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Tolero Pharmaceuticals to highlight new data evaluating investigational agents Alvocidib and TP-1287 at 2018 American Society of Hematology annual meeting

SALT LAKE CITY, Nov. 2, 2018 /PRNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today announced 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), December 1-4 in San Diego, California. 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.

"We look forward to sharing the latest data from our pipeline at the ASH 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 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


 

About 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

About Tolero Pharmaceuticals, Inc. 
Tolero Pharmaceuticals is a clinical-stage biopharmaceutical company researching and developing treatments to improve and extend the lives of patients with hematological and oncological diseases. Our diverse pipeline targets important biological drivers of blood disorders to treat leukemias, anemia, and solid tumors, as well as targets of drug resistance and transcriptional control. Tolero Pharmaceuticals is based in the United States and is an indirect, wholly-owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., a pharmaceutical company based in Japan.

Additional information about the company and its product pipeline can be found at www.toleropharma.com .

Tolero Pharmaceuticals Forward-Looking Statements 
This press release contains "forward-looking statements," as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products.  The forward-looking statements in this press release are based on management's assumptions and beliefs in light of information presently available, and involve both known and unknown risks and uncertainties, which could cause actual outcomes to differ materially from current expectations. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice.

1 Zeidner J, Lin T, Vigil C, et al. 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 to be presented at the American Society of Hematology Annual Meeting. 2018 Dec 1-4; San Diego, CA. 
2 Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748. 
3 Perciavalle RM, Opferman JT. Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29. 
4 Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125. 
5 Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519. 
6 Ocana A, Pandiella A. Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234.

SOURCE Tolero Pharmaceuticals, Inc.