SY-1425

Driving Expression of Differentiation Genes
DanAML Patient

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.

A Need for Well-Tolerated Oral Therapies that Extend Survival and Improve Quality of Life

AML and MDS are complex diseases that are likely to require a broad arsenal of drugs that can be used in combination to address various patient populations and disease subtypes. Based on our clinical and preclinical data, we believe SY-1425 has the potential to combine well with other therapies to benefit RARA and IRF8 biomarker-positive AML and higher-risk MDS patients.

Acute Myeloid Leukemia (AML)

More than 33,000 people each year are diagnosed with AML in the United States, Canada and the five largest European countries, with only 27% of AML patients surviving five or more years from their diagnosis. For patients who either don't respond to existing therapies or relapse over time, there are few treatment options. The same is true for older AML patients who are not suitable candidates to withstand the harsh side effects associated with standard chemotherapy.

Myelodysplastic Syndrome (MDS)

Roughly 32,000 people are diagnosed with MDS each year in the United States, Canada and the five largest European countries. Of those, about one-third are considered at high risk of progressing to AML. The prognosis for these higher-risk patients is poor with a median survival of only two years. Treatment options for MDS are limited, and many MDS patients require regular blood transfusions to help manage their disease.

First-in-Class Selective RARα Agonist

Program Indication Discovery Preclinical Early Clinical Mid-Stage Clinical Pivotal Commercial Rights
SY-1425 (RARα agonist)
SY-1425 (RARα agonist)
Frontline AML (combination with azacitidine)
Discovery Phase complete
Preclinical Phase complete
Early Clinical Phase complete
Mid-Stage Clinical Phase in progress
Pivotal Phase not started
Syros (North America & Europe)
Syros (North America & Europe)
SY-1425 (RARα agonist)
R/R AML and HR MDS (combination with daratumumab)
Discovery Phase complete
Preclinical Phase complete
Early Clinical Phase complete
Mid-Stage Clinical Phase in progress
Pivotal Phase not started
Syros (North America & Europe)

Our Publications

SY-1425 Publications

EARLY RESULTS FROM A BIOMARKER-DIRECTED PHASE 2 TRIAL OF SY-1425 IN COMBINATION WITH AZACITIDINE OR DARATUMUMAB IN NON-APL ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS)

Rachel J. Cook, Tamara K. Moyo, Jane L. Liesveld, David A. Rizzieri, Eytan M. Stein, Stephane de Botton, Gail J. Roboz, Mikkael A. Sekeres, Joseph G. Jurcic, Azra Raza, Robert L. Redner, Dale L. Bixby, Jorge E. Cortes, Kristin Stephens, Angela Volkert, Qing Kang, Emmanuelle di Tomaso, David A. Roth, Carlos E. Vigil
60th American Society of Hematology (ASH) Annual Meeting and Exposition
Abstract Number 2735
2018

ANTITUMOR SYNERGY WITH SY-1425, A SELECTIVE RARα AGONIST, AND HYPOMETHYLATING AGENTS IN RETINOIC ACID RECEPTOR PATHWAY ACTIVATED MODELS OF ACUTE MYELOID LEUKEMIA

Michael R. McKeown, Liv Johannessen, Emily Lee, Christopher Fiore, Emmanuelle di Tomaso Haematologica
DOI: 10.3324/haematol.2018.192807
October 2018

EARLY RESULTS FROM A BIOMARKER-DIRECTED PHASE 2 TRIAL OF SY-1425 IN ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) DEMONSTRATE DHRS3 INDUCTION AND MYELOID DIFFERENTIATION FOLLOWING SY-1425 TREATMENT

Joseph G. Jurcic, Azra Raza, George Vlad, Eytan Stein, Mikhail Roshal, Dale Bixby, Daniel F. Boyer, Carlos E. Vigil, Sergei Syrbu, Mikkael A. Sekeres, Heesun J. Rogers, David Rizzieri, Anand S. Lagoo, Gail Roboz, Robert Redner, David P. Steensma, Rachel Cook, Tamara K. Moyo, Michael Savona, Michael R McKeown, Nigel J. Waters, Kristin Stephens, Angela Volkert, Emmanuelle di Tomaso, David A. Roth, Jorge Cortes
American Society of Hematology Annual Meeting
Abstract Number: 2633
2017

RARA PATHWAY ACTIVATION BIOMARKERS IN STUDY SY-1425-201 DEFINE A NEW SUBSET OF AML AND MDS PATIENTS AND CORRELATE WITH MYELOID DIFFERENTIATION FOLLOWING EX VIVO SY-1425 TREATMENT

Carlos E. Vigil, Joseph Jurcic, Azra Raza, Rachel Cook, Dale Bixby, Mikkael Sekeres, David Rizzieri, Eytan Stein, Robert L. Redner, David Steensma, Gail Roboz, Michael Savona, Michael McKeown, Chris Fiore, Angela Volkert, Curran Murphy, Kristin Stephens, David A. Roth, Emmanuelle di Tomaso, Jorge Cortes.
ESH Conference on AML
Abstract Number: 8882
2017

TARGETING THE NONCODING GENOME: SUPERENHANCERS MEET THEIR KRYPTONITE

Eric Wang and Ioannis Aifantis
Cancer Discovery (7) (10) 1065-1066; DOI: 10.1158/2159-8290.CD-17-0860
October 1, 2017

PHARMACODYNAMIC AND PHARMACOKINETIC EVALUATION OF SY-1425 (TAMIBAROTENE) IN BIOMARKER-SELECTED ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) PATIENTS

Dale Bixby, Carlos E. Vigil, Joseph Jurcic, Rachel Cook, Mikkael Sekeres, David Rizzieri, Jorge Cortes, Robert Redner, David Steensma, Gail Roboz, Tamara Moyo, Michael R McKeown, Nigel J. Waters, Kristin Stephens, Emmanuelle di Tomaso, David A. Roth, Eytan Stein
ESMO Congress
Abstract Number: 1032P
2017

A BIOMARKER-DIRECTED PHASE 2 STUDY OF SY-1425, A SELECTIVE RETINOIC ACID RECEPTOR ALPHA AGONIST, IN ADULT PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS)

Rachel Cook, Eytan Stein, David Steensma, Mikkael Sekeres, Dale Bixby, David Rizzieri, Joseph Jurcic, Carlos E. Vigil, Robert Redner, Gail Roboz, Michael Savona, Michael R. McKeown, Kristin Stephens, David A. Roth, Jorge Cortes
ASCO Annual Meeting
Abstract Number: TPS7071
2017

SUPER-ENHANCER ANALYSIS DEFINES NOVEL EPIGENOMIC SUBTYPES OF NON-APL AML INCLUDING AN RARΑ DEPENDENCY TARGETABLE BY SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST

McKeown M. Et al.
Cancer Discovery
doi: 10.1158/2159-8290.CD-17-0399
2017

MECHANISTICALLY INFORMED COMBINATIONS OF SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST, WITH HYPOMETHYLATING OR ANTI-CD38 TARGETED AGENTS IN AML AND MDS

Michael R McKeown, Kathryn Austgen, Chris Fiore, Emily Lee, Darren Smith, Christian Fritz, Tracey Lodie, Emmanuelle di Tomaso, Eric Olson
EHA 22nd Congress
Abstract Number: P188
2017

SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST, REPROGRAMS AML CELLS FOR DIFFERENTIATION ALONG DISTINCT LINEAGES, UNCOVERING PD MARKERS FOR CLINICAL STUDIES

Michael R McKeown, Chris Fiore, Kathryn Austgen, Emily Lee, Darren Smith, Mei Wei Chen, Matthew L Eaton, Angela Volkert, Curran Murphy, Kristin Stephens, Christian Fritz, Tracey Lodie, Emmanuelle di Tomaso and Eric Olson
EHA 22nd Congress
Abstract Number: E884
2017

SY-1425 (TAMIBAROTENE), A POTENT SELECTIVE RARA AGONIST, INDUCES CHANGES IN THE TRANSCRIPTIONAL REGULATORY CIRCUIT OF AML CELLS LEADING TO DIFFERENTIATION

Chris Fiore, Michael R. Mckeown, Emily Lee, Matthew L. Eaton, Darren Smith, Kathryn Austgen, Mei Wei Chen, Matthew Guenther, M. Ryan Corces, Ravindra Majeti, Eric Olson And Christian Fritz
AACR Annual Hematologic Malignancies Meeting
Poster Section: 6
2017

EPIGENOMIC ANALYSIS OF PRIMARY BREAST CANCER TUMORS REVEALS NOVEL TUMOR CELL VULNERABILITIES AND THERAPEUTIC TARGETS

Matthew G. Guenther, Mei Wei Chen, Christina Kolodzy, Michael McKeown, Emily Lee, Cindy Collins, Matthew Eaton, David Orlando, Emmanuelle di Tomaso,
Christian C. Fritz, Eric R. Olson.
IMPAKT Breast Cancer Conference
Abstract Number: 47P
2017

SY-1425 (TAMIBAROTENE), A SELECTIVE RARA AGONIST, SHOWS SYNERGISTIC ANTI-TUMOR ACTIVITY WITH HYPOMETHYLATING AGENTS IN A BIOMARKER SELECTED SUBSET OF AML

Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Christian Fritz and Eric Olson
AACR Annual Meeting
Poster Section: 3
Abstract Number: 3085
2017

SY-1425, A SELECTIVE RARA AGONIST, INDUCES HIGH LEVELS OF CD38 EXPRESSION IN RARA-HIGH AML TUMORS CREATING A SUSCEPTIBILITY TO ANTI-CD38 THERAPEUTIC ANTIBODY TREATMENT

Kathryn Austgen, Michael R. McKeown, Darren Smith, Emily Lee, Chris Fiore, Matthew L. Eaton, Christian Fritz, Tracey Lodie and Eric Olson
AACR Annual Meeting
Poster Section: 26
Abstract Number: 2644
2017

SUPER-ENHANCER LANDSCAPES REVEAL NOVEL EPIGENOMIC PATIENT SUBTYPES AND DRUGGABLE DEPENDENCIES IN HUMAN AML

Matthew L. Eaton, M. Ryan Corces, Michael R. McKeown, Chris Fiore, Jeremy T. Lopez, Katarzyna Piotrowska, Emily Lee, Mei Wei Chen, Darren Smith, Steven M. Chan, Julie L. Koening, Sarah K. Knutson, Kathryn Austgen, Matt G. Guenther, Dave Orlando, Jakob Loven, Christian Fritz and Ravindra Majeti.
CSHL Systems Biology Meeting
2017

A NOVEL SUBGROUP OF ESTROGEN RECEPTOR POSITIVE BREAST CANCER MAY BENEFIT FROM SUPER-ENHANCER GUIDED PATIENT SELECTION FOR RETINOIC ACID RECEPTOR ALPHA AGONIST TREATMENT

Michael R. McKeown, Chris Fiore, Emily Lee, Matthew L. Eaton, Dave Orlando, Matt G. Guenther, Cindy Collins, Mei Wei Chen, Christian Fritz and Emmanuelle di Tomaso
SABCS Annual Meeting
Session: Treatment: Novel Targets and Targeted Agents
Program Number: P6-11-18
2016

SY-1425 (TAMIBAROTENE) INDUCES PROFOUND TRANSCRIPTIONAL CHANGES IN AML TUMORS WITH HIGH RETINOIC ACID RECEPTOR ALPHA

Chris Fiore, Michael McKeown, Emily Lee, Matthew L. Eaton, and Christian Fritz
ASH Annual Meeting
Poster Section: 128
Abstract Number: 1523
2016

CLINICAL PHARMACODYNAMIC MARKERS AND COMBINATIONS WITH SY-1425 (TAMIBAROTENE) IN A GENOMICALLY-DEFINE SUBSET OF NON-APL AML

Michael R. McKeown, Chris Fiore, Emily Lee, Matthew L. Eaton, Kathryn Austgen, Darren Smith and Christian Fritz
ASH Annual Meeting
Poster Section: 128
Abstract Number: 2898
2016

SUPER-ENHANCER ANALYSIS DEFINES NOVEL AML AND MDS SUB-TYPES

Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Jeremy Lopez, Ryan Corces-Zimmerman, Ravindra Majeti, Kristin Stephens, Christian Fritz, and Eric Olson
EHA 21st Congress
Oral Presentation: Hall A3
Abstract Number: s807
June 12, 2016

SY-1425 IN GENOMICALLY DEFINED SUBSET OF AML AND MDS PATIENTS

Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Jeremy Lopez, Ryan Corces-Zimmerman, Ravindra Majeti, Christian Fritz, and Eric Olson
AACR Annual Meeting
Poster Section: 14
Abstract Number: 1187
2016

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