Tamibarotene for Higher-Risk MDS and AML :: Syros Pharmaceuticals, Inc. (SYRS)

Our Vision for Tamibarotene is to be the Foundation of Care for Patients with RARA Gene Overexpression

Tamibarotene (formerly SY-1425) is an oral selective retinoic acid receptor alpha (RARα) agonist we are developing for genomically defined subsets of patients whose disease is characterized by the overexpression of the RARA gene. Approximately 50% of MDS patients and 30% of AML patients have RARA overexpression. When RARα is expressed in excess of its tightly controlled natural ligand, cells in the bone marrow may not differentiate into healthy myeloid cells, which can lead to hematological malignancies. However, when oral tamibarotene is administered, tamibarotene binds to RARα, allowing for the restoration of gene expression and myeloid differentiation.

A Need for Well-Tolerated Oral Therapies that Improve Outcomes and 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. Hypomethylating agents, or HMAs, are the existing standard of care, but provide limited efficacy with many patients continuing to suffer significant mortality and morbidity. Aside from HMAs, no new therapies have been approved in over a decade.

We believe that tamibarotene has the potential to address these unmet needs and benefit AML and HR-MDS patients with RARA overexpression.

We Aim to Bring Much-Needed Medicines to Patients

We currently developing tamibarotene, an investigational medicine for patients with MDS and AML.

Tamibarotene for RARA Overexpression in MDS and AML

Tamibarotene (formerly SY-1425) is an oral, selective retinoid acid receptor alpha (RARα) agonist that we are developing in newly diagnosed patients with RARA gene overexpression with higher-risk myelodysplastic syndrome (HR-MDS) and newly diagnosed acute myeloid leukemia (AML) patients with RARA gene overexpression who are not suitable candidates for standard intensive chemotherapy.

High response rates, rapid onset of responses and clinically meaningful durability were shown in a Phase 2 study of tamibarotene in combination with azacitidine in newly diagnosed AML patients with RARA overexpression who are not suitable candidates for standard chemotherapy, including in patients with low blast count AML. Data also showed that tamibarotene 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 patients with RARA overexpression may be less likely to respond to the current standard of care.

These data support the advancement of tamibarotene into two ongoing clinical trials: first, our Phase 3 SELECT-MDS-1 trial of tamibarotene in combination with azacitidine in newly diagnosed higher-risk MDS patients with RARA overexpression, a hematologic malignancy that is closely related to AML; and second, our randomized Phase 2 SELECT-AML-1 trial in combination with venetoclax and azacitidine in newly diagnosed unfit AML patients with RARA overexpression.

Downloadable MDS Trial Fact Sheet

Downloadable AML Trial Fact Sheet

Tamibarotene Clinical Trials

USE OF TAMIBAROTENE, A POTENT AND SELECTIVE RARΑ AGONIST, IN COMBINATION WITH AZACITIDINE IN PATIENTS WITH RELAPSED AND REFRACTORY AML WITH RARA GENE OVEREXPRESSION

EYTAN M. STEIN, STEPHANE DE BOTTON, THOMAS CLUZEAU, ARNAUD PIGNEUX, JANE L. LIESVELD, RACHEL J. COOK, PHILIPPE ROUSSELOT, DAVID A. RIZZIERI, THORSTEN BRAUN, GAIL J. ROBOZ, DELPHINE LEBON, MAEL HEIBLIG, KRISTEN BAKER, ANGELA VOLKERT, SOFIA PAUL, NISHA RAJAGOPAL, DAVID A. ROTH, MICHAEL KELLY & PIERRE PETERLIN
LEUKEMIA & LYMPHOMA
DOI: 10.1080/10428194.2023.2243356
AUGUST 2023

TARGETING RARA OVEREXPRESSION WITH TAMIBAROTENE, A POTENT AND SELECTIVE RARΑ AGONIST, IS A NOVEL APPROACH IN AML

Stéphane de Botton, Thomas Cluzeau, Carlos Enrique Vigil, Rachel Cook, Philippe Rousselot, David A Rizzieri, Jane L Liesveld, Pierre Fenaux, Thorsten Braun, Anne Banos, Joseph G. Jurcic, Mikkael A. Sekeres, Michael R. Savona, Gail J. Roboz, Dale Bixby, Kate Madigan, Angela Volkert, Kristin Stephens, Qing Kang-Fortner, Kristen Baker, Sofia Paul, Michael Robert McKeown, John P Carulli, Matthew Lucas Eaton, Graeme Hodgson, Christopher Fiore, Michael Kelly, David A. Roth, Eytan M. Stein
Blood Advances
doi: 10.1182/bloodadvances.2022008806
December 2022

INITIAL RESULTS FROM SELECT-AML-1, A PHASE 2 STUDY OF TAMIBAROTENE IN COMBINATION WITH VENETOCLAX AND AZACITIDINE IN RARA-POSITIVE NEWLY DIAGNOSED AML PATIENTS INELIGIBLE FOR STANDARD INDUCTION CHEMOTHERAPY

Suman Kambhampati, Christine McMahon, Alireza Eghtedar, Daniel Pollyea, Stephane de Botton, Arnaud Pigneux, Mohamad Cherry, Brian Ball, Gautam Borthakur, Thomas Cluzeau, Gary Schiller, Beibei Hu, Angela Volkert, Joanie Aasen Gausman, Graeme Hodgson, David A. Roth, Erica Warlick, Michael J. Kelly, Eytan M. Stein
64th American Society of Hematology (ASH) Annual Meeting
Abstract 1444
2022

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Tamibarotene for HR-MDS and AML