Kronos Bio Highlights Data at AACR Ovarian Cancer Research Symposium that Supports Clinical Evaluation of Istisociclib in Advanced Ovarian Cancer

Rhea-AI Summary

Kronos Bio (NASDAQ: KRON) presented new preclinical data on istisociclib (KB-0742), a CDK9 inhibitor, at the AACR Ovarian Cancer Research Symposium. The data supports the clinical evaluation of istisociclib in advanced ovarian cancer, particularly in platinum and PARP-inhibitor resistant cases.

Key findings include:

• Istisociclib triggered cell death in preclinical ovarian cancer models resistant to platinum and PARP inhibitors
• New PK/PD results show sustained downregulation of CDK9-dependent genes in PBMCs with an 80mg dose on a 4 days on/3 days off schedule
• Preclinical evidence suggests istisociclib induces DNA damage and subsequent cell death
• Istisociclib disrupted homologous recombination DNA damage repair, creating a "BRCAness" phenotype in resistant cells

Kronos Bio is currently evaluating istisociclib in a Phase 1/2 clinical trial expansion cohort for platinum-resistant high-grade serous ovarian cancer (HGSOC).

Positive

• Preclinical data shows istisociclib's effectiveness against platinum and PARP-inhibitor resistant ovarian cancer models
• PK/PD results demonstrate sustained downregulation of CDK9-dependent genes with the current dosing schedule
• Clinical exposures of istisociclib are consistent with efficacious levels observed in preclinical models
• Ongoing Phase 1/2 clinical trial expansion in platinum-resistant high-grade serous ovarian cancer

Negative

• None.

– New data show istisociclib (KB-0742) triggered cell death in preclinical ovarian cancer models of platinum and PARP-inhibitor (PARPi) resistance –

– New PK/PD results demonstrate that istisociclib given at 80mg on a 4 days on/3 days off schedule resulted in sustained downregulation of CDK9-dependent genes in peripheral blood mononuclear cells (PBMCs) –

SAN MATEO, Calif. and CAMBRIDGE, Mass., Sept. 23, 2024 (GLOBE NEWSWIRE) -- Kronos Bio, Inc. (Nasdaq: KRON), a company dedicated to developing small molecule therapeutics that address cancers and other diseases driven by deregulated transcription, today highlighted new preclinical data from a study of istisociclib (KB-0742). The poster presentation took place over the weekend at the American Association for Cancer Research (AACR) 15th Biennial Ovarian Cancer Research Symposium.

Kronos Bio is currently evaluating istisociclib, a CDK9 inhibitor, in an expansion cohort of a Phase 1/2 clinical trial to explore single agent activity in platinum-resistant high-grade serous ovarian cancer (HGSOC).

"We’ve demonstrated preclinical evidence that istisociclib induced DNA damage and subsequent cell death, which further supports our clinical program focused on platinum-resistant high-grade serous ovarian cancer," said Luis A. Carvajal, Ph.D., Director of Translational Development at Kronos Bio, the lead author on the poster. "Importantly, platinum or PARPi insensitive cell lines showed greater sensitivity to istisociclib in cell viability assays. Moreover, ovarian cancer cells with PARPi resistance were sensitized to PARP inhibition in the presence of istisociclib.”

Dr. Carvajal added, “Based on new PK data from our ongoing clinical trial, we conclude that plasma levels were consistent with efficacious exposures observed in preclinical models of ovarian cancer, and we are excited to be enrolling patients into an expansion cohort of patients with platinum-resistant high-grade serous ovarian cancer.”

From the presentation, “Preclinical and clinical data support clinical expansion of istisociclib (KB-0742), an oral CDK9 inhibitor, into platinum-resistant ovarian cancer,” a summary of results is outlined below.

• In vitro data demonstrate that istisociclib induced apoptosis/cell death
• Istisociclib resulted in the accumulation of γH2AX, a sensitive molecular marker of DNA damage
• Istisociclib disrupted homologous recombination (HR) DNA damage repair by downregulating BRCA1 and RAD51 creating a “BRCAness” phenotype in platinum and PARP resistant HR-proficient ovarian cancer cells
  

From the dose escalation portion of the Company's ongoing Phase 1/2 trial of istisociclib in relapsed or refractory transcriptionally addicted advanced solid tumors, new pharmacokinetic/pharmacodynamic (PK/PD) results were presented. From the dose and schedule optimization portion of the trial evaluating 60mg and 80mg of istisociclib administered once daily on a 4 days on/3 days off schedule:

• Clinical exposures resulted in a long half-life of approximately 24 hours, and increased and prolonged weekly exposures consistent with efficacious levels observed in preclinical models
• Concurrent with increased and prolonged istisociclib exposure, deeper and more sustained downregulation of CDK9-dependent genes was observed in peripheral blood mononuclear cells (PBMCs)

The poster from the presentation is available under the Science & Pipeline section of the Kronos Bio website.

About Kronos Bio
Kronos Bio, Inc. (Nasdaq: KRON) is a clinical-stage company dedicated to developing small molecule therapeutics that address deregulated transcription, a hallmark of cancer and other diseases. Our proprietary discovery engine decodes complex transcription factor regulatory networks to identify druggable cofactors. We screen for and optimize small molecules that target these cofactors in a tumor-specific context. These efforts have yielded a preclinical pipeline along with two internally developed drug candidates. Istisociclib (KB-0742) targets CDK9 to address MYC deregulation in solid tumors and KB-9558 targets p300 to address IRF4 dependence in multiple myeloma.

Kronos Bio is based in San Mateo, Calif., and has a research facility in Cambridge, Mass.
For more information, visit https://www.kronosbio.com or follow the Company on LinkedIn.

FAQ

What is the main focus of Kronos Bio's istisociclib (KB-0742) study presented at AACR?

The study focuses on istisociclib's potential in treating advanced ovarian cancer, particularly in cases resistant to platinum and PARP inhibitors. The data presented supports the clinical evaluation of istisociclib in these difficult-to-treat cases.

What are the key findings from the preclinical studies of istisociclib (KRON) in ovarian cancer?

Key findings include istisociclib triggering cell death in platinum and PARP-inhibitor resistant models, inducing DNA damage, disrupting homologous recombination DNA damage repair, and creating a 'BRCAness' phenotype in resistant cells.

What is the current clinical development stage of istisociclib (KRON) for ovarian cancer?

Kronos Bio is currently evaluating istisociclib in an expansion cohort of a Phase 1/2 clinical trial, specifically exploring single agent activity in platinum-resistant high-grade serous ovarian cancer (HGSOC).

What were the results of the PK/PD studies for istisociclib (KRON) presented at AACR?

The PK/PD results showed that istisociclib given at 80mg on a 4 days on/3 days off schedule resulted in sustained downregulation of CDK9-dependent genes in peripheral blood mononuclear cells (PBMCs). The drug also demonstrated a long half-life of approximately 24 hours.