Driving Expression of Differentiation Genes
SY-1425 is an oral first-in-class selective retinoic acid receptor alpha (RARα) agonist that is currently in a Phase 2 clinical trial to assess its efficacy and safety in combination with standard-of-care and targeted therapies in genomically defined subsets of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients.
Using our gene control platform to analyze cells from patients' tumors, we discovered subsets of AML and MDS patients with highly specialized regulatory regions of DNA, known as super-enhancers, associated with the RARA and IRF8 genes. These super-enhancers lock cells in an immature, undifferentiated and proliferative state. We developed biomarkers to identify these subsets of patients, and in preclinical and ex vivo studies, the biomarkers have been shown to be predictive of response to SY-1425. Initial data from the ongoing Phase 2 trial showed that SY-1425 as a single agent improved blood counts, reduced leukemic blasts, stabilized disease and promoted cell differentiation in biomarker-positive relapsed or refractory AML and higher-risk MDS patients. The data also showed that chronic, daily dosing of SY-1425 was generally well-tolerated in this population.
These clinical data, coupled with preclinical data showing the tumor-killing activity of SY-1425 in combination with standard-of-care hypomethylating agents and targeted anti-CD38 therapies, lead us to believe that SY-1425 may provide a meaningful benefit as a combination agent for AML and MDS patients who are positive for our RARA and IRF8 biomarkers.