Biotech Strategy Blog

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

Posts from the ‘Inflammation’ category

T cell activation has been very much to the fore over the last couple of years with many companies looking at different ways to use them against cancer cells, with chimeric antigen receptor (CAR) T cell therapy, vaccines or monoclonal antibodies. There are situations though, where T cells are not necessarily a good thing.

Graft versus Host disease (GvHD) is an area of tremendous unmet medical need that is triggering the interest of a number of biotech and rare disease companies such as Alexion Pharmaceuticals (ALXN).

Houston based Bellicum Pharmaceuticals (BLCM), whose IPO raised around $140M last month, have said they plan to spend most of the funds on bringing to market a new cell therapy that could make stem cell transplants more effective and reduce GvHD. They also have a CAR-T therapy in early development.

Indeed, at last month’s ASH 2014 annual meeting in San Francisco, GvHD was very much a hot topic, with data presented in the plenary session by Dr Wei Li (pictured below) on a novel biomarker for GI GvHD.

Dr Wei Li ASH 2014 GvHD Plenary

This post discusses one of the GvHD oral sessions at ASH 2014, and includes post-presentation commentary from Dr Marcel van den Brink, who is an expert in the area. The related interview Dr Brink kindly gave BSB at the SITC annual meeting is well worth reading if you missed it.

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A scientific meeting that I would have liked to have attended and one where I think attendees will obtain a lot of insight into the future of prostate cancer research is the forthcoming American Association for Cancer Research (AACR) Advances in Prostate Cancer Research meeting.

AACR Advances in Prostate Cancer Research Meeting 2012Chaired by Charles Sawyers (MSKCC) and Arul Chinnayan (Michigan) it has an impressive line-up of speakers and sessions.  The meeting takes place next week (Feb 6-9) in Orlando.

There are two presentations on cabozantib (XL184) that may offer new insights into the mechanism of action of the drug and its potential:

Cabozantinib (XL-184) and prostate cancer: Preclinical and clinical profile of a novel agent

Maha Hussain, University of Michigan Medical School, Ann Arbor, MI

Cabozantinib (XL184) inhibits androgen-sensitive and castration-resistant prostate cancer in the bone and increases bone formation in non-tumored bones
Eva Corey, University of Washington, Seattle, WA

A few of the presentations at the meeting that caught my attention include:

  • Role of inflammation (William Nelson)
  • Influence of tumor microenvironment on progression and resistance (Christopher Logothetis),
  • Novel therapeutic targets in prostate cancer (Arul Chinnaiyan)
  • Overcoming castration-resistant prostate cancer 
(Charles Sawyers)

If you have in an interest in prostate cancer research, February 6-9 in Orlando is the place to be.

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The Oncologist Journal of the Society for Translational Oncology (STO) has published a video recording on prostate cancer that is well worth watching for those with an interest in this area.

At their Sept 8, 2011 CME symposium held in Belfast, a roundtable was held entitled “Prostate Cancer: Progress & Promise.”

Moderated by Bruce A. Chabner (Mass General/Harvard), the panelists were Joe O’Sullivan (Queen’s University, Belfast), Johann De Bono (The Institute for Cancer Research) and David Waugh (Queen’s University, Belfast).

Professor de Bono in the video comments that”

“with regards to our dream of eventually treating men with prostate cancer without castrating them, which must be our ultimate goal and curing them of cancer. I think we will have to focus on for example drugs targeting ERG or ERG signaling.”

Chabner then asks the good question of whether ERG is a druggable target?

To which De Bono replies that you can drug ERG by inhibiting PARP and references a paper by the Chinnaiyan group published in the May 2011 issue of Cancer Cell.

PARP inhibition represents an interesting area of prostate cancer research.

If you would like to know more, Sally Church, PhD has written about this on Pharma Strategy Blog.  See posts on “TMPRSS2: ERG may be a more useful marker than PSA in prostate cancer” and “Personalized Therapy for Prostate Cancer – is it possible?

In the STO video, De Bono discusses why he would like to replace bone scans in prostate cancer with another imaging modality that more accurately reflects the activity of the disease. Future possibilities include use of diffusion weighted magnetic resonance imaging and novel PET tracers.

There’s also a good discussion about Alpharadin for those interested in some anecdotal commentary on experiences with it.

Another notable comment by De Bono is his belief that “taxanes work in prostate cancer primarily by targeting androgen receptor signaling.” Taxanes have typically been thought to target mitosis.

De Bono goes on to say that clinical trial data being submitted for publication shows that patients who are refractory to abiraterone, are also refractory to docetaxel when they progress on it.  The suggestion is that there may be cross resistance between abiraterone and taxanes with a subgroup of patients who just don’t do well on androgen receptor (AR) targeting drugs.  The reason for this isn’t yet clear.

A new phase 2 clinical trial is starting soon that will look at the sequencing of abiraterone and cabazitaxel.  One group will receive abiraterone followed by cabazitaxel, the other cabazitaxel followed by abiraterone.

The Belfast STO symposium was the second in a three part series. The next one will be held during ASCO GU in San Francisco next year.

Another potentially useful meeting in this area is the February 2012 AACR workshop on “Advances in Prostate Cancer Research” chaired by Arul Chinnaiyan & Charles Sawyers.

Prostate cancer remains an exciting therapeutic area to watch with tremendous progress and promise of late.

Biotech Strategy Blog is 1 today!  I can’t believe that a year has gone by so quickly!  Before moving on to year 2, I thought a brief review might be interesting.

What have been the top posts on Biotech Strategy Blog this past year?

In terms of total visitors per post:

  1. Results from NEJM Lucentis v Avastin AMD CATT clinical trial
  2. AUA Results from PIVOT study show no benefit from radical prostatectomy in low risk early stage patients
  3. ASCO 2011 Cabozantinib (XL184) may be an exciting new prostate cancer drug
  4. Merck’s capthepsin-K inhibitor odanacatib in osteoporosis
  5. Update from AACR on new prostate cancer drugs to watch

For those who like metrics:

  • Highest number of reads per month was in May (19,927)
  • Year to date there have been 79,179 visitors
  • Most visited day was September 22, 2011 (2136 reads)

What have been some of the other posts that I enjoyed writing about?

My top 5 (not in rank order) would be:

  1. Alpharadin will be new treatment option for prostate cancer
  2. Patient advocacy session at European Hematology Assocation EHA Congress shows impact of drug adherence on outcome
  3. How nanotechnology may revolutionize the detection of traumatic brain injury using a sensor that changes color
  4. Innovation in Nanotechnology will lead to improved drug delivery, diagnostics & imaging
  5. Insights of the decade

Finally, I have produced 4 videos that you can watch on the biotechstrategy channel on YouTube.


It’s been a busy but enjoyable year. Biotech Strategy Blog is still a work in progress.  If you have enjoyed a particular series of posts or would like me explore a topic or theme in the future, do email me or post a comment.

Everybody who has sat too long in the sun knows how painful sunburn can be, and how ineffective current treatments such as topical creams can be.

Research by John Dawes and colleagues at King’s College London & University College London has shed new light on how sunburn causes pain.

They investigated the inflammatory response associated with ultraviolet B radiation of the skin and found that the chemokine CXCL5 (also known as epithelial-derived neutrophil-activating peptide-78) mediates UVB irradiation-induced pain in the skin of rats.

The results, published in Science Translational Medicine (STM), suggest that CXCL5 mediates UVB irradiation-induced pain and may be a target for the development of new analgesics or pain killers.

The elegant series of experiments done by Dawes and colleagues attempted to overcome one of the main challenges of pain research – the results from animal models don’t always predict pain relief in humans.

They designed custom-made Taqman array cards to determine the expression of inflammatory mediators in UVB treated rat and human skin, and found chemokine CXCL5 expression to be up-regulated in both rat and humans 40 hours after UVB treatment.

They then tested the hypothesis that CXCL5 was the cause of the pain, and that neutralization of this reduced mechanical hypersensitivity in rats and decreased the number of infiltrating cells. The STM paper is well worth reading for the series of experiments they performed.

Inflammation and inflammatory mediators are poorly understood in many diseases such as osteoarthritis (OA), so generating a better understanding of the underlying biology and mediators of inflammation is key to drug development.

It is too early to tell whether CXCL5 will turn out to be a druggable target, but the work by Dawes and colleagues is a good example of translational medical research worth exploring further.

ResearchBlogging.orgDawes, J., Calvo, M., Perkins, J., Paterson, K., Kiesewetter, H., Hobbs, C., Kaan, T., Orengo, C., Bennett, D., & McMahon, S. (2011). CXCL5 Mediates UVB Irradiation-Induced Pain Science Translational Medicine, 3 (90), 90-90 DOI: 10.1126/scitranslmed.3002193

Following on from yesterday’s news that Gilead had acquired Calistoga and CAL-101, another company that is exploring the interface between cancer and inflammation is Paris based AB Science.

Pharma Strategy Blog has an excellent interview with the CEO, Alain Moussy.  AB Science is an emerging French biopharmaceutical company, and I previously wrote about its IPO.

The company has adopted a unique market entry strategy of obtaining approval first in animal health for their tyrosine kinase inhibitor, masitinib.  In 2008, AB Science gained European approval for canine mast cell tumors and in December 2010 FDA approval.

The company recently announced that on February 8, 2011 it had its first US sale of masitinib to vets.

Masitinib is in fact a multi-kinase inhibitor that inhibits wild type and mutant forms of stem cell factor receptor (c-KIT, SCFR), platelet-derived growth factor (PDGFR), fibroblast growth factor 3 (FGFR3) and to a lesser degree, focal adhesion kinase (FAK).

Sally Church on the Pharma Strategy Blog has written about how AB Science’s strategy makes sense – if you look at Pfizer, they obtain more revenue from animal health than they do from oncology.  AB Sciences’ Masivet® in Europe, Kinavet® in the United States competes against Pfizer animal health’s tyrosine kinase inhibitor, Palladia® (toceranib), which also targets mast cell cancer in dogs.

Not only does this growth strategy generate revenue for an early-stage company like AB Science, it also allows the company to build a sales and marketing infrastructure in the United States and Europe while waiting for the results of pivotal phase 3 studies in humans.

The phase 2 clinical trial data for masitinib in combination with gemcitabine in pancreatic cancer were impressive (28% survival at 18 months).  The phase 3 clinical trial results are expected this year.  The clintrials.gov listing shows the date for the estimated primary completion date (Overall Survival) as November 2010 with study completion in November 2011.  Obviously the exact timing depends on how fast subjects were accrued, but I would be surprised if we didn’t see some data presented at ASCO or ESMO, especially if positive.

In terms of targeting inflammation, masitinib is in phase III development for mastocytosis, rheumatoid arthritis (RA) and asthma.  AB Science announced on January 27, 2011 the first patient recruited into their phase 3 study in severe asthma.

The company’s new product development strategy is way ahead of many of its competitors in identifying the links between cancer and inflammation, and choosing to target market opportunities in both areas.

AB Science is an exciting company to watch, and I expect that we will see important new data come out at major scientific meetings this year.

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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I have a long-standing interest in hypoxia (lack of oxygen). Many years ago while completing my Masters degree in human physiology, I undertook research at the RAF Institute of Aviation Medicine at Farnborough on the effects of mild hypoxia on pilot performance.

So I was interested to read an article in the February 17, 2011 issue of the New England Journal of Medicine (NEJM) on hypoxia and inflammation, and how this influences disease.  Inflammation is one of my blog themes for 2011, and in a previous post, I wrote about how its ubiquitous role has been characterized as one of the “Insights of the Decade”.

In the NEJM article on mechanisms of disease, the authors Holger Eltzschig and Peter Carmeliet discuss the cross-talk between hypoxia and inflammation, and how this is implicated in cancer, infections and inflammatory bowel disease.

A lack of oxygen (hypoxia) is something that humans are acutely aware of.  We are all familiar with the flight/fight response that is designed to increase oxygen delivery to the brain and muscles.  Hypoxia can also lead to an inflammatory response.  The flip side is also true, where there is inflammation there is often local tissue hypoxia. An example of this is in solid tumors where the level of oxygen is considerably lower than in normal tissue.

The link between hypoxia and inflammation is regulated by the hypoxia-inducible transcription factor (HIF) that is activated by hypoxia. HIF has two subunits HIF-α (consisting of HIF-1α and HIF-2α) and HIF-β. The article goes into detail (beyond the scope of this blog post) about the interaction between HIF and the nuclear factor kappa-B (NF-κB ) transcription factor that regulates inflammation.

Elevated levels of HIF-1α and HIF-2α correlate with cancer deaths.  HIF-1 overexpression is associated with tumor growth, vascularization and metastasis. This has led to HIF-1 being evaluated as a target for anti-cancer drugs.

EZN-2968, a novel HIF-1α antagonist is in phase I clinical trials.  It is a joint development of two biopharmaceutical companies, Enzon in New Jersey and Santaris pharma in Denmark.

It will be interesting to see whether targeting hypoxia dependent signaling pathways will enable a clinically significant reduction in the inflammatory response.

The December 17, 2010 issue of “Science” has the catchy of title of “Insights of the Decade”, one of which is an article by Jennifer Couzin-Frankel, “Inflammation Bares a Dark Side”, that describes the ubiquitous role of inflammation. She concludes that:

“Mediating inflammation in chronic diseases is a new frontier, its success is still uncertain.”

Inflammation has been shown to play an important role in multiple chronic illnesses such as cancer, and in type 2 diabetes it promotes insulin resistance and the death of pancreatic beta cells.  In 2007, Marc Donath and colleagues published a landmark study in the New England Journal of Medicine where he used the drug anakinra, in patients with type 2 diabetes, to block interleukin-1 (IL-1), a cytokine that mediates the inflammatory response. The conclusion of the paper was that:

“The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation.”

The finding that diabetes patients whose inflammatory response was blocked did better, has led several companies to work on drug development in this area.

One of these is the biotechnology company, Xoma, whose stocked jumped 200% in the week before Christmas.  Although there was no press release or announcement of any company news, it looks like investors decided to take a gamble that the phase 2 trial results for Xoma 052 in type 2 diabetes will be positive.  As often happens, the wisdom of the crowd, led to others joining the share buying frenzy.

Source: Google Finance. Xoma had previously announced on November 4, 2010 (emphasis added) that:

Enrollment completed in Phase 2a trial of XOMA 052 in patients with Type 2 diabetes:

This randomized, placebo-controlled trial, in which 74 patients were enrolled, is designed to evaluate extended biologic activity and safety of XOMA 052. Outcomes will include diabetes measures such as hemoglobin A1c, or HbA1c, and fasting blood glucose, or FBG, and C-reactive protein, or hsCRP, a biomarker of inflammation associated with cardiovascular risk. Interim results from the first three months of treatment in this six month trial are expected to be announced in the first half of January 2011.

Enrollment completed in Phase 2b trial of XOMA 052 in patients with Type 2 diabetes: This randomized, placebo-controlled dose-ranging trial enrolled 420 patients and is designed to further evaluate the safety and efficacy of XOMA 052 dosed once monthly compared to placebo. The results will include data on measurements of HbA1c, FBG and hsCRP. Top line results are expected to be announced in the first quarter of 2011.

Xoma 052 is a high affinity monoclonal antibody that targets the inhibition of IL-1 beta.  Its ultra-high affinity allows for monthly dosing and lower dose levels which supports patient compliance in chronic diseases. Positive phase 2 results for Xoma 052 in Behcet’s Uveitis was presented in November to the American College of Rheumatology.

According to the November 2010 Xoma Corporate Presentation, the overall market size for diabetes is $22B, of which the IL-1 share is $7B, raising the possibility that Xoma 052 could be a blockbuster if shown to be safe and effective.

Source: Xoma November 2010 Corporate Presentation

Looking at the above, perhaps the rush to buy Xoma stock before the holidays, was perhaps not as much of a gamble as one might think. Xoma 052 is certainly a product to watch this year.

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