First clinical stage covalent Werner helicase inhibitor shows proof-of-concept in Phase 1 trial

UT MD Anderson Research News September 29, 2026

  • Data from this first-in-human trial of VVD-133214 (formerly RO7589831) prompted further clinical development, including ongoing Phase 1b and Phase 2 studies 
  • This drug, the first Werner helicase covalent inhibitor, works on a similar principle to other DNA damage repair inhibitors
  • Therapy could benefit many patients with solid tumors carrying certain genetic defects who either do not respond or develop resistance to current approved immunotherapies

For patients with cancers harboring certain genetic defects, the first-in-class targeted therapy VVD-133214 (formerly known as RO7589831), which targets the DNA repair enzyme Werner helicase (WRN), demonstrated promising durable antitumor activity and was generally well-tolerated in a Phase 1 trial led by researchers at The University of Texas MD Anderson Cancer Center.

The results, published today in Nature Medicine, were first presented in a clinical trials plenary session at the American Association for Cancer Research (AACR) Annual Meeting 2025 (Abstract CT016). The trial was led by Timothy Yap, M.B.B.S., Ph.D., professor of Investigational Cancer Therapeutics and vice president and head of clinical development in the Therapeutics Discovery division.

“VVD-133214 appears generally safe and shows promising anti-tumor efficacy,” Yap said. “These are encouraging clinical data, especially because this is a patient population that currently has very limited treatment options. This also further validates Werner helicase as an actionable target, which is exciting because many cancers are highly dependent on it for survival.”

How does VVD-133214 work?

Though this targeted therapy is the first in a new class of drugs, it is part of a wider group of therapies targeting a defective DNA damage repair pathway in patients with solid tumors and genetic changes known as microsatellite instability (MSI) or deficient mismatch repair (dMMR). These can occur in many cancer types, and 40-70% of patients with these types of solid tumors either do not respond to immune checkpoint inhibitors or develop resistance during treatment.

Like other DNA damage repair therapies, VVD-133214 inhibits the function of a DNA repair enzyme, in this case Werner helicase, to create a buildup of DNA damage within tumor cells, ultimately leading to cell death. Because normal cells do not have MSI, these treatments spare normal cells, resulting in more tolerable therapies.

What were the key efficacy and safety data from this trial?

Initial efficacy was evaluated in 66 patients with a median of three prior lines of therapy, including 95.5% who received immune checkpoint therapy. Seven of these patients, representing multiple cancer types with high MSI or dMMR, had partial responses as determined by radiological imaging, and the disease control rate was 74.2%.

Specialized metabolic imaging showed that deeper metabolic responses were associated with both radiological partial responses and longer-term disease control. Median duration of response was 10.2 months, with five of the seven responders remaining in response at the time of data cutoff.

Safety was evaluated in all 88 patients, with the majority experiencing grade 1-2 adverse events. Mild to moderate but manageable nausea, vomiting and diarrhea were the most common adverse events, with one dose-limiting grade 2 nausea observed. Three patients had to discontinue treatment due to adverse events.

This trial prompted further clinical development of VVD-133214. Two international, multi–site clinical trials currently are underway: a Phase 1b evaluating VVD-133214 in combination with bevacizumab in metastatic colorectal cancer that has progressed following immunotherapy and chemotherapy (NCT06004245); and a Phase 2 evaluating VVD-133214 plus pembrolizumab in systemic treatment-naïve metastatic colorectal cancer (NCT07811193).

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This trial was initially funded by Roche and is now supported by Vividion Therapeutics. A full list of collaborating authors and disclosures can be found with the full paper in Nature Medicine.

3D rendering of DNA damage.