On November 2, 2018 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, reported that new data from three abstracts on the Company’s pipeline of investigational agents will be presented at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), December 1-4 in San Diego, California (Press release, Tolero Pharmaceuticals, NOV 2, 2018, View Source [SID1234530690]). Among the presentations, updated data from Zella 201, an ongoing Phase 2 study evaluating the efficacy and safety of alvocidib, a potent CDK9 inhibitor, in combination with cytarabine and mitoxantrone in patients with relapsed or refractory MCL-1-dependent acute myeloid leukemia (AML) will be featured in an oral presentation. Additional data from Tolero’s pipeline will also be presented, including preclinical findings on the activity of alvocidib and decitabine, as well as preclinical data evaluating the activity of TP-1287, an oral CDK9 inhibitor, in combination with bortezomib or venetoclax for the potential treatment of multiple myeloma. Three additional abstracts on Tolero sponsored research will be presented by independent research institutions.
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"We look forward to sharing the latest data from our pipeline at the ASH (Free ASH Whitepaper) Annual Meeting, including updated findings from the Zella 201 study, which further informs our understanding of the potential role of alvocidib in relapsed or refractory MCL-1-dependent acute myeloid leukemia," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals. "These data at ASH (Free ASH Whitepaper) reinforce our commitment and progress in advancing our clinical programs focused on hematologic and oncologic diseases."
Below are the details for the Tolero presentations:
Abstract Title
Details
Presenter
Zella 201: A Biomarker-Guided Phase II
Study of Alvocidib Followed by Cytarabine
and Mitoxantrone in MCL-1 Dependent
Relapsed/ Refractory Acute Myeloid
Leukemia (AML)
Abstract #30
December 1, 8:45 a.m. PT
Oral Presentation
Joshua F. Zeidner,
Lineberger Comprehensive
Cancer Center, University of
North Carolina, Chapel Hill, NC
The Oral CDK9 Inhibitor, TP-1287, Is
Active in Non-Clinical Models of Multiple
Myeloma
Abstract #3269
December 2, 6 – 8 p.m. PT
Poster Presentation
Clifford Whatcott,
Tolero Pharmaceuticals, Inc.
The CDK9 Inhibitor, Alvocidib, Potentiates
the Non-Clinical Activity of Azacytidine or
Decitabine in an MCL-1-Dependent
Fashion, Supporting Clinical Exploration of
a Decitabine and Alvocidib Combination
Abstract #4355
December 3, 6- 8 p.m. PT
Poster Presentation
Wontak Kim, Tolero
Pharmaceuticals, Inc.
Below are selected details for the presentations from Tolero sponsored research:
Abstract Title
Details
The PIM Kinase Inhibitor TP-3654 in Combination with
Ruxolitinib Exhibits Marked Improvement of Myelofibrosis in
Murine Models
Abstract #54
December 1, 8:45 am PT
Oral Presentation
Enhanced Expression of Beta-Catenin and Axl Receptor
Tyrosine Kinase (RTK) in Chronic Lymphocytic Leukemia
(CLL) B-Cells with Co-Culture on Marrow Stromal Cells:
Implications for Leukemic Cell Drug Resistance
Abstract #3125
December 2, 6 – 8 p.m. PT
Poster Presentation
Axl-RTK Inhibition Modulates T Cell Functions and Synergizes
with Chimeric Antigen Receptor T Cell Therapy in B Cell
Malignancies
Abstract #728
December 3, 3 p.m. PT
Oral Presentation
A bout Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in a Phase II study, Zella 201, in patients with relapsed or refractory MCL-1 dependent acute myeloid leukemia, AML, in combination with cytarabine and mitoxantrone ( NCT02520011 ). Alvocidib is also being evaluated in Zella 101, a Phase I clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with (7+3) in newly diagnosed patients with AML ( NCT03298984 ), and Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes, MDS, in combination with decitabine ( NCT03593915 ). In addition, alvocidib is being evaluated in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax ( NCT03441555 ).
About TP-1287
TP-1287 is an investigational oral cyclin-dependent kinase 9 ( CDK9) inhibitor entering into a Phase 1 study in patients with advanced solid tumors ( NCT03604783) . TP-1287 has shown favorable oral bioavailability in preclinical models. TP-1287 is enzymatically cleaved, yielding the parent drug, alvocidib, a potent inhibitor of CDK9.
About CDK9 Inhibition and MCL-1
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.2 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.3 In MCL-1–dependent AML, MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.2,4 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).5,6 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.5 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.2