Biotech Strategy Blog

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

Posts tagged ‘CLL Market’

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.

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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.

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THE data of the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) that starts later this week in Chicago is expected to be the early clinical trial results for new breakthrough immunotherapies that target PD-1/PD-L1.

However, I’m also excited about the data being presented for the treatment of Chronic Lymphocytic Leukemia (CLL), a disease that kills 75,000 people a year around the world. ASCO typically does not have a strong focus on hematology and blood cancers, so it’s a reflection of the clinical significance of the data that it’s a hot topic at the meeting.

Several companies are in the race to bring promising new CLL drugs to market, and have presentations in Chicago.

Earlier this year, the FDA gave it’s new Breakthrough Designation to two CLL new products: ibrutinib, a bruton’s tyrosine kinase inhibitor from Pharmacyclics and obinutuzumab, an anti-CD20 monoclonal antibody from Roche Glycart. The breakthrough therapy designation recognizes the potential of these drugs to change the standard of care in CLL and meet unmet medical needs.

In many ways the changing CLL landscape reminds me of where prostate cancer was a few years ago just before new treatments such as enzalutamide and abiraterone came to market.

If you haven’t already done so I encourage you to watch the ASCO 2013 preview video from Sally Church (@MaverickNY) in which she highlights several of the key CLL oral presentations and posters. Update Sept 18: this video is now available on the Premium Content Video page.

A few of the CLL new products I’ll be looking out for at ASCO 2013 include:

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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 “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.

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.

ASH 2012 Annual Meeting BannerAt 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.

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