Biotech Strategy Blog

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

Posts tagged ‘ABT-199’

It’s exciting times in Chronic Lymphocytic Leukemia (CLL) with a lot of new data in expected at the forthcoming 2013 annual meeting of the American Society of Hematology (#ASH13) in New Orleans.  Several products have received Breakthrough Therapy status from the FDA.

At ASCO 2013, Sally Church (@MaverickNY) interviewed Dr Susan O’Brien who is the Ashbel Smith Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center and someone who is making a difference to the lives of CLL patients.

This video was originally published on Pharma Strategy Blog. It’s long (17minutes – and took a whole weekend to edit in FCP X!) but Dr O’Brien covers a lot of points e.g. IPI-145, what effect does the gamma isoform have in CLL? On ABT-199 she discusses the Tumor Lysis Syndrome seen. Other products discussed include ibrutinib, idelalisib, AV-292 and obinutuzumab.

It’s well worth watching again in the run up to ASH 2013. Subscribers to Premium Content can login in below to view it.

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

This content is restricted to subscribers

Following a death due to tumor lysis syndrome, AbbVie ($ABBV) have suspended the ABT-199 clinical trial program.  ABT-199 is a promising new drug in development for chronic lymphocytic leukemia (CLL) that was about to enter phase 3 drug development by the company.

The company has issued no press release, but the clinicaltrials.gov web site shows that that clinical trials are suspended, information confirmed at the BIO CEO 2013 meeting in New York earlier this week. Here’s a quick snapshot taken on Feb 14, 2013 of what the clinicaltrials.gov site shows:

Clinicaltrials.gov snapshot Feb 14, 2013

I first wrote about ABT-199 last year at the 2012 AACR annual meeting where Steven Elmore from Abbott (the predecessor of AbbVie) presented data showing it to be a new Bcl-2 inhibitor that overcame the side effects seen with navitoclax (ABT-263), which led to dose-dependent thrombocytopenia.

At the 2012 annual meeting of the American Society of Hematology in December, Matthew Davids, MD presented the results from the first-in-human phase 1 multicenter trial in patients with relapsed or refractory CLL and non-Hodgkin lymphoma (NHL).

Dr Davids declined to offer any comment on the suspension of the ABT-199 clinical trial program. By email he wrote, “I’m not able to discuss any data from the ABT-199 study that has not yet been publically presented.” 

I thought this was a rather weak response given the fact the trial suspension is public knowledge. There’s more to being a thought leader than just being a company trial spokesperson who presents company prepared slides at scientific meetings.

It was also disappointing given the expertise at the Dana Farber Cancer Institute with BCL-2 antagonists, as evidenced by a recent publication on ABT-199 in the journal Cell by Dr Davids and Dr Letai earlier this week.  Dr Letai previously wrote in the journal “Blood” that the “antagonizing function of Bcl-2 is an attractive goal in chronic lymphocytic leukemia (CLL) and other lymphoid malignancies.”

According to a reliable source, the ABT-199 clinical trial program has been suspended due to the trial participant dying from tumor lysis syndrome.

Tumor lysis syndrome (TLS) is a life-threatening cancer treatment complication where large number of cells die and deposit their contents into the blood stream. The kidneys and liver are overwhelmed trying to process and excrete the dumped intracellular contents.  Acute renal failure may result.  TLS is most common in fast growing cancers such as acute leukemias and less common in indolent disease such as lymphomas and CLL.

This last factor makes the issue for AbbVie and those medically supervising the trial more challenging in deciding whether the event was a one-off fluke or whether the TLS was drug related i.e. there is something in the way ABT-199 acts that poses a risk of TLS in the same way navitoclax caused dose-dependent thrombocytopenia.  It could be related to dose-scheduling, for example, or the compound structure itself.

A patient death is something to be taken seriously, particularly in early stage development. Far better to find out you have a problem soon before spending multi-million dollars on a phase 3 drug development trial as AbbVie were poised to do.

Hematology industry expert Sally Church, PhD who writes Pharma Strategy Blog tells me that she thinks the ABT-199 clinical trials program will re-start, and sees this as a temporary setback once the dose-scheduling has been modified.  Her view is that:

“There are risks associated with any new drug in development largely because so much is unknown.  We don’t know what dose the patient was taking or for how long, but it’s possible that the agent is very effective and caused a much more rapid effect than expected at a high dose.  They may need to be more cautious about the dosing going forward.”

ABT-199 if it makes it to market will compete against other promising new compounds in development for CLL such as ibrutinib, which received breakthrough designation from the FDA earlier this week.

Update Feb 15, 2013 AbbVie says they expect ABT-199 trials to continue but advise there are 2 patient deaths!

Thanks to Derek Lowe on “In the Pipeline” for picking up on the ABT-199 story this morning and for providing additional commentary and insight on tumor lysis syndrome.

His updated post this afternoon now includes a response from AbbVie, in which the company spokesperson confirms the voluntary suspension of the trials, that the problem is indeed tumor lysis syndrome and they expect dose escalation to control it.

They go on to say in their email that “we have every expectation that the clinical trials will come off hold and that we will be able to initiate Phase 3 trials as planned.”  I encourage you to read Derek’s post if you have not already done so.

Fierce Biotech in their updated piece report that AbbVie have confirmed there are in fact 2 patient deaths.

The fact there are 2 patient deaths from tumor lysis syndrome (I was only aware of one when I wrote this piece) now raises the question of whether the cause of this may indeed be related to the chemical structure of ABT-199. It’s clearly a serious matter that will at the very least delay AbbVie’s phase 3 drug development program for ABT-199.

Update Feb 18, 2013 Tumor Lysis Syndrome explained

Sally Church, PhD has published a post on Pharma Strategy Blog that is well worth reading: “Tumor Lysis Syndrome – what it is and why it is important in cancer research.”

In addition to commenting on ABT-199, Church discusses the potential for delayed Tumor lysis syndrome (TLS) seen with CTL019, the novel Novartis chimeric antigen receptor therapy (CART) in early stage development.

Update May 29, 2013 Clinical data on ABT-199 at ASCO 2013

In my pre-ASCO 2013 post on Chronic Lymphocytic Leukemia (CLL) that I published on May 28, 2013, I included commentary on ABT-199. Here’s the relevant excerpt:

At ASCO 2013 there will be updated phase 1 results for ABT-199 (GDC-0199) in CLL, and the main topic of discussion will be two clinical trial deaths that occurred due to tumor lysis syndrome.

At the recent 2013 AACR annual meeting, Rod Humerickhouse, MD, PhD from AbbVie Global Pharma R&D, said the company plans to start an ABT-199 phase 2 single agent study and a phase 3 combination study in CLL later in 2013/early 2014.

He told the AACR audience that Tumor Lysis Syndrome (TLS) adverse events occurred in 9 out of the 74 patients enrolled in three ABT-199 CLL clinical trials.

Two CLL trial participants died from TLS, and one had acute renal failure.

Notwithstanding the early promise of ABT-199 that I wrote about from the AACR 2012 and ASH 2012 annual meetings, these deaths have in my mind placed a substantial question mark over the safety of ABT-199, especially if other less-toxic therapies are available by the time it potentially comes to market. TLS is a sign of a highly effective drug, but whether dose modification can make it safe while maintaining efficacy remains to be seen. We don’t yet have the data to show this, and even assuming this data is forthcoming at the very least the development of ABT-199 has been set back in terms of time to market.

Whether the tragic deaths should have been avoided we may never know, there remain unanswered questions as to whether the dose escalation was too aggressive, whether the risk of TLS was known, and if so whether patients were properly monitored.

Relatives of both patients who died have sent in comments to the blog, highlighting the personal tragedy of losing a father or husband in this way. I can appreciate that after 33 years of marriage suddenly losing a husband at age 56 is pretty devastating, especially when the AbbVie company response appears to have fallen short in compassion and empathy:

“All I got was a quick phone call, after I left a message that he dropped dead in my bathroom, to thank me for letting them know of his passing and a condolence card.”

Although the development of ABT-199 looks set to continue, in my view it is no longer a front runner in the race to market in CLL. You can read more about the companies in the race to market in CLL in my pre-ASCO 2013 post.

 

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).

This content is restricted to subscribers

Bcl-2 is a signaling pathway for the regulation of apoptosis

Bcl-2 is part of the signaling pathway for apoptosis Image Source: WikiCommons Author: Cybertory

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.

Free Email Updates
Subscribe to new post alerts, offers, and additional content!
We respect your privacy and do not sell emails. Unsubscribe at any time.
error: Content is protected !!