Tolero Pharmaceuticals to Present Preclinical Data Supporting Apoptosis-Inducing Activity of Alvocidib in Acute Myeloid Leukemia

Findings show that alvocidib potentiates the activity of apoptosis-inducing agents cytarabine and daunorubicin (7+3) in non-clinical model

SALT LAKE CITY, April 13, 2018 /PRNewswire-USNewswire/ — Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematologic and oncologic diseases, today announced the presentation of preclinical data supporting the apoptosis-inducing activity of alvocidib, a potent CDK9 inhibitor, in combination with cytarabine and daunorubicin at the American Association for Cancer Research (AACR) Annual Meeting 2018, April 14-18in Chicago.

Data from cell culture models suggest that the three-drug combination more than doubled the induction of apoptosis compared to any of the agents alone. Further, 21.1% and 48.5% tumor growth inhibition (TGI) was observed following either single agent administration of daunorubicin (0.5 mg/kg) or cytarabine (60 mg/kg), respectively. Combination administration with alvocidib, however, resulted in tumor shrinkage yielding 116.2% TGI.

In addition, Tolero will present preclinical data supporting the understanding of CDK9 as a potential therapeutic target, and is consistent with the hypothesis that CDK9 activity is necessary for the expression of miR17-92. This data contributes to the emerging scientific evidence that inhibition of bromodomain and extra-terminal domain (BET) protein by JQ1 suppresses miR17-92 expression. miR17-92 negatively regulates expression of the pro-apoptotic BH3-only protein, BIM, leading to suppression of BIM expression, thereby decreasing the cell's ability to induce apoptosis.1 The findings suggest that alvocidib-mediated inhibition of CDK9 suppresses RNA Polymerase II-mediated expression of miR17-92, which in turn leads to increased expression of BIM.

"We are encouraged by these preclinical data that contribute to our current understanding of alvocidib and the role that CDK9 could potentially play as a therapeutic target in AML," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals. "These data support our ongoing development of alvocidib with cytarabine and daunorubicin, which is currently being studied in relapsed refractory MCL-1 dependent AML, a type of AML in which there are no treatment options."

Below are the details for the poster presentations:

  • "Alvocidib-mediated inhibition of CDK9 upregulates BIM via suppression of miR17-92," 1:00 to 5:00 p.m. CDT, April 15, Hall A
  • "Alvocidib enhances the efficacy of cytarabine and daunorubicin (7+3) in non-clinical models of acute myeloid leukemia," 1:00 to 5:00 p.m. CDT, April 17, Hall A

About Alvocidib 

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in a Phase II study 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 a Phase I clinical study evaluating the safety and efficacy and maximum tolerated dose of alvocidib in combination with (7+3) in newly diagnosed patients with AML (NCT03298984).

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

Tolero 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. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Tolero's business. Tolero undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

1 Leukemia. 2016 Jul;30(7):1531-41. doi: 10.1038/leu.2016.52. Epub 2016 Mar 8
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

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Tolero Pharmaceuticals, Inc.

Tolero is a clinical-stage biopharmaceutical company researching and developing treatments to improve and extend the lives of patients with oncological and hematological 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 is based in the United States and is a wholly owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd., a pharmaceutical company based in Japan.