Acalabrutinib

Ascentage Pharma (6855.HK) today announced that it has released the latest clinical data of lisaftoclax (APG-2575) as a monotherapy or in combinations in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), in a Poster Presentation at the 66th American Society of Hematology (ASH) Annual Meeting, taking place in San Diego, CA, the United States. Dr. Matthew Davids, from Dana-Farber Cancer Institute in the US, is the principal investigator of the study. The ASH Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma’s drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year’s ASH Annual Meeting. These data once again highlighted the therapeutic magnitude of Ascentage Pharma’s Bcl-2 selective inhibitor lisaftoclax, as a monotherapy and in combinations, in patients with relapsed/refractory (R/R) CLL/SLL, particularly the clinical benefit of lisaftoclax in combination with acalabrutinib in patients with prior exposure to venetoclax, including those who progressed on or were intolerant/refractory to venetoclax. Furthermore, no drug-drug interactions (DDIs) or new safety signals were observed in patients treated with lisaftoclax monotherapy or combinations. Dr. Matthew Davids The principal investigator of the study Dana-Farber Cancer Institute “Lisaftoclax continues to demonstrate very strong efficacy in multiple patient subgroups, including those who previously progressed on venetoclax or BTK inhibitors.  The drug also has excellent tolerability and the convenience of a daily dose ramp-up to reach the target effective dose. Based on the promising early phase results, the GLORA global registrational study has now launched and is actively enrolling.” Dr. Yifan Zhai Chief Medical Officer of Ascentage Pharma “Results released at this year’s ASH Annual Meeting reaffirmed the therapeutic potential of lisaftoclax in CLL/SLL. In China, a New Drug Application (NDA) for lisaftoclax has already been accepted and granted the Priority Review designation by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA), potentially leading lisaftoclax to become the second Bcl-2 inhibitor approved anywhere in the world. In the US, a global registrational Phase III study that was cleared by the US Food and Drug Administration (FDA) is currently underway.  Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates such as lisaftoclax to bring more safe and effective therapies to patients as soon as possible.” Highlights of the data this study reported at ASH 2024 are as below: Lisaftoclax (APG-2575) Demonstrates Activity and Safety When Given With Accelerated Ramp-up and Then Combined With Acalabrutinib or Rituximab in Patients (pts) With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Including Those With Prior Exposure to Venetoclax Format: Poster Presentation Abstract#: 4614 Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III Highlights: Background: Bcl-2 inhibition with venetoclax (ven) was a major advance in CLL treatment, but the 5-week dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS) and DDIs challenge treatment optimization. Lisaftoclax is an investigational, oral Bcl-2i with a short half-life, allowing it to be ramped-up on a daily schedule. Introduction: This poster presents updated clinical data of lisaftoclax alone or combined with acalabrutinib or rituximab in patients with treatment-naïve (TN), R/R, or prior ven-treated CLL/SLL. Enrolled Patients and Study Methods: From March 20, 2020, to June 27, 2024, 176 patients were enrolled: 46 in monotherapy and 39 and 91 in the rituximab and acalabrutinib combination cohorts, respectively; 87.5% (154/176) of patients were R/R and 12.5% (22/176) were TN. The median (range) age was 63 (34-80) years; 67% were male; 25.6% had del(17p) and/or TP53 mutation. Median (range) duration of treatment with lisaftoclax was 16.5 (1-54; monotherapy), 24 (3-39; rituximab), and 27 (1-43; acalabrutinib) cycles. Fourteen (9%) patients relapsed on or were intolerant/refractory to prior treatment with ven. Their median (range) age was 65 (51-78) and 79% were male. 50% of those patients had del (17p), 36% had the TP53 mutation, 64% had del (11q), 38% had a complex karyotype (≥ 3 abnormalities), and 92% had unmutated IGHV. Patients were treated with a rapid 4- to 6-day daily ramp-up of lisaftoclax from 20 mg to a target dose of 400, 600, or 800 mg, receiving daily oral lisaftoclax alone or, plus continuous acalabrutinib or 6 cycles of rituximab in 28-day cycles, starting on Cycle 1 Day 8 (C1D8) until disease progression, complete response by C24, or unacceptable toxicity. Efficacy Results: The ORR for lisaftoclax plus acalabrutinib in 87 patients was 98%, and the median duration of response (DOR; 95% CI, 31-NE) and median progression-free survival (PFS; 95% CI, 34-NE) of responders were not reached. Among patients who received lisaftoclax plus acalabrutinib, 14 have relapsed  on or were intolerant/refractory to prior treatment with ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 86%, the median PFS was not reached (11.3-NE), the 12-month PFS rate was 84%, and the 18-month PFS rate was 73%. Among patients who received lisaftoclax plus acalabrutinib, 9 were refractory to ven. Their median (range) cycles of treatment were 16 (3-25), the ORR was 89%. The median PFS was not reached (NE-NE), the 12-month PFS rate was 89%, and the 18-month PFS rate was 89%. Safety Results: Incidence and severity of TEAEs were similar across cohorts. Common (≥20%) any-grade TEAEs in all cohorts combined were infection (107 [61%]), neutropenia (67 [38%]), anemia (51 [29%]), diarrhea (51 [29%]), and thrombocytopenia (38 [22%]). Grade ≥ 3 treatment-emergent AEs (TEAEs; ≥10%) were neutropenia in 15 (33%), 11 (28%), and 27 (30%) patients; infection in 13 (28%), 4 (10%), and 14 (15%) patients; and anemia in 8 (17%), 4 (10%), and 11 (12%) patients in monotherapy, rituximab, and acalabrutinib combination cohorts, respectively.  Lisaftoclax, alone or in combination, demonstrated a favorable safety profile and a rate of clinical tumor lysis syndrome (TLS) of 1.1%. No DDIs or new safety signals were observed in patients who received lisaftoclax in combination with acalabrutinib or rituximab. Conclusions: The presented data suggest that lisaftoclax combined with acalabrutinib was active in patients with TN or R/R CLL/SLL, with a reported 98% ORR and a median DOR that was not reached at 22.3 months of median follow-up. Lisaftoclax combined with acalabrutinib was also effective for patients with prior ven exposure, including those who progress on or were intolerant/refractory to ven. In this updated analysis with longer follow-up, no DDIs or new safety findings were observed in TN or R/R CLL/SLL patients treated with lisaftoclax monotherapy or combinations. Patients with prior ven exposure continue to be accrued in order to further evaluate this promising signal. A global registrational phase III study is recruiting. *Lisaftoclax is an investigational drug that has not been approved in any country and region. 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, 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.

欢迎关注凯莱英药闻 2024年12月9日，Nurix Therapeutics在2024 年 12 月 7 日至 10 日在加利福尼亚州圣地亚哥举行的第 66 届美国血液学会 (ASH) 年会和博览会上，展示了NX-5948的最新临床研究数据。 NX-5948是一种布鲁顿酪氨酸激酶 (BTK) 降解剂，目前正在对患有复发或难治性 B 细胞恶性肿瘤的成年人进行 1a/b 期临床试验评估。 关于最新研究数据 截至 2024 年 10 月 10 日，共有60 名复发或难治性慢性淋巴细胞白血病或小淋巴细胞淋巴瘤 (CLL/SLL) 患者入组。这些CLL/SLL 患者此前接受过包括共价BTK 抑制剂（98.3%）、淋巴细胞瘤-2基因 (BCL2) 抑制剂（83.3%）和非共价 BTK 抑制剂（28.3%）治疗；大量患者具有与 BTK 抑制剂耐药性相关的突变，包括 BTK（38.6%）和 PLC2G（12.3%）的突变。 在可评估疗效的 CLL/SLL 患者（n=49）中，NX-5948 治疗在所有测试剂量中均获得了 75.5% 的稳健客观缓解率 (ORR)，大多数缓解发生在第一次评估（第 8 周）时；随着治疗时间的延长，至少接受过两次反应评估（第 16 周）的患者ORR 增加至 84.2%。所有人群均观察到反应，包括基线 BTK 突变，以及对共价和非共价 BTK 抑制剂治疗耐药性的患者。 在所有评估剂量下均具有良好的耐受性，在 CLL/SLL 患者中，最常见的治疗出现的不良事件是紫癜/挫伤（36.7%，均为 1 级或 2 级）、疲劳（26.7%，均为 1 级或 2 级）、瘀点（26.7%，均为 1 级或 2 级）、中性粒细胞减少症（23.3%，18.3% 为 3 级或更高）和皮疹（23.3%，1.7% 为 3 级或更高）。整个人群只有一例1级心房颤动患者（患者已有心房颤动）发生。 关于NX-5948 NX-5948 是一种口服生物可利用、脑渗透性、BTK小分子降解剂，通过cereblon E3连接酶复合体介导的泛素化和随后的蛋白酶降解，诱导BTK的野生型和突变型的特异性降解，对当前 BTK 抑制剂疗法有抗药性的肿瘤细胞系具有很强的效力。 2024年1月，FDA已授予 NX-5948 快速通道资格，用于治疗复发或难治性CLL/SLL的成年患者；上述患者此前至少经历两种疗法，包括BTK抑制剂和BCL2抑制剂。 2024年10月，公司在第 12 届华氏巨球蛋白血症国际研讨会 (IWWM-12) 上，公布旗下NX-5948在治疗包括复发/难治性华氏巨球蛋白血症 (WM)的1a/1b 期临床试验积极数据，结果显示： （1）9 名可评估疗效的WM 患者中，7 名患者 (77.8%) 有客观反应，2 名患者病情稳定 (22.2%)。（2）所有 7 名患者均在 8 周的首次评估中出现反应，5 名患者仍在接受治疗，2 名患者接受治疗超过一年。（3）无论患者基线 MYD88 和CXCR4突变如何，均观察到反应。（4）以血清 IgM 水平的降低为衡量指标，NX-5948 的疗效可随着时间的推移而加深。 此外，本次会议还披露了NX-5948在原发性中枢神经系统淋巴瘤 (PCNSL) 动物模型中的新临床前数据，显示：（1）NX-5948 可促进BTK 的强力降解、抑制细胞外信号调节激酶 (ERK) 并延长PCNSL患者的生存期。（2）在接受 NX-5948 治疗的动物中，观察到与增强肿瘤抗原呈递和减少肿瘤进展相关的转录变化。 关于BTK降解剂 BTK是一种非受体蛋白酪氨酸激酶（NRTK），属于TEC激酶家族，在B细胞表面受体(BCR)等信号传导通路中发挥重要作用。生理情况下，BTK参与B细胞的发育成熟，以及B细胞的增殖、运输、趋化、黏附等过程。在CLL/SLL等多种B细胞血液瘤中，BTK持续激活下游AKT，ERK和NF-кB等通路，抑制恶性B淋巴细胞的凋亡，导致后者的异常增殖。除此以外，在RA、MS、SLE等多种自身免疫性疾病中，BTK介导与疾病密切相关的病生理过程，包括产生自身抗体、分泌多种促炎因子。 BTK相关信号通路 目前在研的BTK抑制剂主要有三代，分别是： 第一代：伊布替尼为全球首个获批的BTK抑制剂，适应症覆盖最多； 第二代：阿卡替尼、泽布替尼、奥布替尼等第二代抑制剂，着力提高药物靶向性及安全性。其中泽布替尼的适应症覆盖较全，阿卡替尼仅覆盖部分核心适应症； 第三代：以Pirtobrutinib为代表，系采用新的结合位点的非共价抑制剂。 从全球范围来看，近年来BTK抑制剂整体市场稳健增长。2022年五款BTK抑制剂合计销售收入111亿美元，同比增长8.6%。 从PDB样本医院销售数据来看，我国BTK抑制剂市场较快增长。2022年PDB样本医院销售额为5亿元，2018-2022年PDB样本医院BTK抑制剂销售收入年均复合增速为132%。 激酶小分子抑制剂经过一段时间治疗后，往往会产生耐药突变。为了克服新的耐药突变，BTK降解剂策略成为下一代BTK药物开发的选择。 据不完全统计，目前在研的BTK降解剂约二十余种。 关于Nurix Nurix 成立于2009年，拥有独特的DELigase 靶向蛋白调节平台；DELigase 平台具有高度差异化，能够识别可以降低靶向蛋白质降解（TPD）或增加（TPE）蛋白质水平的小分子，也称之为靶向蛋白质调节（TPM）的过程。基于该平台，Nurix 既可以利用E3 连接酶降解特定的靶蛋白（如BTK CTM），也可以抑制特定连接酶以提高底物蛋白水平（如CBL-B 抑制剂）。 公司专注于开发肿瘤学、免疫肿瘤学、过继细胞治疗和免疫疾病领域药物，正在推进多个内部发现和全资拥有的临床阶段候选药物，旨在治疗血液系统恶性肿瘤和实体瘤患者。 本次会议中，公司重点披露的数据还包括一款NX-2127，可降解BTK、Ikaros（IKZF1）和Aiolos（IKZF3）的新型双功能分子，目前正在对患有复发或难治性 B 细胞恶性肿瘤的成年人进行 1a/b 期临床试验评估，数据显示：采用NX-2127 治疗的 CLL 细胞具有明显的免疫调节作用，包括上调干扰素 (IFN) 反应基因 CD38、增强免疫反应、促进 T 细胞向 TH1 表型分化、增强抗肿瘤免疫力、减少 Treg 分化（支持向免疫抑制程度较低的微环境转变并增强免疫突触形成）和 T 细胞介导的细胞毒性。此外，RNA测序揭示了NX-2127处理的CLL细胞中独特的基因表达模式，区分了应答者和无应答者，并进一步证明了其独特的T细胞调节作用。 感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下