CDK2

Dive Brief:Novartis will pay $150 million to gain rights to molecular glue degraders being developed by biotechnology company Monte Rosa Therapeutics to target an immune signaling protein, known as VAV1, that has long been considered undruggable.The deal, announced by the companies Monday morning, could yield up to $2.1 billion in further payments by Novartis to Monte Rosa should the licensed research reach certain development, regulatory and sales milestones.Molecular glue degraders are small molecule drugs that join together a target protein with an enzyme responsible for flagging cellular detritus for disposal. In Monte Rosas case, the company believes degrading VAV1 could weaken certain immune cell functions, thereby slowing the progression of immune-mediated diseases.Dive Insight:Novartis deal with Monte Rosa centers on an early-stage drug candidate dubbed MRT-6160 thats currently in a Phase 1 study of healthy volunteers.Monte Rosa and Novartis see potential for MRT-6160 to treat multiple systemic and neurological autoimmune diseases, Monte Rosa CEO Markus Warmuth said in an email to BioPharma Dive.Under the deal, Monte Rosa will wrap up the ongoing Phase 1 clinical study, while Novartis will handle development from Phase 2 onwards. The biotech will co-fund any Phase 3 testing that occurs and also share in any profits or losses associated with MRT-6160s commercialization, should it get that far.“Novartis has had a long-standing interest in molecular glue degraders, which offer the potential to tackle challenging biological targets, said Fiona Marshall, head of biomedical research at Novartis, in the companies statement. We are excited about their application in immunology and the early progress we have seen by Monte Rosa in this space and with MRT-6160.For Monte Rosa, Novartis support will help it fully explore the potential of MRT-6160 in a variety of immune diseases, Warmuth said in his email. The company plans to use the $150 million it will receive from Novartis to extend its operating runway and advance its own research.In addition to VAV1, Monte Rosa is exploring targeting other proteins, including ones called NEK7, CDK2 and CCNE1, with its molecular glue technology.Monte Rosa previously partnered with Novartis cross-town rival Roche to apply molecular glue degraders to cancer and neurological diseases. Other biotechs are exploring the drug concept as well, and have struck collaborations with Pfizer, Astellas and Bristol Myers Squibb. '

- NKT3964 is a first-in-class, highly potent and selective CDK2 degrader, and causes prolonged CDK2 pathway inhibition without cyclin E accumulation - NKT3964 is designed to treat patients with cyclin E driven cancers WILMINGTON, Del.--(BUSINESS WIRE)--NiKang Therapeutics ® Inc. (“NiKang”) is a clinical stage biotech company focused on developing innovative small molecule oncology medicines to bring transformative therapies to patients in need. The company announced today the unveiling of NKT3964 at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (“Triple Meeting”) during a Poster Spotlight Session. The conference is being held October 23-25, 2024, in Barcelona, Spain. NKT3964 is a first-in-class, orally bioavailable small molecule CDK2 degrader that selectively degrades CDK2, demonstrating high specificity over CDK1 and other CDK family members. Its high potency and unique mechanism of action result in sustained inhibition of CDK2 pathway without causing cyclin E accumulation. NKT3964 is designed to treat patients with aberrant CDK2/cyclin E pathway activation, including those with ovarian, endometrial, gastric and HR+HER2- breast cancers. NiKang has initiated a phase 1, open-label, dose escalation study of NKT3964 as a single agent. This first-in-human study (NCT06586957) is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity to determine the preliminary recommended dose for expansion of NKT3964 in adults with advanced or metastatic solid tumors. “We are excited to share the discovery of NKT3964, a first-in-class oral CDK2 degrader at this year’s Triple Meeting,” said Zhenhai Gao, Ph.D., co-founder, president, and CEO of NiKang. “This is the second of three programs targeting the cell cycle (CDK2 inhibitor NKT3447, CDK2 degrader NKT3964, and a CDK2/4 selective dual degrader) that we have advanced to the clinic. We believe CDK2 plays a critical role in driving tumor growth. Recent clinical data presented at ESMO further validates CDK2 as a key oncology target. We are developing a cutting-edge portfolio of CDK2 and CDK2/4 degraders that can achieve sustained CDK pathway inhibition while avoiding paradoxical cyclin E increase. Our multi-pronged approach allows us to thoroughly and deeply interrogate this pathway. We look forward to exploring NKT3964’s potential in treating patients with advanced or metastatic solid tumors.” Poster Presentation Details: Title: Discovery of NKT3964: a first-in-class, highly potent and selective, orally bioavailable CDK2 PROTAC degrader for cancer therapy Presenter: Jianlin Geng, Ph.D. Abstract Number: PB002 Session: Posters in the Spotlight Date/Time: 2:00 p.m.-2:40 p.m. CEST on October 24, 2024 About NKT3964 NKT3964 is a first-in-class, highly potent and selective, orally bioavailable CDK2 PROTAC degrader, causing prolonged CDK2 pathway inhibition without cyclin E accumulation. It has the potential to maximally inhibit the CDK2 pathway, fully harnessing the therapeutic benefits of CDK2 inhibition. NKT3964 is currently under evaluation in a Phase 1 clinical study in advanced or metastatic solid tumors as a single agent (NCT06586957). About NiKang Therapeutics NiKang Therapeutics is a clinical-stage biotech company focused on discovering and developing innovative small molecule oncology medicines to bring transformative therapies to patients in need. Our target selection is driven by deep insight into disease biology and molecular pathways. Our discovery approach is informed by target structure biology and capitalizes on structure-based drug design. The successful implementation of our strategy enables us to rapidly and efficiently discover and advance proprietary drug candidates with the most desirable pharmacological features into clinical studies. We have successfully advanced three programs into clinical trials, including NKT2152 (HIF2α), NKT3447 (CDK2), and NKT3964 (CDK2). For more information, please visit Contacts Kelsey Chen Chief Financial and Operating Officer IR@nikangtx.com

- 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.