队报道 10月29日，葛兰素史克（GSK）宣布以总金额8.5亿美元收购恩沐生物在研的一款CD19和CD20靶向T细胞接合器（TCE），用于治疗自身免疫性疾病。这是中国创新药领域发生的又一授权合作事件。近几年来，新药授权合作已成为行业重要趋势之一。公开资料显示，仅今年10月以来，全球范围内发生的授权合作事件有近30起，包括渤健、诺华、辉瑞、礼来、默沙东、安斯泰来在内的多家国际药企均有动作，合作产品涵盖分子胶蛋白降解剂、抗体偶联药物（ADC）、小分子抗肿瘤药物、针对肥胖症的双靶点项目、治疗成人神经退行性疾病的基因疗法等等。在这些合作项目中，不乏来自中国的在研管线。公开信息显示，本月以来锐格医药、石药集团、百裕制药、恩沐生物、友芝友生物等多家创新药公司实现新药授权交易，这些交易事件披露的总金额超过50亿美元。本文根据公开资料，介绍2024年10月份以来在全球范围内发生的总金额超5亿美元的新药授权合作项目（这12项新药授权合作公开披露的总金额约170亿美元），看看这些被看好的在研新药有潜力在未来造福哪些患者。图片来源：123RF 授权方：Neomorph 引进方：渤健合作产品：分子胶降解剂 10月29日，渤健（Biogen）和Neomorph宣布达成合作，开发用于治疗阿尔茨海默病、罕见神经疾病和免疫疾病的分子胶降解剂。根据协议条款，双方将合作确定、验证和优化几个高优先级靶点的分子胶降解剂小分子药物，渤健将推进临床候选药物的进一步开发和潜在商业化，Neomorph将获得预付款，并有资格在合作的各个阶段获得相关里程碑付款，总对价高达14.5亿美元。Neomorph成立于2020年，该公司还在2022年登上了由生物医药行业知名媒体网站BioSpace评选出的新一代生物新锐公司（NextGen Bio“Class of 2022”）榜单。授权方：恩沐生物引进方：GSK 合作产品：CD19/CD20/CD3 T细胞接合器 10月29日，葛兰素史克（GSK）宣布从恩沐生物（Chimagen Biosciences）收购CMG1A46，这是一种处于临床阶段的CD19和CD20靶向T细胞接合器（T cell-engager，TCE）。GSK计划开发和商业化CMG1A46用于B细胞驱动的自身免疫性疾病，如系统性红斑狼疮和狼疮肾炎，并有可能扩展到相关的自身免疫性疾病。根据协议条款，GSK将提前支付3亿美元，以获得CMG1A46的全部全球权利。此外，恩沐生物将有资格获得相关的开发和商业化里程碑付款，总额为5.5亿美元。授权方：Monte Rosa公司引进方：诺华合作产品：靶向VAV1的分子胶蛋白降解剂 10月29日，Monte Rosa Therapeutics公司宣布与诺华（Novartis）达成一项全球独家开发和商业化许可协议，以推进靶向VAV1的分子胶蛋白降解剂的开发，包括在研疗法MRT-6160。根据协议条款，诺华将获得MRT-6160及其他靶向VAV1的分子胶蛋白降解剂的全球独家开发、制造和商业化权利，并负责从2期临床试验开始的所有临床开发和商业化工作。诺华同意向Monte Rosa支付1.5亿美元的预付款。此外，Monte Rosa有资格获得最高达21亿美元的开发、监管和销售里程碑付款。 VAV1是T细胞和B细胞受体下游的关键信号蛋白。MRT-6160在临床前模型中显示出可喜的活性，具有潜力成为多种免疫介导疾病的治疗选择，包括多发性硬化、类风湿性关节炎、炎症性肠病和皮肤病。授权方：百裕制药引进方：诺华合作产品：一款小分子癌症新药 10月17日，百裕制药宣布与诺华签订一款在研抗肿瘤小分子药物的独家许可协议。根据协议，百裕制药将收到7000万美元首付款，以及可达11亿美元的开发、注册及商业化等各类里程碑付款和相应特许使用费。诺华将获得该款小分子创新药的全球独家开发及商业化权利。百裕制药小分子创新药研发团队深耕于肿瘤及自身免疫疾病领域。根据百裕制药官网资料，该公司在研管线中包括了十多款在研产品，其中进展较快的新药为DNA损伤领域的BY1298，以及一款靶向PARP7的肿瘤免疫疗法BY1921。授权方：TRIANA Biomedicines 引进方：辉瑞合作产品：分子胶降解剂 10月16日，TRIANA Biomedicines宣布与辉瑞（Pfizer）公司达成一项战略合作与许可协议，在多种疾病领域（包括肿瘤学）共同开发创新分子胶降解剂。根据合作协议条款，TRIANA将获得4900万美元的预付款，并有资格获得超过15亿美元的潜在里程碑付款。TRIANA将利用其靶点优先和邻近优先（proximity-first）的分子胶发现平台，针对多个靶点发现分子胶降解剂。TRIANA将负责潜在候选药物的发现工作。辉瑞拥有排他性选择权，可以获得独家许可并进一步推进临床前和临床开发。授权方：KeyBioscience 引进方：礼来合作产品：淀素/降钙素受体双重激动剂 10月11日，KeyBioscience公司宣布，已与礼来公司（Eli Lilly and Company）达成协议，扩展在开发淀素/降钙素受体双重激动剂（DACRA）这一创新疗法类型治疗肥胖及相关疾病方面的合作。此次合作包括一款预计在今年晚些时候进入2期临床试验的新DACRA分子，用于治疗肥胖和骨关节炎（OA）患者。根据协议条款，礼来公司将获得全球范围内开发和商业化DACRA分子的权益。KeyBioscience将获得一笔预付款，并在达到特定开发、监管和商业化里程碑时，获得总额高达14亿美元的后续款项。 DACRA是一种多肽类药物，它能够以高亲和力与胰淀素和降钙素受体结合并激发它们的活性，同时并不会与相似的CGRP受体和肾上腺髓质激素受体结合，减少了可能出现的副作用。KeyBioscience对DACRA分子的改造让它们能够持久激活受体，降低减轻体重所需要的注射次数。授权方：Circle Pharma 合作方：勃林格殷格翰合作产品：细胞周期蛋白抑制剂 10月10日，勃林格殷格翰（Boehringer Ingelheim）与Circle Pharma宣布达成新的研究合作和许可协议，将共同开发潜在“first-in-class”的细胞周期蛋白抑制剂，用以治疗难治性癌症患者。根据协议，Circle Pharma将获得高达6.07亿美元的预付款和潜在开发、监管等里程碑付款。 Circle Pharma正在推进通过包含口服等多种给药途径的细胞渗透性大环化合物的发现和开发。Circle Pharma的MXMO平台结合了基于结构的理性药物设计和先进的合成化学，旨在开发新一代大环疗法，用于治疗具有挑战性的靶点，以满足未竟的临床需求。Circle Pharma的开发重点是靶向细胞周期蛋白，该公司的在研主打项目细胞周期蛋白A/B RxL抑制剂CID-078目前正在临床试验中接受评估。授权方：Mestag Therapeutics 引进方：默沙东合作产品：治疗癌症和炎症疾病的创新疗法 10月10日，Mestag Therapeutics公司与默沙东（MSD）达成研发合作和许可协议，将利用其模拟成纤维细胞在人类疾病中病理作用的RAFT技术平台，与默沙东共同发现炎症疾病的创新靶点，用于开发新疗法。 Mestag的技术平台通过发掘成纤维细胞和免疫系统之间的相互作用，开发治疗癌症和炎症疾病的创新疗法。根据协议，默沙东拥有获得针对合作发现的靶点进行进一步开发和商业化的权益。Mestag将获得前期付款以及里程碑付款，总计可高达19亿美元。授权方：LigaChem Biosciences 引进方：Ono Pharmaceutical 合作产品：靶向L1细胞粘附分子的ADC 10月10日，Ono Pharmaceutical公司宣布与LigaChem Biosciences达成研发合作和许可协议，获得潜在“first-in-class”抗体偶联药物（ADC）LCB97，用于治疗实体瘤。LCB97是一款基于ConjuAll平台开发的ADC，靶向L1细胞粘附分子，它在多种实体瘤中高度表达。LCB97在多种小鼠癌症模型中已经表现出强力抗癌效果。 Ono公司同时将与LigaChem Biosciences合作，利用后者专有的ConjuAll技术平台开发新一代ADC。根据协议，Ono获得开发、生产和商业化LCB97用于治疗实体瘤的全球独家权益，LigaChem Biosciences将获得前期付款以及潜在高达7亿美元的里程碑付款。授权方：AviadoBio公司引进方：安斯泰来合作产品：一款基于AAV的基因疗法 10月8日，AviadoBio公司和安斯泰来（Astellas Pharma）宣布就AVB-101达成一项独家选择权和许可协议，安斯泰来将获得基于AAV的基因疗法AVB-101在GRN相关额颞叶痴呆（FTD-GRN）和其他潜在适应症的全球独家开发和商业化许可。根据协议，AviadoBio将获得2000万美元的股权投资和最高3000万美元的预付款。如果安斯泰来公司行使其选择权，AviadoBio公司还有资格获得21.8亿美元的许可费和里程碑付款以及特许权使用费。 AVB-101旨在通过AAV9载体，将一个表达颗粒蛋白前体的正常基因拷贝递送至大脑，以恢复颗粒蛋白前体的正常表达。这种疗法设计为在丘脑内给药，并利用大脑的神经网络提高载体的生物分布，实现基因的最大化广泛表达。该产品于今年4月完成首例患者给药，据AviadoBio公司此前新闻稿介绍，这是首次在人类身上用于治疗成人神经退行性疾病的丘脑内基因治疗。授权方：石药集团引进方：阿斯利康合作产品：小分子降脂药物 10月7日，阿斯利康（AstraZeneca）中国宣布和石药集团达成独家授权协议，推进开发一款临床前创新小分子脂蛋白(a) (Lp(a)) 抑制剂。阿斯利康将获得石药集团临床前候选小分子药物YS2302018，一款口服脂蛋白(a)抑制剂，用于开发新型降脂疗法，以及用于多种心血管疾病的单一疗法或联合疗法，包括与口服小分子PCSK9抑制剂AZD0780联用。根据协议条款，石药集团将获得1亿美元的首付款。此外，石药集团未来还将有资格获得高达19.2亿美元的开发和商业化里程碑付款，以及分级特许权使用费。授权方：锐格医药引进方：罗氏合作产品：下一代CDK抑制剂 10月1日，锐格医药（Regor Pharmaceuticals）宣布，已与罗氏（Roche）旗下基因泰克（Genentech）达成协议。基因泰克将收购锐格医药开发的下一代CDK抑制剂研发管线，用于治疗乳腺癌。根据协议，锐格将获得高达8.5亿美元的前期付款，并有资格获得开发、监管和商业化里程碑付款。基因泰克将负责在研项目的临床开发、生产和全球商业化。锐格将负责继续进行正在进行的两项1期临床试验，直至试验结束。锐格医药基于其独有的计算机加速智能发现（CARD）平台开发创新和差异化疗法，治疗具有高度未满足医疗需求的肿瘤、代谢和自身免疫疾病。该公司的研发管线中包含多种在研疗法，包括用于治疗乳腺癌的CDK4抑制剂RGT-419B、可穿越血脑屏障的CDK4选择性抑制剂RGT-587等。希望在合作的助力下，这些在研新药后续研发进展顺利，早日造福患者。参考资料： [1]各公司官网及公开资料本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

并购引进/卖出抗体药物偶联物基因疗法细胞疗法

2024-10-23

·BioSpace

Circle Pharma’s First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, CID-078, Preclinical Data Highlighted at the 36th EORTC-NCI-AACR Symposium

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- #BreastCancer --Circle Pharma, a clinical-stage biopharmaceutical company dedicated to discovering and developing a new generation of macrocycle therapies, today announced that preclinical data from its lead candidate, CID-078, a first-in-class oral macrocycle cyclin A/B RxL inhibitor, has been selected for a late-breaking poster presentation at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, also known as the Triple Meeting. The symposium is taking place from October 23-25, 2024, in Barcelona, Spain. Poster presentation details are below: Author: Wang et al. Title: CID-078, a First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, Demonstrates Anti-Tumor Activity in ESF-driven Cancers Abstract Number: PB-515 Session Title: Late breaking posters Date and Time: October 23, 2024 (6 a.m. EST/12 p.m. CEST) to October 25, 2024 (11 a.m. EST/5 p.m. CEST) The digital poster can be viewed here. The pre-clinical data shows CID-078 demonstrated single-agent tumor activity across tumor cell line and in vivo models with dysregulated cell cycle (CDK-RB-E2F) function. Notably, tumor regressions were observed in small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC) preclinical models. Within specific indications, CID-078 single agent activity was correlated with RB1 mutation, high E2F target, or G2M checkpoint hallmark pathway scores. The cumulative pre-clinical data suggests that CID-078 holds promise as a monotherapy for patients with these cancers. A multi-center phase 1 clinical trial (NCT06577987) is currently enrolling patients. About CID-078 CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple in vivo models. A multi-center phase 1 clinical trial ( NCT06577987 ) is currently enrolling patients. About Circle Pharma, Inc. South San Francisco-based Circle Pharma is advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle Pharma’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop a new generation of macrocycle therapies for challenging targets to address unmet clinical needs. Circle Pharma is focusing its development efforts on cyclins, which are master regulators of the machinery that controls the progression of cells through the cell cycle and are key drivers in many cancers. To learn more about Circle Pharma, please visit . Contacts Media Contact: Roslyn Patterson 650.825.4099 roslyn.patterson@circlepharma.com

临床1期AACR会议

2024-10-17

·创鉴汇

AI制药领域35家公司Q3获得融资

今年的诺贝尔奖相继揭晓，人工智能（AI）无疑成为了焦点。AI学者不仅摘得了2024年诺贝尔物理学奖，诺贝尔化学奖也颁发给了三位与AI相关领域的科学家。谷歌DeepMind公司的Demis Hassabis博士和John Jumper博士，因其在蛋白质结构预测领域的突破性贡献获奖，他们的研究解决了这一领域50年来的重大挑战。与此同时，华盛顿大学的David Baker教授则因其在计算蛋白设计方面的卓越成就获此殊荣。这些AI驱动的科研成果极大地推动了生物医药领域的科学发现，也彰显了AI在制药领域的潜力和价值。在此背景下，AI制药行业也迎来了蓬勃发展。仅在2024年第三季度，全球至少有35家AI制药公司获得了总计超过10亿美元的融资。值得关注的亮点包括：早期融资占比过半：早期融资（B轮及以前）事件占比近70%；全球共有8家AI制药企业获A轮融资，总融资额超2亿美元，8家初创企业获得种子轮融资，总金额超5000万美元。 Flagship Pioneering先后推出两家新锐公司：Flagship分别投资5000万美元，孵化出了AI助力的基因药物递送平台Mirai Bio和可编程生物制剂研发公司Abiologics。公司类型多元：获得融资的公司中，业务类型涵盖小分子药物发现到细胞疗法研发的众多药物类型，并且以打造AI技术平台的平台型公司和专注于AI辅助药物管线发现的研发型公司数量平分秋色。 BioAge Labs成功登陆纳斯达克，IPO募资1.98亿美元 BioAge Labs是一家抗衰老研究公司，目前共有3个研究方向：代谢和肌肉衰老、免疫衰老和大脑衰老。公司致力于通过绘制人类衰老图谱并利用独有的AI药物发现平台，以开发治疗疾病和延长健康寿命的创新药物。BioAge Labs的主要候选药物Azelaprag是一种口服小分子药物，属于Apelin受体激动剂。该产品正在与礼来GLP-1/GI受体激动剂Tizepatide联合开展减肥2期临床试验，它还将于明年上半年与诺和诺德减肥产品Wegovy联合进入2期试验。 9月26日，BioAge Labs在纳斯达克上市，募资1.98亿美元，该融资所得将用于推动其减肥管线的临床试验。 Outpace Bio完成1.44亿美元B轮融资 Outpace Bio是一家细胞疗法公司，利用人工智能蛋白质设计对免疫细胞进行编程，以改善实体瘤患者体内功能。公司的技术平台致力于利用人工智能，设计具有自然界中没有的全新功能的蛋白和调控回路。并且利用这些全新蛋白和调控回路精密调节细胞的分化状态以及信号通路，从而让它们在合适的时间产生合适的作用。 Outpace Bio的主打项目OPB-101是一种针对间皮素的CAR-T细胞，利用Outpace的专有技术OUTSMART、OUTLAST、OUTSPACER和OUTSAFE进行增强，计划于2025年获得IND许可并首次在晚期铂耐药性上皮性卵巢癌、输卵管癌或原发性腹膜癌患者进行给药。 8月1日，公司宣布完成超额认购的B轮融资，筹集1.44亿美元，获得的资金将用于推进多种T细胞候选疗法，以期在实体肿瘤治疗中获得早期临床概念验证。此外，这些资金还将支持Outpace利用其模块化技术平台扩展未来的产品线。 Superluminal Medicines完成1.2亿美元A轮融资成立于2023年，Superluminal Medicines是一家致力于推动小分子药物研发的速度和准确性的开发差异化药物管线的生成生物和化学公司。公司利用深厚的生物学和化学专业知识、机器学习以及专有的大数据基础设施，快速开发创建候选化合物。平台采用预测-设计-测试架构，精确模拟蛋白质形状，并设计高度选择性的化合物，以达到治疗效果。公司由业内领先的AI药物发现上市公司Schrödinger前高管Cony D'Cruz先生和知名风投RA Capital Management的Ajay Yekkirala先生共同创立。目前，Superluminal的开发重点集中于高价值的G蛋白偶联受体（GPCR）靶点药物的开发。 9月9日，Superluminal Medicines公司宣布完成1.2亿美元的A轮融资。获得资金将用于支持该公司的主打在研项目进入临床开发，并增加针对GPCR靶点的小分子药物发现项目。 Circle Pharma完成9000万美元D轮融资 Circle Pharma是一家致力于包括口服等多种给药途径的细胞渗透性大环化合物的发现和开发的生物技术公司，其MXMO平台结合了基于结构的合理药物设计和先进的合成化学，开发了新一代大环疗法，用于靶向具有挑战性的靶点。目前公司将开发重点放在细胞周期蛋白上，这类蛋白是控制细胞在细胞周期中进展机制的主要调节器，也是许多癌症的关键驱动因素。 9月3日，Circle Pharma宣布完成9000万美元的D轮融资，此轮融资的资金将用于资助其细胞周期蛋白A/B（cyclin A/B）RxL抑制剂CID-078的临床开发。CID-078是一种多肽类抗肿瘤药物，目前处于早期临床阶段。 CytoReason获得8000万美元战略投资 CytoReason是一家致力于开发计算疾病模型的技术公司。该公司使用来自医药合作伙伴的真实数据来构建组织和细胞的特定模型以模拟各种疾病，然后利用其机器学习AI探索这些模型，能够突出不同患者群体和治疗方法之间的差异，潜在地为候选新药确定更有效的进攻路径。 CytoReason的平台是由70名经验丰富的生物学家、生物信息学家和数据工程师组成的多学科团队开发的。该平台使医药和生物技术公司能够优先考虑新目标、寻找生物标志物并预测哪些患者可能对新疗法产生最佳的反应，从而缩短试验阶段、降低开发成本并增加药物获批的可能性。 7月17日，公司宣布获得OurCrowd、英伟达（NVIDIA）、辉瑞（Pfizer）和赛默飞世尔（Thermo Fisher Scientific）总计8000万美元的融资。CytoReason将利用这笔投资将其模型的应用扩展到其他适应症，增加其专有的分子和临床数据。 Mirai Bio获5000万美元A轮融资 Mirai由Flagship Pioneering于2021年创立，旨在提供开源技术平台，与生物技术公司合作开发优化的基因药物（genetic medicines）。公司的技术平台包括高通量自动化、体内多重筛选、机器学习等前沿技术，能够产生大量数据并且通过优化的迭代循环，同时优化基因药物的递送、设计和生产，提高疗法开发的成功率和开发速度。 9月28日，公司宣布获得Flagship Pioneering的5000万美元A轮投资，资金将用于促进该公司技术平台的开发，以及在多个疾病治疗领域和治疗模式中加速基因药物的开发。 Flagship推出新锐公司Abiologics Abiologics是一家通过创造名为Synteins的可编程药物，重新定义生物制品的公司。Synteins是一种在自然界中不存在的全新药物类型，它通过计算设计生成，并使用新型的合成构建块，赋予其独特的特性，能够为各类疾病患者提供变革性的治疗。该公司的技术平台依托先进的生成式人工智能，从头计算设计Synteins，使用广泛的人工构建模块，突破了目前生物制品仅依赖20种天然氨基酸的局限。Synteins能够被编程从而与几乎所有治疗靶点相互作用，并且巧妙地规避身体的自然免疫防御机制。 7月24日，Flagship Pioneering初步承诺投资5000万美元以推进该公司的平台并开发多样化的药物管线，初步重点是肿瘤学和免疫学适应症。读者们请星标⭐创鉴汇，第一时间收到推送免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转发/复制至其他平台。转发授权请在「创鉴汇」微信公众号留言联系我们。更多数据内容推荐点击“在看”，分享创鉴汇健康新动态

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药物(靶点)	适应症	全球最高研发状态

Cyclin A/B抑制剂(Circle) ( CCNB1 x cyclin-A )	三阴性乳腺癌更多	临床1期
CXCR7 modulator (Circle Pharma) ( ACKR3 )	-	临床前
CID-016 ( CCNB1 x cyclin-A )	三阴性乳腺癌更多	临床前
Cyclin E抑制剂(Circle) ( CCNE1 )	肿瘤更多	临床前
Macrocyclic peptides targeting p53(Circle Pharma) ( p53 )	肿瘤更多	药物发现