On October 23, 2023 Circle Pharma, in collaboration with the laboratory of Violeta Serra, Ph.D., at Vall d’Hebron Institute of Oncology (VHIO) in Barcelona, Spain, reported preclinical data demonstrating the efficacy of Circle’s oral Cyclin A/B inhibitor macrocycles in patient-derived breast cancer tumor models (Press release, Circle Pharma, OCT 23, 2023, View Source [SID1234636241]). This significant development was presented at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).

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The study in 40 breast cancer cell lines identified an association between hallmark pathway scores in E2F, G2/M, and mitotic spindle pathways and sensitivity to Cyclin A/B inhibition. Most notably, multiple triple-negative breast cancer (TNBC) cell lines and luminal B breast cancer cell lines displayed sensitivity to Cyclin A/B inhibition. These findings were instrumental in selecting TNBC and luminal breast cancer patient-derived tumor models for subsequent in vivo efficacy studies. In these in vivo studies, oral administration of Circle’s Cyclin A/B inhibitor led to substantial tumor regression in both TNBC and luminal breast cancer models, with complete response observed in a luminal B breast cancer model derived from a patient whose tumor had previously progressed following multiple treatments, including with a CDK4/6 inhibitor.

Breast cancer is the second leading cause of cancer-related deaths in women globally. Triple negative breast cancer, which accounts for 10-20% of all breast cancer cases, is an aggressive and challenging subtype of breast cancer, associated with poor prognosis and high risk of relapse1. Because TNBC lacks specific receptors (estrogen, progesterone, or HER2) that some other breast cancers have, many newer therapies used to target these receptors in other forms of breast cancer are not effective. Luminal breast cancers are hormone receptor-positive and generally less aggressive than TNBC. Luminal breast cancers can be further divided into two subtypes: luminal A (HR+/ER+/HER2+) and luminal B (HR+/PR+/HER2-). These two subtypes make up about 70% of all breast cancer cases2.

Dr. Serra expressed optimism about the results, stating, "The responses in both TNBC and luminal breast cancer models are very compelling, and we look forward to evaluating the effects of these first-in-class Cyclin A/B inhibitors in additional models in future studies."

"October is breast cancer awareness month; at Circle our mission is to bring new therapies and new hope to patients who have limited treatment options, and this new research indicates that we may have an opportunity to do just that for patients with breast cancer. We will work assiduously to bring this first-in-class therapy to patients," said David J. Earp, JD, PhD, Circle Pharma’s chief executive officer.

Building on the success demonstrated in small cell lung cancer and ovarian cancer models, Circle Pharma plans to file an investigational new drug (IND) application for its Cyclin A/B inhibitor clinical candidate, CID-078, with the U.S. Food and Drug Administration (FDA) and initiate clinical development in 2024.

ABOUT CIRCLE PHARMA’S CYCLIN A/B INHIBITOR PROGRAM
Circle Pharma has developed an orally bioavailable macrocycle with dual cyclin A and B inhibitory activity that drives synthetic lethality in multiple tumor types. In biochemical and cellular studies, Circle’s Cyclin A/B inhibitor has been shown to potently and selectively disrupt the protein-protein interaction between Cyclins A and B and their key substrates, including E2F (a substrate of Cyclin A) and Myt1 (a substrate of Cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B inhibitors to cause pronounced tumor regression in multiple xenograft models. Circle Pharma plans to file an investigational new drug (IND) application with the U.S. Food and Drug Administration (FDA) for its clinical candidate, CID-078, and initiate clinical development in 2024.