Biotech Strategy Blog

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

Posts tagged ‘BTK inhibitors’

Buried amongst the intense hurly burly of a major medical meeting such as the American Society of Hematology (ASH) are the unsung preclinical researchers whose work largely makes clinical development possible. After all, few sensible companies would bet on an expensive clinical trial program, especially in combination, without first knowing whether such an approach is rational or not and has a decent shot of working efficaciously.

At stake here is the potential for building a blockbuster cancer drug niche by niche.

Venetoclax (BCL-2 inhibitor) got off to a somewhat slow start compared to say, ibrutinib (BTK inhibitor), which had a much broader initial indication and a lower risk of tumour lysis syndrome (TLS), yet it may actually have a wider application across multiple hematologic malignancies. This could well end up as one of those classic tortoise versus hare stories in the long run.

Back in 2013, we posted five interviews conducted with a range of experts including:

  • Dr Oliver Sartor (prostate cancer)
  • Dr Susan O’Brien (CLL)
  • Dr Deepak Sampath (BCL-2 and ABT-199)
  • Dr John Jenkins (then deputy director at the FDA)
  • Dr Renier Brentjens (CAR-T cell therapy)

To put this in context, consider that we just recorded 15 interviews at ASH this year alone!

As regular readers know, we like to follow people and R&D stories over time, so while in Atlanta at ASH17 we took the opportunity to move a particular story forward – we wanted to learn where Dr Sampath and his colleagues are now and also where they are headed next. This gives readers a head start on anticipating what future clinical developments might be mentioned at JPM18 by either Genentech/Roche or AbbVie.

In our latest expert interview, we pick up and continue the discussion with Deepak Sampath to find out what’s happening with venetoclax four years on… it turns out quite a lot and makes for very interesting reading indeed.

Dr Deepak Sampath (Genentech)

Curious to now more about what this scientist and his work in BCL-2 targeting is all about?  Check out this short excerpt:

 

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In our latest thought leader interview from the annual meeting of the American Society of Hematology (ASH) Dr John Leonard (Weill Cornell) provides a lesson on how to interpret key lymphoma data such as ECHELON–1, CAR T cells, and other topics at ASH, as well as what he’d like to see more of in lymphoma clinical trials.

In this hard-hitting interview, Dr Leonard reminds us that the media should not be a mere extension of the PR of companies. Instead he offers his real world insights into what may or may not be practice changing, and how we should interpret CAR T cell therapy data.

Dr John Leonard (Weill Cornell)

It’s a must read for anyone with an interest in lymphoma… here’s an excerpt to give you a flavour of the wide ranging discussion:

 

 

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ASH Exhibit HallIn recent years, there’s been a lot of progress in the treatment of chronic lymphocytic leukemia (CLL). New targeted therapies such as ibrutinib (Imbruvica) and idelalisib (Zydelig) have been approved and have helped extend the lives of patients with this disease further. However, there still remains a need for new treatment options.

Several new drugs are on the horizon for CLL.  At ASH there were a number of presentations for venetoclax, formerly known as ABT-199/GDC-0199, it’s a BCL-2 inhibitor, which is being co-developed by AbbVie and Genentech.  We’ve written extensively about it on the blog.  One of the challenges with venetoclax is the potential for Tumor Lysis Syndrome (TLS) – we heard at ASH that starting a patient on the drug needs to be carefully managed and monitored, with high risk patients hospitalized.

Other new drugs on the longer term horizon for CLL include acalabrutinib (Acerta) and BGB-3111 (BeiGene), both next generation BTK inhibitors and potential competitive threats to ibrutinib. The CLL market is becoming interesting again!

At ASH 2015, I spoke with Ian W. Flinn, MD, PhD. Director, Blood Cancer Research Program at the Sarah Cannon Research Institute in Nashville, TN. At ASH, Dr Flinn presented data for a CLL trial of venetoclax combined with obinutuzumab, a CD20 targeted monoclonal antibody; data was obtained in both the upfront and relapsed/refractory setting.

In a wide ranging conversation, we talked about some of the data of note in Orlando, what the future direction is in CLL, and what to look forward to at ASH 2016.

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It’s time to answer some more subscriber questions. Several readers wrote in and asked about the anti-PD1 checkpoint data that was presented at the recent American Society of Hematology (ASH) meeting in classic Hodgkin’s lymphoma (cHL):

What did we think of it?

Well, for starters it was one of our highlights of the ASH 2014 conference (see quick write-up, open access), with an impressive 87% response rate for nivolumab in refractory cHL. Many of these patients had failed both autologous stem cell transplant and brentuximab (Adcetris), for which FDA granted breakthrough therapy designation.

ASH14 CHECKPOINTSOverall, I agreed with Ron Levy (Stanford) when he noted in the packed Special Session on Checkpoint inhibitors in Hematology that there were only 4 or 5 abstracts to actually discuss (he didn’t spend much time on the preliminary data) and that the results are still very early without seeing how good the durability will be.

As he observed in the session, which was standing room only, figuring out how best to integrate these new agents into clinical practice with other successful approaches will be most interesting.

That said, there are some new data that have emerged since ASH that are worthy of discussion in terms of potential future directions and how they could impact the checkpoint landscape in both hematologic malignancies and even solid tumours.

This is part of our ongoing immuno-oncology series on how we can manipulate T cells in creative ways to kill the cancer cells.  The findings discussed in this article are completely new and have not been discussed here before.

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In my final post about the 2011 American Society of Hematology (ASH) annual meeting, I want to highlight a few of the 4000+ posters that appeared to attract a lot of interest.

American-Society-of-Hematology-2011-Meeting-Poster-SessionThe three ASH poster sessions in the equivalent of an aircraft hangar, had a lot of interesting science and clinical data.

All the posters had merit in order to be selected for publication, so my selection is entirely subjective:

Bruton’s Tyrosine Kinase (BTK)

Two posters on products targeting BTK attracted a lot of traffic:

#3485 Clinical Development of AVL-292; A Potent, Selective Covalent Btk Inhibitor for the treatment of B Cell malignancies 

#3688 Activity of Bruton’s Tyrosine Kinase (Btk) inhibitor PCI-32765 in Mantle Cell Lymphoma (MCL) identifies Btk as a Novel Therapeutic Target

ASH-2011-Abstract-3485-Avila-AVL-292-TBKSally Church on Pharma Strategy Blog has written an in-depth piece on Bruton’s Tyrosine Kinase Inhibitors in B-Cell Lymphomas and talks about the above two abstracts.

She also discusses the oral presentation at ASH by Dr Susan O’Brien on the phase I/II data for PCI-32765 in CLL.

Dr Anas Younes from MD Anderson Cancer Center also picked BTK as a hot lymphoma topic on his blog about the ASH meeting.  On Facebook he notes,

“There is a lot of buzz about the promising clinical results with the oral small molecule inhibitor PCI-32765, which inhibits an enzyme called Bruton kinase (BTK).”

PI3-Kinase Pathway

PI3-Kinase was another topic I noticed there was interest in, and several posters were presented at the meeting.  In particular, those on CAL-101 attracted a lot of attention, I have highlighted a couple below:

#1787 A phase I study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K∂) Inhibitor, CAL-101 (GS-1110), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

#2699 A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor, Cal‑101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Previously Treated, Indolent Non-Hodgkin Lymphoma (iNHL)

CAL-101 is an inhibitor of the PI3K delta isoform, which is thought to play a key role in lymphomas.

I overheard several people comment that the PI3K space was now becoming very crowded.

With multiple companies including Gilead, Novartis, Roche/Genentech, Sanofi-Aventis, Pfizer and Intellikine to name a few, interested in this target, it will be interesting to see how this market segment develops.

Update December 21, 2011

Little did I know how hot PI3K inhibitors were when I wrote the above with the announcement in the past 24 hours of two PI3K related deals:

  • Takeda/Millennium have acquired Intellikine. This deal shows you can still build a biotech company and make money. Congratulations to Intellikine CEO Troy Wilson.
  • Exelixis entered into a licensing deal with Merck for their PI3K-delta inhibitor (XL499) that is still in preclinical development.

Interesting contrasts in the two deals: one a total acquisition of the company, the other a licensing deal, but both highlight the potential strategic importance that companies see in having a PI3-kinase inhibitor in their pipeline.

Sally Church on Pharma Strategy Blog has written more about the Intellikine & Exelixis deals in her lymphoma update from the 2011 American Society of Hematology annual meeting.

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