Tolero Pharmaceuticals Presents Clinical Data from Ongoing Phase 1 Zella 101 Study Evaluating Investigational Agent Alvocidib in Combination with Cytarabine and Daunorubicin in Patients with Newly Diagnosed AML at EHA 2019

SALT LAKE CITY, June 14, 2019 /PRNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today presented data for the first time from the ongoing Phase 1 Zella 101 study evaluating the safety and clinical activity of alvocidib, a potent CDK9 inhibitor, in combination with cytarabine and daunorubicin in patients with newly diagnosed acute myeloid leukemia (AML). These results were presented in a poster presentation at the 24th Congress of the European Hematology Association (EHA), being held June 13-16, 2019 in Amsterdam, The Netherlands.

Preliminary data from the study indicated that alvocidib in combination with cytarabine and daunorubicin has shown clinical activity with acceptable safety in patients with newly diagnosed AML. Of the 18 evaluable patients, more than three-quarters (78%, n=14) achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Of these patients attaining a CR/CRi, 78% (n=11) reached the 30-day post-study evaluation, per the study protocol. A subset of these patients, 27% (n=3 of 11) proceeded to stem cell transplant. Additionally, among adverse cytogenic risk patients (n=9) who generally respond poorly to induction therapy, two-thirds (67%, n=6 of 9), achieved a CR/CRi.¹

Of the patients that attained a CR/CRi (n=14), 10 (71%) are still in remission with a median follow-up of 76 days. In addition, 21 of 22 (95%) enrolled patients are still alive, with a median follow-up of 70 days.

Adverse events (AEs) in the study include diarrhea, tumor lysis syndrome, infections and elevated AST levels and were consistent with those noted in previous alvocidib studies.¹

"These preliminary data from the Zella 101 study in patients with newly diagnosed AML are encouraging, as they add to the growing body of evidence from the alvocidib clinical program," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals. "We look forward to continuing this study to further our understanding of how the combination of alvocidib with cytarabine and daunorubicin may benefit this patient population."

Additional data from Tolero's pipeline will also be presented in an oral presentation at the meeting, highlighting the impact of investigational agent TP-0903, an oral AXL receptor tyrosine kinase (RTK) inhibitor, on Axl-RTK inhibition in patients with several tumors, including chronic lymphocytic leukemia (CLL).

Below are the details for the presentations:

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 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
¹Lee D, Smith BD, Frattini M et al. Zella 101: Phase 1 Study of Alvocidib Followed by 7+3 Induction in Newly Diagnosed AML Patients. In: European Hematology Association; 019 June 14; Amsterdam, The Netherlands; Abstract PF285.
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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