Olverembatinib

ROCKVILLE, Md. and SUZHOU, China, Nov. 17, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily for malignancies, today announced that a New Drug Application (NDA) for its inhouse developed investigational novel Bcl-2 selective inhibitor, lisaftoclax (APG-2575), for the treatment of patients with relapsed or refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has been accepted and recommended the Priority Review designation by the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA). This NDA, the first for a domestically developed Bcl-2 inhibitor in China, could potentially lead lisaftoclax to become the second Bcl-2 inhibitor approved anywhere in the world. This NDA is based on results from a pivotal registrational Phase II study in China (APG2575CC201) that evaluated the efficacy and safety of lisaftoclax in patients with r/r CLL/SLL. The primary endpoint of the study is the overall response rate (ORR). CLL/SLL is a hematologic malignancy caused by mature B-cell neoplasms. It primarily affects older populations and is among the most common leukemia subtypes in the Western World, with over 100,000 new diagnoses reported globally each year1. In China, where the incidence rate of CLL/SLL is lower than that of the western countries, the disease is occurring at a rapidly rising rate, with a younger age of onset and higher aggressiveness2. SLL and CLL are two different manifestations of the same disease and approximately 20% of all SLL cases would progress to CLL3. Treatments such as immunotherapies and Bruton's tyrosine kinase inhibitors (BTKis) have significantly improved patients' responses to initial treatment. However, due to the limitations of existing treatment options, the poor prognosis of patients, severe impact on patients' quality of life and high complexity of the disease, patients with r/r CLL/SLL are in desperate need for new treatment options that are safe and effective. The introduction of Bcl-2 inhibitors has further revolutionized the treatment of CLL/SLL. Bcl-2 is an apoptosis suppressor factor that regulates cell survival by controlling mitochondrial membrane permeability. It suppresses apoptosis by inhibiting the release of cytochrome C from mitochondria or by binding to apoptotic activators to inhibit the activity of caspase. The overexpression of Bcl-2, found in a variety of hematologic malignancies, particularly CLL/SLL, is a key mechanism by which tumor cells evade apoptosis. However, the development of Bcl-2 as a therapeutic target is challenging mainly because its mechanism of action is based on the protein-protein interaction (PPI). The binding interface of Bcl-2 is relatively large, making it difficult for small-molecule inhibitors to exert blocking effects. Additionally, the Bcl-2 protein is located on the mitochondrial membrane, and mitochondria, with its double-membrane structure, is among the most complex and challenging cellular components. Drugs must first penetrate the cell membrane before they can further act on the mitochondrial membrane. In nearly 40 years since the discovery of this target, only one Bcl-2 inhibitor has been approved globally, a reality highlighting the immense difficulty and challenges in this field of research and development. In western countries, the treatment of CLL/SLL has entered a new era of chemotherapy-free and fixed-duration regimens, while no Bcl-2 inhibitor has been approved in China in this therapeutic area. Therefore, patients in China have an urgent unmet need for such novel therapies that can offer both efficacy and safety. Lisaftoclax is a novel, investigational orally administered small-molecule Bcl-2 selective inhibitor being developed by Ascentage Pharma to treat patients with malignancies by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first Bcl-2 inhibitor in China and the second anywhere globally that has demonstrated compelling clinical benefit and entered a pivotal registrational study. Lisaftoclax has broad therapeutic potential for a variety of hematologic malignancies and solid tumors, particularly as a single agent and in combinations in CLL/SLL. Lisaftoclax is a potential drug that may offer patients a safe, effective, and easy to use treatment option. Lisaftoclax is being evaluated in multiple registrational Phase III studies, including a global registrational Phase III study of lisaftoclax in combination with a BTKi in previously treated patients with CLL/SLL (cleared by the US FDA); a global registrational Phase III study of lisaftoclax in combination with acalabrutinib for the first-line treatment of treatment-naïve patients with CLL/SLL; a global registrational Phase III study of lisaftoclax in combination with azacitidine (AZA) for the first-line treatment of elderly/unfit treatment-naïve patients with acute myeloid leukemia (AML) who were intolerant of standard induction chemotherapies; and a global registrational Phase III study of lisaftoclax in combination with AZA for the first-line treatment of newly-diagnosed patients with higher-risk myelodysplastic syndrome (MDS). "Ascentage Pharma's founding team has over 20 years of deep experience in developing apoptosis-targeted therapies and has made significant strides with the Bcl-2 target," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "To date, only one Bcl-2 inhibitor has been approved globally, which is a reality underscoring the immense difficulty and challenges in this field of research and development. This NDA submission for lisaftoclax could potentially pave the way for lisaftoclax to become the first approved China-developed Bcl-2 inhibitor, thus marking another major milestone that is a culmination of the Ascentage Pharma's deep commitment and perseverant work in the past 15 years." Dr. Yang continued, "Globally, r/r CLL/SLL represents an area of urgent unmet clinical needs. To have successfully advanced lisaftoclax to this point, it is a true testament to Ascentage Pharma's robust capabilities in global pharmaceutical innovation. Moving forward, we will accelerate the global development of lisaftoclax in other indications to bring benefit to patients as quickly as possible. Remaining steadfastly committed to our mission of addressing unmet clinical needs in China and around the world, we will strive to develop more novel therapeutics for patients in need." References: 1. Yao, Y., Lin, X., Li, F., et al. The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019. Biomed Eng Online. 2022 Jan 11;21(1):4. DOI: 10.1186/s12938-021-00973-6 2. Liu Peng. Practice guidelines for the diagnosis and treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma in Zhongshan Hospital, Fudan University (v1.2018). [J]. Chin J Clin Med, 2018, 25(1): 157-160. DOI 10.12015/j. issn. 1008-6358. 2018. 20180 3. Li Jianyong, Qiu Lugui. Hematology Committee of Chinese Medical Association; Hematological Oncology Committee of China Anti-Cancer Association; Chinese Working Group for Chronic Lymphocytic Leukemia. The guidelines for diagnosis and treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma in China (2022). Zhonghua Xue Ye Xue Za Zhi. 2022 May 14;43(5):353-358. DOI: 10.3760/cma.j.issn.0253-2727.2022.05.001 About Ascentage Pharma Ascentage Pharma (6855.HK) is a global, integrated biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily in malignancies. 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. The company has built a rich pipeline of innovative drug candidates that includes 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 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 has conducted more than 40 clinical trials in the US, Australia, Europe, and China, including 13 registrational studies (completed/ ongoing/planned). Olverembatinib, the company's first lead asset developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product in China, 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 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted Orphan Drug Designations (ODDs) 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 and other relationships with numerous leading biotechnology and pharmaceutical companies such as Takeda, AstraZeneca, Merck, Pfizer and Innovent; and research and development relationships with leading research institutions such as Dana-Farber Cancer Institute, Mayo Clinic, MD Anderson Cancer Center, National Cancer Institute and the University of Michigan. The company has built a talented team with a wealth of global experience in the discovery and development of innovative drugs and fully functional 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 and expectations or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions and expectations may alter in light of future development. SOURCE Ascentage Pharma WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

下一个国产10亿美元分子上市倒计时。 11月16日，亚盛医药力胜克拉片（APG-2575）新药上市申请（NDA）获得CDE受理并拟纳入优先审评程序，用于治疗难治或复发性CLL/SLL患者。这意味着全球第二个、中国首个Bcl-2抑制剂有望在2025年获批上市。 艾伯维全球首个Bcl-2抑制剂维奈克拉2024H1全球销售额12.51亿美元，同比增长16%。APG-2575凭借BIC潜力，以及4项全球注册III期临床试验，其商业化表现有望反超维奈克拉。 APG-2575的光芒，不仅是盖过维奈克拉，还将成为血液瘤下一代基石药物，基于疗效及安全性优势，可一线可后线，可单药可联用。从药物经济学的角度，APG-2575在血液瘤药物的资源配置中起着重要作用，具有大额BD潜力。 对亚盛医药而言，苦心耕耘多年的双子星座耐立克和APG-2575，先后成功商业化或国际化，将延续现金流改善趋势，公司也将从高质发展阶段，进入高质+高速发展阶段。 01  BCL-2靶点简史 BCL-2抑制剂被称为血液万金油。 BCL-2是一种控制细胞凋亡的关键蛋白，在很多血液系统恶性肿瘤中高表达。当细胞开始高表达BCL-2时，相当于获得免死金牌，不能正常凋亡，从而成为恶性肿瘤细胞，在造血器官中形成堆积，甚至浸润其他组织和器官。如果能够有效抑制Bcl-2蛋白表达，让细胞恢复自杀凋亡的程序，将起到抗癌作用。 通往王冠之路布满荆棘，BCL-2靶点成药性难度极大。 亚盛医药共同创始人、董事长杨大俊博士曾将其总结为3点：第一，Bcl-2靶点的作用机制是PPI（protein-protein interaction），靶点的结合界面相对较大；第二，在诸多类似作用机制（PPI）的靶点中，Bcl-2靶点结合口袋相对较大，大约有13～15个氨基酸；第三，Bcl-2靶点位于线粒体膜上，由于线粒体细胞具有双膜，药物需先通过细胞膜进入细胞后再作用于线粒体膜上。 BCL-2靶点发现至今40年，仅成药一例，艾伯维Bcl-2抑制剂维奈克拉历时约20年研发，终于在2016年获批上市。中国小分子创新药，在此领域也突破在即。 而亚盛医药共同创始人、首席科学顾问、APG-2575发明人王少萌与杨大俊其实从1996年就开启Bcl-2抑制剂的研发，后续筛选出天然产物衍生物AT-101，同时靶向Bcl-2、Mcl-1、Bcl-xL，且做到口服有效。此后，两人回国继续开发Bcl-2靶点药物，APG-2575选择性靶向Bcl-2，其PK/PD的特点决定能够取得更好的安全性，在2018年申报首个 IND。 在门槛如此高的领域，亚盛医药能够杀出来，有赖于核心团队强大的学术背景，近30年心系一处，有着长期积累，掌握know-how。 BCL-2抑制剂在血液瘤领域具有承上启下的战略地位，亚盛医药拿下APG-2575，将站上全球血液瘤市场高地。 生存期长，存量患者多，血液瘤有慢病化趋势，药物有较长销售爬坡周期，容易诞生爆款。2024H1全球畅销药TOP20中有4款肿瘤药，除K药、O药外，其余2款为血液瘤药物，分别是达雷妥尤单抗55.7亿美元、伊布替尼32.25亿美元。 以伊布替尼为代表的BTKi，成为血液瘤患者的最优选择。然而，无论哪种BTKi，随着持续治疗的亚克隆的进化和选择都有很大可能会导致疾病复发和耐药性。因此亟需找到一种可以独立或联合解决BTKi “治疗死角“的新型药物。 BCL-2抑制剂挺身而出，与BTKi联用将革新血液瘤长期治疗的一线标准疗法。相比化疗或单药，这种联合方案在提高疗效和减少耐药方面都有优势：两者分别阻断BCR 信号通路和抑制抗凋亡蛋白 BCL-2，这种搭配相当于给肿瘤细胞增殖“踩刹车”，并为其凋亡“轰油门”，提高抗肿瘤效果；BTKi可以使CLL细胞从淋巴结脱落，然后由BCL-2抑制剂诱导循环系统中的肿瘤细胞凋亡；联合用药可以避免单药治疗时的耐药突变。 BCL-2抑制剂可谓站在巨人肩上，前方海阔天空。 02  三大适应症全胜 血液瘤三大适应症CLL/SLL（慢性淋巴细胞白血病/小淋巴细胞淋巴瘤）、MM（多发性骨髓瘤）、MDS（骨髓增生异常综合征），有望被APG-2575全部拿下。 在维奈克拉做到的领域（CLL/SLL）上，APG-2575做得更好，在维奈克拉尚未做到的领域（MM、MDS），APG-2575也有望大获全胜。 CLL/SLL CLL/SLL是欧美最常见的白血病类型，曾经成就伊布替尼（BTKi）的辉煌，但随着患者用药时间延长，BTKi耐药问题日益突出。既往公布的临床数据验证，APG-2575具备BIC潜力，有望成为难治或复发性CLL/SLL患者的最佳治疗选择。 虽然维奈克拉对Bcl-2的抑制是CLL治疗的重大进展，但为减轻肿瘤溶解综合征和药物相互作用（DDI）风险而进行的5周剂量递增给药的治疗方式，起效较慢，需要一个多月时间才能达到最终治疗剂量，对于晚期R/R CLL患者，不利于肿瘤的控制。而APG-2575采用每日梯度递增的创新给药方式，能够快速达到目标治疗剂量（在4-6天后达到最终目标剂量），有助于缩短患者住院时间，提高治疗依从性。 据中信建投研报，APG-2575在治疗维奈克拉无效的 BTK 耐药患者中显示出有效性，并且与 BTKi 联合使用时，对TN（初治）CLL/SLL 患者达到100%的 ORR，对R/R（复发/难治性）CLL/SLL患者也实现98%的 ORR。在安全性方面，APG-2575中性粒细胞减少症和血小板减少症的发生率分别为30.3 %和13%，相较于维奈克拉显著降低（分别为45%和21%），同时临床肿瘤溶解综合征的风险也较低。APG-2575与 BTKi 的联用中未观察到DDI，且无剂量限制毒性。基于APG-2575+BTKi的联合疗法将在CLL 适应症中大有可为。 据2024年ASH 年会最新摘要，APG-2575联合阿可替尼对既往接受过维奈克拉治疗的患者，ORR为85.7%（12/14），对既往接受过维奈克拉但未接受过BTK抑制剂治疗的患者，ORR为100%（8/8），对既往接受过维奈克拉和BTK抑制剂治疗的患者中，ORR为66.7%（4/6）。这项随访时间较长的更新分析显示，在接受APG-2575单药治疗/联合治疗的TN或R/R CLL/SLL患者中未观察到DDI或新的安全性问题。 好事连连，APG-2575 2025年R/R CLL/SLL有望于国内获批上市。而全球层面APG-2575 2026年将完成联合治疗经治CLL/SLL美国注册III期临床入组，随后在美国递交新药上市申请。 MM MM是全球第二大血液肿瘤，先后成就来那度胺、达雷妥尤单抗（CD38）的辉煌。 MM是一种常见恶性血液瘤，遗传复杂、高度异质性，目前仍无法治愈。VRd方案（硼替佐米+来那度胺+地塞米松）是一线标准治疗方案，对于复发难治患者缺乏标准治疗方案。 维奈克拉治疗MM折戟。2023年9月29日，艾伯维公告称，维奈克拉联合地塞米松（VenDex）治疗t(11;14)阳性R/R MM患者的III期CANOVA研究结果未达到PFS主要终点。VenDex组PFS为9.9个月，泊马度胺＋地塞米松（PomDex）治疗组PFS为5.8个月，HR=0.823，差异不显著。 APG-2575联合新型治疗方案用于R/R MM的 I/II期临床研究，入选2024年ASH 年会口头报告，A 组31例可评估患者中，有3例（9.7%）达到完全缓解（CR），7例（22.6%）达到很好的部分缓解(VGPR)，9例（29.0%）达到部分缓解 (PR)。总反应率（ORR）为61.3%（19例），10例（32.3%）达到≥ VGPR。B组4例可评估患者中，有2例（50%）达到CR，2例（50%）达到≥ VGPR。 这些联合疗法可提高R/R MM患者的缓解深度，并且显示出良好的安全性，尤其是血液学不良反应方面，且无药物相互作用。 MDS MDS患病人群大，现有疗法疗效不足。 MDS全球发病病例约 16-96万，仅美国 MDS 每年新发病例约4万例，相当于美国非小细胞肺癌新发病例人数的 21%。研究表明，阿扎胞苷作为初治中高危MDS 患者的首选治疗方案，可以延长患者的总生存期，但仅有20%~30%的患者能够完全缓解，仍存在巨大的未满足的临床需求。 贫血是 MDS 疾病的重要症状，减少贫血和输血是 MDS 疾病治疗效果的重要指征。维奈克拉一线治疗MDS早在2021年获得FDA突破性疗法认定，至今仍没有进展，可能安全性不过关。 一线治疗MDS是APG-2575的第4项注册III期临床研究，也是决胜维奈克拉的关键。 据2024年ASH 年会最新摘要，APG-2575联合阿扎胞苷在高危TN或R/R MDS患者治疗中呈现良好的有效性和耐受性，60天死亡率和TLS发生率均为0，需要APG-2575减量的患者少，感染率低。在8例R/R MDS患者中，中位治疗时间（DOT）为3.2（1.2-9.4）个月，ORR为75.0%。在40例可评估疗效的TN MDS患者中，中位DOT为4.5（0.5-12.1）个月；根据IWG 2006标准，ORR率为77.5%，CR率为25.0%。 APG-2575在突破MDS适应症后，将直道超车维奈克拉。 除上述适应症及联合疗法外，APG-2575还在更为广阔的世界里驰骋，适应症拓展至AML、WM、T-PLL、MCL、R/R Ph+ ALL、AL淀粉样变性患者、ER+/HER2-乳腺癌及实体瘤，与自家管线耐立克、APG-2449、APG-115、Bcl-xL蛋白降解剂联用。 生物科技企业的成长路径，不能用传统的财务估值模型去预测。亚盛医药呈现出清晰的成长节点，以核心产品上市带动一波非线性跃迁。第一波是耐立克商业化及国际化带来的涟漪效应，变革行业临床治疗格局并使自己的市值大一圈，第二波是APG-2575商业化及国际化的涟漪效应，预计也将变革行业临床治疗格局并催化市值。 据海通国际预计，APG-2575 2033年风险调整后全球销售额为68.2亿元，其中国内5.7亿元，海外62.5亿元。 随着现金流改善的趋势强化，临床效率提速，亚盛医药的跃迁时刻将密集而至。