Alrizomadlin

ROCKVILLE, Md. and SUZHOU, China, April 7, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, age-related diseases, and chronic hepatitis B (CHB), announced today that it releases the latest results from three preclinical studies of its novel drug candidates olverembatinib, MDM2-p53 inhibitor alrizomadlin (R&D Code: APG-115), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and embryonic ectoderm development (EED) inhibitor APG-5918, at the 2024 American Association of Cancer Research Annual Meeting (AACR 2024). This year's AACR annual meeting will be held from April 5-10 2024, in San Diego, California, USA. "We are pleased to present the preclinical research data of four assets in our pipeline at the AACR 2024. The results provided essential support for the potential clinical development and therapeutic combinations of these compounds in SDH-deficient neoplasms, prostate cancer, and ovarian cancer," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will continue to advance these programs toward the clinical stage in order to bring more treatment options to patients in need." The details of these three preclinical studies are as follows: Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms Abstract#: 1971 Time: Monday April 8, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Succinate dehydrogenase (SDH) – deficient (dSDH) neoplasms are identified by the loss of immunohistochemical expression of SDHB due to the bi-allelic inactivation of any of the four components of mitochondrial SDH complex (SDH A-D). Succinate accumulation, due to SDH deficiency, is involved in tumorigenesis of different types of cancers including gastrointestinal stromal tumor (GIST), paraganglioma, pheochromocytoma, renal cell carcinoma, pituitary adenomas, and pancreatic neuroendocrine tumors. The prognosis of patients with dSDH neoplasia, especially GIST, is poor and approved tyrosine kinase inhibitors (TKIs) have limited efficacy. There is a high unmet medical need for these patients. Olverembatinib, a novel multi-kinase inhibitor, targets a broad spectrum of kinases and has demonstrated promising efficacy in dSDH GIST patients in an ongoing phase I clinical trial. In this study, we assessed antitumor effects of olverembatinib in preclinical models of dSDH cancers and dSDH GIST primary tumor cells, and explored potential mechanisms of action. Conclusions: Olverembatinib showed superior anti-tumor activity in dSDH cell lines in vitro and human dSDH GIST primary tumor cells ex vivo. Olverembatinib, as a multi-target kinase inhibitor, exerted antitumor effects by modulating multiple signaling pathways including hypoxia, angiogenesis, apoptosis, proliferation, and survival, which are involved in tumorigenesis of dSDH cancers. Olverembatinib demonstrated more potent in vivo antitumor activity in mice bearing PC12#5F7 (SDHB KD) xenograft tumors than other TKIs. Western blot analysis in tumor tissues collected from mice further confirmed the modulation of the signal pathways by olverembatinib observed in cell lines. In summary, the results provide a rationale for future clinical development of olverembatinib in dSDH cancers. Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa) Abstract#: 3223 Time: Monday April 8, 2024, 1:30 PM - 5:00 PM (Pacific Time) Introduction: Prostate cancer (PCa) is one of the most frequently diagnosed malignancies among elderly males. Androgen deprivation therapy (ADT) with or without androgen receptor (AR) inhibitors is widely used as initial treatment for advanced PCa. However, most ADT-treated patients eventually develop castration-resistant prostate cancer (CRPC), which is in urgent need of novel therapies. Polycomb repressive complexes 2 (PRC2) dysregulation is common in PCa and correlates with poor prognosis. PRC2 mediates histone H3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic marker for gene transcription. embryonic ectoderm development (EED), a PRC2 core component, is crucial for histone methyltransferase activity through direct binding to H3K27me3. MDM2, a negative regulator of the tumor suppressor p53, is frequently amplified or overexpressed in PCa, and associated with poor clinical outcomes and metastasis. The aim of this study was to evaluate antitumor activity and molecular mechanisms of the investigational, clinical-stage EED inhibitor APG-5918/EEDi-5273 and MDM2 selective inhibitor alrizomadlin (APG-115) in PCa preclinical models Conclusions: In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis. APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo. Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis. Therefore, the findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin to treat patients with PCa. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC) Abstract#: 4569 Time: Tuesday April 9, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Ovarian cancer is among the leading causes of cancer-related death in women, and most cases are diagnosed at later stages with distant metastasis. FAK overexpression or activation occurs in a substantial proportion of epithelial ovarian cancers (EOCs) and is predictive of poor clinical outcomes. FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. FAK is therefore emerging as a potential treatment target. The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer. Conclusions: APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant and platinum-sensitive ovarian cancer cell lines. FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells in a dose-dependent manner. APG-2449 in combination with PLD showed enhanced antitumor activity in platinum-resistant OVCAR-3 ovarian cancer CDX model. The combination regimen prolonged ascites-free and survival times in the ID8-Luc peritoneal syngeneic model. These promising results support the future clinical development of this combination treatment for ovarian cancer. About Ascentage Pharma Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK. Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. The company has built a pipeline of 9 clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US, Australia, Europe, and China. Ascentage Pharma has been designated for multiple Major National R&D Projects, including five Major New Drug Projects, one New Drug Incubator status, four Innovative Drug Programs, and one Major Project for the Prevention and Treatment of Infectious Diseases. Olverembatinib, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product, has been granted Priority Review Designations and Breakthrough Therapy Designations by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date, the drug had been included into the China 2022 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company's investigational drug candidates. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology, MD Anderson Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, MSD, and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs and is setting up its world-class commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients. Forward-Looking Statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events, or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. SOURCE Ascentage Pharma

2023年是中国Biotech继续在全球医药市场打响名声的一年，不管是大额授权交易频现的ADC赛道，还是创新成果层出不穷的国际舞台，均可以看到中国Biotech的身影。在全球化开发的趋势之下，中国创新药物加入国际市场竞争已是必然之势。自2023年至今，陆续有多款国产新药获得FDA的通行证，这皆是中国药企的创新能力逐渐获得国际认可的证明。而打入全球市场，也意味着能收获更高的商业回报，泽布替尼、呋喹替尼等产品的销售表现足以说明这一点。中国药企的创新声音在不断传向全球，而以创新药/创新技术为支点的中国Biotech在这个过程的推动中功不可没。昨日，亚盛医药发布2023年度业绩，再次直观地呈现了其商业化成果和研发管线的重要进展，尤其是在全球化开发上取得的成绩。中国Biotech的创新之声将愈加响亮。奥雷巴替尼：打造全球创新版图的先行棋去年，亚盛医药连续第6年参加ASCO会议，携多款产品的研究成果亮相国际舞台，向全球药企展现了中国创新药头部Biotech的创新力量。其中，打头阵的自然是亚盛为等待十年之久的中国慢性髓细胞白血病（CML）患者带来的“及时雨”——奥雷巴替尼（商品名：耐立克）。耐立克所面向的人群是对一代和二代酪氨酸激酶抑制剂（TKI）耐药或不耐受的CML慢性期（CML-CP）成人患者，这是其加入全球市场竞争角逐战的基本盘。今年年初，耐立克被纳入美国国家综合癌症网络（NCCN）CML指南，国际权威指南的认可为这款产品后续的全球化开发提供了助益。上个月，耐立克顺利获得FDA批准开展一项针对CML-CP成人患者的全球注册性III期研究，向其国际化之路迈出了具有里程碑意义的关键一步。作为一款中国自主研发的原创1类新药，更广的耐药性覆盖面和更高的安全性是耐立克攻入全球市场的底气。耐立克治疗对Ponatinib（泊那替尼）或Asciminib耐药的CML患者的I期研究结果已连续两年亮相美国血液学（ASH）年会。数据显示，在既往接受泊那替尼治疗后失败的CML-CP患者中，达到完全细胞遗传学反应（CCyR）的比例为53%（8/15），达到主要分子学反应（MMR）的比例为38%（6/16）[1]。这意味着耐立克具有克服三代TKI泊那替尼耐药性的潜力，可以进一步解决耐药人群的治疗需求。此外，耐立克具有良好的安全性，其导致心血管事件的风险较低，而这类不良事件是限制泊那替尼市场爆发力的重要原因。在临床需求仍未满足和患者基数以每年1%速度增长的情况下，CML的市场规模也在持续扩张。据Credence Research预测，未来8年（2024-2032）CML市场的复合年增长率约为5.44%，市场规模将从2023年的78亿美元增长至2032年的120亿美元[2]。TKI药物作为其中的主要贡献力量，未来的市场空间不容小觑。这也意味着，具有BIC实力的耐立克有望为亚盛医药持续创造可观的收入。全球白血病领域已上市的TKI注：医药魔方整理在解决了CML领域的燃眉之急之后，亚盛医药正在努力攻克另一类常见白血病——急性淋巴细胞白血病（ALL）。2023年8月，亚盛医药启动了耐立克联合化疗治疗新诊断费城染色体阳性（Ph+）ALL患者的注册性III期研究，并选择了伊马替尼作为对照组。值得注意的是，耐立克联合维奈克拉和地塞米松治疗新诊断Ph+ ALL患者的I/II期研究也取得了积极结果，展示了Ph+ ALL进入“无化疗”时代的可能，被认为在该领域去化疗方案中具有核心的治疗地位。在今年1月举办的血液肿瘤创新药高峰论坛暨耐立克新适应症全球上市会上，有多位专家表示，在Ph+ ALL领域的临床实际应用中，耐立克已经呈现出令人惊艳的疗效，随着疗效和安全性数据不断被验证，耐立克有望成为初治Ph+ ALL患者的标准治疗方案；此外，作为强效三代TKI，耐立克在Ph+ ALL患者中的疗效更好，有望实现该领域的“减化疗”甚至是“去化疗”。目前，ALL领域仅3款TKI获批上市，包括伊马替尼、达沙替尼和泊那替尼。据Precedence Research预测，2023-2032年ALL市场的复合年增长率约为10.25%，市场规模将从2022年的31亿美元增长至2032年的83亿美元[3]。作为一款具有BIC优势的创新产品，耐立克有望从中攫取更大的市场份额。APG-2575：展现全球BIC开发实力的重磅产品自两年前上市至今，耐立克已然一步步成为血液瘤领域的重磅产品，也帮助亚盛医药进入了创新药行业的全球视野。不过，耐立克只是亚盛医药为丰富其全球创新版图下的第一步棋，而下一款重磅产品已蓄势待发。亚盛医药竭力打造的Bcl-2抑制剂APG-2575（Lisaftoclax）目前已进入III期阶段。该产品有望覆盖慢性淋巴细胞白血病（CLL）、急性髓系白血病（AML）、多发性骨髓瘤（MM）和骨髓增生异常综合征（MDS）等多种血液恶性疾病，完善其血液瘤布局版图。APG-2575的首发适应症是血液瘤的兵家必争之地——CLL。在BTK抑制剂的推动下，2022年CLL市场规模已达到100亿美元[4]。但BTK抑制剂存在耐药性和需终身用药等局限性，临床上仍需要创新的治疗手段，而Bcl-2抑制剂的出现给CLL的治疗带来了新的希望。目前，BTK抑制剂+Bcl-2抑制剂的联用组合是公认的CLL治疗极富希望的出路。不过，Bcl-2靶点的开发难度较大，近30年来仅维奈克拉一款产品上市。但维奈克拉的安全性隐患不容忽视，其肿瘤溶解综合征（TLS）发生风险一直备受关注。因而，业内始终在期待更具优势的新一代Bcl-2抑制剂问世。APG-2575的开发进度在Bcl-2抑制剂赛道中处于第一梯队，并且已在临床研究中显示出其差异化优势——低TLS风险和便捷的每日递增给药方案，既降低了毒性又可以快速达到治疗剂量。亚盛医药预期今年内在中国提交APG-2575单药治疗复发/难治性CLL的上市申请，此外APG-2575联合BTK抑制剂阿可替尼治疗初治CLL患者的全球注册III期临床于去年获CDE批准。通过注册II期临床迅速上市，抢占复发/难治性CLL市场，进而通过联合用药冲击一线正是亚盛医药就APG-2575制定的临床开发策略。与此同时，亚盛医药也在推进APG-2575的全球临床开发，去年该品种获FDA批准开展一项全球注册III期临床试验，用于治疗经治CLL患者。虽然全球多中心临床已成为国产创新药走出国门的重要一环，但真正有能力且有魄力行动的企业仍在少数。耐立克和APG-2575的全球临床开发工作双双推进，既彰显了亚盛医药主动加入国际竞争阵营的决心，也展现了其产品创新及全球化临床开发的实力。FIC产品接棒，为全球创新版图持续造血作为一家面向全球的创新药企业，亚盛医药一直致力于打造具有first in class（FIC）和BIC潜力的产品管线。除了BIC产品耐立克和APG-2575，亚盛医药管线中的其它在研产品亦值得关注。Alrizomadlin（APG-115）是一款具有全球FIC潜力的MDM2-p53抑制剂，目前，亚盛医药正在全球开展多项APG-115单药或联合治疗实体瘤及血液肿瘤的临床研究，并且已在儿童肿瘤患者中启动临床试验。该药物也可与APG-2575联用触发合成致死机制杀伤肿瘤细胞。APG-5918是一款针对表观遗传学新靶点胚胎外胚层发育蛋白（EED）的潜在FIC小分子抑制剂。目前，APG-5918治疗晚期实体瘤或血液系统恶性肿瘤的I期临床试验已在中国和美国获临床试验许可，同时贫血相关适应症的临床试验也获得中国临床试验许可。APG-2449是一款靶向粘着斑激酶（FAK）、间变型淋巴瘤激酶（ALK）和ROS1的小分子酪氨酸激酶抑制剂，可作为高效ALK/ROS1抑制剂或FAK抑制剂与化疗药物或靶向药物联合用药，以解决耐药问题。APG-1252通过靶向抑制Bcl-2和Bcl-xL起到恢复细胞凋亡的作用，单药应用或与其它抗肿瘤药物联用均有不错的疗效。目前，全球共4款临床在研Bcl-2/Bcl-xL抑制剂，APG-1252的开发进度处于第一梯队。总结回顾亚盛医药在2023年的表现，凭着两款BIC产品冲锋在前，从国内竞技场走向了国际舞台，向全球展现了中国头部创新药Biotech的力量。这与亚盛医药始终坚守全球创新策略密不可分。在竞争激烈的肿瘤领域，创新已是必然之路，但如何创新、能否坚持创新、创新又是否正中临床需求靶心，是研发端始终要考虑的关键问题。“从0到1”的源头创新之路充满未知和风险，但有收获便甘之如饴。接下来这条“从1到10”的持续发展之路，虽未必更加容易，但必将更加从容。参考资料：[1] Update of Olverembatinib (HQP1351) Overcoming Ponatinib and/or    Asciminib Resistance in Patients (Pts) with Heavily Pretreated/Refractory    Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute    Lymphoblastic Leukemia (Ph + ALL).[2] Chronic Myelogenous Leukemia Treatment Market By Treatment Type    (Targeted Therapy, Chemotherapy, Biologic Therapy, Others); By Region – Growth,    Share, Opportunities & Competitive Analysis, 2024 – 2032.[3] Acute Lymphocytic Leukemia Therapeutics Market (By Type:    Paediatrics, Adults; By Drug: Hyper-CVAD Regimen, Linker Regimen, Nucleoside    Metabolic Inhibitors, Targeted Drugs & Immunotherapy, CALGB 811 Regimen,    Oncasper; By Cell: B-cell ALL, T-Cell ALL, Philadelphia Chromosome; By Therapy:    Chemotherapy, Targeted Therapy, Radiation Therapy; By Route of Administration;    By Distribution Channels) - Global Industry Analysis, Size, Share, Growth,    Trends, Regional Outlook, and Forecast 2023-2032.[4] Chronic Lymphocytic Leukemia (CLL) Market, By Type (B-cell, T-Cell,    and Natural), By Route of Administration (Parenteral Route and Oral Route), By    Therapy, By End-Use Industry, and By Region Forecast to 2032.Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。