D3 Bio’s D3S-001 Shows Enhanced Potency Against KRAS G12C Cancers

D3 Bio, a global biotechnology company engaged in the development of innovative cancer treatments, has announced that its leading compound, D3S-001, a next-generation KRAS G12C inhibitor, has shown promising results in recent studies. Published in Cancer Discovery, the findings highlight the compound's effectiveness in targeting KRAS G12C mutations, overcoming limitations associated with nucleotide cycling and receptor tyrosine kinase (RTK) activation, and demonstrating strong preclinical and clinical activities.

The paper, titled "A KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities," revealed that D3S-001 has significantly outperformed other KRAS G12C inhibitors in various studies. Researchers from D3 Bio and its collaborators noted that D3S-001 exhibits superior covalent potency and faster target engagement kinetics compared to approved drugs like sotorasib and adagrasib. This efficiency suggests that D3S-001 can more effectively maintain KRAS G12C in its inactive GDP-bound state, potentially leading to the depletion of active KRAS in cells at clinically relevant doses. Additionally, the compound's high potency and rapid action enable it to block the GDP-to-GTP transition even in the presence of growth factors, a scenario where first-generation inhibitors typically fall short.

In various cancer models, both in cell lines and patient-derived tumor xenografts, D3S-001 showed more potent anti-tumor responses than other inhibitors studied. Notably, the compound also demonstrated the ability to delay disease progression in tumors resistant to FDA-approved KRAS G12C inhibitors and exhibited properties that allowed it to penetrate the brain, resulting in significant intracranial tumor regression in mouse models with brain metastases.

The study also discussed the ongoing Phase 1/2 trial of D3S-001 in solid tumors with KRAS G12C mutations. The trial has shown durable RECIST responses across all dose cohorts, with systemic and intracranial anti-tumor activity observed in patients with non-small cell lung cancer (NSCLC). These findings suggest that D3S-001 holds promise as a robust next-generation KRAS G12C inhibitor capable of overcoming the limitations of earlier drugs.

Additionally, at the ESMO Congress 2024, data from the Phase 1 trial involving 42 patients with advanced or metastatic KRAS G12C-mutated cancers were presented. The trial showed that D3S-001 effectively prevents the transition of KRAS G12C from its inactive GDP-bound state to the active GTP-bound state, even under growth factor stimulation. Results from the dose-escalation study indicated favorable tolerability at various dose levels, with no maximum-tolerated dose identified. The drug also demonstrated consistent and promising efficacy in patients naïve to G12C inhibitors, with a 73.5% overall response rate across different tumor types. Additionally, researchers observed significant brain tumor shrinkage in patients with brain metastases and a rapid reduction in mutant allele frequency in circulating tumor cell DNA shortly after treatment began.

Dr. Byoung Chul Cho, a prominent researcher involved in the study, emphasized that while first-generation KRAS G12C inhibitors have shown limited clinical durability, D3S-001’s rapid target engagement and robust covalent potency could represent a significant advancement. George Chen, MD, Founder, Chairman, and CEO of D3 Bio, further highlighted that D3S-001’s superior target inhibition efficiency and favorable clinical activity validate the company's approach to developing next-generation inhibitors. With promising Phase 1 data, the company anticipates reporting topline Phase 2 results in 2025.

D3S-001 is currently undergoing a Phase 2 global clinical trial for advanced solid tumors with KRAS G12C mutations, including NSCLC and colorectal cancer. The compound has received Orphan Drug Designation from the US FDA for pancreatic cancer and Fast Track Designation for late-line NSCLC and colorectal cancer treatments.

D3 Bio, the company behind D3S-001, is dedicated to the discovery, development, and registration of new cancer and immunology treatments. Funded by prominent investment firms, D3 Bio leverages its proprietary clinical insights and biomarker strategies to create novel therapies that address significant unmet medical needs.