Nimbus Therapeutics Unveils Preclinical Data on WRN Inhibitor NTX-452 at EORTC-NCI-AACR Symposium

Nimbus Therapeutics, a biotechnology company specializing in the design and development of breakthrough medicines, has announced promising preclinical results for their new development candidate, NTX-452. This announcement was made at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. NTX-452 is a novel non-covalent Werner syndrome helicase (WRN) inhibitor, designed to treat tumors with microsatellite instability-high (MSI-H) that are resistant to current immunotherapy and chemotherapy treatments.

WRN is a helicase essential for DNA replication and repair, making it a validated target for tumors exhibiting microsatellite instability (MSI). MSI is a result of defective mismatch repair (dMMR), which occurs in various cancers such as colorectal, gastric, and endometrial cancers. Inhibiting WRN activity could induce synthetic lethality in MSI-H tumors, offering a new therapeutic approach. Nimbus Therapeutics utilized a structure-based drug design to develop both covalent and non-covalent WRN inhibitors, ultimately selecting NTX-452, a non-covalent inhibitor, as their clinical candidate.

The preclinical data presented by Nimbus highlight several significant findings. NTX-452 demonstrated potent and selective inhibition of WRN activity, with properties favorable for drug development. The compound was shown to induce synthetic lethality in MSI-H tumor cells, initiating a DNA damage response that hindered cell viability and promoted cell death. In vivo studies revealed that NTX-452, administered at low doses, resulted in significant tumor regression and complete responses in MSI-H cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, including those for colorectal, gastric, and endometrial cancers. Importantly, these results were observed in tumors that were unresponsive to previous immunotherapy and chemotherapy treatments.

Dr. Peter Tummino, Chief Scientific Officer of Nimbus, expressed optimism about the preclinical results, emphasizing the potential of NTX-452 as a promising therapeutic option for MSI-H tumor patients, particularly those who have not benefited from existing treatments. He noted the novelty of their non-covalent approach to WRN inhibition and the robust efficacy demonstrated across various tumor types and treatment contexts. The low doses required to achieve significant anti-tumor activity in preclinical models suggest a favorable benefit-risk profile for future clinical applications.

The promising preclinical profile of NTX-452 suggests several potential advantages for treating MSI-H tumors. Its non-covalent mechanism may provide more durable on-target activity and a greater safety margin compared to covalent inhibitors. NTX-452’s high potency and favorable pharmacokinetic properties indicate that effective target levels can be achieved at lower doses, which could translate to a reduced risk of adverse effects in clinical settings. The broad efficacy observed across treatment-naïve, chemotherapy-pretreated, and immunotherapy-pretreated models suggests the potential for NTX-452 to be effective in both early-stage and advanced disease contexts. Additionally, its activity in multiple MSI-H tumor types, including those with diverse genetic alterations, points to a wide applicability across dMMR/MSI-H cancers.

Nimbus Therapeutics is preparing to advance NTX-452 into clinical trials, with plans to initiate the first trial in the first half of 2025. This development represents a significant step forward in the company’s efforts to provide new, effective treatments for patients with challenging MSI-H tumors.