Analysis of the Regulatory Genome Provides New Approach for AML Patient Stratification Independent of Genomic Mutations

Super-enhancers Shown to be Associated with Survival Outcomes and Response to Therapies in Development

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, today announced the discovery of a novel genomics based approach to stratify acute myeloid leukemia (AML) patients based on super-enhancer profiles.1 In their research, Syros scientists demonstrated a strong association between distinct super-enhancer profiles of six AML patient clusters and patients’ overall survival outcomes and response to certain therapies in development. These data were presented at the Cold Spring Harbor Systems Biology: Global Regulation of Gene Expression Conference.

“Syros’ finding represents an important observation in the gene regulatory biology of AML patients, with potential clinical implications,” said Ravi Majeti, M.D., Associate Professor, Department of Medicine, Division of Hematology, and Institute for Stem Cell Biology and Regenerative Medicine at Stanford University and collaborator with Syros on the research and abstract. “Despite our understanding of the mutational landscape of AML and the development of targeted therapies to these mutations, not all patients benefit. Syros’ regulatory genomics approach to molecular based stratification of AML patients adds a new dimension to our understanding of the disease biology and has potential implications for prognosis and treatment in the short term and drug discovery and development in the longer term.”

Using proprietary computational algorithms to analyze the regulatory genomes from 66 AML patients’ tumor samples, Syros scientists were able to group tumors into six clusters based on super-enhancer profiles, including one enriched for a super-enhancer associated with the RARA gene. The data show that:

  • Each cluster had a distinct super-enhancer profile consisting of a unique combination of super-enhancer driven transcription factors.
  • Super-enhancer profiles were strongly associated with survival outcomes, with median overall survival ranging from nine months in one patient subset to greater than two years in another patient subset.
  • While some super-enhancer profiles correlated with known genetic mutations in AML, others did not. For example, patients with the super-enhancer associated with the FLT3 gene did not necessarily have a FLT3 mutation, while patients with a FLT3 mutation did not necessarily have the super-enhancer associated with the FLT3 gene. The FLT3 super-enhancer was shown to be predictive of response to a FLT3 inhibitor in AML cell lines, even when a FLT3 mutation was not present.
  • Clusters were associated with response to therapy. For example, AML cell lines and patient-derived xenograft models with the RARA super-enhancer profile demonstrated response to SY-1425, a selective retinoic acid receptor alpha (RARα) agonist, currently in a Syros-sponsored Phase 2 clinical study for AML and myelodysplastic syndrome (MDS) patients with the RARA super-enhancer as identified by a proprietary biomarker.

“These findings in AML are the first to underscore the power of Syros’ gene control platform to identify clinically relevant subsets of patients that would not be detected by other genomic-based approaches,” said Eric Olson, Ph.D., Chief Scientific Officer of Syros. “Drug discovery of targeted cancer therapies has focused on genomic mutations in the protein coding region of the genome, and while some cancers have been well served by this approach, many patients are still unaddressed. The biology insights from our ability to understand the regulatory region of the genome, coupled with our capabilities and infrastructure in small molecule chemistry for transcriptional targets, position us strongly to fulfill our mission of identifying and drugging gene control targets to provide meaningful and durable benefit to patients with diseases that have eluded other genomic-based approaches.”

Syros’ drug discovery and development platform is the first to focus solely on the regulatory genome to systematically and efficiently identify disease-causing alterations in gene expression and create medicines to selectively target transcription to control the expression of genes with the aim of treating cancer, as well as autoimmune and rare genetic diseases. Using its platform, Syros is advancing a growing pipeline of drug candidates, including SY-1425 and SY-1365, a first-in-class selective inhibitor of cyclin-dependent kinase 7 (CDK7), that is on track to begin a Phase 1 clinical trial in the first half of this year in patients with transcriptionally driven solid tumors, including triple negative breast, small cell lung and ovarian cancers.

About Syros Pharmaceuticals
Syros Pharmaceuticals is pioneering the understanding of the non-coding region of the genome to advance a new wave of medicines that control expression of disease-driving genes. Syros has built a proprietary platform that is designed to systematically and efficiently analyze this unexploited region of DNA in human disease tissue to identify and drug novel targets linked to genomically defined patient populations. Because gene expression is fundamental to the function of all cells, Syros’ gene control platform has broad potential to create medicines that achieve profound and durable benefit across a range of diseases. Syros is currently focused on cancer and immune-mediated diseases and is advancing a growing pipeline of gene control medicines. Syros’ lead drug candidates are SY-1425, a selective RARα agonist in a Phase 2 clinical trial for genomically defined subsets of patients with AML and MDS, and SY-1365, a selective CDK7 inhibitor with potential in a range of solid tumors and blood cancers. Led by a team with deep experience in drug discovery, development and commercialization, Syros is located in Cambridge, Mass.

Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, including without limitation statements regarding: the clinical progress of SY-1425, the initiation of clinical development of SY-1365, and the benefits of Syros’ gene control platform. The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘continue,’’ ‘‘could,’’ ‘‘estimate,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’ ‘‘potential,’’ ‘‘predict,’’ ‘‘project,’’ ‘‘target,’’ ‘‘should,’’ ‘‘would,’’ and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: Syros’ ability to: advance the development of its programs, including SY-1425 and SY-1365, under the timelines it projects in current and future clinical trials; obtain and maintain patent protection for its drug candidates and the freedom to operate under third party intellectual property; demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its drug candidates; replicate scientific and non-clinical data in clinical trials; successfully develop a companion diagnostic test to identify patients with biomarkers associated with the RARA super-enhancer; obtain and maintain necessary regulatory approvals; identify, enter into and maintain collaboration agreements with third parties; manage competition; manage expenses; raise the substantial additional capital needed to achieve its business objectives; attract and retain qualified personnel; and successfully execute on its business strategies; risks described under the caption “Risk Factors” in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, which is on file with the Securities and Exchange Commission; and risks described in other filings that the company makes with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Syros expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.

1 Super-enhancers are highly specialized regulatory regions of non-coding DNA which bring together large amounts of transcription factors and other regulatory proteins to drive expression of the set of genes fundamental to cell function.

Media Contact:
Syros Pharmaceuticals, Inc.
Naomi Aoki, 617-283-4298
Investor Contact:
Stern Investor Relations, Inc.
Hannah Deresiewicz, 212-362-1200

Source: Syros Pharmaceuticals, Inc.