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 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 drive high expression of RARA and IRF8, locking cells in an immature, undifferentiated and proliferative state. We developed biomarkers associated with the RARA and IRF8 genes, and in preclinical and ex vivo studies, the biomarkers have been shown to be predictive of response to SY-1425. In the ongoing Phase 2 trial, SY-1425 as a single agent demonstrated clinical and biological activity based on evidence of myeloid differentiation, improved blood counts, reduced leukemic blasts and stabilized disease in biomarker-marker 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 strong 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 the RARA and IRF8 biomarkers.
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.