Roche Reports Promising First-in-Human Data for RO7589831, a First-in-Class WRN Inhibitor, in MSI-H/dMMR Solid Tumors

Apr 28, 2025 17:04 CST Updated 17:04

Roche

Oncology Drug Research, Development, and Manufacturing

At the AACR conference, Roche announced promising early data for its first-in-class Werner helicase (WRN) inhibitor RO7589831 in patients with solid tumors harboring high microsatellite instability (MSI-H) and/or deficient mismatch repair (dMMR) genetic alterations.Roche acquired RO7589831 through a deal with Vividion Therapeutics in 2020, which has now been acquired by Bayer.

This Phase I study enrolled 44 patients across six cohorts to evaluate daily doses of RO7589831, ranging from 150 mg to 2000 mg. Participants had previously received a median of three prior treatment regimens, with 89% having been treated with immune checkpoint inhibitors.

The results showed that, among 32 evaluable MSI-H patients,Four cases achieved partial remission, of which 2 cases were confirmed remission, and 2 cases were unconfirmed remission and still under observation.These remissions were mainly observed in MSI colorectal cancer, ovarian cancer, and endometrial cancer patients treated with immunotherapy, lasting up to 9.5 months or more. The disease control rate was 68.8%, with 62.5% of patients achieving stable disease, and 48.4% of PET-evaluable patients showing metabolic response. Additionally, molecular responses in circulating tumor DNA were observed in patients with partial remission and stable disease.

"These early clinical data are encouraging, especially considering that these patients currently have very limited treatment options," said lead researcher Timothy Yap. "It also further validates [WRN] helicase as a viable target, which is exciting because the survival of many cancers is highly dependent on it."

In terms of safety, the most common treatment-related adverse events (AEs) with RO7589831 were mild and manageable nausea, vomiting, and diarrhea. Grade 3 AEs included nausea, as well as reports of minor elevations in liver enzymes, fatigue, and anemia. No dose-limiting toxicity or grade 4 or higher treatment-related toxicities were reported.

RO7589831 belongs to the First in Class program and is the world's first WRN inhibitor. However, it is also part of a broader therapeutic approach targeting DNA damage response in patients with solid tumors, specifically those with high microsatellite instability (MSI) or deficient mismatch repair (dMMR) genetic alterations. These alterations can occur in various cancer types, and 40%-70% of such patients with solid tumors either do not respond to immune checkpoint inhibitors or develop resistance during treatment.

Like other DNA damage response therapies, RO7589831 inhibits the function of DNA repair enzymes (in this case, Werner helicase), leading to the accumulation of DNA damage within tumor cells and ultimately resulting in cell death. Since normal cells do not have MSI, these therapies do not harm normal cells.

Dr. Yap and his intro slide at AACR 2025