Tolero Pharmaceuticals Announces Clinical Research Collaboration with AbbVie for Acute Myeloid Leukemia Trial

SALT LAKE CITY/PRNewswire/ -- 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.1The 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.

What is VENCLEXTA® (venetoclax tablets)?

VENCLEXTA is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior treatment.

It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests for TLS. It is important to keep your appointments for blood tests. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome.

  • Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
  • Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.

Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

  • Have kidney or liver problems.
  • Have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
  • Have a history of high uric acid levels in your blood or gout.
  • Are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
  • Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA.
  • Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.

What should I avoid while taking VENCLEXTA?   

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

  • Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your healthcare provider right away if you have a fever or any signs of an infection.

The most common side effects of VENCLEXTA when used in combination with rituximab includelow white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone include low white blood cell count, diarrhea, nausea, upper respiratory tract infection, low red blood cell count, tiredness, low platelet count, muscle and joint pain, swelling of your arms, legs, hands, and feet, and cough.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

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 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 Follow @abbvie on Twitter, Facebook or LinkedIn.

VENCLEXTA™ is a trademark of AbbVie, Inc.

Tolero 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 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

Nice Insight

Nice Insight, established in 2010, is the research division of That’s Nice, A Science Agency, providing data and analysis from proprietary annual surveys, custom primary qualitative and quantitative research as well as extensive secondary research. Current annual surveys include The Nice Insight Contract Development & Manufacturing (CDMO/CMO), Survey The Nice Insight Contract Research - Preclinical and Clinical (CRO) Survey, The Nice Insight Pharmaceutical Equipment Survey, and The Nice Insight Pharmaceutical Excipients Survey.

Tolero Pharmaceuticals

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.