fadraciclib (CYC065) / Cyclacel - LARVOL DELTA

Novel Bcl-2/Bcl-xL inhibitor, LP-118, enhances apoptosis induction by the CDK2/9 inhibitor, fadraciclib, in BRAF(V600E) human colorectal cancer cells (AACR 2026) - "LP-118 synergistically enhanced the antitumor activity of fadraciclib plus encorafenib in BRAFV600E human CRC cells, and to a greater extent than did venetoclax. Mechanistically, targeting Bcl-2/Bcl-xL concurrent with inhibition of MCL-1 and CDK2/9 by fadraciclib potently induced apoptosis and suppressed tumor cell growth. These findings suggest a novel and effective therapeutic strategy for BRAFV600E human CRCs."

IO biomarker • Colorectal Cancer • Oncology • Solid Tumor • ANXA5 • BCL2 • BCL2L1 • BRAF • CASP3

Phase I/II Study of the CDK2/9 Inhibitor Fadraciclib in Combination with Chemotherapy in Children with Advanced Malignancies: Arm K of the AcSé-ESMART Trial. (PubMed, Target Oncol) - "This pediatric study was the first to explore the CDK2/9 inhibitor fadraciclib. Fadraciclib combined with temozolomide showed a manageable safety profile with limited clinical activity."

Journal • P1/2 data • Brain Cancer • CNS Tumor • Ependymoma • Hematological Disorders • Oncology • Pediatrics • Rhabdoid Tumor • Sarcoma • Solid Tumor

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris

New P1/2 trial • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=455 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Aug 2027 ➔ Feb 2031 | Trial primary completion date: Aug 2027 ➔ Feb 2031

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=397 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | N=285 ➔ 397 | Trial completion date: Dec 2020 ➔ Jan 2022 | Trial primary completion date: Dec 2020 ➔ Jan 2022

Enrollment change • Trial completion date • Trial primary completion date • Pediatrics

ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (clinicaltrials.gov) - P1/2 | N=460 | Recruiting | Sponsor: Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Jan 2022 ➔ Aug 2027 | Trial primary completion date: Jan 2022 ➔ Aug 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Oncology • Pediatrics

Generation of a Patient Derived T-Cell Prolymphocytic Leukemia Xenograft Model to Evaluate Pre-Clinical Treatment with Small Molecule Inhibitors In Vivo (ASH 2024) - "Combination therapy with the CDK9 inhibitor Fadraciclib and the BCL2 inhibitor Venetoclax was well tolerated, controlled the burden of circulating T-PLL cells in PB better than independent drugs and vehicle, and improved survival of T-PLL mice that were treated with the combination. Such data can provide the rationale for a clinical trial exploring this combination in patients with relapsed or refractory T-PLL."

Preclinical • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • Prolymphocytic Leukemia • PRKDC • PTPRC

Preclinical Evaluation of T-Cell Prolymphocytic Leukemia Demonstrates Heterogeneous BCL2-Family Dependency That May be Effectively Targeted with Small Molecule Inhibitors (ASH 2023) - "Therefore, SUPT11 cells (used as a model of T-PLL) were exposed to venetoclax (25 and 50nM; BCL-2inh), fadraciclib (25 and 50nM; CDK2/9inh – indirect inhibitor of MCL-1 as it decreases mRNAs with high decay rates including MCL1 and MYC) or a combination of venetoclax and fadraciclib. In conclusion, preclinical evaluation of a T-PLL cell line and primary patient samples demonstrate BCL2-family dependency that can be effectively targeted with small molecule inhibitors of BCL2 and CDK2/9. In vivo studies in PDX models of T-PLL are underway to form the basis for clinical trials to study these combinations."

Heterogeneity • IO biomarker • Preclinical • Hematological Malignancies • Leukemia • Lymphoma • Metabolic Disorders • Oncology • Peripheral T-cell Lymphoma • Prolymphocytic Leukemia • T Cell Non-Hodgkin Lymphoma • BCL2 • BCL2L1

Dual targeting of conserved cell cycle and transcription programs in advanced colorectal cancer by fadraciclib. (PubMed, Evol Med Public Health) - "CRC PDOs exhibited greater sensitivity to fadraciclib compared to chemotherapy and palbociclib. Fadraciclib induced G2/M cell cycle arrest, leading to multipolar mitosis and anaphase catastrophe. Our results using patient-derived models suggest that fadraciclib is a promising therapy for advanced CRC by inhibiting CDKs 2 and 9, which affects critical pathways in cell cycle regulation and transcription."

Journal • Colorectal Cancer • Oncology • Solid Tumor

The CDK2/9 inhibitor fadraciclib in Richter transformation (IWCLL 2025) - "In the lymphoma lines, IC₅₀ values ranged from 0.5 to 0.7 µM. CFSE tracking confirmed reduced cell division and Click-iT EdU incorporation assays showed decreased S-phase entry and cell cycle arrest at the G1 phase, consistent with CDK2's role in G1/S transition.In summary, our results demonstrate that fadraciclib is active in RT and Myc-driven lymphoma cell lines by targeting both survival and proliferation pathways, supporting its further clinical evaluation in patients with Richter transformation."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Richter's Syndrome • CDKN2A • HPRT1 • MYC • NOTCH1 • TP53

CDK inhibitors promote neuroblastoma cell differentiation and increase sensitivity to retinoic acid-a promising combination strategy for therapeutic intervention. (PubMed, Cell Death Discov) - "This study investigated three CDKis (abemaciclib, fadraciclib, and dinaciclib) alone or combined with retinoic acid (RA) to assess the effects on morphology, growth, gene expression, and the induction of immunogenic cell death in NB cell lines with (LAN-1 and CHLA-90) and without (CHLA-172) MYCN amplification. CDKi treatments promote NB differentiation via ER stress, with cytotoxicity enhanced by RA co-treatment. This may increase NB immunogenicity and support immunotherapy eligibility."

IO biomarker • Journal • Neuroblastoma • Oncology • Solid Tumor • CALR • CCNE2 • CDK4 • CDKN2A • CRABP2 • MCM4 • MYBL2 • MYCN • ROBO2

Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E) (Nature) - "Fadraciclib decreased phosphorylation of RNA polymerase II, indicating suppression of RNA transcription. The tumor growth inhibitory effect of fadraciclib plus encorafenib was synergistic. Fadraciclib decreased Rb phosphorylation, inhibited cell cycle progression, and promoted DNA damage as evidenced by cleavage of PARP, increased pH2AX (ser139), and activation of p53. In RKO+/+ versus A19+/- or T29-/- cells, drug treatment was associated with greater suppression of p-Rb and inhibition of apoptosis and the cell cycle. In a zebrafish xenograft model, fadraciclib plus encorafenib significantly reduced tumor size, concurrent with increased caspase-3 activation. In human CRCs, BRAF mutation was associated with overexpression of CDK2, and CDK9 overexpression was associated with worse patient survival. In conclusion, fadraciclib depletes MCL-1 to potentiate apoptosis and, combined with encorafenib, synergistically suppresses tumor cell growth in a BRAFV600E gene dose-dependent manner."

Preclinical • Colorectal Cancer

Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E). (PubMed, Oncogenesis) - "In conclusion, fadraciclib depletes MCL-1 to potentiate apoptosis and, combined with encorafenib, synergistically suppresses tumor cell growth in a BRAFV600E gene dose-dependent manner. These data suggest a novel therapeutic strategy in CRCs with BRAFV600E."

Journal • Colorectal Cancer • Oncology • Solid Tumor • BRAF • CASP3 • MCL1

Adamantinomatous Craniopharyngioma tumoroids reveal CDK9 as a potential treatment target (ESPE-ESE 2025) - "High-throughput drug screening (HTS) identifies selective sensitivity to the CDK2/CDK9 inhibitor Fadraciclib and the HDAC inhibitor Romidepsin, while standard chemotherapies were largely ineffective. Our study highlights solo CDK9 inhibition as a promising strategy. Together, these findings underscore ACP tumoroids as a robust model for studying tumor cellular heterogeneity and identifying novel therapeutic vulnerabilities."

Late-breaking abstract • Brain Cancer • CNS Tumor • Endocrine Cancer • Oncology • Pituitary Gland Carcinoma • CDK9

Novel CDK2/CDK9 inhibitor fadraciclib targets cell survival and DNA damage pathways and synergizes with encorafenib in human colorectal cancer cells with BRAF(V600E) (AACR 2025) - "Fadraciclib plus encorafenib potently induced apoptosis and synergistically suppressed tumor cell growth in a gene dose-dependent manner in BRAFV600E CRC cells, and exerted anti-tumor effects in a tumor xenograft model. These data suggest a novel therapeutic strategy in this CRC subtype."

Colorectal Cancer • Oncology • Solid Tumor • BRAF • CASP3 • EGFR • MCL1

Cyclacel Pharmaceuticals Reports Fourth Quarter Financial Results and Provides Business Update (GlobeNewswire) - "'Our new, alternative salt, oral formulation of plogosertib with improved bioavailability is under development.'....Research and development (R&D) expenses were $0.9 million and $6.7 million for the three months and year ended December 31, 2024, as compared to $3.5 million and $19.2 million for the same period in 2023. R&D expenses relating to fadraciclib were $0.8 million and $5.0 million for the three months and year ended December 31, 2024, as compared to $2.7 million and $13.4 million for the same period in 2023 due to decrease in clinical trial and other non-clinical expenditures. R&D expenses related to plogosertib were $0.1 million and $1.6 million for the three months and year ended December 31, 2024, as compared to $0.7 million and $5.0 million for the same period in 2023 due to decrease in clinical trial and other non-clinical expenditures."

Commercial • Pipeline update • Hematological Malignancies • Solid Tumor

Development of 9H-purine scaffold as novel CDK2 inhibitors: Design, synthesis, and biological evaluation. (PubMed, Bioorg Med Chem Lett) - "In this study, three series of compounds were designed and synthesized, using the CDK2 inhibitor fadraciclib (CYC065) as the lead compound, with 9H-purine as the core structure...This study evaluated the impact of substitutions at the 2, 6, and 9 positions of the purine ring on the activity of CDK2 small molecule inhibitors. The findings offer a theoretical foundation for future research, broadening the structural diversity and scope of CDK2 inhibitor studies."

Journal • Oncology • CCNE2

Design, Synthesis and Biological Evaluation of Novel 9H Purine Derivatives as Potent CDK9 Inhibitors. (PubMed, Chem Biol Drug Des) - "Taking the CDK2/9 inhibitor CYC065 as the positive control and an in-house library compound (64) as the lead compound, four classes of 22 target compounds with 9H purine as the core structure were designed to establish structure-activity relationships (SAR)...After conducting selectivity testing against CDK2/9 kinase, compound B5 demonstrated approximately five-fold greater selectivity towards CDK9-cyclinT1 over CDK2-cyclinE2. This work also provides a reference basis for the subsequent research on CDK9 inhibitors."

Journal • Oncology • CCNE2 • CLINT1

Cyclacel Pharmaceuticals Reports New Clinical Data from Ongoing, Phase 2 Study of Oral Fadraciclib at the 2024 EORTC-NCI-AACR Symposium (GlobeNewswire) - P1/2 | N=330 | NCT04983810 | Sponsor: Cyclacel Pharmaceuticals, Inc. | "Cyclacel Pharmaceuticals, Inc...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...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....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)."

P2 data • Cervical Cancer • Cholangiocarcinoma • Laryngeal Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma • Thymus Cancer

FADRACICLIB, AN ORAL CDK2/9 INHIBITOR, IN PATIENTS WITH ADVANCED SOLID TUMORS AND LYMPHOMA WITH CDKN2A AND/OR CDKN2B GENETIC ALTERATIONS (EORTC-NCI-AACR 2024) - P1/2 | "Orally administered fadraciclib was well tolerated with the most common adverse events nausea, vomiting, hyperglycemia and thrombocytopenia.Preliminary clinical activity was higher in patients with CDKN2A/B genetic alterations and a prospective cohort of these patients is currently being enrolled."

Clinical • Metastases • Biliary Cancer • Cholangiocarcinoma • Endometrial Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leiomyosarcoma • Lung Cancer • Lymphoma • Melanoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma • Uterine Corpus Leiomyosarcoma • CDK9 • CDKN2A • CDKN2B • MTAP

The dual CDK2 and CDK9 inhibitor fadraciclib activates immunogenic signaling pathways and increases the immunogenicity of glioblastomas (DGHO 2024) - "Our study confirms the therapeutic potential of dual CDK2/CDK9 inhibition in GBM treatment, evidenced by the successful treatment of 2D and 3D models. In addition to its ability to inhibit proliferation and induce apoptosis, fadraciclib may have the potential to modulate the tumor microenvironment by altering cytokine secretion and facilitating immune-mediated killing of tumor cells."

IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • BCL2 • CALR • CXCL8 • IFNG • IL6 • MGMT

Cyclacel Pharmaceuticals to Present New Clinical Data From Phase 2 Study of Oral Fadraciclib at the 2024 EORTC-NCI-AACR Symposium (GlobeNewswire) - "Cyclacel Pharmaceuticals, Inc...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 as a single agent will be presented as a poster at the 2024 AACR-NCI-EORTC 36th Symposium on Molecular Targets and Cancer Therapeutics ('Triple Meeting'), to be held 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."

P2 data • Lymphoma • Oncology • Solid Tumor

Cyclacel Pharmaceuticals Announces Completion of Enrollment in the Biomarker-Enriched Patient Cohort of Its Phase 2 Study (GlobeNewswire) - "Cyclacel Pharmaceuticals...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....'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 expect to report more mature data as additional patients from Cohort 8 get scanned and followed up'."

Enrollment status • P2 data • Lymphoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma

Absorption, Metabolism, and Excretion of CYC065 in Healthy Male Subjects (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Cyclacel Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Feb 2024 ➔ May 2024 | Trial primary completion date: Mar 2023 ➔ Feb 2024

Trial completion • Trial completion date • Trial primary completion date

Cyclacel Pharmaceuticals Reports Second Quarter Financial Results and Provides Business Update (GlobeNewswire) - "'Following oral fadraciclib data presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the Phase 2 stage of our 065-101 study is enrolling well,'...'We are on track to report in the fourth quarter of 2024 initial data from the precision medicine cohort of 065-101 with our CDK2/9 inhibitor as monotherapy in patients with advanced solid tumors and later on in patients with T-cell lymphoma.'"

Enrollment status • P2 data • Lymphoma • Solid Tumor