Monte Rosa Therapeutics Highlights MRT-6160's Potential for IBD at Digestive Disease Week 2024

Monte Rosa Therapeutics, a clinical-stage biotechnology firm listed on Nasdaq under the ticker GLUE, is pioneering the development of innovative molecular glue degrader (MGD) medications. The company has recently unveiled preclinical data at the Digestive Disease Week (DDW) 2024 event in Washington, D.C., showcasing the potential efficacy of MRT-6160. This novel MGD targets VAV1, a crucial signaling protein in both T and B cells, and has shown promise in treating inflammatory bowel diseases (IBD), particularly ulcerative colitis.

The preclinical findings presented at DDW 2024 reveal that MRT-6160 can significantly inhibit the progression of colitis in a T-cell transfer murine model. By degrading VAV1, MRT-6160 was able to reduce disease progression by 85% compared to the control group, demonstrating a substantial decrease in the disease activity index (DAI) score. Additionally, the treatment led to a notable reduction in colon inflammation and pro-inflammatory cytokine production. These outcomes indicate that MRT-6160 may address the underlying disease mechanisms and provide therapeutic benefits for patients with IBD.

Markus Warmuth, M.D., CEO of Monte Rosa Therapeutics, highlighted the significance of these findings, emphasizing that VAV1 is a validated target with considerable therapeutic potential in autoimmune and inflammatory diseases. He noted that traditional modalities have deemed VAV1 undruggable, but the preclinical data support the hypothesis that targeting VAV1 can be beneficial for IBD treatment. Warmuth expressed optimism about MRT-6160's potential, given the significant reductions in disease activity and the corroborative data showing decreased pro-inflammatory cytokines and IBD-associated gene expression.

Monte Rosa Therapeutics plans to submit an Investigational New Drug (IND) application for MRT-6160 in the current quarter, with the initiation of a Phase 1 single ascending dose/multiple ascending dose (SAD/MAD) study anticipated in mid-2024. The company aims to present clinical data from this study in the first quarter of 2025.

The poster presented at DDW 2024 by Marisa Peluso, Director of Target and Discovery Biology at Monte Rosa, detailed the findings and emphasized the potential of MRT-6160. The data showed that MRT-6160's degradation of murine VAV1 led to a significant drop in disease progression and the disease activity index. Furthermore, transcriptional analysis indicated reduced expression of genes associated with T-cell activation, Th17 differentiation, and inflammation. The treatment also lowered the expression of TNF and IL-17A in CD4+ T-cells, demonstrating a favorable pro to active control compared to anti-TNF antibodies.

In vitro studies with human peripheral blood mononuclear cells (PBMCs) further validated MRT-6160's efficacy. The treatment resulted in concentration-dependent degradation of human VAV1 and inhibited T-cell receptor-mediated cytokine production and proliferation, reinforcing the potential of MRT-6160 in modulating immune responses.

VAV1, a Rho-family guanine nucleotide exchange factor, plays a pivotal role in signaling pathways downstream of T and B cell receptors. Its expression is limited to blood and immune cells, making it an attractive target for autoimmune disease treatments. Preclinical studies have shown that MGDs targeting VAV1 can modulate immune cell activity, reducing cytokine secretion and providing therapeutic benefits in conditions such as multiple sclerosis, rheumatoid arthritis, and IBD.

MRT-6160 stands out as a potent and selective VAV1 degrader, demonstrating deep target degradation without affecting other proteins. Preclinical models have shown that MRT-6160 effectively inhibits disease progression in autoimmune conditions, positioning it as a promising candidate for further clinical development.

Monte Rosa Therapeutics continues to advance its pipeline of MGD-based therapies, leveraging its QuEEN™ discovery engine that integrates AI-guided chemistry, structural biology, and proteomics. This approach aims to identify and develop highly selective MGDs for a range of serious diseases, including oncology, autoimmune, and inflammatory conditions. With a strategic collaboration with Roche, Monte Rosa aims to expand its reach and develop MGDs for targets previously considered undruggable, offering new hope for patients with challenging medical conditions.