Nimbus Therapeutics has begun dosing patients in its first-in-human clinical trial of NDI-219216, a novel non-covalent Werner syndrome helicase (WRN) inhibitor designed to treat microsatellite instability-high (MSI-H) solid tumors. The Phase 1/2 trial is actively enrolling participants across multiple clinical sites, marking a significant advancement in the company's oncology pipeline.
"The initiation of this clinical trial marks an important milestone in advancing our novel WRN inhibitor program," said Dr. Anita Scheuber, Senior Vice President, Therapeutic Head, Oncology at Nimbus. "We are excited to be evaluating NDI-219216 in patients with advanced disease, who currently have limited treatment options when they experience disease progression on standard of care therapies."
Trial Design and Patient Population
The open-label, dose escalation and dose expansion study (NCT06898450) will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of NDI-219216 in patients with advanced cancer. The study is structured in three parts: Part A (dose escalation), Part B (dose optimization), and Part C (dose expansion).
The trial targets patients with MSI-H tumors, which arise from deficiencies in DNA mismatch repair and are observed in several cancer types, including colorectal, gastric, and endometrial cancers. These patients often develop resistance to current standard treatments, creating a significant unmet medical need.
Promising Preclinical Data
Nimbus presented initial preclinical data on NDI-219216 (previously known as NTX-452) at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in October 2024. The results demonstrated that NDI-219216 is a potent and selective WRN inhibitor capable of inducing significant tumor regression and sustained complete responses at low doses in MSI-H tumor models that are refractory to both immunotherapy and chemotherapy.
The company plans to present new comparative data at the upcoming American Association for Cancer Research (AACR) Annual Meeting in Chicago (April 25-30, 2025). These findings will highlight NDI-219216's superior efficacy across multiple preclinical MSI-H tumor models compared with other clinical-stage WRN inhibitors.
Mechanism of Action and Potential Advantages
WRN is a critical DNA helicase involved in DNA replication and repair. MSI-H tumors rely heavily on WRN activity for survival, making WRN inhibition a promising synthetic lethal approach that selectively targets cancer cells while sparing healthy tissue.
Unlike covalent WRN inhibitors in development, NDI-219216's non-covalent mechanism may offer distinct advantages. Dr. Peter J. Tummino, President of Research and Development at Nimbus, explained: "NDI-219216 has the potential for more durable target engagement than covalent inhibitors and maintains potency against potential resistance mutations. Its superior efficacy across multiple MSI-H tumor models, including those less sensitive to other WRN inhibitors and those refractory to current therapies, reinforces our belief that NDI-219216 represents a best-in-class opportunity."
Notably, NDI-219216 maintains efficacy against a known resistance mutation (Cysteine 727) that diminishes the effectiveness of covalent WRN inhibitors, potentially offering a more durable treatment option.
Addressing an Unmet Clinical Need
MSI-H tumors represent approximately 15% of colorectal cancers, 22% of endometrial cancers, and 22% of gastric cancers. While immune checkpoint inhibitors have shown efficacy in some MSI-H tumors, many patients develop resistance or fail to respond to immunotherapy.
"We look forward to generating important additional safety and efficacy data as we advance this promising candidate through clinical development," added Dr. Scheuber. The trial's progress will be closely watched by clinicians treating patients with MSI-H tumors who have exhausted standard treatment options.
About Nimbus Therapeutics
Headquartered in Boston, Nimbus Therapeutics specializes in structure-based drug discovery, combining advanced computational techniques and machine learning to design therapies against challenging biological targets. The company's computational drug discovery engine has enabled the development of several promising candidates, including NDI-219216.
In addition to its WRN inhibitor program, Nimbus is advancing therapies in immunology and metabolism, including an investigational SIK inhibitor. The company's approach to drug discovery has previously yielded success, most notably with the development of an acetyl-CoA carboxylase (ACC) inhibitor that was acquired by Gilead Sciences.
