SHANGHAI--(BUSINESS WIRE)--D3 Bio, a global clinical stage biotechnology company focusing on discovery, development, and registration of innovative cancer drugs, announced that its lead compound, a next-generation KRAS G12C inhibitor, D3S-001, demonstrated rapid target engagement, overcame the limiting factors of nucleotide cycling and RTK activation, and showed robust preclinical and clinical activities in KRAS G12C-mediated cancers, in a study published in Cancer Discovery..

上海--（商业新闻短讯）--D3 Bio是一家专注于创新癌症药物的发现，开发和注册的全球临床阶段生物技术公司，在《癌症发现》杂志上发表的一项研究中宣布，其先导化合物，下一代KRAS G12C抑制剂D3S-001，表现出快速的靶标参与，克服了核苷酸循环和RTK激活的限制因素，并在KRAS G12C介导的癌症中显示出强大的临床前和临床活性。。

In a paper titled, “A KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities”, researchers from D3 Bio and its collaborators demonstrated that D3S-001 performed significantly better than other KRAS G12C inhibitors in multiple pre-clinical and clinical studies designed to profile the class of KRAS G12C small molecule inhibitors.

在一篇题为“具有快速靶标参与动力学的KRAS G12C抑制剂，克服了核苷酸循环，并表现出强大的临床前和临床活性”的论文中，D3 Bio及其合作者的研究人员证明，D3S-001在多项临床前和临床研究中的表现明显优于其他KRAS G12C抑制剂，旨在分析KRAS G12C小分子抑制剂的类别。

Specifically, D3S-001 demonstrated substantially improved covalent potency and better and faster target engagement (TE) kinetics, compared to the approved drugs (sotorasib and adagrasib) in the class. This suggests that D3S-001 has the potential to “lock” KRAS G12C in its inactive (GDP-bound) state more efficiently, possibly resulting in cellular active KRAS depletion in clinically relevant doses.

具体而言，与该类批准的药物（索托拉西布和阿达格拉西布）相比，D3S-001表现出显着改善的共价效力和更好更快的靶标参与（TE）动力学。这表明D3S-001有可能更有效地将KRAS G12C“锁定”在其非活性（GDP结合）状态，可能导致临床相关剂量的细胞活性KRAS消耗。

In addition, D3S-001's high potency and rapid kinetics allow it to block the GDP-to-GTP transition even in the presence of growth factors. In contrast, first-generation G12C inhibitors are less effective in these conditions, which may contribute to their limited clinical efficacy..

此外，D3S-001的高效能和快速动力学使其即使在存在生长因子的情况下也能阻止GDP向GTP的转变。相反，第一代G12C抑制剂在这些情况下效果较差，这可能导致其临床疗效有限。。

In cell line and patient-derived tumor xenograft models across multiple cancer types, D3S-001 demonstrated significantly more robust anti-tumor responses than the other KRAS G12C inhibitors in the study. Importantly, these include a delay in disease progression in tumors that were resistant to an FDA-approved KRAS G12C inhibitor.

在多种癌症类型的细胞系和患者来源的肿瘤异种移植模型中，D3S-001表现出比研究中其他KRAS G12C抑制剂更强大的抗肿瘤反应。重要的是，这些包括延迟对FDA批准的KRAS G12C抑制剂具有抗性的肿瘤的疾病进展。

D3S-001 also exhibited brain penetration properties, resulting in durable intracranial tumor regression in mouse models with brain metastases..

D3S-001还表现出脑穿透特性，导致脑转移小鼠模型中持久的颅内肿瘤消退。。

Citing the ongoing D3S-001 Phase 1/2 trial in KRAS G12C-mediated solid tumors, the study noted that durable RECIST responses were observed across all dose cohorts, as well as systemic and intracranial anti-tumor activity in two highlighted patients with non-small cell lung cancer (NSCLC) enrolled in the first dose cohort of this trial..

引用正在进行的在KRAS G12C介导的实体瘤中进行的D3S-001 1/2期试验，该研究指出，在所有剂量组中均观察到持久的RECIST反应，以及两名突出的非小细胞肺癌（NSCLC）患者的全身和颅内抗肿瘤活性参加了该试验的第一个剂量组。。

The researchers conclude that D3S-001 is a next-generation GDP-bound KRAS G12C inhibitor with robust antitumor preclinical activity and promising durable responses in the ongoing clinical trial, which could overcome the limitations of the first-generation drugs.

研究人员得出结论，D3S-001是下一代GDP结合的KRAS G12C抑制剂，具有强大的抗肿瘤临床前活性，在正在进行的临床试验中具有持久的反应前景，可以克服第一代药物的局限性。

Separately, in an oral presentation at the ESMO Congress 2024, dose-escalation data from the D3S-001 Phase 1 clinical trial in 42 patients of locally advanced or metastatic KRAS G12C-mutated cancers with prior systemic treatments was presented. The presenter and trial investigator, Byoung Chul Cho, MD, PhD, Professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine and Chief of Lung Cancer Center at Yonsei Cancer Center, Yonsei University College of Medicine, highlighted that D3S-001 functionally abolishes the KRAS G12C transition from GDP-bound (inactive) state to the GTP-bound (active) state, depleting cellular active KRAS, even in the presence of growth factor stimulation.

。主持人兼试验研究者Byoung Chul Cho，医学博士，博士，延世大学医学院延世癌症中心医学肿瘤学系教授，延世大学医学院延世癌症中心肺癌中心主任，强调D3S-001在功能上消除了KRAS G12C从GDP结合（非活性）状态向GTP结合（活性）状态的转变，即使在生长因子刺激的情况下也会消耗细胞活性KRAS。

Results from the Phase 1a dose-escalation study (42 patients in total) showed favorable tolerability across different dose levels, with no maximum-tolerated dose reached. In addition, D3S-001 demonstrated consistent and promising efficacy in the G12C-inhibitor naïve population, with a confirmed overall response rate (ORR) of 73.5% across tumor types.

。此外，D3S-001在未使用G12C抑制剂的人群中表现出一致且有希望的疗效，在各种肿瘤类型中，确诊的总有效率（ORR）为73.5%。

Researchers also observed brain tumor shrinkage in patients with brain metastases and a rapid, sustained reduction of mutant allele frequency (MAF), which measures mutated genes, in circulating tumor cell DNA (ctDNA) as early as Day 8 post-treatment. Expansion study cohorts are ongoing and focus on monotherapy and combination therapy regimens in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC)..

研究人员还观察到，早在治疗后第8天，脑转移患者的脑肿瘤缩小，以及循环肿瘤细胞DNA（ctDNA）中突变等位基因频率（MAF）的快速持续降低，MAF可测量突变基因。扩展研究队列正在进行中，重点是非小细胞肺癌（NSCLC），结直肠癌（CRC）和胰腺导管腺癌（PDAC）的单药治疗和联合治疗方案。。

“While promising, the first generation of KRAS G12C inhibitor class has exhibited limited durability in the clinic, which could be addressed by a more efficient mode of action,” said Dr. Cho. “This paper, demonstrating that D3S-001 has a more robust covalent potency and rapid target engagement kinetics, unaffected by RTK activation, unveils a novel mode of action that correlates with pre-clinical anti-tumor activity and promising Phase 1 clinical results.

Cho博士说：“虽然前景看好，但第一代KRAS G12C抑制剂在临床上表现出有限的耐久性，这可以通过更有效的作用方式来解决。”。“本文证明D3S-001具有更强大的共价效力和快速的靶标参与动力学，不受RTK激活的影响，揭示了一种与临床前抗肿瘤活性和有希望的1期临床结果相关的新型作用模式。

Furthermore, the study shows, for the first time, that GDP-bound KRAS G12C inhibitors can deplete cellular-active KRAS as efficiently the GTP-bound inhibitor class, suggesting that D3S-001 could address the issues that have challenged this class of drugs.”.

此外，该研究首次表明，GDP结合的KRAS G12C抑制剂可以像GTP结合的抑制剂类别一样有效地消耗细胞活性KRAS，这表明D3S-001可以解决挑战这类药物的问题。”。

“Believing that a next-generation KRAS-G12C inhibitor with significantly improved target inhibition efficiency could become the backbone of a new standard of care for cancers carrying KRAS G12C mutations and provide profound clinical advantages, we selected D3S-001 for its superior covalent potency and differentiated target engagement kinetics,” said George Chen, MD, Founder, Chairman and CEO, D3 Bio.

D3 Bio创始人、董事长兼首席执行官George Chen博士说：“我们相信具有显着提高靶向抑制效率的下一代KRAS-G12C抑制剂可以成为携带KRAS G12C突变的癌症新标准治疗的骨干，并提供深远的临床优势，因此选择D3S-001具有优异的共价效力和差异化的靶向参与动力学。”。

“This study validates our strategy of discovering a next-generation and differentiated G12C inhibitor with rapid target engagement to deliver more efficacious clinical activity. At the ESMO 2024 Congress, we presented Phase 1 data from 42 patients, showing a consistent and clinically meaningful response across all cancer types.

“这项研究验证了我们发现下一代分化G12C抑制剂的策略，该抑制剂具有快速的靶向参与，以提供更有效的临床活性。在ESMO 2024年大会上，我们介绍了42名患者的第一阶段数据，显示了所有癌症类型的一致且具有临床意义的反应。

We are excited with the progress of D3S-001, a potential best-in-class compound, and expect to report topline Phase 2 data in 2025.”.

我们对D3S-001（一种潜在的同类最佳化合物）的进展感到兴奋，并期望在2025年报告topline第二阶段数据。”。

About D3S-001

关于D3S-001

D3S-001 is a next-generation KRAS G12C inhibitor designed to enhance KRAS G12C target engagement. In preclinical investigations, D3S-001 has demonstrated high covalent potency, the ability to rapidly and completely engage the KRAS G12C target at clinically relevant doses and CNS penetration properties.

D3S-001是下一代KRAS G12C抑制剂，旨在增强KRAS G12C靶标的参与。在临床前研究中，D3S-001表现出高共价效力，能够在临床相关剂量和中枢神经系统穿透特性下快速完全参与KRAS G12C靶标。

D3S-001 is currently in a Phase 2 global clinical trial in patients with advanced solid tumors harboring a KRAS G12C mutation, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other tumor types. For detailed information about D3S-001, please refer to the highlighted Research Article published at the 2024 September issue of Cancer Discovery, titled “D3S-001, A KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities” (Cancer Discovery 1 September 2024; 14 (9): 1675–1698.

D3S-001目前正在对患有KRAS G12C突变的晚期实体瘤患者进行2期全球临床试验，包括非小细胞肺癌（NSCLC），结直肠癌（CRC）和其他肿瘤类型。有关D3S-001的详细信息，请参阅2024年9月出版的《癌症发现》杂志上发表的重点研究文章，题为“D3S-001，一种具有快速靶标参与动力学的KRAS G12C抑制剂，克服了核苷酸循环，并表现出强大的临床前和临床活动”（癌症发现2024年9月1日；14（9）：1675-1698）。

https://doi.org/10.1158/2159-8290.CD-24-0006). D3S-001 has received US FDA Orphan Drug Designation (ODD) for the treatment of pancreatic cancer and Fast Track Designation (FTD) for the treatment of late-line non-small cell lung cancer (NSCLC) and colorectal cancer (CRC)..

https://doi.org/10.1158/2159-8290.CD-24-0006)。D3S-001已获得用于治疗胰腺癌的美国FDA孤儿药指定（ODD）和用于治疗晚期非小细胞肺癌（NSCLC）和结直肠癌（CRC）的快速通道指定（FTD）。。

For more on the D3S-001 clinical trial, please go to: https://clinicaltrials.gov/study/NCT05410145?intr=D3S-001&rank=1

有关D3S-001临床试验的更多信息，请访问：https://clinicaltrials.gov/study/NCT05410145?intr=D3S-001等级=1（&R）

About D3 Bio

关于D3 Bio

D3 Bio is a global biotechnology company that focuses on the discovery, development, and registration of new medicines in oncology and immunology. The D3 Bio discovery and development platform leverages our proprietary clinical insight and biomarker strategy to guide discovery and development for the creation of novel and clinically meaningful new therapies for patients in need..

D3 Bio是一家全球生物技术公司，专注于肿瘤和免疫学新药的发现，开发和注册。D3生物发现和开发平台利用我们专有的临床见解和生物标志物策略来指导发现和开发，为有需要的患者创造新颖且具有临床意义的新疗法。。

D3 Bio is funded by Boyu Capital, Matrix Partners China, HongShan China, Temasek, WuXi AppTec's Corporate Venture Fund, and Medicxi.

D3 Bio由博宇资本、Matrix Partners China、洪山中国、淡马锡、无锡AppTec的企业风险基金和Medicxi资助。