Kronos Bio Showcases Data Supporting Istisociclib for Advanced Ovarian Cancer at AACR Symposium

Kronos Bio, Inc. recently unveiled promising preclinical results for its drug candidate istisociclib (KB-0742) at the American Association for Cancer Research’s (AACR) 15th Biennial Ovarian Cancer Research Symposium. The company, which focuses on developing small molecule therapeutics for cancers driven by deregulated transcription, is advancing istisociclib in a Phase 1/2 clinical trial for platinum-resistant high-grade serous ovarian cancer (HGSOC).

Luis A. Carvajal, Ph.D., Director of Translational Development at Kronos Bio, shared that the preclinical findings support their ongoing clinical program. The data showed that istisociclib induced DNA damage and cell death, particularly in ovarian cancer models resistant to platinum and PARP inhibitors. Carvajal emphasized that cell lines insensitive to platinum or PARP inhibitors demonstrated increased sensitivity to istisociclib. Moreover, ovarian cancer cells with PARP inhibitor resistance were sensitized to PARP inhibition when treated with istisociclib.

The study highlighted several key points:
- In vitro data indicated that istisociclib caused apoptosis and cell death.
- The drug led to the accumulation of γH2AX, a molecular marker of DNA damage.
- Istisociclib disrupted homologous recombination (HR) DNA damage repair by downregulating BRCA1 and RAD51, creating a “BRCAness” phenotype in HR-proficient ovarian cancer cells resistant to platinum and PARP inhibitors.

Carvajal also discussed new pharmacokinetic/pharmacodynamic (PK/PD) results from the ongoing clinical trial, which showed that plasma levels of istisociclib were consistent with effective exposures observed in preclinical models. These findings are promising for the treatment of patients with platinum-resistant HGSOC.

The dose optimization portion of the trial evaluated 60mg and 80mg doses of istisociclib administered on a 4 days on/3 days off schedule. Results demonstrated:
- Clinical exposures had a long half-life of around 24 hours, with increased and prolonged weekly exposures consistent with efficacious levels observed in preclinical models.
- Deeper and sustained downregulation of CDK9-dependent genes was observed in peripheral blood mononuclear cells (PBMCs), concurrent with increased and prolonged drug exposure.

Kronos Bio's efforts are rooted in their proprietary discovery engine that decodes complex transcription factor regulatory networks to identify druggable cofactors. This approach has led to a promising preclinical pipeline and two internally developed drug candidates. Besides istisociclib, which targets CDK9 to address MYC deregulation in solid tumors, the company is developing KB-9558 to target p300 for addressing IRF4 dependence in multiple myeloma.

Kronos Bio operates from San Mateo, Calif., with a research facility in Cambridge, Mass. They continue to leverage their expertise in transcriptional regulation to develop innovative therapies for challenging cancers.