Luxeptinib

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

提到百济神州的BTK，不假思索就会想到泽布替尼，但百济神州的BTK抑制剂不止泽布替尼，管线中在研的BGB-16673是潜在的另一把“利剑”。 近日，百济神州BTK PROTAC分子BGB-16673被FDA授予快速通道资格，用于经过至少二线治疗的CLL/SLL患者，包括BTK抑制剂和Bcl-2抑制剂。 解决耐药性， PROTAC邂逅BTK 自2013年首款BTK抑制剂伊布替尼获批上市以来，目前全球已有6款BTK抑制剂获批上市。 尽管已有多款BTK抑制剂获批上市，且这些药物已经展示出优异的疗效，但它们仍有一定局限性，即耐药性难题。 PROTAC（蛋白降解）是近几年非常火热的研发赛道。 相对小分子抑制剂来说，PROTAC降解剂具有诸多优势：扩展了可成药靶标，可以靶向那些没有小分子抑制剂或小分子抑制剂疗效不佳的靶标蛋白；催化效率高，可以使用催化量起作用，避免了像小分子长时间占有才能发挥药效的情况；克服耐药性，PROTAC降解剂不仅抑制蛋白活性，还可以降解整个蛋白从而破坏蛋白质的酶和非酶功能（例如支架）或转录功能，克服传统小分子的耐药性。 包括礼来的Pirtobrutinib在内，目前获批的BTK药物都属于小分子抑制剂，容易产生耐药问题，为了进一步提高药效和克服耐药性问题，不少企业将目光投向了BTK的PROTAC药物开发，百济神州便是其中之一。 早在2021年，泽布替尼还未曾大显神威的时候，百济神州就开始将PROTAC技术应用到BTK的药物开发上。资料显示，百济神州启动的首个临床PROTAC项目便是BGB-16673，于2021年8月百济神州在ClinicalTrials.gov进行了临床试验登记，2022年3月又在国内启动临床。 BGB-16673通过泛素化诱导BTK降解，展现出在解决BTK抑制剂耐药性问题上的巨大潜力。本次快速通道认定的申请主要基于BGB-16673用于解决发生疾病进展的CLL/SLL患者尚未满足的医疗需求的潜力。 在今年6月举行的2024年欧洲血液学协会年会上，百济神州公布了BGB-16673正在进行的Ⅰ/Ⅱ期首次人体试验（NCT05006716）数据，突显出该药物用于治疗既往接受过多线治疗的R/R CLL/SLL患者具有可耐受的安全性和良好的有效性。此外，还在多种不同类型非霍奇金淋巴瘤（NHL）患者中表现出了可耐受的安全性和初步的有效性。 迄今为止，BGB-16673全球临床开发项目已在15个国家/地区治疗了超过300例患者。目前BGB-16673正在进行BTK抑制剂后线CLL/SLL剂量扩展队列研究，百济神州预计今年底、明年初启动Ⅲ期临床试验。 目前除了BGB-16673，海思科的HSK29116以及Nurix Therapeutics的NX-2127和NX-5948也都是在研的BTK PROTAC降解剂，BGB-16673进展最快。 与泽布替尼互补， 巩固BTK竞争地位 自2013年11月，全球首个BTK抑制剂伊布替尼获FDA批准上市后，带来了血液肿瘤的革命性进展，BTK靶向药物研发热浪开始在全球铺开。 百济神州是BTK赛道的中国骄傲，凭借泽布替尼把老将伊布替尼逐渐逼向“墙角”，在BTK市场大放异彩。 2023年全年泽布替尼全球销售额近13亿美元，成为首个年销售破十亿美元的国产新药。2024年上半年，泽布替尼的全球销售额为80.18亿元，营收占比超60%，是百济神州的“镇山之宝”。 相比之下，由于竞争对手的涌入以及自身耐药性问题，伊布替尼已经在走下坡路，2024年上半年全球销售额为16.71亿美元，同比下滑6.4%。 目前整个BTK赛道，不仅已上市药物你追我赶，临床在研药物也是各显神通。据不完全统计，除已上市药物，全球进入临床的有上百条管线，当下BTK抑制剂的市场角逐早就进入“白热化”阶段，竞争已经从适应症、作用机制、药物类型等方面多元化延伸。 因此对于百济神州而言，虽然目前泽布替尼处在销售猛涨期，但也并非高枕无忧。攻下血液瘤之后，多数的已上市BTK药物拓展适应症势在必行，自免领域的相关适应症成了BTK的下一个用武之地。 据华创证券统计，当前在自身免疫性疾病领域探索的BTK抑制剂超过20款，适应症聚焦在多发性硬化症（MS）、自发性荨麻疹、系统性红斑狼疮、类风湿性关节炎等疾病。 今年4月，赛诺菲已率先领跑，其旗下的BTK抑制剂Rilzabrutinib（SAR444671/PRN-1008）治疗持续性或慢性免疫性血小板减少症（ITP）成年患者的III期LUNA 3研究达到主要终点，并计划于今年年底前向FDA递交Rilzabrutinib的上市申请。 除此之外，赛诺菲的另一款BTK抑制剂Tolebrutinib和诺华的Remibrutinib均瞄准了MS，目前也在临床Ⅲ期；渤健针对MS的BIB091，艾伯维针对系统性红斑狼疮、类风湿关节炎的Elsubrutinib都已进入临床Ⅱ期。 百济神州对泽布替尼也有进行自免领域的探索，不过泽布替尼治疗狼疮肾炎适应症进入II期临床，尚在临床早期。 另外，非共价如礼来的Pirtobrutinib对整个BTK市场也是虎视眈眈，去年上市首年，卖出7500万美元销售额。礼来预计，2030年Pirtobrutinib将在慢淋市场占据60%市场份额，对应30亿美元的年销售额。 基于非共价的耐药优势，目前全球的非共价（可逆）BTK抑制剂赛道也聚集了诸多玩家，国外有默沙东的MK-1026/ARQ531（Nemtabrutinib）、Aptose Biosciences的CG-806、罗氏的Fenebrutinib/GDC-0853等，国内有和黄医药的HMPL-760、信诺维/中国抗体的XNW1011、倍特药业/海博锐的BT-1053等。 总之，百济神州寻找泽布替尼之外的具备差异化优势的BTK抑制剂对于守卫自身在BTK赛道的竞争地位非常重要。 BGB-16673是目前临床开发中进展最快的BTK降解剂，具备成为使用BTK抑制剂后疾病进展、选择有限的患者的重要治疗方案的潜力，同时，BGB-16673将巩固百济神州在血液学领域的领先地位，并与泽布替尼形成优势互补，填补泽布替尼后线市场。 结语 在全球范围内，BTK抑制剂市场增长迅速，2020年达到72亿美元。根据沙利文分析，BTK抑制剂市场规模以22.7%的复合年增长率增长，将在2025年达到200亿美元，并持续以5.5%的复合年增长率扩大到2030年的261亿美元。 显然，百济神州势必不遗余力下好BTK这盘棋，未来，泽布替尼和BGB-16673这两把剑还会舞出怎样的江湖剑影，拭目以待。 参考资料： 1、《BTK竞争红海，后来者如何弯道超车？》贝壳社 2、《BTK抑制剂“后浪”奔涌！AZ、礼来持续发力，百济神州遭遇夹击？》医学经济报 声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。 责任编辑 | 拉夫斯 转载开白 | 马老师 18996384680（同微信） 商务合作 | 王存星 19922864877（同微信）  阅读原文，是受欢迎的文章哦