Tolero Pharmaceuticals Presents Updated Clinical Data from Ongoing Phase 2 Zella 201 Study Evaluating Investigational Agent Alvocidib in Patients with MCL-1 Dependent Relapsed or Refractory AML at ASH 2018

SALT LAKE CITY, Dec. 1, 2018 /PRNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, today presented new data from the ongoing Phase 2 Zella 201 study evaluating the efficacy and safety of the investigational agent alvocidib, a potent CDK9 inhibitor, in combination with cytarabine and mitoxantrone in patients with MCL-1-dependent relapsed or refractory (R/R) acute myeloid leukemia (AML). These results were presented in an oral presentation at the 60^th Annual Meeting of the American Society of Hematology, being held December 1-4, 2018, in San Diego, California.

Updated findings from Stage 1 of the study have shown that alvocidib in combination with cytarabine and mitoxantrone displayed encouraging clinical activity in patients with MCL-1-dependent R/R AML. In 23 evaluable patients, the majority (57%, n=13) achieved a complete remission (CR, n=10) or complete remission with incomplete recovery (CRi, n=3), meeting the predefined criteria to move to Stage 2 of the study. The study found an overall response rate (ORR, CR/CRi/PR) of 61% (n=14) and patients experienced a median overall survival of 11.2 months (N=23; 95% CI [3.0, 16.8]).  Patients that attained a CR/CRi (n=13) experienced a median duration of response of 8.5 months (95% CI [2.1, 15.9]). Additionally, 43% (n=10) of patients proceeded to allogeneic stem cell transplant (SCT).¹

Adverse events (AEs) in the study were consistent with those noted in previous alvocidib studies and included diarrhea, tumor lysis syndrome, elevated ALT and AST levels, sepsis, and hypoxia. Early deaths were noted to be due to sepsis (n=4) and mitral valve rupture (n=1), which were not considered to be related to alvocidib.¹

"Patients with relapsed and/or refractory AML have a dismal prognosis with a lack of effective available therapies, and represent a high unmet need," said Joshua F. Zeidner, MD, lead investigator of the Zella 201 study and assistant professor, Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. "The response rates and clinical activity observed in the Zella 201 study are encouraging and support further evaluation of alvocidib in combination with cytarabine and mitoxantrone in patients with relapsed or refractory MCL-1-dependent AML."

In the Stage 1 portion of the study, a total of 25 patients were enrolled, all of whom were MCL-1 dependent. To date, 23 patients have been evaluated. Based on the findings from Stage 1, Stage 2 of the study has been initiated, in which patients are randomized to receive the alvocidib, cytarabine, and mitoxantrone regimen or cytarabine and mitoxantrone alone.¹

"We are encouraged by these latest findings from the Zella 201 study, as they add to our growing understanding of the clinical activity and tolerability profile of alvocidib in patients with MCL-1-dependent AML," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals. "Completing Stage 1 of the study marks an important milestone for our company, and we look forward to learning more about the potential of alvocidib as we continue to advance Stage 2 of the study."

Additional data from Tolero's pipeline will also be presented in two poster presentations at the meeting, including preclinical findings on the activity of alvocidib and decitabine, as well as preclinical data evaluating the activity of TP-1287, an oral CDK9 inhibitor, in combination with bortezomib or venetoclax for the potential treatment of multiple myeloma.

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 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 TP-1287
TP-1287 is an investigational oral cyclin-dependent kinase 9 (CDK9) inhibitor entering into a Phase 1 study in patients with advanced solid tumors (NCT03604783). TP-1287 has shown favorable oral bioavailability in preclinical models. TP-1287 is enzymatically cleaved, yielding the parent drug, alvocidib, a potent inhibitor of CDK9. 

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 Zeidner, JF, Lin, TL, Vigil CE, et al. Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed by Cytarabine and Mitoxantrone in MCL-1 Dependent Relapsed/Refractory Acute Myeloid Leukemia (AML). In: American Society of Hematology Annual Meeting; 2018 December 1; San Diego, California; Abstract 30.
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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