ROR1 CAR-T (Oncternal Therapeutics)

Oct. 22, 2024 -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT) (the “Company”) today announced updated data from its Phase 1/2 Study of ONCT-534 for the treatment of patients with relapsed or refractory metastatic Castration-Resistant Prostate Cancer (mCRPC). Based on initial pharmacokinetic results, two additional dosing cohorts with twice daily (BID) oral dosing of ONCT-534 had been incorporated in the Phase 1/2 study ONCT-534-101 (NCT05917470). Overall, fifteen patients received ONCT-534 once daily (QD) in six dosing cohorts and six patients received ONCT-534 BID in two dosing cohorts. Based on a data cut off of September 30, 2024, the BID dosing schedule was well tolerated, with no related Grade 3 or higher toxicities. One patient, who experienced a rising PSA on ONCT-534 at 160 mg BID, had a subsequent 50% reduction in PSA after four weeks of ONCT-534 at 300 mg BID, and at the same time the CAT Scan showed a 16% reduction in target lesions compared to baseline. Enumeration and biomarker analysis of circulating tumor cells (CTCs) showed promising effects on expression of androgen receptor (AR)-regulated genes, and AR nuclear translocation in six additional patients. CTC analysis also showed that some patients who did not respond to ONCT-534 had prostate cancer that had developed neuroendocrine features, which are associated with AR independent disease. “While we still believe the decision to discontinue the ONCT-534-101 clinical trial remains the correct one in the current biotechnology environment, the updated clinical results highlight the potential of ONCT-534 in prostate cancer. We believe there is value in exploring BID dosing further, as well as studying ONCT-534 in earlier lines of therapy for advanced prostate cancer,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. “We continue to explore strategic alternatives for our product candidates, including ONCT-534, ONCT-808, zilovertamab and ONCT-216 in an ongoing effort to maximize value to our shareholders.” Oncternal Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of patients with cancers that have critical unmet medical need. Oncternal pursues drug development targeting promising, yet untapped biological pathways implicated in cancer generation or progression, focusing on hematological malignancies and prostate cancer. More information on our company and programs is available at https://oncternal.com/. ONCT-534 is an investigational dual-action androgen receptor inhibitor (DAARI) with demonstrated preclinical activity in prostate cancer models against both unmutated androgen receptor (AR), and against multiple forms of AR mutation and aberration. It is a potential treatment for patients with mCRPC with unmet medical need because of resistance to androgen receptor pathway inhibitors, including those with AR amplification, mutations in the AR ligand binding domain (LBD), or splice variants with loss of the AR LBD. It was investigated in Study ONCT-534-101 (NCT05917470) for the treatment of patients with mCRPC who are resistant to current AR pathway inhibitors. ONCT-808 is an investigational autologous chimeric antigen receptor T (CAR T) cell therapy that targets Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using the binding domain from zilovertamab. ONCT-808 has demonstrated activity in preclinical models against multiple hematological malignancies and solid tumors and has been shown to be specific for cancer cells expressing ROR1. Oncternal has developed a robust and reproducible manufacturing process that has the potential to reduce the time patients must wait for their individual CAR T therapy to be produced compared with currently approved CAR T products. It was investigated in Study ONCT-808-101 (NCT05588440) with relapsed or refractory aggressive B-cell lymphoma, including patients who have failed previous CD19 CAR T treatment. Zilovertamab (previously called cirmtuzumab and UC-961) is an investigational monoclonal antibody designed to inhibit the function of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1). Zilovertamab has been evaluated in Phase 1/2 Study CIRM-0001 (NCT03088878) in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL), which resulted in 100% progression free survival (PFS) at 48 months in CLL patients whose tumors harbored del(17p)/p53 mutation, a population underserved by current treatment options. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to zilovertamab for the treatment of CLL and MCL. The results of an investigator-sponsored, Phase 1b clinical trial of zilovertamab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer were recently published (Shatsky 2023). Zilovertamab was evaluated in an investigator-initiated Phase 1b study of zilovertamab in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (NCT05156905), and an investigator-initiated Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory (R/R) CLL (NCT04501939). ONCT-216 (previously called TK216) is an investigational targeted small-molecule inhibitor of the E26 transformation-specific (ETS) family of oncoproteins including fusion proteins. Tumorigenic fusion proteins involving the EWS protein and an ETS protein can be found in most cases of Ewing sarcoma. ETS-related translocations or overexpression are also found in many other tumors such as acute myeloid leukemia (AML), diffuse large B cell lymphoma (DLBCL), and prostate cancer. In preclinical models, ONCT-216 was observed to bind to EWS-FLI1, blocking the interaction between this fusion protein and other transcriptome proteins such as RNA helicase A, leading to tumor cell apoptosis and inhibiting tumor growth in animal models. The U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease Designation, Orphan Drug Designation and Fast Track Status to ONCT-216 for the treatment of Ewing sarcoma. The results of a Phase 1/ 2 clinical trial of ONCT-216 in patients with Ewing sarcoma (NCT02657005) were recently published (Myers 2024). The content above comes from the network. if any infringement, please contact us to modify.

一个候选药物失败，还能说是小问题。两个核心产品同时出问题，这对于一家Biotech来说，无疑是致命的。 Oncternal Therapeutics的两款临床候选药物ONCT-534（双效雄激素受体抑制剂）和ONCT-808（自体ROR1 CAR-T），分别因疗效和毒性问题停止了临床试验。 同日（2024年9月12日），该公司宣布将考虑战略代替方案，裁员37%。 以及首席医疗官也出走了。 核心管线同时暴雷 Oncternal公司有4条管线，分别是ONCT-534（双效雄激素受体抑制剂）、ONCT-808（自体ROR1 CAR-T）、Zilovertamab（ROR1单抗，被取消了优先级）、以及一款被取消优先级的早期管线ONCT-216。 Oncternal管线（图片来源：参考资料2） 其中，ONCT-534和ONCT-808同时爆雷，停止临床研究。 ONCT-534是一种新型、口服的双效雄激素受体抑制剂，被开发用于治疗转移性去势抵抗性前列腺癌（mCRPC）。 ONCT-534的1期试验中期结果显示：8个给药队列中的20名患者未能显示出疾病改善，包括前列腺特异性抗原（PSA）水平。ONCT-534通常耐受性良好，在最高剂量队列中，3名患者中有2名观察到剂量限制性毒性。 ONCT-808是一款自体的ROR1 CAR-T细胞治疗，也是全球进度最快的ROR1 CAR-T项目之一。被开发用于治疗复发/难治性（R/R）侵袭性B细胞恶性肿瘤。 ONCT-808的更新数据显示：在每个剂量中都表现出具有抗肿瘤活性，包括持续8个月的完全代谢反应和CAR-T细胞的长期持久性。但是CAR-T治疗预期会出现不良事件，以及在最高剂量队列中经历了因休克并发症导致的死亡事件。 Oncternal公司表示，根据现有的临床数据和持续开发的资金要求，决定终止研究。 放弃治疗 在同一份新闻稿中，Oncternal公司表示将专注于探索战略代替方案，以实现股东价值最大化的目标，其中可能包括资产出售、许可，或公司并购、反向并购以及其他业务合并。 在这项战略探索进行期间，Oncternal将停止所有产品的研发活动，同时采取其他措施来降低运营成本，包括裁员。 但实际上，两款临床管线的暴雷原本还不完全致命。因为Oncternal公司还拥有一款后期阶段的管线Zilovertamab。Zilovertamab是全球首个进入3期临床的ROR1单抗。 Zilovertamab的疗效数据看起来还不错。在与ibrutinib联用的1/2期临床中，表达P53突变/del(17p)的CLL患者获得100%的无进展生存期（PFS），持续48个月。 但是在2023年4月，Oncternal公司取消了Zilovertamab的优先级，关闭了其针对MCL的3期研究和1/2期研究。小编未能找到Oncternal降低Zilovertamab优先级的披露原因，部分原因推测为没有足够的资金。 放弃了在全球范围来说都是最领先的管线，后提上的两个管线又一起暴雷，再加上公司紧张的现金流...... Oncternal公司决定放弃治疗。 小结 从Oncternal公司目前的情况来看，可能资产并不怎么值钱了。两款核心管线都出事，不是没效，就是毒性大，这很难不嘀咕Oncternal的研发能力和技术水平。 Oncternal公司的倒下，同时也为ROR1靶向治疗的开发增加了一丝阴霾....... 参考资料： 1.https://investor.oncternal.com/news-releases/news-release-details/oncternal-therapeutics-announces-termination-its-clinical 2.https://www.oncternal.com/pipeline/overview/ 3.https://investor.oncternal.com/static-files/fb10e230-e261-45c2-be43-90a980dd8d81 4.https://www.biospace.com/job-trends/oncternal-to-lay-off-37-of-employees-including-cmo 药渡媒体商务合作 媒体公关 | 新闻&会议发稿 张经理：18600036371（微信同号） 点击下方“药渡“，关注更多精彩内容 免责声明 “药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。 微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！👇👇👇