SY-1425

Driving Expression of Differentiation Genes
DanAML Patient

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.

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

SY-1425 has the potential to address significant unmet needs in genomically defined subsets of cancer patients both as a monotherapy and in combination with other agents.

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. Even among lower-risk MDS patients, the median survival is only about six years from diagnosis. Treatment options for MDS are limited, and many MDS patients require regular blood transfusions to help manage their disease.

Breast Cancer

Despite tremendous progress in treating certain types of breast cancer, more than 158,000 women are diagnosed with metastatic breast cancer each year in the United States, Canada and the five largest European countries and the 5-year survival rate for breast cancer that has metastasized, or spread to other parts of the body, drops precipitously to 26%. In some cases, patients have a type of breast cancer for which there are limited treatment options to stop the spread of the disease. In others, patients either don't respond to approved targeted therapies or relapse after becoming resistant to those targeted therapies, leaving them with few options.

First-in-Class Selective RARα Agonist

Program Indication Preclinical Early Clinical Mid-Stage Clinical Pivotal Commercial Rights
SY-1425 (RARα agonist)
SY-1425 (RARα agonist)
Relapsed or refractory AML
Preclinical Phase complete
Early Clinical Phase complete
Mid-Stage Clinical Phase in progress
Pivotal Phase not started
North America & Europe
North America & Europe
SY-1425 (RARα agonist)
Newly diagnosed, unfit AML (monotherapy and combination)
Preclinical Phase complete
Early Clinical Phase complete
Mid-Stage Clinical Phase in progress
Pivotal Phase not started
North America & Europe
SY-1425 (RARα agonist)
Relapsed or refractory higher-risk MDS
Preclinical Phase complete
Early Clinical Phase complete
Mid-Stage Clinical Phase in progress
Pivotal Phase not started
North America & Europe
SY-1425 (RARα agonist)
Lower-risk transfusion-dependent MDS
Preclinical Phase complete
Early Clinical Phase complete
Mid-Stage Clinical Phase in progress
Pivotal Phase not started
North America & Europe
SY-1425 (RARα agonist)
Breast cancer
Preclinical Phase in progress
Early Clinical Phase not started
Mid-Stage Clinical Phase not started
Pivotal Phase not started
North America & Europe

Our Publications

SY-1425 Publications

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).

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).

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).

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).

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).

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).

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).

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 (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).

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).

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).

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)

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).

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 Steensma9, 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).

Interested in Participating in a Clinical Trial?

If you’re interested in participating in a clinical trial, check to see if a trial is open near your area and if you meet the requirements to participate.

Learn More