Tolero Pharmaceuticals Announces First Patient Dosed with Investigational Agent Alvocidib in Phase 1b/2 Zella 102 Study in Patients with Myelodysplastic Syndromes (MDS)

SALT LAKE CITY /PRNewswire/ -- Tolero Pharmaceuticals a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today announced that the first patient has been enrolled in a Phase 1b/2 study, Zella 102, evaluating the investigational agent alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor, plus decitabine in patients with myelodysplastic syndromes (MDS). The Phase 1b/2, open-label, dose-escalation study will evaluate the safety and preliminary clinical activity of alvocidib when administered in sequence after decitabine in patients with MDS.

"We are pleased to initiate this Phase 1b/2 clinical trial of alvocidib in myelodysplastic syndromes," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals, Inc. "We hypothesize that downregulation of MCL-1 via CDK9 inhibition following decitabine exposure may result in enhanced antileukemic activity. We believe that there are some patients with MDS that may have disease dependent on MCL-1. This milestone supports our commitment to understanding the potential of alvocidib in this patient population."

The primary objective of the Phase 1b study is to determine the incidence of dose-limiting toxicities and treatment emergent adverse events over the course of 28 days. Once the maximum tolerated dose or preliminary recommended Phase 2 dose is identified, the study will progress to Phase 2. The primary objective of the Phase 2 study is to determine the objective response rate. The trial is being conducted at sites in the United States. Additional information on this trial, including comprehensive inclusion and exclusion criteria, can be accessed at www.ClinicalTrials.gov (NCT03593915).

MDS is a form of cancer that can occur when cells in the bone marrow are abnormal, resulting in the production of defective blood cells that often die earlier than normal cells. In one of three patients, MDS can progress into acute myeloid leukemia (AML), a rapidly growing cancer of bone marrow cells.¹

About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in a Phase 2 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 1 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 MDS in combination with decitabine (NCT03593915). In addition, alvocidib is being evaluated in a Phase 1 study in patients with relapsed or refractory acute myeloid leukemia 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 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.

References

¹ What Are Myelodysplastic Syndromes? American Cancer Society. https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html. Published January 22, 2018. Accessed July 31, 2018.

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

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SOURCE Tolero Pharmaceuticals, Inc.