▎药明康德内容团队编辑
本期看点
1. 泛RAS抑制剂RMC-6236在携带RAS突变或野生型RAS的晚期实体瘤患者中展现出令人鼓舞的抗肿瘤活性和安全性，携带任意RAS突变的胰腺导管腺癌（PDAC）患者的6个月生存率达97%。
2. 在肿瘤激活T细胞接合器（TRACTr）JANX007治疗晚期或转移性去势抵抗性前列腺癌（mCRPC）患者的1a期临床试验中，100%的患者达到PSA 50（PSA水平下降≥50%）标准。
3. 在一项早期临床试验中，DFP-17729联用TS-1作为晚期胰腺癌患者三线或三线以上治疗，与对照治疗相比能够显著延长患者的中位总生存期（OS）近3个月。
药明康德内容团队整理
RMC-6236：公布两项1/1b期临床试验的新数据
Revolution Medicines公司公布了其在研泛RAS抑制剂RMC-6236的 。RMC-6236是一款口服、可靶向突变和野生型RAS在GTP结合（具活性，ON）状态下的选择性抑制剂。此次公布的1/1b期多中心、开放标签、剂量递增和剂量扩展研究RMC-6236-001旨在评估RMC-6236作为单药治疗携带RAS突变或野生型RAS晚期实体瘤患者的效果。
分析显示，RMC-6236单药作为转移性PDAC患者二线疗法时显示出显著疗效，支持3期临床试验RASolute 302的持续推进，具体数据如下：
▲接受RMC-6236单药治疗PDAC患者的总生存率结果（图片来源：参考资料[2]）
KRAS G12X突变患者（n=22）：中位无进展生存期（PFS）为8.8个月（95% CI：8.5个月–不可估计[NE]），中位OS仍不可估计（95% CI：NE–NE）。
任意RAS突变患者（n=37）：中位PFS为8.5个月（95% CI：5.9个月–NE），中位OS仍不可估算（95% CI：8.5个月–NE）。
6个月生存率：KRAS G12X突变患者为100%，任意RAS突变患者为97%。
客观缓解率（ORR）：KRAS G12X突变患者为36%，任意RAS突变患者为27%。
▲接受RMC-6236治疗NSCLC患者的总生存期结果（图片来源：参考资料[2]）
RMC-6236在经治NSCLC患者中的表现同样亮眼。截至2024年9月30日，最新数据涵盖了124名携带RAS突变的经治NSCLC患者，这些患者接受了每日一次120至300毫克的RMC-6236治疗。在此剂量范围内，RMC-6236展现良好的耐受性。在40名二线或三线NSCLC患者（这些患者既往接受过免疫疗法和铂类化疗，但未接受多西他赛）中，中位PFS为9.8个月（95% CI：6–12.3个月），中位OS为17.7个月（95% CI：13.7个月–NE），ORR为38%。
JANX007：公布1a期临床试验数据
Janux Therapeutics公司公布了在研疗法JANX007的积极 。JANX007目前正在针对晚期或转移性去势抵抗性前列腺癌患者进行的1a期临床试验中接受评估。JANX007是一款靶向前列腺特异性膜抗原（PSMA）的肿瘤激活T细胞接合器，分别靶向PSMA和T细胞表面表达的CD3受体。它的设计让JANX007在肿瘤微环境中经过蛋白酶切割而被激活，从而在降低了其潜在毒性的同时，最大化抗肿瘤免疫反应。
截至2024年11月15日的数据，共有16名患者以每周一次的给药方案接受2-9 mg的目标剂量治疗。在所有剂量组中均观察到了高比例的PSA应答率和显著的PSA水平下降：100%的患者达到PSA 50标准，63%的患者达到PSA 90，31%的患者达到PSA 99。在目标剂量≥2 mg时，PSA下降具有持久性：75%的患者在≥12周内维持PSA 50，50%的患者在≥12周内维持PSA 90。不论患者的耐药驱动基因状态或是否接受过紫杉烷类药物或其它药物治疗，均观察到了深度且持久的PSA应答。在可按RECIST评估的患者中，观察到抗肿瘤活性，50%（4/8）的患者出现确认或未确认的部分缓解。
安全性方面，JANX007耐受性良好，细胞因子释放综合征（CRS）及CRS相关的不良事件主要局限于治疗第一个周期，且为1级和2级。同样，与治疗相关的不良事件（TRAEs）主要也局限于第一个周期，且为1级和2级。目前尚未达到JANX007的最大耐受剂量。
DFP-17729：公布1/2a期临床试验的新数据
Delta-Fly Pharma公司宣布，DFP-17729联用TS-1或TS-1单药作为晚期胰腺癌患者的三线后治疗的2/3期临床试验已获日本医药品医疗器械综合机构（PMDA）批准。DFP-17729是一种新型方法，旨在中和酸性的肿瘤微环境。该公司首先评估了DFP-17729作为难治性胰腺癌的治疗方法，未来将寻求把其适应症扩展到其他类型的癌症。
在针对晚期胰腺癌患者的1/2期研究中，与对照治疗（TS-1或吉西他滨）相比，接受DFP-17729联用TS-1作为三线或三线以上治疗超过6周的患者的中位OS有显著延长（9.0个月对比6.1个月）。此外，在接受DFP-17729治疗的胰腺癌患者中，尿液碱化与中位OS之间存在显著相关性，可作为关键的概念验证。
MBX 2109：公布1期临床试验数据
MBX Biosciences公司宣布在The Journal of Clinical Endocrinology and Metabolism杂志上发表了其候选疗法MBX 2109的1期研究结果。MBX 2109是其基于精确内分泌肽（PEP）平台开发的甲状旁腺激素（PTH）多肽前药，能够以一周一次的给药频率，提供长效的PTH活性，旨在作为治疗甲状旁腺功能减退症（HP）的潜在长效激素替代疗法。此药物于2022年7月获得美国FDA的孤儿药资格，用于治疗HP。
此次公布的结果显示，MBX 2109的前药和活性药物的半衰期均较长，分别为79-95小时和184-213小时，支持每周一次的给药频率。每周给药后，药物在体内的浓度变化相对平稳，峰谷比值根据给药剂量的不同在1.47到1.79之间。此外，观察到与剂量成正比增加的白蛋白调整后的血清钙浓度以及内源性PTH（1-84）的抑制，这与健康受试者中预期的PTH药理学效果一致。安全性方面，MBX 2109重复给药在所有测试剂量下通常耐受性良好，大多数不良反应轻微，最常见的问题是注射部位反应，没有报告与药物剂量相关的严重不良事件或死亡。
RES-010：在荷兰启动1期临床试验
Resalis Therapeutics公司宣布启动RES-010的首次人体1期研究。RES-010是一种靶向脂质生物合成、线粒体功能和脂肪组织转化的主要调节因子miR-22的反义寡核苷酸（ASO）疗法，旨在重编程代谢途径，对肥胖和脂肪肝疾病具有持久的疾病缓解治疗作用。临床前研究表明，RES-010能减少脂肪量、保持瘦体重并增强能量消耗。RES-010以减少身体各部位（包括内脏和肝脏）的脂肪为目标，有望补充和增强现有抗肥胖药物（如GLP-1受体激动剂）的疗效，支持可持续的长期体重管理。1期临床试验将在健康、超重和中度肥胖受试者中探索RES-010的安全性、耐受性、药代动力学、药效学和疗效。
SRSD107：公布1期临床试验数据
Sirius Therapeutics公司宣布，其用于预防和治疗血栓栓塞性疾病的下一代小干扰RNA（siRNA）疗法SRSD107的1期临床试验的初步数据将在第66届美国血液学会（ASH）年会上公布。SRSD107是该公司开发的新型双链siRNA，特异性靶向编码人凝血因子XI（FXI）的mRNA并抑制FXI蛋白表达，从而阻断内在凝血途径并促进抗凝/抗血栓作用。此次公布的结果显示，SRSD107具有良好的安全性和有效性，可以预防血栓形成事件，并且不会增加出血风险，有望为需要慢性抗凝剂的患者提供只需每半年一次甚至每年一次的治疗。该公司计划在未来几个月内开始2期研究。
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参考资料（可上下滑动查看）
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[10] Senti Bio Announces Positive Initial Clinical Data in Phase 1 Clinical Trial of SENTI-202, a Logic Gated, Selective CD33/FLT3-Targeting CAR-NK Cell Therapy for the Treatment of Relapsed/Refractory Hematologic Malignancies Including AML. Retrieved December 2, 2024, from https://www.globenewswire.com/news-release/2024/12/02/2989665/0/en/Senti-Bio-Announces-Positive-Initial-Clinical-Data-in-Phase-1-Clinical-Trial-of-SENTI-202-a-Logic-Gated-Selective-CD33-FLT3-Targeting-CAR-NK-Cell-Therapy-for-the-Treatment-of-Relap.html
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[18] MAPLIGHT THERAPEUTICS ANNOUNCES RESULTS FROM PHASE 1 TRIAL OF NOVEL M1/M4 MUSCARINIC AGONIST IN DEVELOPMENT FOR TREATMENT OF SCHIZOPHRENIA AND ALZHEIMER'S DISEASE PSYCHOSIS. Retrieved December 6, 2024, from https://www.prnewswire.com/news-releases/maplight-therapeutics-announces-results-from-phase-1-trial-of-novel-m1m4-muscarinic-agonist-in-development-for-treatment-of-schizophrenia-and-alzheimers-disease-psychosis-302317925.html
[19] Palisade Bio Announces Preliminary Data from Phase 1 Clinical Study of PALI-2108 for the Treatment of Moderate-to-Severe Ulcerative Colitis Appears to be Safe and Well Tolerated in Treated Subjects. Retrieved December 6, 2024, from https://www.globenewswire.com/news-release/2024/12/03/2990602/0/en/Palisade-Bio-Announces-Preliminary-Data-from-Phase-1-Clinical-Study-of-PALI-2108-for-the-Treatment-of-Moderate-to-Severe-Ulcerative-Colitis-Appears-to-be-Safe-and-Well-Tolerated-in.html
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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。
