Pieter Droppert | Biotech Strategy Blog

Chemotherapy Foundation Symposium Prostate Cancer Update

This morning the 8am session at the Chemotherapy Foundation Symposium (The Greenspan Meeting) in NYC featured a review of current developments in Prostate Cancer.

The informative 1.5 hour session covered a lot of ground with the presenters reviewing clinical data for:

Radium-223 Chloride: a new option for CRPC (Oliver Sartor)
Pomegranite extract for Rising PSA (Michael Carducci)
XL184 in mCRPC (David Smith)
Optimizing patient selection for sipuleucel-T (Simon Hall)
Intermittent androgen suppression for prostate cancer (Laurence Klotz)
Lenolidomide/docetaxel in CRPC (Daniel Petrylak)

The highlight, in my opinion, was Oliver Sartor’s excellent presentation on radium-223 chloride (Alpharadin) in which he cogently outlined its mechanism of action. He explained that radium-223:

targets osteoblastic bone metastases by acting as a calcium mimic
is a bone-seeking calcium mimetic that binds to hydroxyapatite
has preferential uptake in areas of new bone formation

As mentioned previously on this blog, there are critical differences between an alpha emitter such as radium-223 and other bone-seeking radiopharmaceuticals that are beta emitters.

Sartor presented some excellent slides that showed how alpha emitters require much fewer DNA hits to kill cells, are short range and have a higher initial energy per particle. In other words they are very effective at short range within the bone microenvironment, something that Chris Parker from The Royal Marsden Hospital mentioned in his interview from ECCO/ESMO in Stockholm.

Sartor concluded his Chemotherapy Foundation Symposium presentation by reflecting on “where do we go from here” in prostate cancer? Some of his observations were:

We are currently in a sequencing paradigm. Drug A then B then C
We need to combine active agents to give the best results, that is our next challenge
How are we going to afford it all?

Sartor succinctly highlighted where the rubber currently hits the road, and left the audience with plenty to reflect upon. I am sure we can expect further debate on sequencing and combination possibilities at medical and scientific meetings in 2012.

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Blocking Sema4D may be a new osteoporosis target

Bone is a tissue in constant state of remodeling by osteoclasts (cells responsible for bone resorption) and osteoblasts (cells responsible for new bone formation).

Osteoporosis is a disease of progressive bone loss that is associated with increase risk of fractures. Particularly debilitating are hip fractures in the elderly that are costly to treat and also lead to increased death and reduction in quality of life. It’s estimated that osteoporosis affects 44 million people in the United States over the age of 50.

Most treatments for osteoporosis inhibit bone resorption e.g. bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid). By inhibiting or reducing bone resorption, there is a lower amount of bone loss.

Recent research published in the November 2011 issue of the journal Nature Medicine has highlighted a new potential target for osteoporosis drug development that acts on osteoblasts and promotes bone formation.

In a series of elegant experiments, Takako Negishi-Koga and colleagues found that osteoclast-derived Semaphorin 4D (Sema4D) inhibits bone formation.

They found that the transmembrane protein Sema4D is expressed by osteoclasts and inhibits osteoblastic bone formation. In other words, Sema4D is a critical mediator of osteclast-osteoblast communication.

They reported that:

In osteoblastic cells, Sema4D stimulation decreased the expression of cadherin-11 at the cell-cell contact region suggesting that Sema4D stimulates cell motility through an impairment of cell-cell adhesion, which in turn results in the reduction in bone-forming activity.

Osteoclast-derived Sema4D inhibits bone formation:

The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility.

The implication of these findings is that blocking Sema4D could promote osteoblastic bone formation without affecting osteoclastic bone resorption. The researchers successfully tested this hypothesis using an antibody to Sema4D.

They concluded that:

These results suggest that the blocking Sema4D–Plexin-B1 interaction is a new and potentially effective strategy for increasing bone formation in humans.

This preclinical work using an animal model is highly promising and suggests that as we learn more about the bone microenvironment, new therapeutic and molecular targets for drug development may emerge.

Negishi-Koga, T., Shinohara, M., Komatsu, N., Bito, H., Kodama, T., Friedel, R., & Takayanagi, H. (2011). Suppression of bone formation by osteoclastic expression of semaphorin 4D Nature Medicine, 17 (11), 1473-1480 DOI: 10.1038/nm.2489

A potential new Immunotherapy in Breast and Ovarian Cancer

There has been a lot of negative publicity around Dendreon and sipuleucel-T (Provenge) recently, and the lack of a clear mechanism of action remains a concern to many.

Irrespective of the company’s commercial performance, sipuleucel-T remains an FDA approved therapeutic cancer vaccine that provides a benefit to some patients. It provided a proof-of-concept that immunotherapy can offer a survival advantage, albeit for a median of 4.1 months in asymptomatic advanced prostate cancer.

Dendreon is learning the hard way the failings in its commercial strategy, and no doubt these will be absorbed by others with other therapeutic vaccines in development.

Which brings me to an interesting paper published online first on November 8, 2011 in the American Association for Cancer Research journal, Clinical Cancer Research.

Researchers from the National Cancer Institute (NCI) published data from a small pilot trial showing a clinical response to a poxviral vaccine (PANVAC) in metastatic breast cancer and ovarian cancer patients.

Twenty six patients were in involved in the pilot NCI trial with PANVAC, a recombinant poxviral vaccine expressing the tumor-associated antigens (TAA), carcinoembryonic antigen (CEA) and mucin-1 (MUC-1).

The results showed a median overall survival of 13.7 months in the 12 breast cancer patients with four patients having stable disease, and one patient on study for 37 months. One patient had a 17% reduction in mediastinal mass.

In ovarian cancer, median overall survival for the 14 patients treated was 15.0 months.

This is promising early stage data in very sick patients. Mahsa Mohebtash and colleagues conclude in their paper that:

“Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted.”

Immunotherapy holds a lot of promise. Research suggests that cancer vaccines once they have provoked a response may improve a patients’ response to subsequent therapies through enhanced T-cell response.

The NCI researchers in their paper noted that time to progression and tumor shrinkage may not be good endpoints for evaluating immunotherapies given that it can take a few months for the optimal result after vaccination and there is often little impact on the tumor size, as judged by classical RECIST measurement.

Instead, overall survival (OS) should be considered a more relevant endpoint. Sipuleucel-T failed to show a benefit in progression free survival (PFS), but did show an impact on OS. In prostate cancer, OS remains the gold standard for regulatory approval, which is why Exelixis recently took a hit for not making this the primary endpoint in their phase III trial (306) for cabozantinib (XL184).

There are several challenges to consider with vaccine therapies:

How do we identify upfront which patients are most likely to respond to the vaccine?
The ideal setting is likely to be adjuvant rather than metastatic disease, but these trials will take a very long time and significant funding to come to fruition.
Cancer vaccines may allow some patients to live longer, but they have yet to show any meaningful benefit in other clinical measures such as bone pain, symptoms etc.
There are fewer side effects, but how do we evaluate how well patients are doing without clinically validated surrogate markers to aid in assessment?

This early research with a vaccine in breast and ovarian cancer, albeit on a very small number of patients, adds further support to the notion that vaccines may offer treatment benefits in the future.

We still, however, have a long way to go in understanding how best to use immunotherapy effectively and incorporate it into clinical treatment guidelines. We should also be wary of false hope and hype – I look forward to following the progress of PANVAC going forward.

Mohebtash, M., Tsang, K., Madan, R., Huen, N., Poole, D., Jochems, C., Jones, J., Ferrara, T., Heery, C., Arlen, P., Steinberg, S., Pazdur, M., Rauckhorst, M., Jones, E., Dahut, W., Schlom, J., & Gulley, J. (2011). A Pilot Study of MUC-1/CEA/TRICOM Poxviral-Based Vaccine in Patients with Metastatic Breast and Ovarian Cancer Clinical Cancer Research, 17 (22), 7164-7173 DOI: 10.1158/1078-0432.CCR-11-0649

MDV3100 shows survival in Advanced Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men, so it was good news this morning when Medivation & Astellas issued a press release that showed positive data from the phase 3 AFFIRM trial for MDV3100.

MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo.

MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

To put the 4.8 month survival advantage in context, this compares favorably with 3.9 months for abiraterone (Hazard Ratio =0.646), in the COU-AA-301 trial.

Positive data was expected given the sound scientific rationale behind MDV3100 and the preliminary data (abstract 4501) presented at the ASCO annual meeting this year. J Clin Oncol 29: 2011 (suppl; abstr 4501).

The drug has a high affinity for the androgen receptor (AR) that is highly expressed on prostate cancer cells. You can read an excellent interview on Pharma Strategy Blog with Charles Sawyers, who was one of the co-inventors.

MDV3011 blocks the androgen receptor (AR) from moving into the nucleus and activating growth genes and is a more complete inhibitor of AR than bicalutamide.

One hot topic of conversation at ASCO was the potential to combine MDV3100 (androgen receptor blocker) with abiraterone acetate (Zytiga) (androgen synthesis inhibitor), thereby shutting down upstream and downstream activity of the driving receptor in advanced prostate cancer. The scientific rationale for this appears sound, so it is likely that a combination clinical trial may well be done to test this hypothesis at some point in the future.

MDV3100 has a significant advantage over abiraterone acetate (Zytiga) in that concomitant steroids are not required. Daily steroids have their side effects. Urologists in particular will be attracted to MDV3100 and its ease of use.

Clinical trials in prostate cancer are ongoing with a multitude of new emerging therapies including TAK-700, Cabozantinib (XL184), radium-223 chloride (Alpharadin), BPX-101, Prostvac-VF, ipilumumab, Custirsen (OGX-011), dasatinib (Sprycel), lenalidomide (Revlimid) and ARN-509 to name but a few.

It is a therapeutic area with a lot going on after very little activity for a decade. The positive interim data for MDV3100 announced today is good news for prostate cancer patients, and we await presentation of the data next year.

Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012, so US approval could be possible later next year.

New Imaging Agents may improve Glioblastoma Surgery

Cancer Research UK issued a press release today about a phase 2 trial (GALA-5) in glioblastoma that caught my attention.

The trial, led by Colin Watts from the University of Cambridge, will treat patients with 5-Amino-Levulinic Acid (5-ALA), a metabolic marker of malignant glioma cells. 5-ALA is preferentially taken up by brain tumor cells and then converted into a strongly fluorescing porphyrin.

This conversion by the body of 5-ALA to a fluorescent chemical, shows the location of the glioblastoma when imaged under ultraviolet light.

The practical application of this is that it allows better identification of the tumor margins and avoids the removal of unnecessary brain tissue.

The use of fluorescent imaging to aid surgery is also being investigated in other tumors. Sally Church on Pharma Strategy Blog recently wrote about the use of folate receptor alpha fluorescence imaging in ovarian cancer.

It will be interesting to see how the GALA-5 phase 2 clinical trial in glioblastoma progresses. The fluorescent imaging technology while promising is not without its pitfalls and potential risks.

As Jörg-Christian Tonn and Walter Stummer note in Vol 55 of “Clinical Neurosurgery” (2008) some of the pitfalls with fluorescence-guided resection using ALA include:

Problem of overhanging margins i.e. inability to see all the tumor in the field of vision
Cysts leading to collapse of parts of the tumor with the result that areas are missed
Wrongly placed craniotomies preclude complete resection of contrast-enhancing tumor
Some cases of gliosarcoma show only modest fluorescence accumulation
Delay in drug administration may lead to less than optimal fluorescence
Exponential decrease in light with growing distance to fluorescent tissue, resulting in weak fluorescence intensity

No doubt many of the above issues will be controlled for in the GALA-5 trial. The challenge with imaging techniques is, however, in consistency and reproducibility outside of experienced clinical research investigation sites.

It will be interesting to see whether the potential pitfalls can be overcome such that this promising experimental imaging becomes routine in glioblastoma surgery.

Story Source: BBC Health

Insights from Society for Translational Oncology Prostate Cancer Symposium

By Pieter Droppert on October 31, 2011

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.

A year in review on Biotech Strategy Blog

By Pieter Droppert on October 26, 2011

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:

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:

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

http://youtu.be/nDvY7opm3Fs

http://youtu.be/_oAJ1fU0PT4

http://youtu.be/hM_wmjaqDyc

http://youtu.be/i5GNBmuISqQ
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.

Biotech Strategy Blog now available on Kindle

By Pieter Droppert on October 17, 2011

For those readers who would like to access Biotech Strategy Blog on their Kindle, this is a quick post to let you know it is now available on the Amazon Kindle Store for $0.99/month. You can also continue to read it for free on the web.

Of course, after Amazon takes its cut there is a (very) small royalty fee that ends up coming my way, so I have vested self-interest in promoting this. However, it’s not something I anticipate getting rich from!

In a world of multi-channel marketing, it is good to try out new ideas that may make it easier for people to access content and information.

Vitamin E may improve gemcitabine effectiveness in pancreatic cancer

It’s been a bad week for vitamins, especially with the publication of data from the SELECT trial that showed healthy men taking 400 IU/day of Vitamin E had a 17% increased risk of prostate cancer.

However, there is some evidence in support of tocotrienols (unsaturated form of Vitamin E) having a potential role to play in anti-cancer therapy. One paper that caught my attention was the work by Kazim Husain and colleagues from the Moffitt Cancer Center and Research Institute in Tampa.

Published Online First (October 4, 2011) in the American Association for Cancer Research (AACR) journal, “Molecular Cancer Therapeutics” they showed that δ- tocotrienol may have potential to improve the effectiveness of gemcitabine in pancreatic cancer.

In their laboratory and animal based research, the authors showed that δ-Tocotrienol:

“augments inhibition of pancreatic cancer cell proliferation by gemcitabine”
“augments gemcitabine-induced apoptosis in pancreatic cancer cells”
“down-regulates constitutively activated NF-κB in gemcitabine-treated pancreatic cancer cells”
“enhances the in vivo therapeutic effects of gemcitabine in a pancreatic tumor model in SCID nude mice”

Pancreatic cancer patients have a poor prognosis with less than <5% of patients surviving 5 years. Current treatment revolves around the chemotherapy gemcitabine, but as the authors note in their Molecular Cancer Therapeutics paper, “tumor resistance is common.”

Various researchers are working on how to improve treatment options for pancreatic cancer. One company I’m watching is AB Science and their phase 3 trial for masitinib. You can read more about this on Pharma Strategy Blog and Sally Church’s excellent interview with CEO, Alain Moussy.

The work on the δ-tocotrienol form of Vitamin E shows that it may have a role to play in cancer treatment, notwithstanding the negative data that was published earlier this week in prostate cancer.

Husain and colleagues from Moffitt showed for the first time that δ-tocotrienol inhibited NF-κB activity and the expression of NF-κB regulated gene products. They note that inflammatory transcription factor NF-κB is involved in tumorigenesis, so inhibition of NF-κB may be how tocotrienols exert their anti-cancer effects.

These preclinical results are promising and show that:

“δ-tocotrienol is the most bioactive tocotrienol against human pancreatic cancer cells and provide the rationale for selecting δ-tocotrienol as the lead tocotrienol compound for further studies of the use of tocotrienols for pancreatic cancer prevention and treatment.”

A phase I clinical trial is ongoing (NCT00985777) evaluating the use of δ-tocotrienol in patients with pancreatic tumors.

While Vitamin E supplementation may yet be of benefit to healthy individuals, it could have benefit in patients with pancreatic cancer, so it will be interesting to see how this develops.

Husain, K., Francois, R., Yamauchi, T., Perez, M., Sebti, S., & Malafa, M. (2011). Vitamin E -Tocotrienol Augments the Anti-tumor Activity of Gemcitabine and Suppresses Constitutive NF- B Activation in Pancreatic Cancer Molecular Cancer Therapeutics DOI: 10.1158/1535-7163.MCT-11-0424

Innovation in combination trials of cancer targeted therapies

By Pieter Droppert on October 12, 2011

Academic institutions are now bringing pharma/biotech companies together and facilitating rational combination trials that make solid scientific sense.

Combining at least two targeted drugs looks to be increasingly necessary in order to develop innovative new cancer treatments, where turning off one target may stimulate another, thus both need to be targeted for there to be an overall effect.

However, one company may not have all the pathways and drug targets covered by their portfolio. The result is that companies may have to work together in combination trials with each providing one drug from their portfolio.

That was one of the key messages I took from Gordan Mills (UT MD Anderson Cancer Center) in his recent video interview with Sally Church from Pharma Strategy Blog:

http://youtu.be/FXkcSry6EtQ

Sally Church’s video interview with Professor Mills is well worth watching if you have not already done so.

Not only are universities and research institutions well placed to judge the scientific merits, but as Mills points out they can facilitate things as an independent third party and actively help bring partnerships together. Given that combination therapies may be needed in order to turn off different parts of signaling pathways and cross-talk, I think we are likely to see more of this approach.

It’s going to be new territory for many companies – how to enter into a potential joint venture or alliance? However, if it results in a therapy that works, it is going to be win-win for all parties. It may also improve efficiency in drug development and lead to better use of patients in early stage development.

Some examples of where this is happening already in oncology include AstraZeneca and Merck with their MEK-AKT approach and GSK (MEK) with Novartis (PI3K), to name a couple. This is a new trend we are likely to see more of in the future.

I can see universities hiring alliance managers who have industry experience to ensure these collaborations run smoothly.

The topic of the industry/academia interface in rational cancer drug development will also be discussed in a plenary session at the forthcoming American Association for Cancer Research (AACR) meeting on Molecular Targets and Cancer Therapeutics (November 12-16, 2011) in San Francisco.

How academia can better help the pharma/biotech industry bring innovative, rational drug combinations to market is a topic that I think we will be reading more about in coming months.

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