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ASH 2013 Novel Agents in Lymphoma – notes from the road

New Orleans – 5pm on Sunday at the annual meeting of the American Society of Hematology (ASH) saw the start of the oral sessions, where the latest research and clinical trial data is presented.

I attended the novel agents in lymphoma session, and this post offers some top-line “notes from the road” on the following presentations:

Abstract 85: Idelalisib Ph2 data in patients with double (Rituximab and Alkylating Agent) refractory indolent Non-Hodgkin Lymphoma (iNHL).

Abstract 86: SAR245409 Monotherapy in relapsed/refractory Follicular Lymphoma from phase 2 ARD12130 study.

Abstract 87: Phase 2 study of BAY 80-6946 (copanlisib) in relapsed/refactory, indolent or aggressive lymphomas.

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ASCO 2012 What is the Optimal Sequencing of Advanced Prostate Cancer Drugs?

At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?

There is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.

Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?

The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.

A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.

Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.

The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.

I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy. Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.

Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.

Which posters were hot at ASH 2011?

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.

The 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

Sally 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.

Gilead acquires Calistoga and CAL-101 for $375M

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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