Driving Expression of Differentiation Genes
SY-1425 (tamibarotene) is an oral first-in-class selective retinoic acid receptor alpha (RARα) agonist that is currently in a Phase 2 clinical trial to assess the efficacy and safety of SY-1425 as both a monotherapy and combination agent 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 drive high expression of RARA and IRF8, locking cells in an immature, undifferentiated and proliferative state. In preclinical studies, the RARA and IRF8 super-enhancers were shown to be predictive of response to treatment with SY-1425, promoting differentiation of AML cells with high RARA or IRF8 expression but not in AML cells with normal RARA and IRF8 expression. These studies also showed that SY-1425 inhibits the growth of cancer cells and prolongs survival in preclinical models of AML with high RARA expression. SY-1425 also demonstrated promising preclinical activity with standard-of-care hypomethylating agents and targeted anti-CD38 therapies. Based on these data, we believe that SY-1425 may provide a meaningful benefit as both a monotherapy and combination agent for AML and MDS patients who are positive for biomarkers associated with either the RARA or IRF8 super-enhancers, or both.
Beyond AML and MDS, we also discovered subsets of breast cancer patients with the RARA super-enhancer and have shown that it is predictive of response to SY-1425 in multiple preclinical models of breast cancer, including those resistant to treatment with standard-of-care therapies. Notably, the RARA super-enhancer is present across known subtypes of breast cancer.
SY-1425 is approved in Japan as Amnolake® (tamibarotene) to treat relapsed/refractory acute promyelocytic leukemia (APL), a form of AML driven by a distinct alteration of the RARA gene, and has a well-established clinical efficacy and safety profile in these patients. We in-licensed SY-1425 to develop and commercialize it in North America and Europe for all cancers after discovering the RARA super-enhancer in subsets of AML, MDS and breast cancer patients.