Biotech Strategy Blog

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

Posts tagged ‘ABT-199 CLL’

Previously, we discussed the role of new agents being developed for aggressive non-Hodgkins lymphoma (NHL) with Dr Nancy Valente of Genentech, particularly how their antibody drug conjugates (ADCs) could have a potential role to play in revolutionizing treatment for patients with an otherwise poor prognosis.

The second half of the interview from ASCO 2014 focuses on more indolent disease, namely chronic lymphocytic leukemia (CLL) and the role of their novel therapeutics obinutuzumab (Gazyva) and ABT–199/GDC–0199.

We’ve heard a lot of positive data about the anti-CD20 monoclonal antibody, obinutuzumab, but the Bcl2 inhibitor undergoing co-development with AbbVie has had a bit of a chequered history to date. There is no doubt that ABT–199/GDC-0199 is highly potent, while lacking the severe myelosuppressive effects (thrombocytopenia) of its predecessor, navitoclax — which can be both a blessing and a curse — as the phase I single agent investigators discovered recently when severe tumour lysis lead to two sudden patient deaths.

It is important to address these issues expeditiously in a safe and rational way to ensure patient safety for those who enroll in both current and future trials. This is a critical issue we discussed at length with Dr Valente and how the company has been handling it.

At the AACR Molecular Targets meeting last November, many readers will remember that we learned about Genentech’s research plans for combinations with GDC–0199 in CLL and NHL in an interview with one of the scientists for that program, Dr Deepak Sampath.

Today, it’s time to look at where and how this exciting agent might impact CLL. Obviously, both CLL and NHL have commonalties and overlap, since they are both B cell disorders, so often what works in one disease often works well in the other too, as rituximab has clearly demonstrated.

To learn more about these insights and how ABT–199/GDC–0199 could impact the future CLL landscape, you can sign in or sign up below.

New Orleans – the hematology diehards were up early yesterday for the 7.30 am oral session on some of the most interesting data at the annual meeting of the American Society of Hematology (ASH) on potential new treatments for Chronic Lymphocytic Leukemia (CLL).

Just to make sure everyone’s Fitbits were well exercised, the organizers put the session in the farthest end of the Convention center! Like many of the CLL sessions, it was a full house with multiple financial analysts sitting in the row behind me taking copious notes and pictures.  Unlike at ASCO, there is no virtual meeting, so you can’t replay any of the oral scientific sessions at a later date. If you didn’t see it, you missed it! There’s no substitute for boots on the ground.

What this post is about is my subjective opinion and top-line impressions of the information presented and some of the key strategic issues and challenges that came across listening to a full presentation of the latest data. I’m not going to rehash the press releases and the abstract data, most readers have already assimilated that.

It’s what it says — notes from the road — the kind of things I’d write in a trip report if I were in a company.

The four presentations covered in this post are:

Abstract 871: Dinaciclib (SCH 727965) Is a Novel Cyclin-Dependent Kinase (CDK) Inhibitor That Exhibits Activity In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia (CLL).

Abstract 872: Bcl-2 Inhibitor ABT-199 (GDC-0199) Monotherapy Shows Anti-Tumor Activity Including Complete Remissions In High-Risk Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL).

Abstract 873: Randomized, Phase II Dose Optimization Study Of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) In Patients With Relapsed, Refractory CLL.

Abstract 874: Phase I Trial Of Autologous CD19-Targeted CAR-Modified T Cells As Consolidation After Purine Analog-Based First-Line Therapy In Patients With Previously Untreated CLL.

Subscribers to Premium Content can read more below:

New Orleans – it is rare to see a doctor publicly hang another out to dry, let alone an investigator in a clinical trial, but that’s what appeared to happen earlier today in the CLL press briefing at the 2013 Annual Meeting of the American Society of Hematology.

ASH 2013 CLL Media BriefingReaders of this blog will recall that the phase 1 first-in-man CLL trial for ABT-199/GDC-0199 (AbbVie/Genentech), a selective bcl-2 inhibitor was suspended earlier this year after 2 patient deaths due to Tumor Lysis Syndrome.  It was shocking to many to hear that a 56 year old man on the trial dropped dead in his bathroom having been dose escalated straight from 150mg to 1200 mg of this highly potent drug.

In response to my question today at the ASH media briefing about the protocol that allowed such an aggressive dose escalation, Professor John F. Seymour, Chair of the Department of Hematology at the Peter MacCullum Cancer Center in Melbourne, Australia told the assembled media:

“There was certainly protocol specified monitoring requirements at 8, 12 and 24 hours after each dose escalation. The circumstances where the death occurred there was not vigilance around the monitoring of those results, nor action around some of those changes. So I think it was a combination of circumstances of previously unrecognized risk at a dose escalation step and inattention to some of the protocol required monitoring criteria.”

I was surprised by the above response, given that my question must have been anticipated by AbbVie, and presumably Prof Seymour was media briefed beforehand given the AbbVie “media minder” was in the press room.

The answer also raises the question of whether the trial was adequately monitored by AbbVie. All clinical trials conducted under an IND have to be monitored by clinical research associates (CRAs) employed by the trials sponsor or a Contract Research Organization (CRO) acting on their behalf.  Their job it is to ensure a site follows the protocol and that everything is conducted according to good clinical practice (GCP) standards.  Did AbbVie trial monitors review the monitoring requirements with the site, and follow-up to ensure these were complied with?

In addition to the ABT-199 single agent first in man CLL dose escalation death, Professor Seymour told the media about another ABT-199 death:

“There is another currently accruing study of combination of ABT-199 + Rituxmab and there was one death on that trial also.”

This has not previously been reported.

You can listen to Professor Seymour’s complete answer to my question in this SoundCloud:

After the press briefing, the AbbVie Program Director for ABT-199 sought to justify the dose escalation clinical trial strategy arguing that although they had seen tumor lysis syndrome in initial doses, they were not aware it could be a problem on subsequent doses, and that having dose escalated from 150mg to 800mg without problem, this justified a dose escalation from 150mg to 1200mg.  I leave it to readers with more experience in hematology to judge the merits of this approach.

As Professor Seymour noted, all the IRB and ethics committees in the trial did approve the study protocol, which raises questions about how effective these are at judging the merits and risks of first-in-man trials with novel agents or whether they are just a rubber stamp.

ABT-199 is an exciting drug with a lot of promise, but the AbbVie handling of the tumor lysis syndrome deaths remains a PR failure in my book.

Not only that, but what I think was an overly aggressive clinical trial strategy, irrespective of who designed it and signed off on it, cost the company several months of time in a highly competitive market when they had to suspend recruitment.

I have no idea whether AbbVie have sought FDA Breakthrough Therapy designation, but it’s hard to believe the FDA would consider granting it to ABT-199 in CLL while there are patient deaths and concerns remain about tumor lysis syndrome.

Professor Seymour will be presenting updated results for ABT-199 in CLL on Tuesday at ASH (Abstract 872).

Update December 14, 2013

Prof Seymour presents ABT-199 CLL data at ASH 2013Premium Content Subscribers can read about::

1) the ABT-199 phase 1 CLL results presented at ASH 2013 by Professor Seymour and the modified clinical trial design put in place when the trial resumed in June 2013: ASH 2013 Novel Treatments for CLL.

2) a new target for ABT-199 for which there is a strong preclinical rational: ASH 2013 BH3 profiling identifies new targets for Bcl-2 inhibitors.

3) the future potential of ABT-199 in combination with obinutuzumab (Gazyva) that was discussed in an interview with Deepak Sampath from Genentech that took place at the AACR-NCI-EORTC Molecular Targets meeting in Boston: Gazyva and ABT-199 in CLL and NHL, an interview with Genentech’s Deepak Sampath.

Update Jan 3rd, 2014: Study CRA says protocol violations and non-compliance were known and ignored by CRO & AbbVie

I was shocked to receive today a comment that you can read below by the former Clinical Research Associate (CRA) for the ABT-199 CLL first-in-man study who says the sponsor (AbbVie) and Clinical Research Organization responsible for study management both ignored protocol violations at the site where a patient subsequently died due to tumor lysis syndrome.

If protocol non-compliance was known to the CRO & Sponsor it’s hard to understand why those concerns were not acted upon and whether the patient death that occurred might have been avoided if they had been addressed or the site discontinued.

Given the public interest in ensuring that anyone participating in a clinical trial can be assured the protocol will be followed, and that trials will be run in accordance with good clinical practice (GCP) & Federal Regulations, I contacted AbbVie and Genentech (who are co-developing ABT-199/GDC-0199) for a response to the allegations made, which if true are quite shocking.

Greg Miley, AbbVie Vice President of Commercial & Health Communications did not respond to a voicemail left. Genentech Product Public Relations responded to an email sent to a company spokesperson by saying they would look into this. I will update the post when a corporate response is received.

Update Jan 6th, 2014: Genentech & AbbVie Response

This evening I received an email from David Freundel, Director of Public Relations for AbbVie, who offered the following reply on behalf of Genentech and AbbVie:

“Patient safety is a priority for both companies, and we take the conduct and management of clinical trials extremely seriously. We are reviewing the details raised in the recent post.”

14 Comments

New Orleans – Saturday at the annual meeting of the American Society of Hematology (ASH) is mainly focused on education and science, although there are also several hundred posters available for those in need of a data injection.

What I like about the ASH education and scientific program is the high quality of the presentations from thought leaders who not only share where things are at, but just as importantly, where they may be going.

Yesterday, I attended a scientific session on Targeting Apoptosis in Lymphoid Malignancies. Organized by the Scientific Committee on Lymphoid Neoplasia, it featured three world-class speakers:

  • Douglas Green, PhD (St Jude Children’s Research Hospital)
  • Andreas Strasser, PhD (Walter and Eliza Hall Institute of Medical Research)
  • Anthony Letai, MD, PhD (Dana Farber Cancer Institute).

Regular readers of this blog will know that I have been following the development of ABT-199/GDC-0199 a novel Bcl-2 inhibitor in development by Abbvie & Genentech for a while now.

It’s a drug with a lot of promise, notwithstanding the tumor lysis syndrome (TLS) deaths seen in the phase 1 CLL dose escalation trial.

In the ASH 2013 scientific session, Dr Letai shared his insights on potential new drug development targets for a small molecule inhibitor of Bcl-2 such as ABT-199 that have come about as a result of BH3 profiling.

Subscribers to premium content can read more below.

Earlier this month, Janssen/Pharmacyclics announced they had submitted a New Drug Application (NDA) for Food & Drug Administration (FDA) approval of ibrutinib, an oral Bruton’s tyrosine kinase inhibitor (BTK) in chronic lymphocytic leukemia (CLL) for the treatment of patients with a deletion of the short arm of chromosome 17 (del17p). Here’s a link to July 10 press release.

The company have requested Priority review; approval later this year or in early 2014 is highly likely given that the agent has also been designated a Breakthrough Therapy by the FDA.

This is great news for CLL patients!

CLL is an incurable disease. It is the most common leukemia in the United States with 15,500 new diagnoses a year.

Chromosomal abnormalities are fairly common in CLL and predict both time to first treatment and overall survival i.e. how long someone will live. Sadly, those with a 17p deletion have the worst outcome and a poor prognosis.

Subscribers can login to read more or you can purchase access by clicking on the blue icon at the end of the post.

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 – 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.

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 “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.

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).

error: Content is protected !!