Tegatrabetan

▎药明康德内容团队编辑本期看点1. 可局部外用的小分子BRAF抑制剂LUT014在早期临床研究中的结果积极，75%患有放射性皮炎的乳腺癌患者的皮炎实现完全消退。2. Arvinas公司开发的首个口服PROTAC蛋白降解剂ARV-102在临床前研究中可使大脑深部的目标蛋白LRRK2降解近90%，其1期临床试验已于近期完成了首例患者给药。3. 口服PI3K/mTOR双抑制剂paxalisib联用放射疗法治疗PI3K通路突变实体瘤的脑转移患者，1期临床试验由于结果积极已提前结束。药明康德内容团队整理LUT014：公布1/2期临床试验数据Lutris Pharma于近日公布了其新型小分子BRAF抑制剂LUT014治疗乳腺癌患者放射性皮炎的1/2期临床试验的积极结果。BRAF抑制剂具有矛盾效应，阻断肿瘤细胞中的该通路会导致细胞凋亡和肿瘤缩小，但阻断正常细胞中的该通路会导致MAPK通路激活，细胞开始生长。LUT014利用的正是这种矛盾效应来增强细胞增殖、平衡细胞破坏，这也是放射性皮炎的典型特征。LUT014是一种可局部外用的凝胶，在该研究中的耐受性良好，可能对2级放射性皮炎有效。在该试验的第一部分中，75%（6/8）患者的放射性皮炎获得了完全消退，即改善至0级皮炎。第二部分的研究结果显示，与安慰剂相比，LUT014组患者的临床相关治疗优势约为30%，患者的生活质量也得到了改善。ARV-102：1期临床试验完成首例患者给药Arvinas公司于近期宣布，其开发的首个口服PROTAC蛋白降解剂ARV-102的1期临床试验已完成首例患者给药。ARV-102旨在降解一种大型多结构域支架激酶LRRK2，拟用于治疗神经退行性疾病。LRRK2活性和表达的增加在遗传上参与多种神经疾病的发病机制，包括帕金森病和进行性核上性麻痹。在非人灵长类动物研究中，ARV-102已被证明可以穿过血脑屏障到达大脑深部区域，并使近90%的LRRK2蛋白降解。Paxalisib：公布1期临床试验数据Kazia Therapeutics公司于近期宣布，基于迄今为止观察到的积极的安全性和良好的临床缓解结果，一项由两部分组成的重要1期试验已提前结束。这项由研究者发起的试验评估了paxalisib（一种口服PI3K/mTOR双抑制剂）联用放射疗法治疗PI3K通路突变实体瘤脑转移患者的效果。在这项研究的第一部分中，paxalisib联用放射疗法在所有9名可评估的患者中均显示出潜在的临床活性迹象。该研究的第二部分也被确认达成主要终点，研究人员还在扩展队列中观察到了令人鼓舞的缓解迹象，这部分的详细结果尚待公布。2023年7月，paxalisib联用放射疗法被美国FDA授予了快速通道资格，用于治疗PI3K通路突变实体瘤脑转移患者。OCU410ST：1/2期临床试验完成首个队列给药Ocugen公司于近期宣布，其针对Stargardt病开发的候选基因疗法OCU410ST的1/2期临床试验已完成首个队列的给药。OCU410ST利用腺相关病毒（AAV）递送平台在视网膜递送RORA基因，可调节与Stargardt病相关的通路，例如脂褐素形成、氧化应激、炎症、细胞存活网络等。RCT2100：1期临床试验开始为首批受试者给药ReCode Therapeutics公司于近期宣布，其在研吸入性mRNA疗法RCT2100的1期临床试验中，第一批健康受试者已开始接受治疗。RCT2100使用了新型选择性器官靶向的脂质纳米颗粒（LNP）递送平台，能够将基因药物高度精确地直接递送至与疾病有关的器官、组织和细胞，从而提高疗效和效力。RCT2100旨在将CFTR mRNA递送至靶细胞并指导它们制造CFTR蛋白的功能版本，从而治疗携带CFTR基因I类突变、对目前批准的CFTR调节剂没有反应的囊性纤维化患者，这类患者在囊性纤维化总患者人群中占约10-13%。ALETA-001：1/2期临床试验完成首例患者给药Aleta Biotherapeutics公司于近期宣布，其潜在“first-in-class” CAR-T细胞接合器ALETA-001的1/2期临床试验已完成首例患者给药。ALETA-001拟用于治疗已接受CD19靶向CAR-T细胞治疗且有失败风险的B细胞恶性肿瘤患者。该疗法通过增加CD19抗原密度和恢复癌细胞上丢失的CD19表达，来提高CD19靶向CAR-T细胞疗法的有效性。ALETA-001含有CD19靶蛋白，该靶蛋白进一步与CD20抗体结构域相连，使得CD19+/CD20+癌细胞很容易被已经在患者体内循环的CD19靶向CAR-T细胞识别并杀死。NPX887：1a/b期临床试验完成首例患者给药NextPoint Therapeutics公司于近期宣布，在治疗表达HHLA2（B7-H7）实体瘤患者的1期临床试验中，首例患者已开始接受其靶向HHLA2的全人源单克隆抗体NPX887的治疗。HHLA2是一种独立于PD-L1的新型免疫检查点和肿瘤靶向抗原，在许多癌症中高表达。NPX887旨在通过阻断与HHLA2结合导致的KIR3DL3介导的免疫抑制来防止实体瘤中的免疫逃逸。NPX887被认为可以促进肿瘤微环境中的T细胞和NK细胞的抗肿瘤活性。Tegavivint：启动1b/2a期临床试验的患者招募Iterion Therapeutics公司于近期宣布，其主打产品tegavivint的1b/2a期临床试验正在招募接受过至少一线系统治疗后失败的晚期肝细胞癌（HCC）患者。Tegavivint是一种有效的选择性小分子，能与Wnt/β-catenin通路中的TBL1结合。TBL1与核β-catenin结合会形成活性转录复合物，从而阻止核β-catenin的核降解，并激活Wnt/β-catenin通路中癌基因的转录。Tegavivint通过与TBL1结合，破坏β-catenin与TBL1之间的相互作用来发挥抗癌作用。除HCC外，Iterion公司正在推进针对多种癌症类型的临床项目，包括非小细胞肺癌、弥漫性大B细胞淋巴瘤和小儿实体瘤等。Shigella4V：公布1/2期临床试验数据LimmaTech Biologics公司公布了其候选四价生物结合疫苗Shigella4V（S4V）的1/2期临床试验的积极中期数据。2023年7月，LimmaTech公司从GSK获得了开发的S4V的许可，该疫苗旨在预防志贺菌（Shigella）引起的志贺菌病。志贺菌病是一种严重的传染病，是致命性腹泻疾病的第二大病因，尤其是在中低收入国家的婴儿中。此次公布的来自472名9个月大婴儿的初步数据证实了S4V具有良好的安全性和耐受性，没有报告与疫苗相关的严重不良事件。S4V对四种最常见的病原体血清型（S. flexneri 2a、3a、6和S. sonnei）具有显著的免疫原性。在第一次或第二次注射后，受试者的血清IgG水平均会有统计学意义上的明显增加，具体取决于所使用的剂量和配方。该结果支持进一步开发，LimmaTech公司计划于2024年启动下一项临床试验。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Arvinas Announces First-in-Human Dosing of ARV-102, an Investigational PROTAC® Protein Degrader for Neurodegenerative Disease. Retrieved February 21, 2024, from https://www.globenewswire.com/news-release/2024/02/20/2831684/0/en/Arvinas-Announces-First-in-Human-Dosing-of-ARV-102-an-Investigational-PROTAC-Protein-Degrader-for-Neurodegenerative-Disease.html[2] Monopar Receives Clearance to Proceed with First-in-Human Phase 1 Trial of Novel Radiopharmaceutical MNPR-101-Zr in Advanced Cancers. Retrieved February 21, 2024, from https://ir.monopartx.com/press-releases/detail/81/monopar-receives-clearance-to-proceed-with-first-in-human[3] NextPoint Therapeutics Announces First Patient Dosed in Phase 1a/b Clinical Trial of NPX887, a Novel Therapeutic Targeting HHLA2 to Reactivate Exhausted T and NK Cells in HHLA2+ Solid Tumors. Retrieved February 21, 2024, from https://www.businesswire.com/news/home/20240220381798/en[4] Iterion Therapeutics Announces First Patient Dosed in Phase 1b/2a Clinical Trial of Tegavivint in Patients with Advanced Hepatocellular Carcinoma Who Have Failed One or More Systemic Treatments. Retrieved February 21, 2024, from https://www.prnewswire.com/news-releases/iterion-therapeutics-announces-first-patient-dosed-in-phase-1b2a-clinical-trial-of-tegavivint-in-patients-with-advanced-hepatocellular-carcinoma-who-have-failed-one-or-more-systemic-treatments-302065477.html[5] Kazia Therapeutics Reports Early Conclusion of Clinical Trial After Reaching Primary Endpoint. Retrieved February 21, 2024, from https://www.prnewswire.com/news-releases/kazia-therapeutics-reports-early-conclusion-of-clinical-trial-after-reaching-primary-endpoint-302067134.html[6] ReCode Therapeutics Announces First Participants Dosed in a Phase 1 Healthy Volunteer Clinical Study of Inhaled mRNA-Based Genetic Medicine, RCT2100, for the Treatment of Cystic Fibrosis. Retrieved February 21, 2024, from https://www.businesswire.com/news/home/20240221731121/en[7] Aleta Biotherapeutics and Cancer Research UK’s Centre for Drug Development Announce First Patient Dosed in ALETA-001 Phase 1/2 Clinical Trial in Patients with Relapsed/Refractory B-Cell Malignancies. Retrieved February 21, 2024, from https://www.businesswire.com/news/home/20240221259676/en[8] Lutris Pharma Announces Publication of Positive Data From Its Phase 1/2 Trial of LUT014 to Treat Radiation Dermatitis in Patients with Breast Cancer. Retrieved February 21, 2024, from https://www.prnewswire.com/news-releases/lutris-pharma-announces-publication-of-positive-data-from-its-phase-12-trial-of-lut014-to-treat-radiation-dermatitis-in-patients-with-breast-cancer-302066519.html[9] LimmaTech Biologics Reports Positive Interim Phase I/II Clinical Data on Tetravalent Shigella Bioconjugate Vaccine S4V. Retrieved February 22, 2024, from https://www.businesswire.com/news/home/20240222411799/en[10] ONCOC4 ANNOUNCES FIRST PATIENT WITH ADVANCED PROSTATE CANCER DOSED IN PHASE 1/2 TRIAL OF BIONTECH-PARTNERED BNT316/ONC-392 PROGRAM. Retrieved February 22, 2024, from https://www.oncoc4.com/index.php/blog/news-releases/item/19-oncoc4-announces-first-patient-with-advanced-prostate-cancer-dosed-in-phase-1-2-trial-of-biontech-partnered-bnt316-onc-392-program[11] OCUGEN, INC. ANNOUNCES DOSING COMPLETION OF SUBJECTS WITH STARGARDT IN COHORT 1 OF PHASE 1/2 CLINICAL TRIAL EVALUATING THE SAFETY AND EFFICACY OF OCU410ST. Retrieved February 22, 2024, from https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-dosing-completion-subjects-stargardt-cohort[12] Celcuity Announces First Patient Dosed in Phase 1b/2 CELC-G-201 Clinical Trial of Gedatolisib for the Treatment of Metastatic Castration Resistant Prostate Cancer. Retrieved February 22, 2024, from https://ir.celcuity.com/press-releases/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。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

HOUSTON, Feb. 20, 2024 /PRNewswire/ -- Iterion Therapeutics, an oncology-focused biopharmaceutical company developing small molecule inhibitors of Transducin beta-like protein 1 (TBL1), a downstream target in the Wnt/beta-catenin signaling pathway, announced today it is actively enrolling a Phase 1b/2a clinical trial of its lead molecule, tegavivint, in patients with advanced hepatocellular carcinoma (HCC) that have failed at least one line of systemic therapy. Activation of the Wnt/beta-catenin pathway is a hallmark of several forms of cancer, including HCC, in which approximately half of patients have tumors with Wnt-activating mutations. Unfortunately, key members of this pathway (including beta-catenin) have either been resistant to conventional drug development or plagued with off-target toxicities. Extensive pre-clinical study results across multiple tumor types suggest that TBL1 is a downstream target that is necessary for Wnt/beta-catenin-activated oncogenesis. TBL1 binds nuclear beta-catenin thus stabilizing the transcription complex necessary to turn on cancer-causing genes. Tegavivint's direct binding to TBL1 displaces beta-catenin and disrupts this complex, allowing the degradation of free nuclear beta-catenin and preventing downstream oncogenic gene transcription. "By targeting TBL1, tegavivint promotes potent inhibition of nuclear beta-catenin oncogenic activity without inducing toxicities observed for other drugs that are upstream in the Wnt-pathway" stated Rahul Aras, Ph.D., President & CEO for Iterion Therapeutics. "HCC is a devastating cancer with a high prevalence of Wnt-activated tumors, and we are committed to developing tegavivint for this patient population that otherwise has very few therapeutic options". HCC is the sixth most commonly diagnosed cancer and the third leading cause of cancer death globally. In 2023, the National Cancer Institute (NCI) estimated 41,210 new HCC cases diagnosed in the US, with 29,380 deaths. The overall prognosis is poor, with a 5-year survival rate of 21.6%. Wnt-activation plays multiple roles in the pathogenesis of HCC by initiating tumorigenesis, promoting metastasis, and enhancing an immunosuppressive tumor microenvironment. Patients with elevated nuclear beta-catenin and TBL1 demonstrate particularly poor outcomes. Despite this, there are no FDA-approved therapies targeting this pathway. "There is a desperate need for novel targeted therapies to address the large unmet clinical need in HCC" expressed Casey Cunningham, M.D., Chief Medical Officer for Iterion Therapeutics. "Tegavivint has demonstrated excellent tolerability and has the potential to address a large portion of this population by directly inhibiting beta-catenin's oncogenic activity". The ongoing clinical trial will enroll approximately 35 patients in dose escalation and optimization cohorts of patients with unresectable locally advanced or metastatic HCC that have failed at least one line of systemic treatment. The study will evaluate safety and clinical efficacy in addition to pharmacokinetic and pharmacodynamic markers to determine a Recommended Phase 2 Dose (RP2D) in HCC. Tegavivint has demonstrated safety, clinical and pharmacodynamic activity in a Phase 1 clinical study of patients with desmoid tumors. For more information about this Phase 1b/2a clinical trial of tegavivint in patients with advanced HCC, please visit using the identifier NCT05797805. About Iterion Therapeutics Iterion Therapeutics is a clinical-stage biotechnology company developing novel cancer therapeutics. The company's lead product, tegavivint, is a potent and selective small molecule that binds to Transducin beta-like protein 1 (TBL1), a newly characterized target in the Wnt/beta-catenin pathway. TBL1 binds to nuclear beta-catenin, forming an active transcription complex that prevents nuclear degradation of beta-catenin and activates genes necessary for the Wnt/beta-catenin oncogenic activity. Tegavivint binds to TBL1 and disrupts the interaction between beta-catenin and TBL1, thus promoting the degradation of nuclear beta-catenin and preventing the transcription of Wnt/beta-catenin targeted oncogenes. Iterion is currently advancing multiple clinical programs investigating tegavivint in cancer indications where nuclear beta-catenin overexpression is a known factor. These include Iterion-sponsored programs in hepatocellular carcinoma (HCC), as well as investigator-sponsored programs in non-small cell lung cancer (NSCLC), diffuse large B-cell lymphomas (DLBCL), and pediatric solid tumors. Iterion is the recipient of combined a $18.9 million in Product Development Awards from the Cancer Prevention and Research Institute of Texas (CPRIT). For more information on Iterion, please visit . SOURCE Iterion Therapeutics