MRT-6160, a VAV1-directed molecular glue degrader (MGD), inhibits colitis disease progression and colon inflammation, lowers inflammatory mucosal cytokines, and reduces expression of IBD-associated genes in a colitis model
Initiation of MRT-6160 Phase 1 SAD/MAD study anticipated in mid-year 2024 with Phase 1 clinical data expected in Q1 2025
Poster presentation today at
“VAV1 is a well-validated target with significant therapeutic potential in autoimmune and inflammatory diseases but is generally considered undruggable via conventional modalities. These promising preclinical data support our hypothesis that VAV1 is an important target in inflammatory bowel disease (IBD) and also demonstrate MRT-6160's ability to potentially address the underlying disease biology and provide therapeutic benefit,” said
The poster, entitled “MRT-6160, a VAV1-Directed Molecular Glue Degrader, Inhibits Disease Progression in a T-cell Transfer Mediated Murine Colitis Model Concomitant with Reduced Calprotectin Expression” (Poster Number Tu1727), will be presented today by
Summary of findings:
- MRT-6160 was shown to inhibit disease progression, prevent colon inflammation, and reduce pro-inflammatory cytokine production in a murine T-cell transfer model of colitis.
- MRT-6160-mediated murine (m)VAV1 degradation prevented disease progression by 85% compared to vehicle (P<0.0001), and also reduced the disease activity index (DAI) score compared to a standard of care control.
- Transcriptional analysis of colon tissue showed reduced expression of inflammatory-disease associated T-cell activation, Th17 differentiation, chemokine, and calprotectin subunit genes.
- MRT-6160 reduced CD4+ T-cell expression of TNF and IL-17A, demonstrating a highly favorable profile compared to active control of anti-TNF antibodies.
- Additionally, in vitro treatment of human PBMCs with MRT-6160 led to concentration-dependent degradation of human (h)VAV1 in immune cells and inhibited T-cell receptor (TCR)-mediated expression of pro-inflammatory cytokines and proliferation.
About VAV1 and MRT-6160
VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T-and B-cell receptors. VAV1 expression is restricted to blood and immune cells, including T and B cells. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor-mediated activity. This modulation is evident both in vitro and in vivo, demonstrated by a significant decrease in cytokine secretion, proteins vital for maintaining autoimmune diseases. Moreover, VAV1-directed MGDs have shown promising activity in preclinical models of autoimmune diseases and thus have the potential to provide therapeutic benefits in multiple systemic and neurological autoimmune indications, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and dermatological disorders.
MRT-6160 is a potent, highly selective, and orally bioavailable degrader of VAV1, which has shown deep degradation of its target with no detectable effects on other proteins. Preclinical studies demonstrate MRT-6160 inhibits disease progression in in vivo autoimmunity models.
About Monte Rosa
Forward-Looking Statements
This communication includes express and implied “forward-looking statements,” including forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements that are not historical facts and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or other comparable terminology intended to identify statements about the future. Forward-looking statements contained herein include, but are not limited to, statements about our ability to grow our product pipeline, statements around the Company’s QuEENTM discovery engine and the Company’s view of its potential to identify degradable protein targets and rationally design MGDs with unprecedented selectivity, statements around the power and differentiation of the QuEEN discovery engine and the potential of the Company’s MGDs against a broad spectrum of targets, statements about the advancement and timeline of our preclinical and clinical programs, pipeline and the various products therein, including the ongoing development of MRT-6160, and the planned submission of an IND to the FDA for MRT-6160 in the second quarter of 2024, our expectations of timing for initiation of a Phase 1 SAD/MAD study mid-2024 and the timing for our disclosure of Phase 1 clinical data of MRT-6160 in the first quarter of 2025, as well as our expectation to present additional preclinical data in models of autoimmune and inflammatory diseases at the upcoming medical meetings and our expectation to initiate POC studies for MRT-6160 in autoimmune/inflammatory diseases including ulcerative colitis and rheumatoid arthritis, with additional potential POC studies, dermatology, rheumatology, and neurology indications in mid-2025, our expectations of success for our programs and the strength of our financial position, our use of capital, expenses and other financial results in the future, availability of funding for existing programs, ability to fund operations into the first half of 2027, among others. By their nature, these statements are subject to numerous risks and uncertainties, including those risks and uncertainties set forth in our most recent Annual Report on Form 10-K for the year ended
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