CDK2 x CDK9

- Interim data for fadraciclib monotherapy in patients with advanced solid tumors preselected for CDKN2A and/or CDKN2B abnormalities -BERKELEY HEIGHTS, N.J., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing innovative cancer medicines, today announced that initial safety and efficacy data from twelve patients with advanced solid tumors enrolled in the Phase 2 part of the 065-101 clinical study of fadraciclib, or “fadra”, as a single agent was presented as a poster at the 2024 EORTC-NCI-AACR 36th Symposium on Molecular Targets and Cancer Therapeutics (“Triple Meeting”), in Barcelona, Spain (October 23-25, 2024). The patients were enrolled in the biomarker-enriched, Cohort 8 of the proof of concept study and were preselected for CDKN2A and/or CDKN2B abnormalities. “We are encouraged by the interim data of cohorts 6 and 8 in our Phase 2 study of fadra,” said Spiro Rombotis, President and Chief Executive Officer. “Although the data in Cohort 8 is immature with ongoing patients still to have a first scan and being followed up, we continue to see good tolerability and signals of efficacy in patients with CDKN2A/B abnormalities that have had their first scan and follow-up evaluation. We are grateful to our investigators, the patients and their families for their support of this important study.” Interim Phase 2 Data Fadraciclib was well tolerated in Cohort 8. Most common drug-related adverse events included diarrhea, nausea, vomiting and were similar to those seen at this dose in Phase 1. There were no Grade 3 or higher treatment-emergent adverse events in the Phase 2 study this far, consistent with the Phase 1 data. The majority of patients (12/14) had ECOG performance status of 1 and median number of prior therapies was 3. In Cohort 8, four patients had pancreatic cancer, and one each cholangiocarcinoma, duodenal, melanoma, cervical, laryngeal, ovarian, squamous cell cancer with unknown primary (CUP) and thymus cancer. Out of six patients evaluable for efficacy, two achieved stable disease: a melanoma patient whose treatment duration was 125 days and a squamous cell CUP patient who achieved 11% tumor shrinkage in the sum of all lesions on first scan with treatment duration of over 85 days (ongoing). Two additional patients with ovarian and laryngeal cancer are ongoing but have not had their first scan yet. The most common molecular characteristics of Cohort 8 patients were loss of function or deletion of CDKN2A and/or CDKN2B tumor suppressor genes. Other pharmacogenomic observations included CDKN2A/B, KRAS and/or TP53 mutations. Study Design Two Phase 2 dose expansion cohorts in the 065-101 study were initiated. Cohort 8 prospectively enrolled 12 patients with known CDKNA/B genetic alterations between April and September 2024. The rationale was to further evaluate observations of clinical activity in Phase 1 patients with known CDNK2A or CDKN2B genetic alterations. Cohort 6 is enrolling patients with T-cell Lymphoma with two patients treated so far. The rationale was to further evaluate observations of partial response (PR) in 2/3 Phase 1 patients with T-cell lymphoma. Certain T-Cell lymphomas are known to harbor CDNK2A genetic alterations. All patients were treated with oral fadraciclib 100mg BID, M-F, week 1-4 in 28-day cycles which was the Recommended Phase 2 dose (RP2D). The primary objectives of the 065-101 study in the Dose Escalation stage are to determine maximum tolerated dose (MTD) and/or RP2D and in the Phase 2, Proof of Concept stage to evaluate preliminary efficacy of fadraciclib as measured by overall response rate (ORR). The secondary objectives in Dose Escalation are to assess safety and tolerability, pharmacokinetics, and ORR, while in Phase 2, Proof of Concept, to assess safety and tolerability, evaluate disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). The study is utilizing a Simon two-stage optimal design to evaluate clinical activity. Exploratory objectives include investigation of clinical pharmacodynamics (PD) and pharmacogenomics (PGx). Further information from the poster is available at: Link to poster About Fadraciclib Fadraciclib is a highly selective CDK2 (IC50=5 nM) and CDK9 (IC50=26 nM) inhibitor causing anaphase mitotic catastrophe and apoptotic death of cancer cells at sub-micromolar concentrations. Retrospective review of the dose escalation portion of Phase 1 studies suggested clinical activity in patients with known CDNK2A or CDKN2B genetic alterations. In a Phase 1 study of intravenous fadraciclib monotherapy (065-01) a heavily pretreated endometrial cancer patient with CDNK2A, CDKN2B and PRMT5 loss achieved confirmed complete response (CR). In the Phase 1 oral fadraciclib monotherapy study (065-101), 7/38 treated patients were found to have known CDKN2A/B genetic alterations, of which 6 were evaluable for efficacy. A PTCL patient with CDKN2A P114L mutation reported a partial response (PR). A squamous cell NSCLC patient with CDKN2B loss reported stable disease (SD) and 22% reduction in tumor volume in the sum of all target lesions. A metastatic, testicular Leydig germ cell cancer patient with CDKN2A, CDKN2B and MTAP loss reported 12% reduction in tumor volume in the sum of all target lesions. The overall response rate (ORR) was 17% (1/6) and the disease control rate (DCR) was 100% (6/6). About Cyclacel Pharmaceuticals, Inc. Cyclacel is a clinical-stage, biopharmaceutical company developing innovative cancer medicines based on cell cycle, transcriptional regulation and mitosis biology. The transcriptional regulation program is evaluating fadraciclib, a CDK2/9 inhibitor, and the anti-mitotic program plogosertib, a PLK1 inhibitor, in patients with both solid tumors and hematological malignancies. Cyclacel's strategy is to build a diversified biopharmaceutical business based on a pipeline of novel drug candidates addressing oncology and hematology indications. For additional information, please visit www.cyclacel.com. Forward-looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include, among other things, statements related to the efficacy and safety profile of fadraciclib in an incomplete clinical trial, Cyclacel’s future plans and prospects, Cyclacel’s anticipated cash runway and the planned timing of data results and continued development of fadraciclib. Factors that may cause actual results to differ materially include market and other conditions, the risk that product candidates that appeared promising in early research and clinical trials do not demonstrate safety and/or efficacy in larger-scale or later clinical trials, trials may have difficulty enrolling, Cyclacel may not obtain approval to market its product candidates, the risks associated with reliance on outside financing to meet capital requirements, the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates and Cyclacel’s ability to regain and maintain compliance with Nasdaq’s continued listing requirements, although no assurance to that effect can be given. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "believes," "estimates," "projects," "potential," "expects," "plans," "anticipates," "intends," "continues," "forecast," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to our most recent Annual Report on Form 10-K and other periodic and other filings we file with the Securities and Exchange Commission and are available at www.sec.gov. Such forward-looking statements are current only as of the date they are made, and we assume no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contact Company: Paul McBarron, (908) 517-7330, IR@cyclacel.com © Copyright 2024 Cyclacel Pharmaceuticals, Inc. All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks of Cyclacel Pharmaceuticals, Inc.

国产创新药出海的记录不断被刷新。 最新的记录创造者是锐格医药。近日，锐格医药宣布已与罗氏集团旗下的基因泰克就下一代CDK抑制剂达成收购协议。 根据协议条款，锐格医药将获得8.5亿美元的预付款，并有资格根据特定的开发、监管和商业里程碑的实现获得额外的现金付款。 这笔交易也刷新了国产创新药出海的预付款记录。之前的记录，由百利天恒的EGFR×HER3双抗ADC BL-B01D1对百时美施贵宝的授权交易保持（8亿美元）。 记录的不断刷新，不仅证明了国产创新药的质量，而且从产业角度来看，也反映了一个趋势： 经过十余年的缠斗，下一代CDK抑制剂的研发正在迈入一个新的高度。 卡位下一代CDK抑制剂 自从发现细胞周期蛋白依赖性激酶（CDK）以来，科学家们一直试图以它们为靶点来破坏癌细胞的分裂和增殖。 乳腺癌尤其依赖于这个过程来生长。也正因此，靶向CDK4和CDK6的第一代CDK抑制剂，大获成功。 2015年2月，由辉瑞研发的首款CDK4/6抑制剂哌柏西利在美国获批上市，用于治疗HR+/HER2-的局部晚期或转移性乳腺癌。 乳腺癌患者众多，2020年全球新增乳腺癌患者超230万人，成为全球第一大癌种。基于庞大的患者规模，哌柏西利的销售规模也颇为可观。 2016年，哌柏西利上市首个完整年度的销售额就已经达到21.35亿美元，成为一款当之无愧的重磅炸弹药物。此后，礼来、诺华、勃林殷格翰、恒瑞医药的CDK4/6抑制剂陆续获批上市。 2023年，仅辉瑞、诺华、礼来三家CDK4/6抑制剂，销售总额就接近100亿美元。基于CDK4/6抑制剂在乳腺癌领域的成功商业表现，Nature Reviews Drug Discovery预计，到2029年，CDK4/6抑制剂预计将贡献200亿美元，占乳腺癌药物销售市场份额的42%。 不过，已经上市的CDK4/6抑制剂并非完美，它们都或多或少有一些缺点。首先，困扰CDK4/6抑制剂的一个问题就在于毒性问题。目前，CDK4/6抑制剂最常见的不良反应是中性粒细胞减少，哌柏西利和瑞波西利出现比例最高，3-4级中性粒细胞减少的比例为60%-66%。 此外，骨髓抑制也是CDK4/6抑制剂最常见的毒性反应，在服用哌柏西利或瑞波西利的女性中出现率高达80%，在服用阿贝西利时出现率则高达50%。 这些不良反应限制了CDK4/6的给药剂量，在一定程度上影响了CDK4/6抑制剂的临床应用。也正因此，下一代CDK抑制剂的研发如火如荼。 备受关注的CDK2 CDK抑制剂的潜力不仅限于靶向CDK4和CDK6。 CDK家族成员众多，目前已发现有20个不同的亚型，根据其功能可分为两类：一类CDK参与细胞周期调控，如CDK1、CDK2、CDK4、CDK6等；另一类CDK参与转录调节，主要包括CDK7、CDK8、CDK9、CDK10、CDK11等。 其中，许多家族成员都是有潜力的药物靶点，CDK2是目前研究的热点之一。 与罗氏达成重要合作的锐格医药，其产品线中有两个在研的CDK抑制剂，均以CDK2为靶点：一款是CDK2/4/6抑制剂RGT-419B，另一款是CDK2抑制剂QR-6401。 同样，去年11月21日，百济神州与昂胜医药合作，获得了后者在研口服CDK2抑制剂ETX-197的全球独家权益。 CDK2受到关注并不意外，关键在于其巨大的潜力。 例如，CDK2可能有助于解决CDK4/6抑制剂的耐药问题。CDK4/6抑制剂作为一线治疗，无论是联合芳香化酶抑制剂还是氟维司群，都有15%-20%的患者会出现原发性耐药，而且在CDK4/6抑制剂使用后期几乎都会发展出继发性耐药。一旦产生耐药，患者的治疗选择将非常有限。 看来，CDK2是一个潜在的突破口。研究表明，在CDK4被抑制后，CDK2会接管其作用并促进癌细胞增殖。这些癌细胞不仅会继续生长，还可能对之前的CDK抑制剂治疗产生耐药。这表明CDK2可能是CDK4/6耐药机制之一。 这一点也得到了辉瑞的初步验证。在临床试验中，16名接受过2线CDK4/6i+内分泌单药治疗的转移性乳腺癌患者，在经过辉瑞研发的CDK2选择性抑制剂PF-07104091治疗后，有3名患者达到部分缓解，6名患者达到疾病稳定。初步结果显示，PF-07104091对CDK4/6抑制剂耐药的HR+/HER2-乳腺癌患者具有良好的疗效。 这意味着，CDK2与CDK4/6联合使用，可能有助于解决耐药问题。 锐格医药进展较快的RGT-419B，其研发目标也是解决对CDK4/6和其他激素受体调节疗法的耐药性问题。临床前数据显示，在对目前批准的CDK4/6抑制剂耐药的ER+乳腺癌细胞中，RGT-419B显示出对癌细胞增殖的完全抑制。在这些实验中，RGT-419B与选择性雌激素受体降解剂或PI3K信号通路抑制剂联合使用时，其对肿瘤细胞的抑制作用进一步增强。 站队进行时 面对CDK抑制剂百亿美金市场的巨大诱惑，已经有不少国内外药企开始跃跃欲试。 目前，针对CDK2以及CDK4/6的药企布局已经相当广泛。在国内，辰欣药业、石药集团、齐鲁制药、同源康医药等都在进行CDK2/4/6抑制剂的临床试验。 在海外，辉瑞的研发进展最快，在去年的ASCO大会上，辉瑞已经公布了其候选药物PF-07104091的1/2a期临床数据，并且正在进行为期三年的研究。此外，Incyte的INCB123667、Blueprint的BLU-222等CDK2抑制剂也都处于临床研究阶段。 现在，随着罗氏的加入，围绕新一代CDK抑制剂的竞争无疑将更加激烈。对于生物技术公司来说，在研发更优秀的分子的同时，可能还需要考虑关于战略选择的问题。 毕竟，大型药企的加入会时刻改变竞争格局。一方面，像罗氏这样的巨头引进项目的核心，本质上是利用其“临床开发实力、制造能力和商业影响力”来创造更多价值的交易。在这三个方面，biotech并不占优势。 另一方面，一些大型药企在乳腺癌领域已经形成了生态突破的能力。最典型的例子就是罗氏，从HER2到PI3K靶点，罗氏引领了乳腺癌领域靶向药物的研发热潮，并且至今仍在推动这一领域向更高层次发展。换句话说，这些大型药企在这些特定领域的竞争力将进一步得到加强。 对于biotech而言，需要做得更快，也需要确保商业化预期的实现，在这种背景下，战略选择可能是最关键的。 那么，在这一领域，国内biotech是否还会创造新的BD记录呢？ 来源 | 氨基观察（药智网获取授权转载） 撰稿 | 郑晓 责任编辑 | 八角 声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。 商务合作 | 王存星 19922864877（同微信）  阅读原文，是受欢迎的文章哦

- Patients are preselected for CDKN2A and/or CDKN2B abnormalities - - Safety and efficacy data to be reported at an upcoming oncology medical conference - BERKELEY HEIGHTS, N.J., Sept. 25, 2024 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing innovative cancer medicines, today announced that enrollment of 12 patients has been completed as per protocol in Cohort 8 of its Phase 2 stage, proof of concept 065-101 study of fadraciclib (“fadra”), a CDK2/9 inhibitor, in patients with advanced solid tumors and lymphoma. Enrollment of Cohort 5 in patients with T-Cell Lymphoma is continuing. “We are pleased to report that the Cyclacel team has achieved another important milestone by completing enrollment of the patient cohort with CDKN2A/B abnormalities,” said Spiro Rombotis, President and Chief Executive Officer. “The rapid pace of enrollment of approximately six months, since opening the cohort in mid-May, underscores the great unmet medical need of cancer patients with CDKN2A/B abnormalities. Updated safety and efficacy data from the 065-101 study of fadra has been accepted for presentation during the upcoming 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (ENA 2024, October 23-25, 2024).” “We are grateful to the patients and their families, international investigator group and our collaborators participating in the 065-101 study for their support in achieving target enrollment of Cohort 8,” said Brian Schwartz, M.D., interim Chief Medical Officer. “We are excited to observe stable disease and tumor shrinkage in a Phase 2 squamous cell cancer patient with unknown primary and CDKN2A abnormalities after two cycles of fadra oral tablets. As previously reported at ASCO 2024, in the Phase 1 study of oral fadra a patient with squamous non-small cell lung cancer (NSCLC) and CDKN2A/B abnormalities achieved 22% reduction in tumor burden at 4 weeks per RECIST 1.1 criteria. We expect to report more mature data as additional patients from Cohort 8 get scanned and followed up.” 065-101 Study of Oral Fadraciclib The Phase 2 part of the 065-101 study of oral fadra, a CDK2/9 inhibitor, is designed to evaluate fadra safety and efficacy in up to 8 cohorts defined by histology and/or biomarkers of interest. The 7 histology-based cohorts include: Cohort 1: endometrial and ovarian; 2: cholangiocarcinoma or biliary tract; 3: hepatocellular; 4: breast, including HR positive, HER2 negative, triple negative, and HER-2 positive; 5: T-Cell lymphoma; 6: B-Cell lymphoma; and 7: colorectal cancers. Cohort 8 is biomarker selected, specifically including patients with CDKN2A and/or CDKN2B abnormalities. The Phase 2 part of the study employs a Simon 2-stage design and is powered to demonstrate response in the molecular subtype suggested by the Phase 1 data and others that may be sensitive. The Phase 1 dose escalation part of the study enrolled a total of 48 unselected, all comer patients with advanced solid tumors and lymphoma who were treated with oral fadra as monotherapy. Recommended Phase 2 dose (RP2D) was determined as 100mg twice daily for 5 days per week, 4 out of 4 weeks. To date single agent activity with oral or intravenous fadra, including CR, PR and SD, has been observed in patients with advanced endometrial, squamous NSCLC lung cancer and T-cell lymphoma. Encouraging signals of activity were observed in patients with advanced cervical, hepatocellular, ovarian and pancreatic cancers. The Company believes that fadra’s inhibition of CDK2 and CDK9 may be superior to inhibiting either CDK2 or CDK9 alone. Fadra tablets can be given orally with repeat dosing which has led to transient suppression of anti-apoptosis proteins with generally good tolerability and no Grade 3 or higher hematological toxicity in the first cycle. CDKN2A, CDKN2B Abnormalities The most frequent CDKN2A or CDKN2B abnormalities are deletions or loss of function. CDKN2A gene deletions occur in over 40% of several solid tumors, including glioma, head and neck, pancreatic, esophageal, lung (incl. squamous), bladder, melanoma, and others. CDKN2B deletions occur in over 30% of several solid tumors, including bladder, glioma, pancreatic, esophageal, lung (incl. squamous), head and neck, melanoma, and others.1 About Cyclacel Pharmaceuticals, Inc. Cyclacel is a clinical-stage, biopharmaceutical company developing innovative cancer medicines based on cell cycle, transcriptional regulation and mitosis biology. The transcriptional regulation program is evaluating fadraciclib, a CDK2/9 inhibitor, and the anti-mitotic program plogosertib, a PLK1 inhibitor, in patients with both solid tumors and hematological malignancies. Cyclacel's strategy is to build a diversified biopharmaceutical business based on a pipeline of novel drug candidates addressing oncology and hematology indications. For additional information, please visit www.cyclacel.com. Forward-looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include, among other things, statements related to Cyclacel’s future plans and prospects, Cyclacel’s anticipated cash runway and the planned timing of data results and continued development of fadraciclib. Factors that may cause actual results to differ materially include market and other conditions, the risk that product candidates that appeared promising in early research and clinical trials do not demonstrate safety and/or efficacy in larger-scale or later clinical trials, trials may have difficulty enrolling, Cyclacel may not obtain approval to market its product candidates, the risks associated with reliance on outside financing to meet capital requirements, the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates and Cyclacel’s ability to regain and maintain compliance with Nasdaq’s continued listing requirements. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "believes," "estimates," "projects," "potential," "expects," "plans," "anticipates," "intends," "continues," "forecast," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to our most recent Annual Report on Form 10-K and other periodic and other filings we file with the Securities and Exchange Commission and are available at www.sec.gov. Such forward-looking statements are current only as of the date they are made, and we assume no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contact Company:Paul McBarron, (908) 517-7330, IR@cyclacel.com © Copyright 2024 Cyclacel Pharmaceuticals, Inc. All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks of Cyclacel Pharmaceuticals, Inc. ______________________________1 www.cbioportal.org.