Cyclacel
Research & Development

CYC065 – Second Generation CDK Inhibitor

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Cyclacel's second generation CDK2/9 inhibitor, CYC065, is being evaluated in an ongoing, first-in-human, Phase 1 trial in patients with advanced solid tumors. In part 1, CYC065 was well tolerated, there were robust and durable effects on the Mcl-1 biomarker and the recommended Phase 2 dose has been selected. Evidence of target engagement was observed by decreases in target cyclin-dependent kinase substrate phosphorylation accompanied by robust and prolonged Mcl-1 suppression in peripheral blood cells in patient samples from the study, consistent with the Company's preclinical data. CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, and improved metabolic stability than seliciclib, Cyclacel's first generation CDK inhibitor. As with palbociclib, the first CDK inhibitor approved by FDA in 2015, and ribociclib approved in 2017, CYC065 may be most useful in combination with other anticancer agents, including Bcl-2 antagonists, such as venetoclax, or HER2 inhibitors, such as trastuzumab.

CYC065 is a highly-selective, orally- and intravenously-available, second generation inhibitor of CDK2 and CDK9. It causes apoptotic death of cancer cells at sub-micromolar concentrations. Antitumor efficacy has been achieved in vivo with once a day oral dosing at well tolerated doses in preclinical models. Evidence from published nonclinical studies show that CYC065 may benefit patients with adult and pediatric hematological malignancies, including certain Acute Myeloid Leukemias (AML), Acute Lymphocytic Leukemias (ALL), Chronic Lymphocytic Leukemias (CLL), B-cell lymphomas, multiple myelomas, and certain solid tumors, including breast and uterine cancers and neuroblastomas. Independent investigators published nonclinical evidence that CYC065 induced regression or tumor growth inhibition in a model of HER2-positive breast cancer addicted to cyclin E that is resistant to trastuzumab, reduced tumor growth in models of CCNE1-amplified uterine serous carcinoma and reduced tumor burden and prolonged survival in several neuroblastoma models in vivo.

A Cyclacel-sponsored Phase 1b study is open for enrollment to evaluate CYC065 in combination with venetoclax in relapsed/refractory CLL patients. Studies in other mechanistically relevant cancers are being planned. Preclinical data presented at The American Association of Cancer Research 2018 annual meeting demonstrate that CYC065–venetoclax combination mediated synergistic cell killing in CLL models, irrespective of 17p deletion status and induced prolonged suppression of both Bcl-2 and Mcl-1. Importantly, the combination showed activity in certain CLL samples that were not affected by each compound individually.

CYC065 monotherapy continues to be evaluated in part 2 of a Phase 1 trial in patients with advanced solid tumors. In part 1 of the study, CYC065 was well tolerated and showed ability to durably suppress Mcl-1 biomarkers at the recommended Phase 2 dose (RP2D) as well as evidence of target engagement in clinical samples. At least 24 hours of Mcl-1 suppression in peripheral blood cells was observed in 11 out of 13 evaluable patients treated at the RP2D. Stable disease (≥6 cycles) was observed in patients with molecular features associated with CYC065's mechanism, including Mcl-1, MYC or cyclin E.

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Research & Development