Tolero Pharmaceuticals Announces Expansion of the Zella 102 Study in Patients with Intermediate and High-Risk Myelodysplastic Syndromes (MDS)

SALT LAKE CITY, Utah, May 14, 2020 /PRNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today announced that the first patient has been dosed with a one-hour dosing schedule for investigational agent alvocidib, a potent CDK9 inhibitor, administered in sequence after azacitidine, in the expansion of the Phase 1b/2 Zella 102 study in patients with myelodysplastic syndromes (MDS).

The Zella 102 study is being conducted in patients with previously untreated MDS and patients with MDS who have received fewer than six cycles of treatment with a hypomethylating agent. The initial study design was to evaluate the safety and efficacy of alvocidib using a 30-minute bolus followed by a four-hour intravenous infusion (IVI), in combination with decitabine. An amendment was made to the study design to include treatment with azacitidine, in sequence before a one-hour infusion of alvocidib.

"We are pleased that this study now includes both standard of care hypomethylating agents for patients with myelodysplastic syndromes. In addition, the expansion of this study offers an alternative alvocidib dosing schedule, which reduces the amount of time patients spend in infusion," said David J. Bearss, Ph.D., Chief Executive Officer, Tolero Pharmaceuticals, and Chief Scientific Officer and Global Head of Research, Global Oncology. "Preclinical research suggests that treatment with hypomethylating agents may sensitize MDS blast cells to suppression of MCL-1 through alvocidib. We look forward to building our understanding of the potential role of alvocidib in this patient population."

MDS is a form of cancer that can occur when cells in the bone marrow are abnormal and create defective blood cells, which often die earlier than normal cells. In one of three patients, MDS can progress into AML, a rapidly growing cancer of bone marrow cells.¹

About the Zella 102 Study

The Zella 102 study is an open-label, dose-escalation Phase 1b/2 study evaluating the safety and efficacy of alvocidib, when administered in sequence after either decitabine or azacitidine, in patients with previously untreated MDS and patients with MDS who have received fewer than six cycles of treatment with hypomethylating agents. The primary objective of the Phase 1b portion of the study is to determine the maximum tolerated dose and recommended Phase 2 dose of alvocidib, when administered in these regimens. Secondary objectives are to determine the complete response rate and if treatment with alvocidib, administered in sequence after decitabine or azacitidine, results in improvements in transfusion dependence and/or hemoglobin level.

The primary objective of the Phase 2 portion of the study will be to determine the objective response rate of alvocidib, when administered to untreated patients with de novo or secondary MDS in sequence after a hypomethylating agent, using revised International Working Group (IWG) criteria.

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).

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the Phase 2 studies Zella 202, in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with decitabine or azacitidine (NCT03969420) and Zella 201, in patients with relapsed or refractory MCL-1 dependent 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 cytarabine and daunorubicin (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 or azacitidine (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 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

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. Tolero has a diverse pipeline that 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. Tolero works closely with its parent company, Sumitomo Dainippon Pharma, and Boston Biomedical, Inc., also a wholly owned subsidiary, to advance a pipeline of innovative oncology treatments. The organizations apply their expertise and collaborate to achieve a common objective - expediting the discovery, development and commercialization of novel treatment options.

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. What Are Myelodysplastic Syndromes? American Cancer Society. https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html. Published January 22, 2018. Accessed April 9, 2020.
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.

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