Syros Presents Data at AACR Further Supporting Clinical Potential of SY-1425, Its First-in-Class Selective RARα Agonist, for Genomically Defined AML and MDS Patients

– New Preclinical Data Demonstrate Synergistic Anti-Tumor Activity of SY-1425 with Standard-of-Care AML and MDS Therapies, Providing Evidence for Expansion of Ongoing Phase 2 Clinical Trial to Include Combination with Azacitidine –

– New Preclinical Data Show SY-1425 Sensitizes AML Cells with High RARA Expression to Approved Multiple Myeloma Drug by Inducing Expression of CD38, Providing Rationale for Clinical Investigation of SY-1425 in Combination with Anti-CD38 Therapies –

– Exploratory Biomarker for High IRF8 Expression Revealed as One of Two Biomarkers for Patient Selection in Ongoing Phase 2 Clinical Trial –

CAMBRIDGE, Mass.--()--Syros Pharmaceuticals (NASDAQ:SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, announced today that new preclinical data on SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist currently in a Phase 2 clinical trial in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), were presented at the American Association of Cancer Research (AACR) Annual Meeting in Washington, D.C.

“Our clinical strategy with SY-1425 is to quickly and efficiently explore its potential as both a single agent and in combination for AML and MDS patients whose disease is driven by the abnormal expression of RARA pathway-associated genes, including RARA and IRF8”

“Our clinical strategy with SY-1425 is to quickly and efficiently explore its potential as both a single agent and in combination for AML and MDS patients whose disease is driven by the abnormal expression of RARA pathway-associated genes, including RARA and IRF8,” said Nancy Simonian, M.D., Chief Executive Officer of Syros. “The new data presented at AACR provide the foundation for our rational combination strategy, supporting the expansion of our ongoing Phase 2 clinical trial to include a combination dosing arm with hypomethylating agent therapy, as well as the future clinical investigation of SY-1425 in combination with anti-CD38 therapies.”

SY-1425 in Combination with Hypomethylating AML and MDS Therapies

Data generated and presented by Syros scientists show SY-1425 increases the anti-tumor activity of hypomethylating agents (HMAs), including azacitidine, a therapy used as a standard-of-care in AML and MDS, in in vitro and in vivo models of AML with high levels of RARA expression. HMAs prime the DNA for gene activation, thus enhancing SY-1425’s gene activation and differentiation properties. In patient-derived xenograft (PDX) models of AML with high RARA expression, SY-1425 in combination with azacitidine shows:

  • Greater clearance of tumor cells and duration of response, compared to either azacitidine or SY-1425 alone.
  • Reduction of tumor burden to less than 5 percent in bone marrow and other tissues.

Based on these data, Syros has expanded its ongoing Phase 2 clinical trial to include an arm to explore 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 have been prospectively identified as positive for one of the Company’s two biomarkers. The treatment regimen for patients in the combination arm is consistent with the one identified in preclinical studies to maximize tumor suppression and tolerability, with seven days of azacitidine treatment followed by 21 days of SY-1425 treatment. In these preclinical studies, both agents were administered at full doses and no unexpected safety events were observed.

SY-1425 Sensitizes RARA-High AML Cells to Anti-CD38 Therapeutic Antibody

Data generated and presented by Syros scientists demonstrate that SY-1425 induces the cell surface protein CD38 in AML cells from patient samples with high levels of RARA expression. By inducing CD38, SY-1425 sensitizes the cancer cells to daratumumab, an anti-CD38 monoclonal antibody that flags CD38-positive tumor cells for immune cell-mediated killing. Daratumumab is approved to treat various multiple myeloma (MM) populations. Results from the in vitro studies show SY-1425:

  • Induces levels of CD38 expression in RARA-high AML cells comparable to those in MM cells that are known to be responsive to daratumumab; notably, AML cells do not normally express high levels of CD38.
  • Triggers robust activation of natural killer cells when combined with daratumumab in RARA-high AML cells.
  • Leads to potent immune cell-mediated tumor cell death in RARA-high AML cells when combined with daratumumab.

Based on these data, Syros believes SY-1425 in combination with a therapeutic anti-CD38 antibody represents a promising immunotherapy approach for defined subsets of AML and MDS patients and plans to pursue clinical development of the combination in patients identified using the Company’s biomarkers.

High IRF8 Expression Predicts Response to SY-1425 in Models of AML

Using its gene control platform, Syros identified a super-enhancer associated with the IRF8 gene in a subset of AML tumors that, like the RARA super-enhancer, is predictive of response to treatment with SY-1425. The IRF8 super-enhancer drives overexpression of the IRF8 gene, which codes for the IRF8 transcription factor. IRF8 works cooperatively with the RARα transcription factor to induce differentiation and reduce proliferation in AML cells. While the IRF8 and RARA super-enhancers as well as high IRF8 and RARA expression are correlated, a subset of AML patient tumors has high IRF8 expression in the absence of high RARA expression.

Data presented by Syros scientists show that cell-line models of AML with high expression of IRF8 are 1,000 times more sensitive to SY-1425 than AML models with low IRF8 expression. SY-1425 induced differentiation in AML cells with high IRF8 expression as well as in an ex vivo clinical sample from a patient positive for a biomarker for the IRF8 super-enhancer discovered by Syros.

Syros’ patient selection strategy for the ongoing Phase 2 clinical trial incorporates biomarkers for both the RARA and IRF8 super-enhancers. Syros estimates that about one-third of AML and MDS patients will have one or both biomarkers.

About the Phase 2 Clinical Trial of SY-1425

The Phase 2 clinical trial of SY-1425 is a biomarker-directed multi-center, open-label trial exploring safety and efficacy in relapsed or refractory AML and higher-risk MDS patients, newly diagnosed AML patients 60 years of age or older who are not suitable candidates for standard chemotherapy and lower-risk transfusion-dependent MDS patients. The trial also includes an arm to explore the safety and efficacy of SY-1425 in combination with azacitidine in newly diagnosed AML patients 60 years of age or older who are not suitable candidates for standard chemotherapy. All patients in the trial are prospectively selected using the Company’s proprietary biomarkers. The primary endpoint is overall response rate for AML and higher-risk MDS patients and red blood cell transfusion-independence rate for lower-risk MDS patients. Other endpoints include assessment of pharmacodynamic markers, duration of response, safety and tolerability, and overall and progression-free survival. Additional details about the trial can be found using the identifier NCT02807558 at www.clinicaltrials.gov. Syros is on track to report initial clinical data on SY-1425 in fall 2017.

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 acute myeloid leukemia and myelodysplastic syndrome, 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: presentation of initial clinical data for SY-1425; initiation of combination dosing of SY-1425, including the planned combination of SY-1425 with daratumumab; the potential of SY-1425 as an immunotherapy approach when combined with an anti-CD38 antibody; and the percentage of AML and MDS patients with the RARA or IRF8 biomarkers. 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 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 Syros’ Annual Report on Form 10-K for the year ended December 31, 2016, which is on file with the Securities and Exchange Commission; and risks described in other filings that Syros 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.

Contacts

Media:
Syros Pharmaceuticals
Naomi Aoki, 617-283-4298
naoki@syros.com
or
Investors:
Stern Investor Relations, Inc.
Hannah Deresiewicz, 212-362-1200
hannahd@sternir.com

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