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Flip This Asset: San Diego’s Advanced BioHealing ‘Fixed Up’ Dermagraft for Profit and Growth #BIO2010
Posted by Mary Canady May 5th, 2010 .
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Wednesday I attended a regenerative medicine-focused breakfast at the BIO convention and learned about San Diego company Advanced BioHealing (ABH), who took a ‘fallen’ asset, Dermagraft, and not only turned it into an $85M/year product, but is also looking for new indications. Dermagraft was sold by Advanced Tissue Sciences, who had invested hundreds of millions into developing it, and even got FDA approval for the product to treat diabetic foot ulcers.
I spoke with Advanced BioHealing’s Senior VP Dean Tozer, and he describes their methodology as ‘reverse biotech,’ meaning that they first focused on commercializing products, and just recently hired their CSO Charles Hart. Hart will be spearheading the efforts to find soft tissue indications for Dermagraft. This is counter to how most biotechs in San Diego form, and it appears to be working for ABH as they are predicting 30-50% growth over the next few years.
This growth translates to jobs in San Diego, with 15 listed on the ABH careers page currently. ABH has locations in Westport, Connecticut and Nashville, Tennessee as well, and plans to continue manufacturing products in their 70,000 square foot La Jolla site near the Burnham Institute, and has recently acquired 20,000 square feet of office space nearby in an old Pfizer site. I asked Tozer whether the jobs will continue to be created in San Diego, and he said yes, because the talent pool here is so valuable to them.
What can other San Diego biotechs learn from this example? At BIO this year, I have seen successful repurposing of assets and information. It may simply be the product of a down economy, but I wonder what we can learn, and what could be gained by investigating failed assets that exist from local companies who have not survived? Tozer also believes strongly that the right people make the difference, and they were lucky to bring together a team which understands biotech commercialization. Surely, attracting or training more commercially focused professionals in the area would be a great start.

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How Does Biomarker Stratification Affect Drug Development Cost? It Depends. #BIO2010
Posted by Mary Canady May 5th, 2010 .
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On the San Diego Biotechnology Network LinkedIn group, we asked you what you wanted to hear about from the BIO Convention in Chicago, and you requested to hear about Biomarkers. Tuesday I attended a breakout session titled ‘Impact of Biomarkers on Drug Development Complexity and Cost,’ and it described a study done by panel members Federico Goodsaid of the FDA, Michael Palmer of Adaptive Pharmacogenomics, Mark Trusheim of MIT, Steven Averbuch of BMS, Theresa Long of the Van Andel Institute. The study modeled different scenarios utilizing biomarker information and the financial impact on estimated net present value (eNPV) of developed drugs. The group was truly interdisciplinary, and it was clear from the quality of the presentations that they likely worked well together due to their communication skills.
The session described a workshop held in October of 2009 in which case studies on oncology and alzheimers were discussed (featured in Nature Reviews Drug Discovery as well–requires login).
MIT economist Mark Trusheim began by describing the ‘pharmaeconomics’ of choosing patient populations for clinical trials. There are obvious benefits to using biomarkers to enrich populations, but there are many factors which need to be considered, and ultimately it depends on the science behind the drug and the market. The group determined three factors to be the most important: variability in the therapeutic effectiveness of the drug, prevalence of the biomarker, and the quality of companion diagnostics. Trusheim also described modeling different long term scenarios ranging from Phase II extending through to the end of market exclusivity, from the perfect ‘Nirvana’ situation, where everything goes perfectly, to ‘pharmageddon’ where it goes bad at every turn. Trusheim indicated that in both the oncology and Alzheimer’s study, a very significant increase in eNPV could be achieved by utilizing biomarker information.
Steven Averbuch, VP of Oncology at BMS, covered the study results for Herceptin and Vectibix for oncology indications. In the case of Herceptin, it had a large effect on a small population, saving money and adding to the eNPV by allowing a smaller clinical trial, but perhaps precluding the discovery of other biomarkers or indications for the drug, as was found to be important for drugs such as Gleevec. Vectibix had a large effect on a large population, obviating the need for biomarker stratification but giving the drug a higher eNPV because of a larger market size. Averbuch reiterated Trusheim’s three important factors, and the need for increased communication between all the stakeholders to utilize biomarker information to help move from the ‘pharmageddon’ to nirvana drug development situation.
Theresa Long, presented the study on the Alzheimer’s drug Bapineuzumab, and the effect of biomarker stratification on a chronic condition. They used the ApoE4 biomarker and started with data past Phase 2. Three different scenarios were modeled, from an all-inclusive to stratified, with an 80% increase in eNPV in the biomarker study. Long stressed the importance of knowing the prevalence of the biomarker in the population, even for chronic conditions such as Alzheimer’s which has blockbuster potential.
This session was inspiring as it showed how science can drive drug development and how biomarker stratification could lead pharma and healthcare towards a path of increased communication resulting in lower costs. The study has been submitted for publication and the modeling tools that were used will be available. Federico Goodsaid indicated that the tool could be made available to those who contact him.

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Translational Research Forum at #BIO2010: Learning From the Land of Lincoln
Posted by Mary Canady May 4th, 2010 .
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I attended the translational research forum Monday morning at the BIO 2010 convention in Chicago. The morning started with Congressman Dan Lipinski from Illinois, who was a great choice as he is a member of the House Committee for Science and Technology, as well as the House Committee on Small Business. He is sponsoring the NSF Reauthorization Bill, which will increase the NSF budget to $20B by 2015 and include funding for higher risk/reward projects. The bill will also have provisions for research infrastructure and education. This bill is slated to be brought to the House in the Memorial Day work period, and its passage will of course be beneficial to academic researchers, key to translational research efforts.
Congressman Lipinski also discussed the status of SBIR/STTR reauthorization, which is currently in limbo as there are House and Senate bills which must be reconciled. I did not realize that these programs are currently in a temporary extension and thus vulnerable to be no longer available for small businesses. One of the issues plaguing the reauthorization is the disagreement about whether venture capital (VC) funded companies should be eligible. Lipinski was vague as to the future of this bill, but assured us that these business grants are a high priority, especially since they will help to create jobs in this down economy.
The forum continued with a panel themed ‘From Science to Invention’ containing mostly academic panelists from Illinois, with a representative from Pfizer St. Louis (on the Missouri-Illinois border). Ted Mazzone of University of Illinois Chicago explained the organization of their CTSA (Clinical and Translational Science Awards) center, which has sophisticated infrastructure to support collaboration and commercialization across a ‘mini consortium’ that exists within the CTSAs in Illinois. Stephen Kent from the University of Chicago talked about his experience with translational research from early challenges in vaccine research to studies of the decreasing chiralty of drugs and its affects on NCE approvals. David McCormick from the IIT Research Institute talked about the importance of bioinformatics and stratification of patients.
Dean Welsch, Research Fellow at Pfizer, described his work in the Indications Discovery Unit, where drugs are being repurposed to treat new indications. Efforts to streamline internal information around compounds has been key to making these efforts successful. Pfizer is also looking externally, including a pharma portal within the CTSA to exchange materials or information. He also described how they find new partners and technologies, including utilization of resources such as this web-based network of research centers for Idiopathic Pulmonary Fibrosis. Pfizer also creating a model which they hope will also be adopted more universally called Foci of Expertise, in which CTSA experts can be found and connect. In Welsch’s three years using these methodologies, their modestly sized group has moved 5 compounds into the clinic, which is impressive. Welsch also hinted that a ‘creative’ collaboration between Pfizer and Washington University in St. Louis will be announced soon.
The panel discussed the future of translational research as well. Access to biobanking information, software and informatics challenges, and the traversing the ‘valley of death’ appeared to be the common thread among the discussions. The question that kept nagging me revolves around which entity is ultimately responsible for funding translational research, if any. Government initiatives such as CTSA and NIH Roadmap are certainly important, but are they enough to stimulate the level of collaboration needed? I was encouraged by the level of creativity demonstrated by Pfizer, and I’m guessing this has been driven by the need to economize. Hopefully, lessons that are learned will be applicable more generally. Interesting that I had never heard of a CTSA until today–they seem to be more prevalent in the midwest/east coast, but the Scripps Translational Science Institute is a CTSA. How could we apply these lessons in translational research collaboration in Illinois/Missouri to San Diego biotech?

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#EB10 Conference Report: Lee Hood – A Systems Biology approach to prion disease
Posted by Dr. Gunn April 26th, 2010 .
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This is a post from the 2010 Experimental Biology meeting in Anaheim, part of the SDBN conference reporting channel.

Leroy Hood probably doesn’t need any introduction here, but for those who don’t know, he’s a leader in using a systems biology to address large, complex medical problems. One such problem is prion disease, a disorder caused by a proteinaceous infectious agent which results in neurodegenerative symptoms as the proteins accumulate in the brain. After decreasing in recent years subsequent to the slaughter of 4.4 million potentially prion-bearing cattle in the UK and establishment of new industry practices, deaths due to prion disease are now as high as they were at their height in 2003.

As prion proteins accumulate and physiology is disturbed, there’s a change in gene expression of over 7400 genes. using 8 mouse strains, Dr. Hood used subtractive biology techniques to narrow the list of relevant genes to 333. Of this number, 2/3 were already known to be involved from previous work. An additional 100+ genes discovered were newly implicated. To study the dynamics of accumulation co-occurring with prion accumulation, Hood developed a massive dataset consisting of transcriptme analysis, histopathological studies, and tissue distribution studied, combining these data with known protein interaction data and clinical signs of disease. This massive analysis identified the accumulation networks and revealed the dynamics of the process as it happens over 20 weeks. In the human, prion disease can gestate for 4 years, so 20 weeks is a reasonable time for a mouse model.
One of the neatest things to come out of this work was a a means of predicting the cell type involved, based on the differential expression of the genes. All the novel prion-associated genes were correctly predicted this way. From within this dataset, they further identified 15 proteins found in the blood which track the clinical course of the disease. Instead of a definitive diagnosis only being possible upon autopsy, now the disease state can be monitored via blood markers, resulting in much easier monitoring of at risk populations and a far safer food supply.
Dr. Hood took a few moments to mention that he’s founded a company, Integrated Diagnostics, which is undertaking some fascinating projects. Among these are creation of a human proteome atlas, which will yield a quantitative assay for every known human protein, and a microfluidic chip platform with some impressive stats. He said the chip would be able to assay 50 proteins in 5 minutes using a volume of 300nL of serum (not whole blood, I assume) at attomolar sensitivities. With that level of sensitivity, they’re well within clinically significant ranges for most proteins.
To do this, they invented a novel protein capture technique that used a combination of low-affinity 6mers and click chemistry to create highly stable chips with antibody-like specificity. he cited 5 years until their availability.
In 10 years, he expects genome sequencing to be routinely done as part of medical practice, costing no more than a couple hundred dollars (as the inventer of automated DNA sequencing, I’d believe him). What this would allow, for example, is capturing of an individuals MHC locus during allergy testing and identification of specific auto-antibodies.

Update: The slides for this talk (PDF) are now available, as gave the same presentation at the SAGE Congress.

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All change is local: Small environmental changes have can have very large local effects
Posted by Dr. Gunn April 24th, 2010 .
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I’ll be blogging for the next couple days from the 2010 Experimental Biology conference. Today’s session that caught my eye was on measuring the effects of climate change on organisms in their own niches. It turns out that some microenvironments act like lenses, focusing small changes in climate into much larger effects on resident organisms. I also attended a good session on science communication and policy, which will receive a longer and more thoughtful post to come later.

When people hear that the global temperature has increased about 1 degree C in recent years as a result of global warming, it’s understandable that they aren’t really impressed. “One degree? It changes more than that day to day!” Speakers during this session showed how in certain ecological niches, the real difference in terms of physiological effects on an organism are quite larger.
Brian Helmuth from the University of South Carolina kicked off the session with a discussion of tools and models for downscaling the global phenomena to microenvironments. He showed that there’s little correlation between the internal temperature of an animal and the air or water temperature surrounding it. Furthermore, the air or water temperature changes don’t result in the same relative change in temperature for all the organisms in the microenvironment. In other words, a 1 degree rise in air temp tells you pretty much nothing about what effect that has on an organism. Using air temps as a proxy for environmental stress is like trying to guess how what the weather is like outside based on what color shoes people are wearing.

To address this, he developed a sophisticated model for predicting the differential effect of climate change on different organisms, basically an internal “weather forecast” for an organism. They measure a few coefficients such as radiant heat transfer (based on how much insulation the organism has) and evaporative heat loss (from sweating, for example). What this then allows them to do is to properly predict the actual temperature shift as it’s experienced by the individual organism.
It doesn’t take too much imagination to realize that this approach could be extended to look at ocean acidification and other environmental stressors as well. With these new tools, scientists can now predict the effect that microenvironmental changes will have on habitats and start to look at how this interacts with pollution exposure and other challenges facing an organism.

_{Data guys, he mentioned a huge amount of time series temperature data on organisms, stretching back 10 years at a 10 minute resolution. Impressive?}

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San Diego Biotechnology Network Partner Event May 27th: Rondaxe Drug Development Symposium
Posted by Mary Canady April 22nd, 2010 .
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Drug development is an area that, according to our 2010 poll, you are interested in, and in previous meetings we’ve discussed that San Diego biotech could grow if we would better complement our drug discovery capabilities with drug development. The SDBN was approached by Rondaxe, a drug development services company, with an idea for an event which will highlight companies they work with from outside the San Diego region. The event will be held May 27th, from 9:00 a.m. to 2:15 p.m., and a light breakfast and lunch will be provided. Please join us, the full description and agenda follows, and you can register here.
In coordination with one major consulting firm and one important CRO in the Pharma arena (Rondaxe and TD2), Helsinn Advanced Synthesis is organizing a drug development symposium. Three major companies involved in API Manufacturing, CMC Services/Consulting and Clinical Development will give a short technical and educational presentation related to their expertise.
The symposium will also offer the opportunity to share your ideas with other participants. At the end of this event, the organizers cordially invite you to join them for lunch.

Rondaxe Drug Development Workshop

Synopsis

Helsinn Advanced Synthesis: The choice of the right CMO to avoid pitfalls by successfully transferring your API / HPAI process. Implementing a roadmap to avoid potential problems and extra costs.

TD 2: Integrates world-class preclinical, clinical and regulatory expertise with “-omic” science and provides unique drug development strategies and services aimed at minimizing the risk for clients in the oncology drug development industry.

Rondaxe: De-risking CMC through experience, project and knowledge management; utilizing virtual business development expertise to maximize value realization

Program

9:00 AM	Check-in, Continental Breakfast
10:15 AM	Welcome Speech Pierre Vitaloni, Manager Business Development Helsinn Advanced Synthesis
10:30 AM	Helsinn: Supply chain challenges for the Biotech / Pharma Industry Dr. Waldo Mossi, Senior Director Sandra Moro, Deputy Director Business Development
11:15 AM	TD2: Innovation and Precision – The future of oncology clinical development Linda Vocila, Director of Clinical Operations
12:15 PM	Rondaxe: Improving value realization with de-risked CMC and virtual business development Jeffrey Evans, Rondaxe Managing Member
12:40 PM	Rondaxe: How to stay compliant in the currently changing regulatory environment Karl Hofmann, Rondaxe Quality, President
1:00 PM	Participants’ Discussion & Closing Speech
1:15 PM	Lunch

Event Details

Who: Biotechnology professionals in the greater San Diego area
What: San Diego Biotechnology Network Partner Event May 27th Rondaxe Drug Development Symposium
When: Thursday, May 27th, 9:00-2:15 p.m.
Where: Tango Del Rey, 3567 Del Rey Street, San Diego 92109 (Directions below)
Cost: $20/$15 Academic, +$5 at the door (cash/check only)
Contact: http://sdbn.org/contact
For more information about the event: http://sdbn.org/may

Directions: From the North: South on Interstate 5, Exit Balboa Ave, Straight to 4th Traffic Light then left on Bunker Hill St. Building directly ahead 3 blks. From the South: North on Interstate 5, Exit Grand/ Garnet Ave, Straight to 3rd Traffic Light then right on Bunker Hill St. Building directly ahead 3 blks. Park on the street or in the structure just past Tango del Rey.

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#SBS10 Day 4 Meeting report: Cracking the histone code
Posted by Dr. Gunn April 15th, 2010 .
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Today is the final day of reports from the 2010 meeting of the Society for Biomolecular Science in Phoenix. The meeting organizers have been excellent hosts and I’d like to express my sincerest thanks for their hospitality. After this, I have one last post containing all the interesting little observations and snippets of info that I deserve a mention, but didn’t fit into the larger topical posts. I also had some interesting discussions outside the official event that I’d love to continue online.

This morning’s session was on epigenetics and it probably won’t surprise my academic audience that pharma has, for the most part, passed on debating whether or not there is a histone code and has instead devoted itself to developing tools for writing, reading, and erasing epigenetic modifications. So what are they doing, then? (more…)

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#SBS10 Day 3 – Smart mice and blowing House, M.D.’s mind: Drug discovery in epigenetics
Posted by Dr. Gunn April 14th, 2010 .
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At the afternoon session of the Society for Biomolecular Science in Phoenix, it’s all about epigenetics, the study of heritable changes that don’t involve changes in genetic sequence.  Epigenetics explains why identical twins turn out a little different and even clones won’t be exactly identical.

Manfred Jung from Freiberg kicked off the session giving an overview of recent developments in epigenetics and presented what would become the central theme of the afternoon: Here are some diseases which haven’t received the amount of attention they deserve, here are some enzymes and proteins that cause the diseases when there’s something wrong with them, here’s how to target those enzymes. Go get ‘em, boys! (more…)

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#SBS10 report: iPS disease models coming of age for neurology
Posted by Dr. Gunn April 14th, 2010 .
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I went to a morning session on stem cells on day 2 of the Society for Biomolecular Science meeting in Phoenix, a meeting focused on advancements in drug discovery and screening technology.  After this, it’s all epigenetics.

Stephen Haggarty, Director of the Stanley Center Department of Chemical Neurology spoke on stem cells as genetically accurate disease models. The idea here is that you can take cells from a patient (and relatives) and use the clever trick first reported by Yamanaka et al. to convert skin fibroblast cells into stem cells, called induced pluripotent stem cells, or iPS cells.  What this gets you is a genetically identical population of cells to do experiments or drug screening on. Since they all share the genetic mutation or mutations that are responsible for the disease affecting the patient, they’ll give you an early indication of how the drug would affect the patient. The challenge here is getting a population of cells that actually act in the dish as they would in the patient, and Dr. Haggerty reports progress his group has made in this area.

Ever since Yamanaka’s paper came out, the promise of the technique was to create patient specific stem cells for either rejection-free transplants or drug screening, yet we’re only just starting to see cell lines become available for use in this way.  There are many issues related to the technique of inducing the stemness that causes cells to behave in ways that isn’t true to the disease, and the degree to which one cell within a tissue differs from neighboring cells in the same diseased tissue varies are problems that are only just beginning to be addressed. However, using a heritable and common neurological disorder, Fragile X syndrome,  in which the genes involved are known, he’s derived some patient specific cells which act like the disease cells do in the body.  Using fibroblasts from the Coriell repository, a repository of cells including those from diseased individuals, they derived some iPS cell lines that accurately behave as do cells isolated from a diseased individual and therefore make a good disease model.  This approach could still run into complications from the effects of the stem cell induction process, but it seems fairly promising.

Work on a more complex genetic disorder, Bipolar disorder, is ongoing.

‘Technical note: Lithium for bipolar disorder is an old therapy, but Li also inhibits GSK3beta, activating Wnt and promoting cell division and other stem cell properties, so expect some interesting hits to be found in this area.

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SBS Meeting report shows strong growth of Pubchem database #SBS10
Posted by Dr. Gunn April 14th, 2010 .
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I’m blogging this week from the 2010 Society for Biomolecular Science meeting with my colleague Mary Canady.  I’ll be covering the scientific sessions and sharing interesting developments in drug discovery and screening technologies. You can also follow the #SBS10 hashtag on twitter for updates.

On Tuesday, Steve Bryant from NIH gave a report on the increasing utility of the NIH Pubchem database for pharma drug screening programs.  The Pubchem database, named after Pubmed, the go-to resource for life science research abstracts, is an open repository for structure and activity information about molecules which have drug potential. The database is being developed under the Genbank model, wherein researchers are encouraged to upload the results of screening runs so that this information can be linked to in publications and accessible to others.

As a resource, Pubchem has seen strong adoption by researchers in industry and academia.  To give a quick snapshot, the number of contributing organizations have grown 5-fold over the past 5 years. 60000 users submit data daily, with the number unique substances now numbering around 70 million.  For each of these compounds, information on bioactivity is also being collected. Over 90 million activities are associated with these compounds, and the rate of increase of this bioassay data is on the steep part of the exponential growth curve, meaning that number I just wrote is already wrong. While the bioassay information currently requires direct upload, there are plans to derive additional data from published literature.

Following Steve’s report, Josh Bittker gave a brief summary of how the Broad Institute is using Pubchem. They have a reporting mandate as part of a grant and are developing a pipeline for automatically submitting machine readable assay results to Pubchem.  As part of this automatic reporting, there’s an automatic embargo on the data for 1 year.

Simone Graeber then gave an update on an EU effort along the lines of Pubchem.  They go a little further than just a database, developing their own library of 0.5 million compounds, with a 17000 compound subset derived from this covering much of the “activity space” of the larger set and more usable by smaller groups without the resources to screen the whole larger library.  You may be wondering, as someone in the audience did, why they’re developing their own database instead of submitting to Pubchem. Apparently they included some proprietary compounds in their library and there are legal issues complicating the assay result reporting.