Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Immunotherapy

Posts tagged ‘ABT-199 Chronic Lymphoid Leukemia’

The “Hallmarks of Cancer” paper by Douglas Hanahan and Robert Weinberg is a classic, and a must read (allow plenty of time) for anyone interested in cancer drug development.

The original 2000 paper, updated in 2011, identified six hallmarks of cancer, “distinctive and complementary capabilities that enable tumour growth and metastatic dissemination:”

  • Sustaining Proliferative Signaling
  • Evading Growth Suppressors
  • Activating Invasion and Metastasis
  • Enabling Replicative Immortality
  • Inducing Angiogenesis
  • Resisting Cell Death

Apoptosis or programmed cell death according to Hanahan and Weinberg is “a natural barrier to cancer development.” One of the ways cancer cells survive is by resisting cell death and disrupting the apoptosis signaling pathway; in other words the normal signals that trigger cell death don’t get through.

Researchers have shown that apoptosis is controlled at the cellular level, in the mitochondrion, by the Bcl-2 family of regulatory proteins (BCL-2, BCL-XL). Targeting BCL-2 (a protein that prevents apoptosis) could induce cell death and be a potentially successful anti-cancer strategy.

The result of our increased understanding of cancer biology has been the development of novel targeted drugs such as ABT-199, a potent and selective BCL-2 inhibitor. This is in early clinical development by AbbVie ($ABBV), a new biopharmaceutical company spun off from Abbott Laboratores ($ABT) last week.

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I previously wrote about the potential for ABT-199 in Chronic Lymphocytic Leukemia (CLL) following Steven Elmore’s presentation at the April, 2012 annual meeting of American Association for Cancer Research (AACR).

The data presented at AACR has now been published in Nature Medicine, online ahead of print (AOP) on 6 January 2013: ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.”

Andrew Souers and colleagues from AbbVie and other institutions discuss how they re-engineered the since-discontinued navitoclax (ABT-263) to create a different and less toxic BCL-2 inhibitor. This new compound, unlike navitoclax, does not cause the thrombocytopenia associated with BCL-2-like1 (BCL-XL) inhibition.  It’s a compelling story of science-based cancer drug development.

At the December 2012 annual meeting of the American Society of Hematology (ASH) in Atlanta interim data was available from the phase 1 clinical trial of ABT-199 in Non-Hodgkin Lymphoma (abstract #304).

Matthew S. Davids, MD, Instructor in Medicine at Harvard Medical School & attending physician at the Dana Farber Cancer Institute, presented the results from the first-in-human phase 1, open-label, dose escalation, multicenter international trial in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL).

Of the 30 NHL patients enrolled, Dr Davids told the audience that 20 remained active, with a median time on study of 80 days (range 7 to 413).

ABT-199 particularly active in CLL & MCL

In 7 patients who had mantle cell lymphoma (MCL) in the 30 subject NHL trial, all seven (100%) obtained a partial remission.  A 72 year old man with stage IV MCL obtained complete clinical resolution of auxiliary node clinically and 2 x 1 cm neck nodes by day 8.

ABT-199 is also active in CLL. Dr Davids briefly shared data previously presented at the 2012 Congress of the European Hematology Association (EHA) last year.  The waterfall plot was quite impressive, unfortunately I could not obtain permission to share an iPhone photograph here.  However, by my eye, the plot appeared to show that 30 of the 37 evaluable patients had a greater than 50% reduction in nodal size!

Dr Davids shared by email some additional commentary on the potential of ABT-199 in CLL:

“ABT-199 appears to be very active in patients with relapsed refractory CLL irrespective of high risk features such as del(17p).

Given its distinct mechanism of action from the BCR pathway antagonists, it has the potential to become an important additional treatment option in the armamentarium of CLL therapies.

Whether ABT-199 will be most useful as a signal agent, in combination with chemotherapy, or in combination with other novel agents will be an important question moving forward.”

ABT-199 has an acceptable safety profile

ABT-199 related grade 3 / 4 neutropenia was experienced in 3 of the 30 NHL phase 1 trial participants (10%).  Dr Davids noted there were:

  • No discontinuations due to adverse events
  • No dose limiting toxicities observed in NHL patients
  • No evidence of dose-dependent thrombocytopenia

He concluded that ABT-199 had an acceptable safety profile and further research is ongoing in NHL, both as a single agent and in combination with bendamustine/rituximab.  The lack of severe thrombocytopenia is a definite improvement on its predecessor navitoclax.

Overall, ABT-199 is an exciting new agent in development with potential as a new treatment option for CLL & MCL.  I look forward to hearing more about it at future scientific meetings.

The New Drugs on the Horizon session at the recent annual American Association for Cancer Research (AACR) meeting in Chicago showcased several drugs that I expect we will be hearing more of in the future.  I previously wrote about AZD3514 in prostate cancer.

Another small molecule that particularly impressed me in this AACR session was ABT-199, a potent and selective inhibitor of Bcl-2. Steven Elmore from Abbott Laboratories presented impressive early data from an ongoing phase I trial in patients with chronic lymphocytic leukemia (CLL).

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The Bcl-2 (B-cell lymphoma 2) gene has a potential involvement in many cancers including melanoma, breast cancer, CLL and lung cancer.

As an example, Sally Church, PhD on Pharma Strategy Blog has written about how the Bcl-2 family protein Mcl-1 is involved BRAF resistance, and how RNA silencing of Mcl-1 enhances ABT-737 mediated apoptosis in melanoma.

Inhibition of Bcl-2 presents a particularly promising target in CLL

Anthony Letai (Dana-Farber Cancer Institute) wrote in “Blood” last year, “antagonizing function of Bcl-2 is an attractive goal in chronic lymphocytic leukemia (CLL) and other lymphoid malignancies.” (doi: 10.1182/blood-2011-08-370346)

The Bcl-2 family of proteins regulates the programmed cell death (apoptosis) that takes place in the mitochondrion. One way that cancer cells can survive is by disrupting the apoptosis signaling pathway, and thereby avoiding cell death.

Proteins that prevent apotosis (anti-anti-apoptotic proteins) include Bcl-2, Bcl-xl, Mcl-1.  Targeting Bcl-2 can therefore induce apoptosis or cell death, and has been shown to be a successful strategy to kill leukemia and lymphoma cells.

For those interested in more information, the 2009 article (full text free) by Josyln Brunelle and Anthony Letai published in the Journal of Cell Science offers considerable insight into the Control of mitochondrial apopotosis by the Bcl-2 family” (doi 10.1242/ jcs.031682).

ABT-199 is a potent & selective Bcl-2 inhibitor

Abbott & Genetech have previously targeted Bcl-2 and Bcl-xl with navitoclax (ABT-263), currently in clinical trials for CLL & NHL.

As Steven Elmore of Abbott mentioned in his AACR presentation, the problem with navitoclax is that circulating platelet survival is dependent on Bcl-xl.  When you inhibit Bcl-xl you end up with dose-dependent thrombocytopenia in patients.  This has been a dose-limiting side effect with navitoclax.

So the goal in the development of ABT-199 was to inhibit Bcl-2, which is critical for the survival of cancer cells & avoidance of apoptosis, while at the same time not inhibiting Bcl-xl which is critical for the survival of circulating platelets.

ABT-199 is a reverse engineered version of ABT-263, that has a high affinity for Bcl-2 and lower affinity for Bcl-xl.

I captured some of the AACR live-tweets about ABT-199 in the Storify below (if you can’t see the embedded information, click here to read this on Storify).

http://storify.com/3nt/aacr-2012-abt-199-bcl-2-inhibitor

ABT-199 is an exciting new Bcl-2 inhibitor with a solid scientific rationale for success in CLL and promising initial data.  From what I saw at AACR, it is definitely a compound to watch.

According to Steven Elmore, full results from the Phase 1 CLL trial with ABT-199 will be presented at the 2012 European Hematology Association (EHA) Congress held in Amsterdam from June 14 -17.

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