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The company is using a clinical trial assay to identify AML and MDS patients with elevated levels of RARA and IRF8 mRNA for inclusion in a Phase 2 clinical trial assessing the safety and efficacy of SY-1425 in combination with azacitidine, a hypomethylating agent, and in combination with daratumumab, an anti-CD38 therapeutic antibody.
2012) IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype.
IRF8 binds directly to the promoter loci of IRF5 and activates the transcription of IRF5, resulting in the increase of IRF5.
RARA and IRF8mRNA serve as biomarkers for super-enhancers, which are highly specialized regulatory regions of DNA, associated with the RARA and IRF8 genes.
All patients enrolled in the trial are prospectively selected using the RARAand IRF8 biomarkers.
Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8, and identified proprietary biomarkers related to these super-enhancers which are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated and proliferative state, and leading to disease.
In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.
Based on these data, Syros expanded its ongoing Phase 2 clinical trial to include an arm assessing the safety and efficacy of SY-1425 in combination with azacitidine in newly diagnosed AML patients 60 years or older who are not suitable candidates for standard chemotherapy and who are positive for the company's biomarkers of high expression of the RARA-pathway associated genes RARA and IRF8.