Biotech Strategy Blog

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

Posts tagged ‘Hematology New Products’

For many attendees, the most exciting news at the 2012 annual meeting of the American Society of Hematology (ASH) held last December in Atlanta was the prospect of personalized T cell therapy for the treatment of patients with B cell cancers such as chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).

The potential of this new treatment option was recognized at ASH 2012 by the award to Dr Bruce R. Blazar, MD and Carl H. June, MD of the Ernest Beutler Lecture and Prize for research that generated major translational advances in T-Cell Infusions.

ASH 2012: Carl June, MD receives Ernest Beutler Prize

ASH 2012: Carl June, MD receives Ernest Beutler Prize

Dr June, in his accompanying lecture discussed preliminary data for the trial of CTL019 (formerly CART-19), a novel chimeric antigen receptor-transduced T cell therapy against CD19. Subscribers to premium content can login to read more below:

In the 12 patients (10 adults CLL and 2 children with ALL) who have received CTL019, the responses have been extremely promising with a clinical response (CR+PR) seen in 9 out of the 12.

There have already been several reports in the media about this trial with many news outlets reporting that one of the children with ALL had been “cured.” That this treatment has tremendous potential is undisputed, but in my view it is a case of “hype over hope” at this stage to say that anyone has been cured in the absence of long-term follow up over at least five years.

In August 2012, Novartis announced they had formed an alliance with the University of Pennsylvania and had obtained a worldwide license to commercialize CART-19 (now CTL019). In December 2012, Novartis purchased a NJ manufacturing facility from Dendreon for $43M that will used for the production of personalized immunotherapy.

Novartis, through their recent acquisition of the Dendreon facility in NJ, are fortunate to gain access to the technology, state-of-the-art tracking system that matches the product to each patient, as well as the Good Manufacturing Practices (GMP) that were pioneered in the production of sipuleucel-T (Provenge).

In the immediate future, Novartis and U Penn have the challenge of showing that the dramatic results seen in some of the initial patients are reproducible in a larger trial and also at institutions other than Penn.

ASH 2012 Carl June Ernest Beutler Prize LectureIn his ASH lecture, Dr June noted that there are side effects and toxicities associated with CTL019 including tumor lysis syndrome (TLS), and Cytokine Release Syndrome (CRS) was seen in all patients.

This suggests it is unlikely this therapy will be used outside of the hospital setting.  In the United States, I would not be surprised to see it only used at hematology transplant centers, where there is the necessary expertise to deal with both the process and any complications that arise. Novartis may end up with a high priced therapy targeted at a small niche market.  It will be interesting to see the commercial strategy that Novartis decide to adopt.

I expect we will hear a lot more about chimeric antigen receptor technology in 2013. Personalized immunotherapy is a complex topic and one that will require significant investment in medical education by Novartis if a broader audience is the intended target. Dendreon failed miserably at launch in explaining how sipuleucel-T (Provenge) worked and did not convince large numbers of medical oncologists that their immunotherapy worked.  Even to this day, there remains considerable sceptism amongst that physician segment.

If you would like to know more about the science behind CAR therapy and it’s potential in hematology, Sally Church, PhD (who co-launched Gleevec in the US while at Novartis Oncology) will be offering insights in a monthly newsletter to be launched soon. Check out Pharma Strategy Blog for more information.

 

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).

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.

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