Translational Medicine | Biotech Strategy Blog

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.

Scientific Symposia at ECCO ESMO 2011 Stockholm Cancer Congress

By Pieter Droppert on September 17, 2011

I will be flying to Stockholm next week for the European Multidisciplinary Cancer Congress (twitter #EMCC2011), more commonly known as ECCO or ESMO 2011.

What are the sessions that look interesting at the meeting? I previously wrote about the phase III ALSYMPCA trial data for Alpharadin that will be presented as a late breaking abstract.

In addition, the best abstract at ECCO 2011 is on vismodegib in basal cell carcinoma. Sally Church on Pharma Strategy Blog has written extensively about the hedgehog pathway and role of smoothend inhibition in the treatment of cancer.

What else has attracted my attention at ECCO 2011 in Stockholm? In looking at the preliminary program I was struck by the large number of scientific symposia throughout the meeting. However, many occur at the same time! On Saturday 24th two in particular caught my attention:

Molecular Imaging of Hypoxia

Nanotechnologies for Targeted Drug Delivery

Having written about hypoxia and nanotechnology on this blog, I will probably go to one of those two sessions.

Later in the conference, there is another block of scientific symposia on Monday 26^th, again all at the same time! Several that look particularly interesting include:

How to understand and to Reverse Drug Resistance in Metastatic Breast Cancer
From New Targets to New Drugs in Prostate Cancer
Tailoring Personalized Medicine for the Future
The Role of IGFs/IGF-1R Pathway in Paediatric Malignancies

And in case one still hasn’t had enough science, there’s another group of scientific symposia on the final day of the conference on Tuesday, 27 September including:

Unravelling Ras PI3 Kinases Targets
PARP inhibiting strategies: from Molecular Mechanisms to Rational Clinical Applications

I expect Stockholm to be expensive, they jokingly say you can buy a brewery in America for the price of a beer in the city, but it looks like there’ll be some interesting news and scientific data from the meeting. Hopefully I’ll have a few hours sometime to see something of what looks like a stunningly beautiful city.

If you plan to be in Stockholm do let me know. I can be reached via twitter (@3NT).

BioPharm America 2011 Biotech Partnering Conference #BPA11

A conference I regretably will not be at, but would have like to have attended is BioPharm America 2011 – 4th International Biotechnology Partnering Conference that is taking place in Boston from today until this Friday, September 9th.

The program overview suggests that it will be an interesting meeting with sessions on personalized medicine, business development and strategy and partnering. On friday there’s a briefing on Regenerative Medicine and Cell Therapy: The Road to Commercialization. If like me, you are unable to attend, you can follow the conversation on twitter using the hashtag #BPA11 (nice and short!). I noticed there’s already some excellent live tweeting from the event. I’ve added an aggregator below to make it easier to follow or catch up on the news. Just click on the play button to see the tweets:

Innovation – should companies take bigger risks and outsource pharma R&D?

According to a forthcoming article published in Forbes, excerpts of which appear on Matthew Herper’s blog “The Medicine Show,” big pharma should take bigger risks and outsource R&D to smaller, innovative companies.

At least that’s the philosophy of Bernard Munos, the former Lilly sales executive who has focused on the innovation problems faced by the pharmaceutical industry. According to Forbes, he believes that big pharma should “cut research and development” and “rather than do research in house, companies should close their labs and outsource the work to tiny, nimble startups that can explore bigger, crazier ideas.”

However, as Munos goes on to say in an excerpt published by Matthew Herper:

“You cannot script innovation,” Munos says. “You cannot boil it down to a code of best practices. Because it is unpredictable and the opportunities in science do not match the opportunities in markets.”

That is why Munos’ strategy of outsourcing drug discovery may not be the right one – there is no formula that you can give a vendor on how to be innovative. Indeed, leveraging the innovation of small biotechnology companies is nothing new – isn’t that what big pharma already does with its licensing deals and alliances?

The question that comes to mind from the provocative Forbes article is whether innovation of drug development is a service like clinical trials that can be outsourced? Contract Research Organizations (CRO) are now the route by which the majority of companies conduct clinical research. They possess the efficiency and economies of scale to do what is a mundane, process driven task of setting-up, monitoring and processing data associated with a clinical trial on a global basis. Those models works reasonably well and are now the norm. Standard Operating Procedures (SOPs) exist for everything a CRO does in what is a heavily regulated process of gathering data for regulatory submissions.

Is this the same for drug discovery? I am not so sure. Firstly, if you outsource you have to give direction. You have to have a commercial or scientific target, and resources have to be allocated accordingly. Who decides where R&D investment should be spent? Ultimately in any outsourced venture, the company spending the money makes that decision. So all you are doing is shifting the execution of the task, not the development of the strategy, which is where the innovation needs to take place.

Indeed, if one looks at the clinical trial service model, what has happened is that consolidation of small and medium size CRO’s continues to take place. Small companies simply lack the resources to get the job done. I am not convinced that small is necessarily best when it comes to drug discovery.

What’s more, Munos, in the recent Science Translational Medicine (STM) commentary on innovation that he wrote with William Chin, appears to argue for a different model than the one he proposes in Forbes. He states that:

“pharmaceutical companies cannot mitigate risk adequately by pursuing “safe” incremental innovation, instead the industry should reengage in high risk discovery research on a broad scale and only take genuine breakthroughs to the clinic.”

This is easy to say in practice, and may not be a realistic strategy when there is money and sales to be made from me-too and follow-on compounds. How many companies are going to say we are not going to continue with this business model?

According to Munos in Science Translational Medicine (STM) the options open to big pharma are to:

Participate more decisively in collaborative networks
Form precompetitive consortia and other partnerships to share costs
Adopt new research models such as public-private partnerships

To me, there seems to be a disconnect between what Munos says in the Forbes article and what he says in his STM commentary. If he has a clear vision for the future of pharma innovation, he should at least be consistent.

Where I do agree with Munos is the conclusion of his STM commentary that success starts with breakthrough science. This message was also clearly stated at BIO 2011 by the panel on innovation that included GSK’s Moncef Slaoui.

Pharma R&D $ needs to be spent more wisely. In my opinion there is a role for incremental, as well as breakthrough, innovation. The two are not mutually exclusive.

Is cutting R&D and outsourcing discovery the route to success as Munos suggests in Forbes? Only time will tell as pharma R&D retools and refocuses for the future.

Munos, B., & Chin, W. (2011). How to Revive Breakthrough Innovation in the Pharmaceutical Industry Science Translational Medicine, 3 (89), 89-89 DOI: 10.1126/scitranslmed.3002273

Innovation is seeing round the corners

By Pieter Droppert on July 12, 2011

Innovation involves insight that allows you to see around the corners. That’s the perspective according to Andrew Marks, Professor of Physiology & Cellular Biophysics at Columbia University Medical Center, who recently wrote a Commentary on Innovation in Science Translational Medicine.

Entitled “Repaving the Road to Biomedical Innovation Through Academia”, Professor Marks’ commentary captures the reader’s attention in the first sentence:

“The path to biomedical innovation requires a synthesis of seemingly unrelated observations.”

He goes on to say, “innovation requires joining the pieces to solve the puzzle.”

Innovation according to Marks is difficult to define, something I also noticed at BIO 2011 in the industry panel that I attended.

However, like pornography, “we know it when we see it” to paraphrase Justice Potter. Mark gives examples of innovation in the biological sciences: germ theory of disease by Lister, discovery of antibiotics exemplified by Fleming, Watson & Crick’s work on the structure of DNA.

I don’t disagree that these are examples of paradigm shifting scientific discovery fueled in some cases by serendipity. But are they the best examples of innovation in the biological sciences? Has nothing innovative happened in the past 50 years that is worth mentioning?

In his commentary, Marks goes on to outline the reasons he thinks biomedical research is threatened in the current environment. This includes the standard litany of woes expressed by many academics today:

increased costs
insufficient support
limited industry support
prolonged postdoctoral training
limited opportunities for research careers in academic medicine

Interestingly, however, he suggests that part of the fault for this lies with academia.

Academia and the National Institutes of Health (NIH) have failed to evolve with the times, he writes. They “have been guilty of a lack of innovation” in how they support science.

Today’s challenge according to Marks is the need to balance revolutionary research that is innovative with incremental research necessary to further knowledge.

Marks goes on to say that the NIH is not well equipped to judge innovative groundbreaking research. Moreover, “the unwritten rule, often said tongue in cheek, is that when applying for NIH funding one should only propose experiments that one has already done and for which one can show convincing preliminary data.”

The solution he proposes is to change the way federal funding of biomedical research takes place. The NIH should divert to industry the costs of clinical trials and establish distinct funding mechanisms for high-risk research. I am not sure I agree with this, as many clinical trials would not be funded by industry and translational research is not just about basic science, but is from bench to bedside.

The solution proposed by Marks also predisposes that you can properly assess and judge innovative research when you see it. This is not as easy as it seems. As Marks points out:

“NIH likely would not have funded proposals to test the germ-theory, antibiotic-action, or DNA double–helix hypotheses because these projects either would have been deemed too risky (that is, they have a low likelihood of success) or too speculative (lacking in sufficient “preliminary data”) or because the approach would have been criticized as being misguided.”

Instead of looking for new ways to fund basic science, Marks proposes a rework of the way NIH funds research. Cutting the same cake in a different way is unlikely to solve the fundamental problem: there is simply not enough government funding to go around. In the face of the US budget deficit, it is hard to imagine a significant increase in NIH funding to create new funding opportunities.

Would a more innovative approach be to ask academics to rethink how research is funded in their institutions? Focusing on the NIH and Federal Government funding is not the optimal solution in my opinion.

Marks is right in that Academia needs to innovate how science is supported. Incremental change of the way NIH funding takes place may fill in some potholes, but will not repave the road to biomedical innovation.

Marks, A. (2011). Repaving the Road to Biomedical Innovation Through Academia Science Translational Medicine, 3 (89), 89-89 DOI: 10.1126/scitranslmed.3002223

How does sunburn cause pain?

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.

Dawes, 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

BIO 2011 What is the future for innovative medicines in our industry’s pipeline?

What is innovation? Like “strategy” and “leadership” it’s a term we frequently use, something we all seek in the biotech/pharma industry, yet it’s hard to define, even harder to develop or predict.

What is the future for innovative medicines in our industry’s pipeline? was the title of a session that I attended yesterday afternoon at BIO 2011, the annual meeting of the Biotechnology Industry Association (BIO) in Washington DC.

Moderated by John Mendlein, the panel contained some R&D heavy weights:

Tom Daniel, President of Research & Early Development, Celgene
Charles Homcy, Venture Partner, Third Rock Ventures
Moncef Slaoui, Chairman R&D, GlaxoSmithKline
Doug Williams, Executive VP, R&D, Biogen Idec

Several people in the audience live tweeted the key messages of the speakers, and I encourage you to review them, if interested. The take homes that I took from this session were:

Innovation can be incremental or major breakthroughs

Many people think of innovation as a major breakthrough. Well worn clichés such as “ground breaking”, “game changing” come to mind. In pharma, I’d cite imatinib (Glivec®/Gleevec®) in CML as an example. In the consumer world, the Dyson vacuum cleaner jumps out to me. Something completely redesigned and made better = innovation.

However, incremental change can also be innovation if it has an impact. Take a new drug formulation that instead of daily dosing moves it to monthly doses and in the process improves patient compliance and adherence. That’s incremental innovation.

“Incremental versus major breakthrough” reminds me of scientific research. Most published papers are incremental, only rarely is there a major paradigm shift and landmark study. Only a few PhD students undertake truly novel research, instead the majority pursue incremental avenues associated with their supervisor’s interests. An oversimplification perhaps but there’s some truth to it.

Understanding science enables Innovation

Companies should focus their energies on disease mechanisms where the basic science has reached an inflection point of knowledge i.e. there is enough information for us to apply. This is why the work of research organizations such as the National Institutes of Health (NIH) is so important. In an area where there is the disease knowledge emerging, you can then put together a team of people who understand the science and biology of the disease. This does not guarantee innovation, but allows the identification of opportunities and in my view “enables innovation.”

Innovation will come from focus on molecular pathology of disease

Drug development is no longer focused on treating symptoms but on the underlying mechanism of a disease. Medicine itself is moving in this direction with personalized medicine and drugs that target specific mutations of genes e.g crizotinib in lung cancer. In a complex world of overlapping pathways (cancer and inflammation was the example cited), drug development innovation is going to come from understanding the molecular pathology of a disease. The terms “translational medicine” was not used in the session, but this is what comes to mind. Understanding science is key to success.

What is the future for innovative medicines in our industry’s pipeline? The panelists didn’t actually answer this question directly, but my view is that it is promising.

Prostate Cancer Market to expand from $1B to $5B by 2015

The market for prostate cancer therapies is set to expand from $1 billion currently to $5 billion by 2015, according to analysts reported by this morning’s Washington Post/Bloomberg news. This is perhaps no surprise given the recent approval of abiraterone acetate (Zytiga®) from Ortho Biotech (JNJ).

New clinical data on prostate cancer clinical trial results is expected at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago this weekend from many of the prostate cancer therapies in development such as MDV3100, TAK700, ARN-509, cabozantinib (XL184), ipilimumab, custirsen (OGX-11), BPX-101, alpharadin, denosumab (Xgeva®) and Prostvac-VF.

Indeed, one could argue that prostate cancer is becoming a competitive marketplace. Any emerging biotechnology company that is not already developing a prostate cancer drug is likely to find it a hard market in which to create a blockbuster. By the time any drug comes to market, there will be incumbents with effective products who have captured market share.

Prostate cancer is an exciting market to watch from a marketing strategy and patient perspective, as several companies potentially bring new products to market over the next few years.

However, the bottom line is that patients will live longer as a result of all the innovation that is taking place. Not only that but physician education and awareness of how to treat this disease is also likely to improve as they seek out knowledge on new therapies and treatments. This to many will make a major difference. At the recent American Urological Association (AUA) annual meeting, the sessions on treatment of prostate cancer were standing room only. There is clearly a demand for knowledge out there as the treatment paradigms change.

At the other end of the spectrum, there is also innovation taking place in terms of improved diagnosis and treatment of prostate cancer. Whether we should screen all men for PSA remains a controversial topic, although use of risk calculators do appear to offer less false positives. Indeed, calculating risk is going to be one of the key areas that primary care physicians and urologists need to focus on, particularly in the light of the PIVOT trial data that was presented at AUA, showing radical prostatectomy (with risks including incontinence and erectile dysfunction) was not better than watchful waiting in low-risk, early stage disease.

However, a presentation I am looking forward to at ASCO 2011 is on circulating tumor cells (CTC) and whether these can be a prognostic or even a predictive biomarker. Both the phase III MDV3100 and abiraterone acetate clinical trials captured CTC data. It will be exciting news at ASCO 2011 if circulating tumor cells that require only a blood sample offer an improvement over PSA not only for detection of prostate cancer, but in monitoring the disease over time.

I will be at ASCO 2011 this weekend, and look forward to writing more on prostate cancer from the conference!

Nanoparticles using layer-by-layer technology provide targeted cancer drug delivery

At the recent ARVO meeting, one of the symposia that I live tweeted from was on “Nanotechnology for Drug and Gene Delivery.” During his presentation on “Nanomedicines: From Bench to Bedside” Vladimir Torchilin from Northeastern described how nanotechnology can use methods from other scientific disciplines including layer-by-layer (LbL) polymer chemistry.

Which leads me into an interesting paper that came across my desk from Zhiyong Poon and colleagues at the Koch Institute for Integrative Cancer Research at MIT.

In their paper published online on April 23, 2011 in ACS Nano. they describe how nanoparticles with a pH-sheddable layer can be used to target tumor hypoxia.

In other words, the nanoparticle can travel in the blood to the tumor, then in the changed acidity and pH of the tumor microenvironment, the outer stealth layer is eroded and shedded, exposing another layer of the nanoparticle that delivers drug to the target hypoxic tumor region.

Image Source: ACS Nano. The author’s conclusion is that “this concept for tumor targeting is potentially valid for a broad range of cancers, with applicability for therapies that target hypoxic tumor tissue.”

This proof of principle research is further progress towards the development of nanomedicines in oncology.

Poon, Z., Chang, D., Zhao, X., & Hammond, P. (2011). Layer-by-Layer Nanoparticles with a pH-Sheddable Layer for Targeting of Tumor Hypoxia ACS Nano DOI: 10.1021/nn200876f

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