GSK-4418959 Advanced Drug Monograph

GSK-4418959 Report

Name: GSK-4418959 English Name: GSK-4418959

Drug Type: Small molecule drug Target: Werner syndrome ATP-dependent helicase (WRN) Action: Inhibitor Mechanism: WRN RecQ-like helicase inhibitor

Therapeutic Areas: Neoplasms, Digestive System Disorders, Urogenital Diseases

Active Indication: Colonic Cancer, Endometrial Carcinoma, Rectal Cancer (specifically MSI-H solid tumors)

Inactive Indication: Not yet specified

Development Stage: Preclinical and Phase 1 clinical trials

Clinical Trials:

• SYLVER (NCT05764117): A Phase 1 study investigating the safety, pharmacokinetics, and preliminary effectiveness of GSK4418959 alone or in combination with a PD-1 inhibitor in participants with advanced solid tumors. The study includes dose escalation and expansion phases for both monotherapy and combination therapy. Specific cohorts include patients with advanced colorectal or endometrial cancer who have received prior lines of therapy including immune checkpoint inhibitors.

Preclinical Findings:

• Demonstrated a potential best-in-class preclinical profile in the MSI-H setting.
• Unique binding mode compared to previously reported WRN inhibitors.
• Potent and selective inhibition across MSI-H models.
• Induced single-agent tumor regressions in MSI-H patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models for endometrial, colorectal, and gastric cancers.

Potential Benefits:

• Potential for a new therapeutic approach for MSI-H cancers, including endometrial, colorectal, and gastric cancers, where MSI-H prevalence is significant.
• May be developed as a monotherapy or in combination with PD-1 inhibitors.

Safety and Tolerability:

• Safety and tolerability are being evaluated in the ongoing Phase 1 clinical trial (SYLVER). No specific side effect data are yet publicly available for GSK-4418959.

Collaboration:

• Discovered through a collaboration between IDEAYA Biosciences and GSK.
• GSK is responsible for the majority of global research and development costs and holds an exclusive global license for development and commercialization.

Note: This report is based on currently available information and is subject to change as new data emerge from ongoing clinical trials and further research.