CDKN2A

BERKELEY HEIGHTS, N.J., March 07, 2024 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing innovative medicines based on cancer cell biology, today announced that preclinical proof-of-concept data with the Company’s fadraciclib will be presented at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2024, being held April 5-10 in San Diego, California. The data will be presented at three poster sessions and report activity and antitumor effects of fadraciclib in biliary tract cancer, lung cancer, Richter transformation and lymphoma cell lines. Details of the presentations are as follows: Title: The CDK2/9 inhibitor fadraciclib is active in Richter transformation and lymphoma cell lines by targeting both cell survival and proliferation Abstract No: 518 / 15 Session Topic: Session PO.ET05.01 - Cell Cycle, Transcription Regulation, and Anticancer Drug Action Date and Time: April 7, 2024, 1:30 PM - 5:00 PM PT Location: Exhibition Hall, Section 21 Title: Elucidation of the fates of CDK2 inhibited aneuploid and residual lung cancers Abstract No: 2117 / 8 Session Topic: Session PO.ET07.02 - Pharmacodynamic Biomarkers of Drug Response Date and Time: April 8, 2024, 9:00 AM - 12:30 PM PT Location: Exhibition Hall, Section 30 Title: Anti-tumor effects of fadraciclib, CDK2/9 inhibitor, in biliary tract cancer Abstract No: 5711 / 11 Session Topic: Session PO.MCB01.01 - Pharmacologic Targeting of Cell Cycle Proteins Date and Time: April 9, 2024, 1:30 PM - 5:00 PM PT Location: Exhibition Hall, Section 18 About Cyclin-Dependent Kinases and Fadraciclib Cyclin-dependent kinases (CDKs) are critical for cell cycle control and transcriptional regulation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased cancer cell survival. Fadraciclib is a highly selective, potent, orally and intravenously available, next generation inhibitor of CDK2 and CDK9. By inhibiting CDK2 and CDK9 fadraciclib causes apoptotic death through anaphase catastrophe of cancer cells at sub-micromolar concentrations. To date single agent activity, 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. 065-101 Study of Oral Fadraciclib Oral fadraciclib is being tested in a Phase 1/2 trial for the treatment of advanced solid tumors and lymphoma (065-101; NCT#04983810). A total of 29 patients have been treated as monotherapy in this ongoing study. The study is enrolling unselected, all comer patients with advanced solid tumors and lymphoma. The Phase 2 part of the 065-101 study is designed to further evaluate fadra safety and efficacy in up to 8 cohorts defined by histology and/or NGS. The study is powered to demonstrate response in the molecular subtype suggested by the Phase 1 data and others that may be sensitive. CDKN2A, CDKN2B, MTAP deletions 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. MTAP deletions occur in over 25% of several solid tumors, including glioma, mesothelioma, pancreatic, bladder, esophageal and others. MTAP deletion confers dependency on the PRMT5 enzyme in cancer cells which was identified as a synthetic lethal target for MTAP deleted cancers. 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 CYC140, 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 . 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 statements regarding, among other things, the efficacy, safety and intended utilization of Cyclacel’s product candidates, the conduct and results of future clinical trials, plans regarding regulatory filings, future research and clinical trials and plans regarding partnering activities. Factors that may cause actual results to differ materially include 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 potential effects of the COVID-19 pandemic, and the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates. 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 the Securities and Exchange Commission and are available at . 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. Contacts Company: Paul McBarron, (908) 517-7330, pmcbarron@cyclacel.com Investor Relations: Grace Kim, IR@cyclacel.com © Copyright 2024 Cyclacel Pharmaceuticals, Inc. All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks of Cyclacel Pharmaceuticals, Inc.

Updated preclinical data will be presented from Ryvu's synthetic lethality pipeline, including PRMT5 inhibitors in MTAP-Deficient cancers, WRN inhibitors for the treatment of microsatellite unstable (MSI-H) tumors, and Ryvu's cutting-edge synthetic lethality platform based on primary cancer cells. Poster presentation to highlight the synergistic effects of RVU120 in combination with ruxolitinib in myeloproliferative neoplasms. Ryvu's partner Menarini to present data on MEN1703 (SEL24), demonstrating promising anti-tumor activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib. KRAKOW, Poland, March 6, 2024 /PRNewswire/ -- Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, announced today that preclinical data from its synthetic lethality pipeline and RVU120 project, as well as on MEN1703 (SEL24), will be presented at the upcoming 2024 AACR Annual Meeting, scheduled for April 5-10 in San Diego, California. "We are excited to present our latest preclinical data at the AACR Annual Meeting, showcasing our significant progress in advancing novel small molecule therapies for oncology. This year, we will present data from our most advanced preclinical project on MTA-cooperative PRMT5 inhibitors, the lead program within Ryvu's synthetic lethality pipeline. Our PRMT5 inhibitors have demonstrated remarkable efficacy and selectivity in preclinical models of tumors with MTAP gene deletion, providing a strong foundation for further development," said Krzysztof Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics. "Our discovery platform continues to produce novel precision medicine targets and drugs, and we are proud to highlight platform data based on primary cancer cells, specifically in colorectal cancer models with broader applicability across cancers. " Details on the poster presentations are as follows: Abstract Title: "Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers." Session Name: HDAC and Methyltransferase Inhibitors Session date and time: Tuesday, April 9, 9:00 AM - 12:30 PM EST Poster Number: 4598 Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced, which makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors showing favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding. Structure-based lead optimization has enabled rapid expansion and delivery of two independent chemical series with novel intellectual property, characterized by high target engagement in cells, and selective potency in MTAP-deleted cell lines, along with favorable DMPK profiles allowing an oral administration. The antitumor activities were compared in vitro and in vivo in MTAP null tumors. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Performed studies confirm that MTA-cooperative PRMT5 inhibitors exert a strong synthetic lethal phenotype in MTAP-deleted cancers, offering an exciting therapeutic opportunity for a large patient population. Abstract Title: "A comprehensive platform for identification of KRAS-specific synthetic lethal targets using patient-derived cells." Session Name: New Targets, Technologies, and Drug Delivery Systems Session date and time: Tuesday, April 9, 9:00 AM - 12:30 PM EST Poster Number: 4684 Ryvu's cutting-edge drug discovery platform uniquely combines high throughput capabilities with the precision and translational impact traditionally associated with later, lower throughput stages. Our approach taps into the power of primary cells to transform cancer treatment, focusing especially on colorectal cancer (CRC). By leveraging human stem cell derived model cells (PDC), patient-derived xenografts (PDXs) and clinical samples we have created a groundbreaking approach to identify synthetic lethal (SL) targets specific to oncogenic pathways. We integrate CRISPR/Cas9 technology, phenotypic screening, RNA-seq, and whole-exome sequencing (WES), enabling rapid identification of molecular vulnerabilities. We present results obtained in engineered intestinal primary models which represent frequently altered genes in CRC, including KRAS G12D mutation. Notably, our use of normal hISCs facilitates the identification of genes essential only for transformed cells, amplifying the precision tumor targeting of our novel discoveries. Beyond CRC, our platform could extend to personalized medicine approaches in various cancer types. By spearheading the identification of KRAS-specific SL inhibitors, we pave the way for novel, targeted therapies, offering hope to patients battling this heterogeneous malignancy and beyond. Abstract Title: "Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors." Session Name: Novel Antitumor Agents 4 Session date and time: Tuesday, April 9, 1:30 PM – 05:00 PM EST Poster Number: 5942 The synthetic lethality resulting from the inhibition of the WRN helicase protein has been observed in tumors characterized by high levels of microsatellite instability (MSI-H). This instability stems from a deficiency in the DNA mismatch repair (MMR) mechanisms, leading to the accumulation of DNA damage. This phenomenon is notably prevalent in 10-30% of colorectal, gastric, endometrial, and ovarian cancers. Structure-based optimization performed at Ryvu facilitated the rapid expansion and delivery of a compound library with novel intellectual property (IP), demonstrating target engagement in cells and selective potency over other RecQ family members. The pharmacokinetic properties of these compounds were favorable and allowed progressing to in vivo studies which confirmed efficacy of our compounds in xenograft MSI-H cancer models. These data provide pharmacological proof-of-concept for the synthetic lethal effect of our inhibitors and support WRN inhibition as a new, targeted oncological therapy. Abstract Title: "Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms." Session Name: Targeted, Combination, and Differentiation Therapies Session date and time: Wednesday, April 10, 9:00 AM - 12:30 PM EST Poster Number: 7225 The presentation, prepared in collaboration with Prof. Raajit Rampal's group from Memorial Sloan Kettering Cancer Center, includes the assessment of RVU120, a highly selective and potent CDK8/19 inhibitor, both in monotherapy and combination with ruxolitinib (RUX), a JAK1/2 inhibitor, for the treatment of myeloproliferative neoplasms (MPN) and hydroxyurea-resistant/intolerant polycythemia vera (PV). The combination of RVU120 and RUX demonstrated biochemical synergy and differential inhibition of STAT5 phosphorylation in vitro. Further, in vivo treatment with RVU120/RUX+RVU120 resulted in significant reductions in disease manifestation (splenomegaly, WBC, fibrosis scoring, hematopoiesis) compared to VEH/RUX. These data suggest that JAK1/2 and CDK8/19 inhibition could be a potential novel therapeutic strategy in MPNs. Additional work on nascent RNA expression and cytokine profiles aims at elucidating the exact mechanism of synergy between tested compounds. Abstract Title: "MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as single agent and combined with ruxolitinib." Session Name: Novel Antitumor Agents 2 Session date and time: Sunday April 7, 01:30 AM – 0500 PM EST Poster Number: 665 MEN1703 (SEL24) is an oral, first-in-class, dual PIM/FLT3 kinase inhibitor in development for hematologic malignancies. The presented study aims to investigate the efficacy of MEN1703 alone and in combination with the JAK inhibitor ruxolitinib (RUX) in preclinical models of myelofibrosis (MF) and to elucidate the underlying signaling pathways. MEN1703 demonstrated anti-tumoral efficacy in MF preclinical models, exhibiting in vitro activity at clinically relevant concentrations. Importantly, the combination of MEN1703 with the standard of care, RUX, exhibited synergistic effects, and molecular analyses confirmed the inhibition of downstream targets of PIM. The results support the therapeutic potential and relevance of MEN1703 in the treatment strategies for myelofibrosis. All abstracts are now available online and can be obtained from the conference site: About Ryvu Therapeutics Ryvu Therapeutics is a clinical-stage drug discovery and development company focused on novel small-molecule therapies that address emerging targets in oncology. Internally discovered pipeline candidates use diverse therapeutic mechanisms driven by emerging knowledge of cancer biology, including small molecules directed at kinase, synthetic lethality, and immuno-oncology targets. Ryvu's most advanced programs include RVU120, a selective CDK8/CDK19 kinase inhibitor with the potential to treat hematological malignancies and solid tumors, currently in Phase II development (i) as a monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS) as well as (ii) in combination with venetoclax for the treatment of patients with r/r AML. Another clinical program, SEL24 (MEN1703), is a dual PIM/FLT3 kinase inhibitor licensed to the Menarini Group. Ryvu Therapeutics has signed multiple partnering and licensing deals with global companies, including BioNTech and Exelixis. The Company was founded in 2007 and is headquartered in Kraków, Poland. Ryvu is listed on the Warsaw Stock Exchange and is a component of the mWIG40 index. For more information, please see . SOURCE Ryvu Therapeutics

- Patient Pharmacodynamic Data Show Decrease in CDKN2A, CDKN2B, and PRMT5 Protein Levels - - A Squamous Non-Small Cell Lung Cancer Patient with CDKN2B Deletion Achieved Marked Tumor Shrinkage after One Cycle - - Retrospective Analysis Identified CDKN2A, CDKN2B and/or MTAP Deletions in Four Patients Previously Dosed with Fadra Achieving Responses or Stable Disease - - Forthcoming Phase 2 Study to Further Evaluate Fadra Efficacy - BERKELEY HEIGHTS, N.J., Dec. 18, 2023 (GLOBE NEWSWIRE) -- Cyclacel Pharmaceuticals, Inc. (NASDAQ: CYCC, NASDAQ: CYCCP; "Cyclacel" or the "Company"), a biopharmaceutical company developing innovative medicines based on cancer cell biology, announced today interim results from its Phase 1, dose escalation 065-101 study of fadraciclib (“fadra”) in patients with advanced solid tumors and lymphoma. “As we approach the end of the year we are excited to report that fadra continues to demonstrate anticancer activity as a single agent based on interim data reviewed to date from our 065-101 study,” said Spiro Rombotis, President and Chief Executive Officer. “The data suggest tumor sensitivity in patients with one or more of three abnormalities, CDKN2A, CDKN2B and/or MTAP deletion subject to confirmation in further studies. We believe there is great unmet medical need and industry interest in the cancer patient populations identified by these abnormalities, which are closely located on chromosome 9 and are often co-deleted. The Phase 2 part of 065-101 is designed to evaluate fadra safety and efficacy in cohorts defined by histology and/or next generation sequencing (NGS). In addition, our plogosertib dose escalation study is progressing well. Based on interim data reviewed to date, good tolerability and anticancer activity of plogosertib as a single agent have been observed in multiple patients with various solid tumors.” “We are excited to see shrinkage of 22% in the sum of all target lesions after one cycle of fadra monotherapy in a squamous non-small cell lung cancer (NSCLC) patient with CDKN2B deletion refractory to standard of care chemotherapy and immunotherapy,” said Mark Kirschbaum, M.D., Chief Medical Officer. “After retrospectively analyzing a subset of previously treated Phase 1 patients who experienced clinical benefit with fadra, we found four patients with CDKN2A, CDKN2B and/or MTAP deletions. These included an endometrial cancer patient who achieved CR and over three years of treatment in a previous study of fadra monotherapy and was found to have all three abnormalities. Further, pharmacodynamic data from patient biospecimens at dose levels 5 and 6A suggest that CDKN2A, CDKN2B, and PRMT5 protein levels are transiently decreased over the 4 to 8 hour half-life of the fadra dose, which we believe makes the tumor sensitive to CDK2 inhibition by fadra. Although these hypothesis-generating data are limited and cannot be generalized, we believe that patients with these types of tumors should be evaluated in the ongoing and subsequent studies.” 065-101 Study of Oral FadraciclibIn the ongoing 065-101 study of oral fadra, a CDK2/9 inhibitor, a total of 29 patients have been treated as monotherapy. The study is enrolling unselected, all comer patients with advanced solid tumors and lymphoma. Six patients have been treated on dose level 6A (125mg twice daily for 5 days per week, 4 out of 4 weeks). The sixth patient on dose level 6A with pancreatic cancer and CDKN2A deletion enrolled on the study experienced dose-limiting toxicity (DLT) of hyperglycemia. The patient, who has a diabetic profile history and was on metformin treatment, remains on study as blood glucose level was managed. A previous patient on dose level 6A with a pre-diabetic profile had DLT of hyperglycemia which also resolved rapidly. The previous dose level 5 (100mg twice daily for 5 days per week, 4 out of 4 weeks) on this schedule accrued six patients with no DLT and per protocol is safe for continued development. Dose level 6B (150mg once daily for 7 days per week, 4 out of 4 weeks) continues accrual with two patients treated, which are ongoing at three and five cycles of treatment. To date single agent activity, 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. The Phase 2 part of the 065-101 study is designed to further evaluate fadra safety and efficacy in up to 8 cohorts defined by histology and/or NGS. The study is powered to demonstrate response in the molecular subtype suggested by the Phase 1 data and others that may be sensitive. CDKN2A, CDKN2B, MTAP deletionsCDKN2A 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. MTAP deletions occur in over 25% of several solid tumors, including glioma, mesothelioma, pancreatic, bladder, esophageal and others.1 MTAP deletion confers dependency on the PRMT5 enzyme in cancer cells which was identified as a synthetic lethal target for MTAP deleted cancers. 140-101 Phase 1 Study of Oral PlogosertibIn the 140-101 study of oral plogosertib, PLK1 inhibitor, as monotherapy, patients are being recruited at dose level 5. The anticancer activity observed at low levels of continuous exposure may be due to plogosertib’s novel epigenetic mechanism. To date, 15 patients have been recruited at five dose escalation levels. Encouraging signals of activity were observed in five patients with advanced biliary, ovarian, NSCLC and other cancers. The Company expects to announce details of plogosertib’s differentiated, epigenetic mechanism and biomarkers which may identify patients with sensitive tumors, after preclinical studies at collaborating laboratories are completed. About Cyclacel Pharmaceuticals, Inc. Cyclacel is a clinical-stage, biopharmaceutical company developing innovative cancer medicines based on cell cycle, transcriptional regulation, epigenetics and mitosis biology. The transcriptional regulation program is evaluating fadraciclib, a CDK2/9 inhibitor, and the epigenetic/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 StatementsThis 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 statements regarding, among other things, the efficacy, safety and intended utilization of Cyclacel’s product candidates, the conduct and results of future clinical trials, plans regarding regulatory filings, future research and clinical trials and plans regarding partnering activities. Factors that may cause actual results to differ materially include, without limitation: interim results of a clinical trial are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and as more patient data becomes available, including the risk that unconfirmed responses may not ultimately result in confirmed responses to treatment after follow-up evaluations; 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; potential delays in the commencement, enrollment and completion of clinical trials; Cyclacel may not obtain approval to market its product candidates; the risks associated with reliance on outside financing to meet capital requirements; the potential effects of the COVID-19 pandemic; and the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates. 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, as amended, 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. Contacts Company:Paul McBarron, (908) 517-7330, pmcbarron@cyclacel.comInvestor Relations:Grace Kim, IR@cyclacel.com © Copyright 2023 Cyclacel Pharmaceuticals, Inc. All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks of Cyclacel Pharmaceuticals, Inc. SOURCE: Cyclacel Pharmaceuticals, Inc. _______________ 1 www.cbioportal.org.