Biotech Strategy Blog

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

Posts tagged ‘PI3K’

We hope that everyone had a relaxing holiday break and now it’s time to get back to work.  Tomorrow I will review some more of my thoughts in the immuno-oncology space, since that area had a tremendous amount of progress in San Diego with lots of new ideas to process and summarise.

In the meantime, a few people have written in and asked about what was happening with overcoming resistance in various tumour types, was there anything new to say in that space that was in addition to the the detailed previews we covered before the conference?

Actually, there was a quite a few posters and presentations that caught my eye, so I thought this would be a good idea to review them here:

Lung Cancer: HER2, VEGF, T790M, EGFR, erlotinib, gefitinib, trastuzumab, bevacizumab, CO-1686, AZD9291

Prostate Cancer: mTOR, PI3K, Androgen Receptor, enzalutamide, abiraterone, CC214–2, ARN–509, BET Bromodomian inhibition, ODM–201, GDC–0980, GDC-0068, PF–04691502, BKM120, BEZ235

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“You may say I’m a dreamer

But I’m not the only one.”

John Lennon, Imagine

As part of our ongoing series on the AACR Previews, today I want to take a closer look at some interesting scientific and clinical data in triple negative breast cancer (TNBC).  One reason for this is that we need to remember that the disease, as currently defined, is essentially what’s left after taking out the ER+, HER2+ and inflammatory breast cancer subsets. In other words, it’s a very heterogeneous catch-all population, making clinical trials rather challenging at best. It also means that the chances of success in general all-comer trials is rather low.

It is my hope that as we learn more about the biology of this disease, we may see further subsets be defined by molecular peculiarities, much in the same way that gastrointestinal stromal tumours (GIST) were defined by KIT expression and CD117. Once we have more homogenous subsets, it will be easier to conduct trials just looking at those specific patients, thereby improving the chances of clinical success with therapeutic intervention.

There’s been a lot of work focused on this area over the last few years, so it seems a good point to find out where the progress has got to.

Without much further ado, what can we learn about the biology of TNBC from AACR this year and which potential new targets might emerge?

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Following on from yesterday’s post on the potential for small basket trials in ER+ breast cancer with the ESR1 mutation, I wanted to highlight another area where these type of highly focused and rational studies appear to be not only useful but also potentially produce stunning responses.

Some of you will recall the fascinating and widely told story of a single bladder cancer patient at Memorial Sloan Kettering who was resistant to multiple lines of therapies. The team sequenced the genome and found a rare TSC1 mutation. Importantly, this is known from pediatric astrocytoma studies, to be sensitive to an mTOR inhibitor, everolimus (Afinitor). The refractory patient was given the drug and responded well. The rest is history, as they say.

Can we learn more from these type of appraches, i.e. genomic sequencing of patients who have relapsed after initial therapy?

Can we also learn more from the few exceptional responders in clinical trials – what was unique about their response that elicited such a stunning effect?

The short answer is a resounding yes.

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Boston: Fallowing on from yesterday’s post about learnings from the AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.

We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?

Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.

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Genentech’s next generation PI3-kinase inhibitor, GDC-0032, was the topic of two presentations yesterday at the 2013 annual meeting of the American Association for Cancer Research (AACR) taking place in Washington D.C.

Genentech have put substantial resources into developing new agents that target different elements of the PI3K pathway.  These include: GDC-0941, GDC-0980, GDC-0084, GDC-0349, GDC-0068.  At this year’s AACR, data on their latest compound, GDC-0032, was presented. This agent is a selective inhibitor of PI3K alpha, delta and gamma but spares inhibition of the PI3K-beta isoform.

In the New Drugs on the Horizon session, Alan Olivero from Genentech gave a fascinating talk (if you are a medicinal chemist) on how the chemical structure of GDC-0032 was rationally developed. He described how a slight change in structure can lead to a very different selectivity profile.

One way in which GDC-0032 is novel, is that it spares the beta-isoform of PI3K, which Genentech hypothesize may reduce some of the undesired side effects such as effects on metabolism, previously seen with pan PI3K inhibitors such as GDC-0941.

Olivero noted that GDC-0032 has greater maximal efficacy and more potency than GDC-0941 in PI3K alpha mutant xenograft tumors as compared to wild-type ones.

The results of a first-in-human phase 1a dose escalation study for GDC-0032 were presented at AACR 2013 in yesterday’s Clinical Trial Symposium (Abstract LB-64).

Dejan Juric MD (Massachusetts General Hospital) presented promising early clinical data for GDC-0032 in PI3KCA mutant cancers, especially breast cancer.

The results showed that in PI3KCA mutant breast cancer there were 4 cPR (RECIST -30 to -70%) and 2 SD out of 6 patients, all of whom had measurable disease with pre-treatment.  

One confirmed partial response in PI3KCA mutant breast cancer took place after 11 lines of prior therapy in a 74 year old woman with HER2- breast cancer, who subsequently became triple negative.  Another patient with a confirmed partial response had HER2+ ER+ metastatic breast cancer.

While this early data is promising, further clinical trials are needed to validate it.  Dr Juric concluded his presentation by noting that,

“GDC-0032 is being further explored as a single-agent in solid tumors and in combination with endocrine therapies in breast cancer including letrozole and fulvestrant.”

If you are interested in GDC-0032, then other presentations at AACR this week to watch out for are:

Abstract 2382 (Tuesday Apr 9, 8-12 am Poster Section 2, Board 2) Development of predictive biomarker gene expression signatures that associates with drug sensitivity and kinase activation in breast cancer.

Abstract 4470 (Tuesday Apr 9, 1-5 pm Poster Section 41, Board 28) Mechanisms of acquired resistance to the PI3K inhibitors in colorectal cancer cell lines.

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.

In an acquisition that highlights the importance of cancer and inflammation, Gilead Sciences today announced the acquisition of Seattle based Calistoga Pharmaceuticals for $375M.

Calistoga’s pipeline is focused on the development of PI3 kinase inhibitors for cancer and inflammation. Sally Church on Pharma Strategy Blog has written extensively about “The potential of the PI3K pathway inhibitors in lung cancer”, and discussed Calistoga’s CAL-101 compound and its development for hematological malignancies in her report on “What’s hot at ASH in 2010”.

I encourage you to read (if you already don’t) Sally’s excellent Pharma Strategy Blog for further information on the science and mechanism of action of the PI3K pathway (way beyond my pay grade) and her view on CAL-101’s potential.

Sally will also be at the timely AACR meeting on targeting PI3K/mTOR signaling in cancer that is being held in San Francisco later this week.

What makes CAL-101 interesting to me is its potential in targeting inflammatory mediators. CAL-101 is a first in class PI3K delta specific inhibitor; the delta isoform of phosphoinositide-3 kinase (PI3K) is expressed in leukocytes involved with a variety of inflammatory, autoimmune and hematological cancers. Increasingly I think we will see companies investigating the cross-talk between inflammation and other diseases.

In addition to the upfront payment of $375M, there are potential milestone payments of $225M.  The deal is set to close in the second quarter of 2011.

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