SALT LAKE CITY, June 15, 2017 /PRNewswire/ -- Tolero Pharmaceuticals, Inc., a clinical-stage company developing treatments for serious hematological diseases, today announced that the Company will present preclinical data from its alvocidib program at the European Hematology Association (EHA) 22nd Annual Congress, June 22-25 in Madrid. Alvocidib is an investigational inhibitor of cyclin-dependent kinase 9 (CDK9), which is in Phase II development for the treatment of MCL-1-dependent relapsed/refractory acute myeloid leukemia (AML).
The preclinical findings elucidate alvocidib's mechanism of action in AML, support the rationale for evaluating alvocidib and 7+3 (ACD) versus 7+3 alone in newly diagnosed AML patients, and suggest it has potential utility in high-risk AML. The posters will be displayed on e-poster screens throughout the Poster Session, spanning Friday, June 23, 09:30 CEST – Saturday, June 24, 19:00 CEST.
"These additional data add to our growing body of evidence which supports the ongoing development of alvocidib for the treatment of MCL-1-dependent relapsed/refractory acute myeloid leukemia," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals. "The findings, to be presented at EHA, reinforce our understanding of alvocidib's mechanism of action in AML. Inhibition of CDK9-driven expression of MCL-1 by alvocidib thus bolsters our confidence that the alvocidib-containing regimen may be effective in patients with MCL-1-dependent AML."
Alvocidib enhances the activity of cytarabine and daunorubicin (7+3) in non-clinical models of acute myeloid leukemia
The prognosis of patients with AML remains poor, with an expected 5-year survival of approximately 25%. The standard-of-care regimen for newly diagnosed patients, cytarabine and daunorubicin (7+3 treatment), has persisted largely unchanged for more than 30 years, leaving a significant unmet clinical need for improved therapeutic options in these patients. These non-clinical data demonstrated that alvocidib treatment reduced the expression of the key survival factor, MCL-1, at the protein and mRNA levels in a time and concentration-dependent manner in AML cells. Treatment with ACD resulted in the enhanced induction of apoptosis in AML cell lines and in regressions in an AML tumor xenograft model. These findings provide a clear rationale for evaluating ACD versus 7+3 in newly diagnosed AML patients.
By an MCL-1-dependent mechanism, alvocidib potentiates the activity of cytarabine and mitoxantrone when administered in a time sequential regimen in AML
Treatment with alvocidib has shown improvements in the complete remission rates of newly diagnosed AML patients when administered before cytarabine and mitoxantrone (ACM regimen) in a randomized Phase II study compared to 7+3. Although the ability of alvocidib to inhibit CDK9-driven expression of MCL-1 is documented, the mechanism underlying the improved activity found in the ACM regimen is not fully understood. Results of this in vitro study demonstrated that alvocidib, followed by cytarabine and mitoxantrone, was more active than cytarabine and mitoxantrone alone and correlated with the downregulation of MCL-1 at the protein and mRNA levels. Further, the data suggest that MCL-1 repression is the primary mechanism of action for alvocidib, and that the ACM regimen may be effective in high-risk AML, because of this activity.
Alvocidib is an investigational agent which is a small molecule inhibitor of cyclin-dependent kinase 9 (CDK9). It is currently in development as part of combination therapy for frontline and relapsed/refractory AML. CDK9 is a protein critical to the regulation of gene expression, including the MCL-1 gene and other important genes involved in cancer. Given the potential role CDK9 de-regulation plays in expression of cancer-associated genes related to cell division and proliferation, CDK9 may be an attractive target for the treatment of various cancers.
Tolero Pharmaceuticals 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 wholly owned by 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.
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