On June 22, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematologic and oncologic diseases, reported findings on the investigational cyclin-dependent kinase 9 (CDK9) inhibitor alvocidib and TP-1287, an oral prodrug of alvocidib (Press release, Tolero Pharmaceuticals, JUN 22, 2020, View Source [SID1234561362]). These data, highlighting a novel biomarker detection method for CDK9 inhibition and evaluating the anti-tumor activity of alvocidib and TP-1287 in hematologic cancer cells, are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Meeting II, taking place June 22-24, 2020.

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The virtual poster presents a novel biomarker detection method to assess CDK9 inhibition through reduction of myeloid cell leukemia-1 (MCL-1) expression and of phosphorylation of RNA polymerase II (p-RPB1). Using peripheral blood mononuclear cells (PBMCs) as a surrogate tissue, this method was able to identify CDK9 inhibition in healthy donor PBMCs treated with alvocidib, the active form of TP-1287, ex vivo. This was also identified in a Phase 1 study participant receiving TP-1287 in an ongoing trial in patients with refractory solid tumors. These data may suggest a novel clinical biomarker approach for assessing overall CDK9 inhibition in patients.1

In preclinical studies, TP-1287 and alvocidib also showed potent cell-based activity in vitro and tumor growth inhibition in vivo across multiple hematologic cell lines, including acute myeloid leukemia (AML) and multiple myeloma (MM). Alvocidib was found to suppress p-RPB1 and the transcription of MCL-1, both downstream effectors of CDK9 activation, across cell lines and in normal PBMCs. Separately in a MM xenograft model, TP-1287 was shown to inhibit tumor growth, suppress p-RPB1 and the transcription MCL-1, and induce apoptosis.1

"Together, the results presented at AACR (Free AACR Whitepaper) show the inhibitory downstream effects of TP-1287 and its active form, alvocidib, across multiple AML and MM cell lines and in in vivo mouse models, which can be measured by a novel biomarker detection method," said David J. Bearss, Ph.D., Chief Executive Officer, Tolero Pharmaceuticals, and Chief Scientific Officer and Global Head of Research, Global Oncology. "Given the identification of this novel biomarker detection method to assess CDK9 inhibition, and the ability of TP-1287 to deliver alvocidib in the clinic, these findings support continued evaluation of the potential of CDK9 inhibition and the use of surrogate biomarkers in the ongoing study of TP-1287."

Below are the details for the presentation:

Abstract Title

Details

Author

Pharmacodynamic biomarker strategies
for CDK9 inhibition

Abstract# 5813

June 22, 2020

9 a.m. ET

Poster Presentation

Yuta Matsumura, Tolero
Pharmaceuticals

About TP-1287

TP-1287 is an investigational oral cyclin-dependent kinase 9 (CDK9) inhibitor under evaluation in a Phase 1 study in patients with advanced solid tumors (NCT03604783). TP-1287 has shown favorable oral bioavailability in preclinical models.

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the ongoing Phase 2 Zella 202 study in patients with acute myeloid leukemia (AML) who have either relapsed on or are refractory to venetoclax in combination with azacitidine or decitabine (NCT03969420). Alvocidib is also being evaluated in Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with azacitidine or decitabine (NCT03593915), and in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

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 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