Luxeptinib

▲点击图片，了解详情 作者：嘤嘤嘤 12月16日，信达生物和礼来制药共同宣布，就礼来非共价（可逆）BTK抑制剂捷帕力®（匹妥布替尼100毫克和50毫克片剂）在中国大陆的权益达成以下合作协议：信达生物将负责捷帕力的进口、销售、推广和分销工作；礼来将负责捷帕力的研发和上市后医学事务相关工作。 套细胞淋巴瘤（MCL）是一种非霍奇金淋巴瘤（NHL）亚型，占所有NHL病例的约6%。MCL的命名来自其发病区域——套区，也就是淋巴结中的环形细胞，B细胞（一种淋巴细胞）产生于此并发挥特定的功能。从表现上来看，MCL可以是侵袭性的，也可以是快速增长的。虽然目前MCL没有治愈方法，但有一些治疗方案可能有助于控制MCL。然而，MCL的预后相对较差，有着巨大的临床未满足需求。 1 匹妥布替尼的优势 捷帕力®（匹妥布替尼片）是一种高选择性BTK抑制剂。由于其采用的是新型非共价结合机制，因此可以在既往接受过共价BTK抑制剂（已上市的包括伊布替尼、阿可替尼、泽布替尼、或奥布替尼）治疗的MCL患者中重新建立BTK抑制作用，并持续获益。大大满足了这部分患者的临床治疗需求。 匹妥布替尼于2023年1月获得美国FDA批准，成为全球首个且唯一获批的非共价（可逆）BTK抑制剂。于2024年10月获得我国国家药品监督管理局（NMPA）批准，单药适用于既往接受过至少两种系统性治疗（含BTK抑制剂）的复发或难治性MCL成人患者。 在中国2期临床试验JZNJ研究（开放标签、II期、单臂、多中心研究）中，研究者评估了匹妥布替尼单药治疗在中国B细胞恶性肿瘤患者中的疗效和安全性。该研究共纳入了87名中国B细胞恶性肿瘤患者，其中35名是曾接受过BTK抑制剂治疗的MCL患者。来自这35名患者的研究结果显示，经独立评审委员会评估确定的总体缓解率（ORR）为62.9%（95% CI：44.9-78.5）。 在中国人群中，匹妥布替尼的耐受性良好，未出现新的安全性信号，仅3%的患者因治疗相关不良反应而停药。中国研究结果与全球BRUIN研究结果一致，表明匹妥布替尼在中国人群中具有临床意义和持久的抗肿瘤活性。礼来之所以选择与信达生物合作，考虑的是充分利用信达生物在血液肿瘤领域丰富的商业化经验。 2 BTK抑制剂的成果 BTK是B细胞受体（BCR）信号通路中的重要组成部分，而BCR信号通路在B细胞的增殖、分化、发育和存活中起着关键作用。BTK的异常活化会导致BCR信号通路过度活跃，这与B细胞恶性肿瘤的发生、发展密切相关。因此，BTK成为B细胞肿瘤治疗的重要靶点。BTK抑制剂通过抑制BTK的自我磷酸化抑制其活性，从而阻断B细胞受体下游信号通路，诱导恶性B细胞凋亡。 最近十年来，BTK抑制剂一路高歌猛进，几乎称霸血液瘤领域，市场规模也已超百亿美元。越来越多的玩家参与进来，提供新的治疗选择，优化治疗策略。与此同时，市场竞争也变得越来越激烈。第一代不可逆抑制剂有伊布替尼，第二代不可逆抑制剂有泽布替尼、阿可替尼、奥布替尼、替拉鲁替尼，第三代可逆抑制剂匹妥布替尼。 由艾伯维与强生开发的首款BTK抑制剂伊布替尼2013年在美国获批上市，此后持续放量。其2021年全球销售额逼近百亿美元，之后有所下滑，2023年仍有超60亿美元（约合人民币436.76亿元）的销售收入。 二代BTK抑制剂也在近年来持续放量。2024年上半年，百济神州的泽布替尼销售额达到11.26亿美元，诺诚建华的奥布替尼2024年上半年销售额为4.2亿元，同比增长30%。根据弗若斯特沙利文数据，全球BTK抑制剂市场规模预计2025年达219亿美元，2030年达251亿美元。 此外，正在研究中的小野制药的Tirabrutinib是第二代高选择性共价BTK抑制剂，已在日本获批用于复发性和难治性原发性中枢神经系统淋巴瘤治疗，并正在中国等地进行更多适应症的研发。宜诺凯的奥布替尼于2021年6月被美国FDA指定为复发性和难治性MCL的突破性疗法，目前正在更多的适应症中进行研发。 Telios Pharma的TL-895（以前称为M7583）是另一款高效、高选择性的第二代BTK抑制剂，临床试验显示其在多种B细胞恶性肿瘤中疗效显著。浙江海正药业的DTRMWXHS-12则是另一款选择性共价BTK抑制剂，正在与mTOR抑制剂及免疫调节剂联用进行临床试验。 3 非共价BTK抑制剂的发展 从作用机制看，趋势是从不可逆共价升级到可逆非共价。不可逆抑制剂的治疗作用较强，可提高药物利用效率，但在高浓度下存在一定的脱靶毒性，如果患者产生BTK耐药突变，疗效将大打折扣。而可逆抑制剂则副作用较小，已经成为BTK抑制剂开发和应用领域的前沿。 除了联合疗法外，共价与非共价双重抑制剂正在开发中，取长补短，旨在最大限度地减少副作用并降低耐药性。LP-168就是这样一种双重抑制剂，能够根据突变是否存在进行共价和非共价结合。一项1期研究（NCT04993690）已经验证了LP-168的安全性和有效性。另一项1期研究（NCT04775745）发现，LP-168在患者中具有良好的耐受性，高达300mg的剂量都没有达到最大耐受剂量。 从clinicaltrials网站查询结果来看，目前开放中的BTK抑制剂临床试验有80多个，其中匹妥布替尼有17项。其他第三代BTK抑制剂包括默克的奈米他替尼、Aptose Biosciences的Luxeptinib以及和黄医药的HMPL-760等。奈米他替尼通过氢键可逆抑制野生型和C481S突变型BTK，但选择性较低。Luxeptinib是一种多激酶抑制剂，能非共价抑制多种激酶，包括野生型和突变型BTK、FLT3等。HMPL-760是一种高效、选择性、可逆BTK抑制剂，临床前模型显示其抑制活性高于匹妥布替尼片。 结语 相较于第一代BTK抑制剂，第二代BTK抑制剂在安全性上有显著提高，而非共价可逆BTK抑制剂的加入，为未来的临床治疗提供了更多的选择。BTK抑制剂单药或联合治疗模式在MCL治疗中逐渐成为趋势，并且有望作为一线诱导和维持治疗，让更多的MCL患者获得更佳的缓解和更长的无进展生存和总体生存。未来，第三代BTK抑制剂也会布局到更多适应症中。 参考来源： 1. Hematology Oncology Committee of China Anti-Cancer Association; Society of Hematology at Chinese Medical Association; Union for China Lymphoma Investigator at Chinese Society of Clinical Oncology. Zhonghua Xue Ye Xue Za Zhi. 2022;43(7):529-536. doi:10.3760/cma.j.issn.0253-2727.2022.07.001 2. 信达生物官网 3. 礼来官网 4. 行业深度报告 BTK 抑制剂问世开启靶向治疗，新型疗法突破耐药难题, 平安证券 5. Cool, Allison, et al. "BTK inhibitors: past, present, and future." Trends in Pharmacological Sciences (2024). 6. Stanchina, Michele D., et al. "Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia." Nature Reviews Clinical Oncology (2024): 1-21. 关于贝壳社 贝壳社是国内领先的医健创新创业服务平台，为医健创业者提供全路径创业服务。通过产业空间运营、创业教育、投资孵化、数字化赋能、企业价值增长等服务体系，给医健创业企业提供产业空间、人才战略培养、投融资、产业生态资源、数字化转型等服务。同时，贝壳社布局澳洲，帮助国内生物医药企业加速走向海外；成立“泰格-泰珑-贝壳社企业经营服务中心”为企业成长提供全生命周期的增值服务，提高企业运营效率，加快企业成长发展。我们深度链接政府、科研院所、临床机构、投资机构、第三方服务商、CXO等行业资源，致力于赋能医疗健康创业公司成长，推动创新技术造福人类生命健康。 往 期 推 荐 1 百亿大药，难逃“内卷”魔咒 2 破局！国内首款CD19 ADC药物获批上市 _ 3 最饥渴的大厂，全力扫货中国 _ *声明：本文仅为作者观点，不构成任何投资建议，且非治疗方案推荐。 投稿请添加小助手：bioclub666

Aptose and Hanmi Pharmaceutical Co-developing Triplet Therapy of Tuspetinib with Azacitidine and Venetoclax for Newly Diagnosed AMLSAN DIEGO and TORONTO, Nov. 08, 2024 (GLOBE NEWSWIRE) -- Aptose Biosciences Inc. (“Aptose” or the “Company”) (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral targeted agents to treat hematologic malignancies, today announced financial results for the three months ended September 30, 2024, and provided a corporate update. "Triple drug therapies (triplets) that build on the standard of care in AML have yielded higher response rates yet are limited to specific subpopulations and often cause myelosuppression and other toxicities,” said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer of Aptose. “Tuspetinib, with its breadth of activity and unique safety profile, is a potential game-changer as part of a triplet therapy regimen and we continue to advance its development.” Key Corporate Highlights Aptose Facility Agreement with Hanmi – During the quarter, Aptose announced that it received a $10 million loan through a Facility Agreement with Hanmi Pharmaceutical Co. (“Hanmi”), and that the companies are actively negotiating a new tuspetinib co-development collaboration agreement intended to provide additional support to accelerate the clinical development of tuspetinib. The loan is convertible as prepayment of milestone obligations under the future collaboration agreement or repayable after the expected completion of a triple drug combination trial with tuspetinib in newly diagnosed AML patients. Aptose plans to use the proceeds from such loan for the development of tuspetinib.Tuspetinib Data Drives Interest as Treatment Paradigm for AML Shifts to Triplet Therapy – During our APTIVATE trial, tuspetinib (TUS) as a monotherapy and in combination treatment with venetoclax in a very ill AML patient population safely demonstrated broad clinical activity in AML patients with diverse mutation profiles, including those with adverse genetics. As presented at the European Hematology Association (EHA) 2024 Congress in June, tuspetinib potently targets SYK, FLT3, mutated KIT, JAK1/2, and RSK2 kinases, yet avoids many typical toxicities, drug-related discontinuations, and deaths observed with other agents. In the APTIVATE trial, TUS achieved broad activity across AML patients with a diverse array of mutations, both as a single agent (TUS) and in combination with venetoclax (TUS+VEN) in very ill relapsed/refractory (R/R) and heavily pre-treated AML populations. Responses were observed in patients with Prior-VEN, Prior-FLT3 inhibitor (FLT3i), and Prior-HSCT therapies, those with highly adverse genetics, including mutations in TP53 and RAS genes, and those with mutated or unmutated (wildtype) FLT3 genes. Patients naïve to VEN therapy achieved higher response rates. TUS appears to be an ideal third agent to add to a venetoclax and hypomethylating agent regimen. These data support the launch of the triplet therapy trial in newly diagnosed AML patients who are ineligible to receive induction chemotherapy, irrespective of their FLT3 mutation status. Other triplet therapies in development can achieve high response rates but are limited by toxicities and inability to treat certain AML populations, leaving an unmet need that may be addressed with the addition of tuspetinib. With Hanmi’s support, Aptose plans to initiate its planned triplet combination study during the quarter and to treat patients with and without FLT3 mutations. In addition, the company is evaluating other co-development opportunities to further expand the role of tuspetinib in other settings.Nasdaq – Aptose has a scheduled meeting with the Nasdaq Listing Qualifications during the current quarter to address compliance with the minimum requirement of $2.5 million in stockholders’ equity (the "Stockholders’ Equity Requirement") and Aptose continues to work on its compliance with minimum $1.00 per share closing bid price for thirty (30) consecutive business days, needed for continued listing on Nasdaq (the "Minimum Bid Price Requirement").On April 2, 2024, the Company received a deficiency letter from Nasdaq stating that the Company was not in compliance with the Stockholders’ Equity Requirement. The Company submitted a Compliance Plan to Nasdaq on this issue on May 17, 2024 and received an extension to meet this Nasdaq requirement by September 30, 2024. On October 1, 2024, the Company received a letter from Nasdaq stating that the Company did not meet the terms of the extension because it did not complete its proposed financing initiatives to regain compliance. On October 8, 2024, the Company requested an appeal and hearing; such hearing is scheduled for November 21, 2024.On July 16, 2024, Aptose announced that it had received a deficiency letter notifying the Company that was not in compliance with the Minimum Bid Price Requirement. This deficiency letter has no immediate effect on the listing of the Company's common shares, and its common shares will continue to trade on The Nasdaq Capital Market under the symbol "APTO" at this time. The Company's common shares continue to trade on the Toronto Stock Exchange ("TSX") under the symbol "APS". The Company's listing on the TSX is independent and will not be affected by the Nasdaq listing status. In accordance with Nasdaq Listing Rule 5810(c)(3)(A), the Company has been given one hundred and eighty (180) calendar days, or until January 13, 2025, to regain compliance with the Minimum Bid Price Requirement. If the Company does not regain compliance with the Minimum Bid Price Requirement by January 13, 2025, the Company may, at Nasdaq’s discretion, be afforded a second one hundred and eighty (180) calendar day period to regain compliance, but if Nasdaq does not grant such extension, the Company’s common shares could be delisted from Nasdaq. Multiple Planned Value-creating Milestones Ahead 2024: Q4​ Initiate dosing of TUS+VEN+AZA triplet in newly diagnosed AML​Completion of Hanmi/Aptose Collaboration ~ Year-end 2024​ 2024: ASH​ Report CR/Safety data from APTIVATE TUS+VEN doublet study ​Report dosing accrual from TUS+VEN+AZA triplet study ​ 2025: 1H​ Enroll two dose cohorts in TUS+VEN+AZA triplet study​Report CR/MRD/Safety data from TUS+VEN+AZA triplet study​ 2025: EHA​ Report maturing data readout from TUS+VEN+AZA triplet study​ 2025: ASH​ Select TUS dose for TUS+VEN+HMA triplet Ph 2/3 PIVOTAL trials​Prepare for Ph 2 portion of Ph 2 / Ph 3 pivotal program​ FINANCIAL RESULTS OF OPERATIONSAptose Biosciences Inc.Statements of Operations Data(unaudited)($ in thousands, except per share data) Three months endedNine months ended September 30, September 30, 2024 2023 2024 2023 Expenses: Research and development$4,702 $8,256 $15,560 $27,649 General and administrative 2,263 3,425 8,510 12,580 Operating expenses 6,965 11,681 24,070 40,229 Other income, net 12 234 225 977 Net loss$(6,953) $(11,447)$(23,845)$(39,252)Net Loss per share, Basic and diluted$(0.37) $(1.76)$(1.48)$(6.14)Weighted average number of common shares outstanding used in computing net loss per share, basic and diluted (in thousands) 18,560 6,495 16,107 6,391 Net loss for the three-month period ended September 30, 2024 decreased by $4.5 million to $7.0 million, as compared to $11.4 million for the comparable period in 2023. Net loss for the nine-month period ended September 30, 2024 decreased by $15.5 million to $23.8 million, as compared to $39.3 million for the comparable period in 2023. Aptose Biosciences Inc.Balance Sheet Data(unaudited)($ in thousands) September 30, December 31, 2024 2023Cash, cash equivalents and short-term investments$7,962 $9,252 Working capital 477 (3,375)Total assets 10,929 12,989 Long-term liabilities 10,305 621 Accumulated deficit (539,382) (515,537)Stockholders’ equity (9,134) (2,901) Total cash and cash equivalents and investments as of September 30, 2024, were $8 million. Based on current operations, the Company expects that cash on hand and available capital provides the Company with sufficient resources to fund planned Company operations including research and development through to January 2025.As of November 8, 2024, we had 19,521,183 Common Shares issued and outstanding. In addition, there were 1,212,355 Common Shares issuable upon the exercise of outstanding stock options and there were 16,946,491 Common Shares issuable upon the exercise of the outstanding warrants. RESEARCH AND DEVELOPMENT EXPENSES The research and development expenses for the three months and nine months ended September 30, 2024, and 2023 were as follows: Three months ended Nine months ended September 30, September 30,(in thousands) 2024202320242023Program costs – Tuspetinib$4,067 $5,814 $10,656 $18,659Program costs – Luxeptinib (225) 648 287 2,643Program costs – APTO-253 - 2 13 28Personnel related expenses 941 1,523 4,274 5,108Stock-based compensation (81) 259 317 1,182Depreciation of equipment - 10 13 29Total$4,702 $8,256 $15,560 $27,649 Research and development expenses decreased by $3.6 million to $4.7 million for the three-month period ended September 30, 2024, as compared to $8.3 million for the comparative period in 2023. Changes to the components of our research and development expenses presented in the table above are primarily as a result of the following events: Program costs for tuspetinib were $4.1 million for the three-month period ended September 30, 2024, compared with $5.8 million for the comparative period in 2023. The lower program costs for tuspetinib in the current period represent the reduction of activity in our APTIVATE clinical trial, reduced manufacturing costs, and related expenses. In the comparative period in 2023, tuspetinib program costs included the healthy volunteer study, which was completed in 2023.Program costs for luxeptinib decreased by approximately $873 thousand, primarily due to lower clinical trial and manufacturing activities.Program costs for APTO-253 decreased by approximately $2 thousand. The Company discontinued further clinical development of APTO-253.Personnel-related expenses decreased by $582 thousand, related to fewer employees in the current three-month period.Stock-based compensation decreased by approximately $340 thousand in the three months ended September 30, 2024, compared to the three months ended September 30, 2023, primarily due to stock options granted with lower grant date fair values in the current period and option forfeitures recorded in the current period. Research and development expenses decreased by $12.0 million to $15.6 million for the nine-month period ended September 30, 2024, as compared to $27.6 million for the comparative period in 2023. Changes to the components of our research and development expenses presented in the table above are primarily as a result of the following events: Program costs for tuspetinib were $10.7 million for the nine-month period ended September 30, 2024, a decrease of $8 million compared with $18.7 million for the comparative period in 2023. The lower program costs for tuspetinib in the current period represent the reduction of activity in our APTIVATE clinical trial, reduced manufacturing costs, and related expenses. In the comparative period in 2023, tuspetinib program costs included the healthy volunteer study, which was completed in 2023.Program costs for luxeptinib decreased by approximately $2.4 million to $287 thousand for the nine months ended September 30, 2024, as compared to $2.6 million in the comparative period, primarily due to lower clinical trial and manufacturing activities.Program costs for APTO-253 decreased by approximately $15 thousand, due to the Company’s decision on December 20, 2021 to discontinue further clinical development of APTO-253.Personnel-related expenses decreased by $834 thousand, related to fewer employees in the current six-month period and partially offset by salary increases.Stock-based compensation decreased by approximately $865 thousand in the nine months ended September 30, 2024, compared to the nine months ended September 30, 2023, primarily due to stock options granted with lower grant date fair values, in the current period. About Aptose Aptose Biosciences is a clinical-stage biotechnology company committed to developing precision medicines addressing unmet medical needs in oncology, with an initial focus on hematology. The Company's small molecule cancer therapeutics pipeline includes products designed to provide single agent efficacy and to enhance the efficacy of other anti-cancer therapies and regimens without overlapping toxicities. The Company’s lead clinical-stage compound tuspetinib (TUS), is an oral kinase inhibitor that has demonstrated activity as a monotherapy and in combination therapy in patients with relapsed or refractory acute myeloid leukemia (AML) and is being developed as a frontline triplet therapy in newly diagnosed AML. For more information, please visit www.aptose.com. Forward Looking Statements This press release contains forward-looking statements within the meaning of Canadian and U.S. securities laws, including, but not limited to, statements regarding the Company’s clinical development plans, the clinical potential, anti-cancer activity, therapeutic potential and applications and safety profile of tuspetinib, clinical trials, the enrollment in clinical trials and the data therefrom, the submission of a compliance plan to Nasdaq and available options to regain compliance, upcoming milestones, financing activities, expectations regarding capital available to the Company to fund planned Company operations, maintenance of the Nasdaq and TSX listings and statements relating to the Company’s plans, objectives, expectations and intentions and other statements including words such as “continue”, “expect”, “intend”, “will”, “hope” “should”, “would”, “may”, “potential” and other similar expressions. Such statements reflect our current views with respect to future events and are subject to risks and uncertainties and are necessarily based upon a number of estimates and assumptions that, while considered reasonable by us, are inherently subject to significant business, economic, competitive, political and social uncertainties and contingencies. Many factors could cause our actual results, performance or achievements to be materially different from any future results, performance or achievements described in this press release. Such factors could include, among others: our ability to obtain the capital required for research and operations; the inherent risks in early stage drug development including demonstrating efficacy; development time/cost and the regulatory approval process; the progress of our clinical trials; our ability to find and enter into agreements with potential partners; our ability to attract and retain key personnel; changing market and economic conditions; unexpected manufacturing defects and other risks detailed from time-to-time in our ongoing current reports, quarterly filings, annual information forms, annual reports and annual filings with Canadian securities regulators and the United States Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should the assumptions set out in the section entitled "Risk Factors" in our filings with Canadian securities regulators and the United States Securities and Exchange Commission underlying those forward- looking statements prove incorrect, actual results may vary materially from those described herein. These forward-looking statements are made as of the date of this press release and we do not intend, and do not assume any obligation, to update these forward-looking statements, except as required by law. We cannot assure you that such statements will prove to be accurate as actual results and future events could differ materially from those anticipated in such statements. Investors are cautioned that forward-looking statements are not guarantees of future performance and accordingly investors are cautioned not to put undue reliance on forward-looking statements due to the inherent uncertainty therein. For further information, please contact: Aptose Biosciences Inc.Susan PietropaoloCorporate Communications & Investor Relations201-923-2049spietropaolo@aptose.com