Elraglusib

点击蓝字 关注我们 本 期 看 点 胰腺癌素有“癌中之王”之称，预后极差、治疗选择有限。近年来，随着分子通路研究的深入，针对KRAS突变驱动的信号异常成为新的突破口。最新研究显示，MEK抑制剂及GSK-3β抑制剂联合吉西他滨-白蛋白紫杉醇等化疗方案在胰腺癌一线治疗中展现出令人鼓舞的生存获益。该策略通过阻断RAS/RAF/MEK/ERK及Wnt/GSK-3β通路的双重信号轴，重塑肿瘤细胞代谢与免疫微环境，显著延长无进展生存期（PFS）并改善总生存（OS）。从传统化疗主导到分子靶向联合的精准治疗时代，胰腺癌正迎来新的转折点——这一“破局”方案不仅为KRAS突变型患者提供了新的治疗希望，也为未来免疫联合、代谢靶向等多维策略奠定了基础。 本期内容 01 MEK抑制剂+化疗丨胰腺癌一线 02 GSK-3β抑制剂+化疗丨胰腺癌一线 03 GSK-3β抑制剂纵览 04 总结与展望 【01 MEK抑制剂+化疗丨胰腺癌一线】 2025年9月，Immuneering公司宣布了其正在进行的atebimetinib（IMM-1-104）联合改良吉西他滨/白蛋白紫杉醇（mGnP）在一线胰腺癌患者（N=34）中的Ⅱa期临床试验最新结果。 中位随访9个月的数据展示了积极的生存与安全性信号。这标志着公司在治疗这一最致命、最具耐药性的实体瘤领域迈出了重要一步。 Immuneering首席执行官Ben Zeskind博士表示： “总生存期是肿瘤学的金标准，也是Immuneering自始至终的目标。在癌症治疗中，没有什么比延长患者生存并帮助他们重获生活质量更重要。我们非常激动地看到，先前公布的6个月94%的总生存率不仅在更长随访中得以保持，而且9个月86%的总生存率与标准治疗基准的差距进一步扩大。如此显著的生存优势与良好的耐受性相结合，可能真正改变一线胰腺癌的治疗格局。” 在一线胰腺癌患者（N=34）中，中位随访9个月时，Atebimetinib（320 mg，每日一次）+ mGnP 展现出卓越的总生存期（OS）和无进展生存期（PFS）。相比之下，标准治疗（吉西他滨/白蛋白紫杉醇的MPACT关键试验）在9个月时的OS和PFS明显较低。 9个月OS：接受atebimetinib + mGnP治疗的患者为 86%；截至数据截止日，中位OS尚未达到；而标准治疗约为 47%。 6个月OS：此前公布的数据为 94%；标准治疗为 67%。 9个月PFS：联合治疗组为 53%；标准治疗约为 29%。 6个月PFS：联合治疗组为 70%；标准治疗约为 44%。 Atebimetinib联合治疗总生存率结果 截至数据截止日，在一线胰腺癌患者（N=34）中，Atebimetinib（320 mg，每日一次）+ mGnP 继续展现出良好的耐受性。仅有两类不良事件在超过10%的患者中出现3级水平（中性粒细胞减少和贫血，均为标准化疗常见的不良反应）。未发现新的安全性信号。 所有数据均基于2025年8月26日的数据截止日，来自与6月公布相同的患者队列（N=34）。其中，关于9个月随访的标准治疗数据为公司根据公开可得的第三方 MPACT 关键试验结果进行推算和重建；而6个月随访的标准治疗数据则直接引用自该试验的公开结果。需注意，公司正在进行的 Atebimetinib 1/2a 期临床试验并未与其他药物直接头对头对比，跨试验比较时应保持谨慎。 公司认为，这些令人信服的最新生存数据，显示出 Atebimetinib + mGnP 具备带来持久且复合生存获益的潜力。 Atebimetinib 是一种深度循环抑制剂（Deep Cyclic Inhibitor，DCI）：靶向治疗的新范式Immuneering 的专有 DCI 挑战了肿瘤学中传统的“持续抑制”模式。 传统疗法通常依赖持续抑制，肿瘤因此快速适应并产生耐药性，导致肿瘤缩小虽快但难以持久； DCI 的设计理念是以快于肿瘤适应的脉冲方式抑制，使肿瘤缓慢但持久缩小 。 Atebimetinib 靶向 MEK：更广泛且潜在更持久的治疗策略MEK 是 MAPK 通路（RAS-RAF-MEK-ERK）的关键调控点，该通路在多数癌症中被病理性激活，在胰腺癌中比例更高达 97%。靶向 MEK 可以阻断更下游的关键信号，从而覆盖更广泛的通路异常，具备获得更持久临床获益的潜力。 但也需要注意的是该研究尚存在诸多局限性： 样本量与随访：N=34、随访中位9个月，中位OS未达属利好但仍需更长期观察。 跨试验比较风险：历史对照易受人群差异、管理差异影响，慎作过度推断。 尚需更完整的客观缓解（ORR）/亚组与转化标志物数据来指导精准用药。 未来展望 预计 2025年Q4 获得关键试验设计反馈；2025年底有望启动 Ⅲ期（一线 mGnP 联合）。2026年拟开启更多联合臂，包含 NSCLC 等 MAPK 驱动肿瘤；并建议并行推进生物标志物（ctDNA 动力学、MAPK 信号、免疫微环境）与真实世界研究（RWE）。 若Ⅲ期结果延续当前趋势，Atebimetinib + mGnP有望成为胰腺癌患者的新标准方案。 02 GSK-3β抑制剂+化疗丨胰腺癌一线 2025年ASCO大会上，胰腺癌领域迎来新突破：GSK-3β抑制剂Elraglusib联合标准化疗方案（吉西他滨+白蛋白紫杉醇），在转移性胰腺导管腺癌（PDAC）一线治疗中展现良好的疗效！2期Actuate-1801试验3B部分数据显示，该组合疗法显著延长患者总生存期（OS），有望为胰腺癌的治疗重塑标准。 研究背景： Elraglusib（9-ING-41）是首个GSK-3β抑制剂，在小鼠胰腺癌模型中，elraglusib联合化疗增强了抗肿瘤效果和生存率。在单臂临床研究中，elraglusib/GnP在mPDAC患者中显示出抗肿瘤活性和延长的生存期。 研究方法： 该研究为开放标签，2期临床研究，既往未接受治疗的mPDAC患者按2:1的比例随机分配至GnP联合elraglusib（9.3 mg/kg，每周一次静脉注射）组或单独GnP组。 主要终点是主要分析集的1年总生存率（OS）。次要终点包括疾病控制率（DCR）、客观缓解率（ORR）、中位无进展生存期（mPFS）以及治疗期间出现的不良事件（TEAEs/TRAEs）。计划纳入207例可评估患者（elraglusib/GnP组130例，GnP组77例）。研究于2024年2月完成入组。 研究结果： 截至2024年11月15日（初步数据截止日期），主要分析集包括elraglusib/GnP组155例患者和GnP组78例患者，其中男性占52.8%，ECOG PS 1分占57.5%。elraglusib/GnP组的中位（范围）CA 19-9水平为1568 U/mL（1至381,904 U/mL），GnP组为1590 U/mL（2至501,000 IU/mL）。 具体疗效数据如下： 此外，多种生物标志物（包括IFNβ和PD-L1）似乎是OS的预测因子，有待于进一步确认。elraglusib/GnP最常见的治疗相关不良事件（TRAE）是1-2级一过性视力损害，发生在>60%的患者中（GnP组为9%）。elraglusib/GnP组中≥3级TEAEs发生率为89.7%，GnP组为80.8%。elraglusib/GnP组最常见的≥3级TEAEs（vs GnP组）为中性粒细胞减少症51.6%（vs 29.5%）、贫血24.5%（vs 29.5%）和疲劳16.1%（vs 5.1%）。 研究结果： 初步结果显示，与GnP相比，elraglusib/GnP在1年OS和mOS方面具有统计学显著优势，且在ORR和DCR方面呈现出有利趋势，同时安全性可控。GnP组的mOS低于MPACT和NAPOLI-3研究，但与近期真实世界荟萃分析相当，这可能是由于本研究中疾病负担较重且前4个月死亡率较高。  Elraglusib丨在研进展梳理 作为重磅潜力产品，elraglusib也在加速适应症扩展与全球布局，主要整理如下： 孤儿药资格：2023年获FDA胰腺癌孤儿药资格，2024年扩展至软组织肉瘤。   多癌种探索：   尤文氏肉瘤：早期试验中，6例患者2例完全缓解，生存期超900天。   软组织肉瘤：联合吉西他滨+多西他赛，疾病控制率42.6%，中位PFS达5.6个月。   商业化冲刺：2025年下半年启动美欧新药申请（NDA），III期全球多中心试验筹备中。   【03 GSK-3β抑制剂纵览】 GSK-3β 是哺乳动物真核细胞中广泛存在的丝氨酸/苏氨酸激酶，高度保守，通过磷酸化调控超 100 种底物蛋白，参与细胞多项生命活动。在代谢调控中，它是胰岛素信号通路关键节点，能抑制糖原合成酶活性，影响血糖稳态及细胞能量平衡。在信号通路方面，磷酸化 β-catenin 抑制肿瘤发生，受 Akt 磷酸化后失活参与细胞存活与凋亡平衡，还通过炎症因子调控免疫应答。同时，它能磷酸化相关蛋白调控细胞周期进程及凋亡相关蛋白活性。 GSK-3β活性的调控机制 （来源：DOI: 10.7717/peerj.16635/fig-1） 在疾病中，GSK-3β 角色复杂。在肿瘤领域，它既能促癌，如在胰腺癌、结肠癌中高表达促进细胞增殖转移，又能抑癌，如在胃癌、肺癌中诱导细胞凋亡延缓肿瘤进展。在神经退行性疾病中，它异常磷酸化 Tau 蛋白导致神经原纤维缠结，加速神经元死亡。在代谢性疾病中，它抑制胰岛素信号传导致胰岛素抵抗，促进胰岛 β 细胞凋亡加剧糖尿病进展。 GSK-3β 抑制剂研发有多种类型，包括 ATP 竞争性抑制剂、非 ATP 竞争性抑制剂及天然产物抑制剂，各有优缺点。临床有突破性药物如 Elraglusib、AR-A014418 等。 虽然GSK-3β 抑制剂前景广阔，但研发面临选择性难题、耐药性机制、长期安全性及精准医疗等挑战，未来需开发亚型特异性抑制剂、探索联合疗法、建立动态监测体系、基于生物标志物分层治疗。总之，GSK-3β 抑制剂研发正迈向多维度干预，有望在多领域实现突破应用，开启精准治疗新时代。 04 讨论与总结 在过去二十年里，胰腺癌几乎被视为“药物研发的荒原”。FOLFIRINOX与吉西他滨-白蛋白紫杉醇的出现虽略有改善，但总体生存期依然徘徊在一年上下，五年生存率不足10%。如今，以MEK抑制剂与GSK-3β抑制剂为代表的信号通路靶向策略正在重新定义胰腺癌治疗的逻辑，期望胰腺癌能够早日迎来具有长生存获益的创新药的获批上市的一天。 ★

Elraglusib represents a potential back bone therapy in pancreatic cancer with three ongoing trials in combination with current standards of care and novel immunotherapies Recent financing provides extended runway through key anticipated regulatory inflection points Additional nonclinical studies are ongoing combining elraglusib with RAS inhibitors based on potential synergies and complimentary mechanisms of action CHICAGO and FORT WORTH, Texas, Sept. 22, 2025 (GLOBE NEWSWIRE) — Actuate Therapeutics, Inc. (NASDAQ: ACTU) (“Actuate” or the “Company”), a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers through the inhibition of glycogen synthase kinase-3 beta (GSK-3β), today announced a corporate update on the regulatory path for elraglusib in pancreatic cancer and anticipated milestones enabled by the recent $17.25 million public offering. Actuate has amended its investigational new drug (IND) application with updated clinical data from its international randomized Phase 2 trial in first-line treatment of metastatic pancreatic cancer (Actuate-1801 Part 3B), which showed a statistically significant improvement in median overall survival with the combination arm of elraglusib plus gemcitabine/nab-paclitaxel (GnP) versus GnP alone. These data are intended to support planned regulatory submissions with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) beginning later this year and continuing into early 2026. The 1801-3β Phase 2 study is currently ongoing, with 22 patients in the elraglusib plus GnP arm either in active treatment or survival follow-up, ranging from 20 to 42 months in time on study, while only 3 patients remain in survival follow-up in the GnP arm, with time on study ranging from 21 to 23 months. These compelling results of elraglusib in combination with GnP, combined with early data demonstrating significant and durable long term responses in patients with highly metastatic disease treated with the combination of elraglusib/FOLFIRINOX/losartan in the ongoing clinical trial in patients with mPDAC led by Havard/MGH, plus the new clinical collaboration with Incyte and UPMC Hillman Cancer Center in patients with advanced pancreatic cancer using the combination of modified FOLFIRINOX and Incyte’s anti-PD-1 retifanlimab, further strengthen the case for elraglusib as a back-bone therapy that can be combined with different regimens used to treat this highly aggressive and deadly disease. “We are confident that our recently completed financing provides sufficient capital to support our corporate initiatives into the second half of 2026, and well through our upcoming anticipated interactions with the FDA and EMA. We have already updated the clinical data package on file with the FDA, and during the remainder of this year and into the first quarter of 2026, we expect to gain clarity on elraglusib’s regulatory path forward for the first-line treatment of metastatic PDAC,” said Daniel Schmitt, President & Chief Executive Officer of Actuate. “The survival benefit we’ve observed with elraglusib to date is compelling, and both its mechanism of action and safety profile support combination with chemotherapy, immunotherapy and potentially RAS inhibitors, increasing elraglusib’s potential as a backbone therapy, specifically in pancreatic cancers, where clinicians have limited options to extend and improve the lives of patients.” About Actuate-1801 Part 3β Study The Actuate-1801 Part 3β study (NCT03678883) is a randomized, controlled Phase 2 trial of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) versus GnP alone in first-line metastatic pancreatic adenocarcinoma (mPDAC). The trial enrolled 286 mPDAC patients with no prior systemic treatment for metastatic disease, who were randomized 2:1 to the elraglusib treatment arm (elraglusib + GnP) or the control arm (GnP alone). Elraglusib is administered at a dose of 9.3 mg/kg by IV infusion on Day 1 of each week of a 28-day cycle. In the Phase 2 study, elraglusib in combination with GnP met its primary endpoint, showing a significant increase in median overall survival, a 37% reduction in the risk of death, and a doubling of the 12-month survival rate. In addition, increased CD8-positive and granzyme B-positive T cells, increased NK cells, and decreased myeloid-derived suppressor cells were observed in tumor biopsies only from elraglusib-treated patients, demonstrating elraglusib’s proposed immune modulating mechanism of action in patients with mPDAC. Inhibition of GSK-3β may inhibit pancreatic tumor growth and improve survival through several complimentary mechanisms that include enhancement of chemotherapy activity, regulation of anti-tumor immunity, and regulation of tumor gene expression, leading to alterations in tumor metabolism and Epithelial-to-Mesenchymal Transition (EMT). About Actuate Therapeutics, Inc. Actuate is a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers. Actuate’s lead investigational drug, elraglusib (a novel GSK-3β inhibitor), targets molecular pathways in cancer that are involved in promoting tumor growth and resistance to conventional cancer drugs such as chemotherapy through the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and DNA Damage Response (DDR). Elraglusib may also mediate anti-tumor immunity through the regulation of multiple immune checkpoints and immune cell function. For additional information, please visit the Company’s website at http://www.actuatetherapeutics.com or follow us on LinkedIn, X and Facebook. Forward-Looking Statements This press release contains forward-looking statements about us, including our and other parties’ clinical trials and development plans, and our industry. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “ongoing,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would,” or the negative of these terms or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements related to present facts or current conditions or of historical facts, contained in this press release are forward-looking statements. Accordingly, these statements involve estimates, assumptions, substantial risks and uncertainties which could cause actual results to differ materially from those expressed in them, including but not limited to that preliminary and unpublished data may be subject to change and further interpretation following the availability of more data or following a more comprehensive review of the data and should not be relied upon as a final analysis; clinical and preclinical drug development involves a lengthy and expensive process with uncertain timelines and outcomes, results of prior preclinical studies, early clinical trials and sub-group studies are not necessarily predictive of future results and may not correlate with improved responses, and elraglusib may not achieve positive clinical results or favorable preclinical results or receive regulatory approval on a timely basis, if at all; that we may not successfully enroll additional patients or establish or advance plans for further development, including through conversations with the FDA or EMA and the standards such bodies may impose for such development; that elraglusib could be associated with side effects, adverse events or other properties or safety risks, which could delay or preclude regulatory approval, cause us to suspend or discontinue clinical trials or result in other negative consequences; our reliance on third parties to conduct our non-clinical studies and our clinical trials; our reliance on third-party licensors and ability to preserve and protect our intellectual property rights; that we face significant competition from other biotechnology and pharmaceutical companies; our ability to fund development activities, including because our financial condition raises substantial doubt as to our ability to continue as a going concern and we require additional capital to finance our operations beyond the second quarter of fiscal year 2026, and a failure to obtain this necessary capital in the near term on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our development programs, commercialization efforts or other operations. In addition, any forward-looking statements are qualified in their entirety by reference to the factors discussed under the heading “Item 1A. Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2024, filed with the SEC on March 13, 2025, and our Quarterly Reports on Form 10-Q, and other filings with the SEC. Because the risk factors referred to above could cause actual results or outcomes to differ materially from those expressed in any forward-looking statements made by us or on our behalf, you should not place undue reliance on any forward-looking statements. Further, any forward-looking statement speaks only as of the date on which it is made. New factors emerge from time to time, and it is not possible for us to predict which factors will arise. In addition, we cannot assess the impact of each factor on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Unless legally required, we do not undertake any obligation to release publicly any revisions to such forward-looking statements to reflect events or circumstances after the date of this press release or to reflect the occurrence of unanticipated events. Investor Contact Mike MoyerManaging DirectorLifeSci Advisors, LLCmmoyer@lifesciadvisors.com Media Contact Ignacio Guerrero-Ros, Ph.D., or David SchullRusso Partners, LLCIgnacio.guerrero-ros@russopartnersllc.comDavid.schull@russopartnersllc.com(858) 717-2310 or (646) 942-5604