Companies to collaborate on clinical trial evaluating the potential benefits of venetoclax and alvocidib combination in relapsed/refractory AML
SALT LAKE CITY, UT, USA I August 17, 2018 I Tolero Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company focused on developing treatments for hematologic and oncologic diseases, has entered into a clinical research collaboration with AbbVie, a research-based global biopharmaceutical company, exploring the potential of combination therapy with AbbVie’s venetoclax and Tolero’s investigational agent, alvocidib, for the treatment of relapsed/refractory acute myeloid leukemia (AML).
Alvocidib is a small molecule inhibitor of cyclin-dependent kinase 9 (CDK9), which controls the expression of a survival factor, MCL-1. Venetoclax is a small molecule inhibitor of B-cell lymphoma-2 (BCL-2). Both MCL-1 and BCL-2 are key proteins used by certain cancer cells to avoid apoptosis, and non-clinical studies have shown that cancer cells can resist inhibition of BCL-2 by using MCL-1 to avoid cell death. Alvocidib is currently in Phase II development for the treatment of MCL-1-dependent AML.
“We are very pleased to announce our clinical research collaboration with AbbVie, as it marks an important step in the development of this novel agent for patients with relapsed/refractory AML,” said David J. Bearss, Ph.D., Chief Executive Officer of Tolero. “Preclinical data suggest that the mechanisms of action for venetoclax and alvocidib may synergistically drive apoptosis in cancer cells. We hope to further investigate this hypothesis with our planned trial of this combination therapy in patients with relapsed/refractory AML.”
“This is a unique opportunity to bring together and investigate two first and only in class compounds to help patients with AML,” said Neil Gallagher M.D., Ph.D, Vice President, Head of Global Oncology Development, AbbVie. “There is an urgent need for new therapies, particularly in patients who either did not respond well to initial therapy or who subsequently relapsed. AML is a complex disease at the cellular level. Therefore, combining alvocidib with venetoclax, which have distinct but potentially complementary mechanisms for targeting the leukemia cells, makes a lot of sense from a scientific perspective.”
Under the terms of the agreement, Tolero and AbbVie will equally share all development expenses. Tolero will retain full commercial rights for alvocidib and AbbVie will retain full commercial rights for venetoclax.
About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a rapidly progressing cancer that is most common in the elderly.1 The disease forms in the bone marrow and impairs the normal function of the bone marrow to make healthy blood cells. Following an intensive regimen of chemotherapy treatment, a large portion of patients experience a relapse or have residual (or refractory) leukemic cells in their marrow. Patients with AML have a poor prognosis and those with relapsed or refractory disease currently have limited treatment options.
About Venetoclax
VENETOCLAX is an oral B-cell lymphoma-2 (BCL-2) inhibitor that targets a specific protein in the body called BCL-2.2 When you have CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally.2 VENCLEXTA™/VENCLYXTO™ targets BCL-2 in order to help restore the process of apoptosis.2 Through apoptosis, your body allows cancer cells and normal cells to self-destruct.2
VENETOCLAX is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in clinical trials in several hematologic cancers.
VENETOCLAX is currently approved in more than 50 nations, including the U.S., and in the EU. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.
About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in Zella 201, a Phase II study 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).
About CDK9 Inhibition and MCL-1
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.3 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.4 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.3,5 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).6,7 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.6 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.3
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 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 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.
About AbbVie
AbbVie is a global, research-driven biopharmaceutical company committed to developing innovative advanced therapies for some of the world’s most complex and critical conditions. The company’s mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn.
1 Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leukemia Research Reports. 2016;6:1-7. doi:10.1016/j.lrr.2016.06.001.
2 Venclexta (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
3 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.
4 Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29.
5 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.
6 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.
7 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
Post Views: 21
Companies to collaborate on clinical trial evaluating the potential benefits of venetoclax and alvocidib combination in relapsed/refractory AML
SALT LAKE CITY, UT, USA I August 17, 2018 I Tolero Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company focused on developing treatments for hematologic and oncologic diseases, has entered into a clinical research collaboration with AbbVie, a research-based global biopharmaceutical company, exploring the potential of combination therapy with AbbVie’s venetoclax and Tolero’s investigational agent, alvocidib, for the treatment of relapsed/refractory acute myeloid leukemia (AML).
Alvocidib is a small molecule inhibitor of cyclin-dependent kinase 9 (CDK9), which controls the expression of a survival factor, MCL-1. Venetoclax is a small molecule inhibitor of B-cell lymphoma-2 (BCL-2). Both MCL-1 and BCL-2 are key proteins used by certain cancer cells to avoid apoptosis, and non-clinical studies have shown that cancer cells can resist inhibition of BCL-2 by using MCL-1 to avoid cell death. Alvocidib is currently in Phase II development for the treatment of MCL-1-dependent AML.
“We are very pleased to announce our clinical research collaboration with AbbVie, as it marks an important step in the development of this novel agent for patients with relapsed/refractory AML,” said David J. Bearss, Ph.D., Chief Executive Officer of Tolero. “Preclinical data suggest that the mechanisms of action for venetoclax and alvocidib may synergistically drive apoptosis in cancer cells. We hope to further investigate this hypothesis with our planned trial of this combination therapy in patients with relapsed/refractory AML.”
“This is a unique opportunity to bring together and investigate two first and only in class compounds to help patients with AML,” said Neil Gallagher M.D., Ph.D, Vice President, Head of Global Oncology Development, AbbVie. “There is an urgent need for new therapies, particularly in patients who either did not respond well to initial therapy or who subsequently relapsed. AML is a complex disease at the cellular level. Therefore, combining alvocidib with venetoclax, which have distinct but potentially complementary mechanisms for targeting the leukemia cells, makes a lot of sense from a scientific perspective.”
Under the terms of the agreement, Tolero and AbbVie will equally share all development expenses. Tolero will retain full commercial rights for alvocidib and AbbVie will retain full commercial rights for venetoclax.
About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a rapidly progressing cancer that is most common in the elderly.1 The disease forms in the bone marrow and impairs the normal function of the bone marrow to make healthy blood cells. Following an intensive regimen of chemotherapy treatment, a large portion of patients experience a relapse or have residual (or refractory) leukemic cells in their marrow. Patients with AML have a poor prognosis and those with relapsed or refractory disease currently have limited treatment options.
About Venetoclax
VENETOCLAX is an oral B-cell lymphoma-2 (BCL-2) inhibitor that targets a specific protein in the body called BCL-2.2 When you have CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally.2 VENCLEXTA™/VENCLYXTO™ targets BCL-2 in order to help restore the process of apoptosis.2 Through apoptosis, your body allows cancer cells and normal cells to self-destruct.2
VENETOCLAX is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in clinical trials in several hematologic cancers.
VENETOCLAX is currently approved in more than 50 nations, including the U.S., and in the EU. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.
About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in Zella 201, a Phase II study 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).
About CDK9 Inhibition and MCL-1
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.3 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.4 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.3,5 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).6,7 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.6 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.3
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 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 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.
About AbbVie
AbbVie is a global, research-driven biopharmaceutical company committed to developing innovative advanced therapies for some of the world’s most complex and critical conditions. The company’s mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn.
1 Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leukemia Research Reports. 2016;6:1-7. doi:10.1016/j.lrr.2016.06.001.
2 Venclexta (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
3 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.
4 Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29.
5 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.
6 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.
7 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
Post Views: 21
