SY-1425 for MDS and AML

Our Vision for SY-1425 is to be the Foundation of Care for RARA-positive Patients
DanAML Patient

Our Vision for SY-1425 is to be the Foundation of Care for RARA-positive Patients

SY-1425 is an oral first-in-class selective retinoic acid receptor alpha (RARα) agonist that we are developing for genomically defined subsets of patients whose disease is characterized by the overexpression of the RARA gene. We are advancing SY-1425 into two planned clinical trials in RARA-positive patients: a Phase 3 trial in newly diagnosed higher-risk myelodysplastic syndrome (HR-MDS) and a randomized Phase 2 trial in newly diagnosed unfit acute myeloid leukemia (AML).

Data from an earlier, now fully enrolled Phase 2 study showed that SY-1425 in combination with azacitidine had high response rates, rapid onset of responses, and clinically meaningful durability in RARA-positive newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. The data also showed that SY-1425 in combination with azacitidine was generally well-tolerated with no increase in toxicities beyond what has been previously seen with either agent alone. Additionally, data from a translational analysis of these trial patients also suggest that RARA-positive patients may be less likely to respond to the current standard of care.

Taken together, these data supported our decision to advance SY-1425 in combination with azacitidine into a Phase 3 trial in RARA-positive newly diagnosed patients with higher-risk MDS, a hematologic malignancy that is closely related to AML, and into a randomized Phase 2 trial in combination with venetoclax and azacitidine in RARA-positive newly diagnosed unfit AML patients.

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

AML is a complex disease that is likely to require a broad arsenal of drugs that can be used in combination to address various patient populations and disease subtypes. Despite recent treatment advances, roughly one-third of newly diagnosed unfit AML patients do not respond to the current standard of care and virtually all patients eventually relapse, leaving them with few options.

HR-MDS is closely related to AML, and more than half of HR-MDS patients eventually progress to AML. No new therapies have been approved for HR-MDS in a decade, and approved therapies offer limited benefit.

We believe that SY-1425 has the potential to address these unmet needs and benefit RARA-positive AML and HR-MDS patients.

SY-1425 Clinical Trials

Our Publications

SY-1425 Publications

SELECTION OF RARA-POSITIVE NEWLY DIAGNOSED UNFIT AML PATIENTS WITH ELEVATED RARA GENE EXPRESSION ENRICHES FOR FEATURES ASSOCIATED WITH PRIMARY RESISTANCE TO VENETOCLAX AND CLINICAL RESPONSE TO SY‑1425, A POTENT AND SELECTIVE RARΑ AGONIST, PLUS AZACITIDINE

Christopher Fiore, Michael Kelly, Angela Volkert, Li Zhou, Kate Madigan, Matthew Eaton, Graeme Hodgson, David A. Roth, Qing Kang-Fortner
62nd American Society of Hematology (ASH) Annual Meeting
Abstract Number: 137323
2020

SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST, IN COMBINATION WITH AZACITIDINE DEMONSTRATES A HIGH COMPLETE RESPONSE RATE AND A RAPID ONSET OF RESPONSE IN RARA-POSITIVE NEWLY DIAGNOSED UNFIT ACUTE MYELOID LEUKEMIA

Stephane de Botton, Thomas Cluzeau, Carlos E. Vigil, Rachel J. Cook, Philippe Rousselot, David A. Rizzieri, Jane L. Liesveld, Pierre Fenaux, Thorsten Braun, Anne Banos, Michael Savona, Don Park, Michael Kelly, Angela Volkert, Li Zhou, Qing Kang-Fortner, David A. Roth, Eytan M. Stein
62nd American Society of Hematology (ASH) Annual Meeting
Oral Presentation
Abstract Number: 134600
2020

INITIAL RESULTS FROM A BIOMARKER-DIRECTED PHASE 2 TRIAL OF SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST, IN COMBINATION WITH AZACITIDINE IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA

Eytan M. Stein, Stephane de Botton, Thomas Cluzeau, Arnaud Pigneux, Jane L. Liesveld, Rachel J. Cook, Philippe Rousselot, David A. Rizzieri, Thorsten Braun, Dale L. Bixby, Gail J. Roboz, Delphine Lebon, Mael Heiblig, Michael Kelly, Angela Volkert, Li Zhou, Qing Kang-Fortner, David A. Roth, Pierre Peterlin 62nd American Society of Hematology (ASH) Annual Meeting
Oral Presentation
Abstract Number: 134602
2020

SY-1425, A POTENT AND SELECTIVE RARΑ AGONIST, IN COMBINATION WITH AZACITIDINE DEMONSTRATES HIGH RESPONSE RATES AND A RAPID ONSET OF CLINICAL RESPONSES IN RARA-POSITIVE NEWLY DIAGNOSED UNFIT AML

Stephane de Botton, Carlos E. Vigil, Thomas Cluzeau, Jane L. Liesveld, David A. Rizzieri, Tamara K. Moyo, Philippe Rousselot, Anne Banos, Don Park, Eytan M. Stein, Gail J. Roboz, Joseph G. Jurcic, Robert L. Redner, Dale L. Bixby, Jeffrey Baker, Pierre Fenaux, Gabrielle Roth-Guepin, Thorsten Braun, Jorge E. Cortes, Mikkael A. Sekeres, Michael Kelly, Angela Volkert, Li Zhou, Qing Kang, David A. Roth, Rachel J. Cook
European School of Haematology (ESH) Conference on AML
Abstract Number: 16081
2019

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

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