Next Generation Sequencing—Pass the Pipeline, Please

August 25th, 2009 by Nancy Miller Latimer, M.S.

The drug discovery landscape has morphed into a larger playing field.  Move over small molecule; make room for biologics, diagnostics, biomarkers, and translational research–all key players as medicine gets personal and the division between research and the clinic narrows.  The “one drug, many people” paradigm now has a sibling “one person – just the right drug” paradigm.   Deep sequencing is a technology that figures prominently in the new birth.

As large pharma scrambles to figure out what the new landscape will mean for them, they (1) have reorganized along therapeutic lines with translational research and biomarker departments and (2) have placed their orders for or taken delivery of the next generation of sequencers. And this is not just pharma that is interested.  Biotech, academic and commercial core sequencing facilities, and government research organizations worldwide are actively acquiring the next generation of sequencers—no one wants to be left out.  Obama has pumped billions of dollars into US research.  At some point, sizable chunks will find their way into sequencing facilities[1].

The deep sequencing technologies have moved very fast, while the price of sequencing a human genome has plummeted.  It is no surprise that this inverse relationship is fueling sequencer sales and some anxiety about analyzing all those reads.  The price of sequencing a human genome will soon be under $1K.  “…the much-discussed goal of the $1,000 genome could be attained in two or three years. That is the cost, experts have long predicted, at which genome sequencing could start to become a routine part of medical practice.”[2] An intense desire for an unprecedented “look” into the genome, coupled with analytic inexperience, has created an unmet need in the marketplace.  Hardware vendors are keen to make NGS[3] data analysis as user-friendly as possible, setting the stage for a perfect Pipeline Pilot application.

Accelrys has been investing in a pipelining solution for NGS for over a year now.  Pipeline Pilot is an integration backbone for many hard-working scientific “collections” and third party applications.  Many IT and domain scientists are “hooked” on Pipeline Pilot to deploy robust and easily modified “protocols”.  I know from firsthand experience about the Pipeline Pilot “addiction”.  Oh, and if you aren’t aware, Pipeline Pilot is not just about chemistry anymore.  Complementing our released collections for Imaging, Sequence Analysis, Gene Expression, Plate Data Analytics, and Mass Spec for Proteomics, we look forward to releasing on our first version of our NGS Collection.   You can expect the same drag and drop functionality that you have come to expect and enjoy with the other Pipeline Pilot Collections.

In our first version of our NGS collection, we are making choices about which use cases to support. I am in the process of collecting input from our customers and those awaiting this new product—but I’d like to hear from you, too.  Do your plans for NGS analysis include cloud computing?  If you would like to participate in this survey, please send your name and contact information to me at nlatimer@accelrys.com.  Also, if you are interested in being an alpha or beta tester, let me know!

[1] http://blogs.wsj.com/health/2009/07/08/genetist-francis-collins-nominated-to-head-nih/

[2] http://www.nytimes.com/2009/08/11/science/11gene.html?_r=1&hp

[3] NGS stands for Next Generation Sequencing

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What do the latest animal testing figures tell us?

July 31st, 2009 by Gerhard Goldbeck-Wood, PhD

The UK Home Office released new statistics on animal testing in the UK last week (21 July 2009). As reported by the BBC , the figures show a strong upward jump.  In 2008, 3.7 million procedures using animals were carried out in the UK, representing an increase by 455,000 or 14% in 2007. Digging a bit deeper into the statistics shows some interesting trends.

The increase in number comes almost entirely from a strong increase in the number of fish procedures (278,000), followed by mice (197,000).

Animaltestingchart1

Whereas others have remained stable or declined:

Animaltestingchart2

According to the report, these seem to be strongly related to increases in biological research. That’s got to do with the increasing attention and promise of personalized medicine and genetic targeting.

It’s also interesting to note that, apart from breeding related activities, medical research and pharmaceuticals safety dominate by far. Procedures relating to ecology, and substances used for example in industry, agriculture and food only sum to about 100,000, or just a few percent of the total. Also, these procedures have seen a decline overall, for example, by 20% for substances used in industry. There have been no tests at all on cosmetic substances, in fact none since 1998.

So what’s it telling us?

There have been great advances over the last 10 years in making use of alternative testing methods. In vitro testing has become more established for cosmetics, and animal testing either has been phased out already or is on its way out very soon in Europe as a result of the 7th Amendment to the  Cosmetics  Directive.

While similar trends hold for substances used in industry, it will be interesting to follow this trend in 2009 and 2010, as the majority of substance assessments for the submission of dossiers due to the REACH legislation are taking place. By anecdotal evidence, talking to folks during the recent SETAC conference, labs are getting busy, and in some cases completely booked already with REACH related work. However, that work load also includes massive amounts of data gathering, literature searching, analytical testing, as well as in-silico methods such as QSAR and read-across. Quote: “Some people will soon get in a panic about closing the data gaps.”

The question is, how are organisations accessing, processing and handling the information, and making best use of data and information in the literature that’s already out there?  How about a web based ‘workbench’ that’s geared up to support toxicologists and other scientists as well as managers in the field to gather, process, share and report that information? We’ve built out a proof-of-concept for anyone to take a look and try, which includes examples of different functions, from database and document searches, and predictive toxicology analysis to facility monitoring. The trick is that as it is built on the basis of Pipeline Pilot protocols, it’s highly configurable and extensible with almost any third party tool. So it can be built or re-modelled to match the user’s routine practices.

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Another Oncology Win in Personalized Medicine

June 1st, 2009 by Accelrys Team

header09_r1_c12At the World Biomarker Congress in Philadelphia this past week, I had a chance to catch up with a colleague, now a senior executive at a European-based global pharma company. Our conversation inevitably turned to Personalized Medicine, a shared interest of ours.

He updated me on some pre-release data that will be shown at Sunday’s meeting of the American Society of Clinical Oncologists (ASCO), concerning Iressa, Astra Zeneca’s lung cancer medication. Previously thought to be a commercial and scientific failure, Iressa is now at the vanguard of therapies “rescued by targeting.” iressa_logo

Targeted therapies are drugs that are shown to have a particular effectiveness in a subset of the overall population. “Targetting” in this context refers to the identification of a genetic difference which corresponds to better clinical outcomes for a particular group of patients. In the case of Iressa, the data that will be presented tomorrow shows that cancer progression is halted for over nine months in patients with the mutation, compared with 6 months for patients receiving chemotherapy (median values).

About one in ten cancer patients has this mutation. Overall, lung cancer kills 1.3 million people per year.  

But what if a patient doesn’t have the mutation? Then Chemotherapy is the better treatment option, which can hold back the cancer progression for five months, compared to only 1 month for Iressa (again, median values).

logo-herceptinIf these results are confirmed, Iressa will join the growing list of personalized medicine success stories in Oncology, which began with world’s first targeted therapy, Genentech’s Herceptin, in 1998. Since Herceptin, we’ve seen other highly publicized therapies with genetic targeting, such as Erbitux.

imcloneBut why so much genetic targeting in cancer, and not (yet) in other indications? Is it the serious nature of the disease or the quality of the data (high compliance in large populations) or something else? The Iressa story gives us a clue.

Astra Zeneca didn’t give up on it, and pursued semi-anecdotal findings of efficacy in some patients, even though it was not effective in the larger clinical trial population. Because of the large potential revenues resulting from effective cancer treatments, it becomes economic for companies to invest in risky clinical trials for treatments that might only be effective in 10% of the population.

Rittenhouse Square

Rittenhouse Square

As my colleague summed it up during lunch at a café on Rittenhouse Square in Philadelphia, “It’s about the money, of course. Cancer kills, and so cancer treatments cost.”

 

Oncology is clearly the vanguard for targeted therapies. But as scientists and marketing executives become more familiar and comfortable with a development process that results in a fragmented market, the techniques will inevitably be replicated in treatments that can only demand lower prices because they treat less serious diseases.

 

And that will make us all winners, no matter what mutations we have.

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More Personalized Medicine Surprises at ASCO Meeting?

May 12th, 2009 by Accelrys Team

am09-general1The abstracts for the semi-annual meeting of the American Society of Clinical Oncologists (ASCO) go up on their website this Thursday, May 14 at 6PM EST. This is a scientific conference that consistently reverberates on Wall Street, because so much of pharmaceutical sales is driven by cancer indications. Many of the largest mergers over the last six months had oncology as the subtext, such as Roche & Genentech and Eli Lilly & ImClone.  

 

kras1At a recent ASCO conference in January, 2009, “personalized medicine” went from a theoretical concept from science to a genuine business reality. At that conference, ASCO recommended a genetic test for a mutation in a crucial gene on human chromosome 12, called “KRAS,” that regulates cell division via signal transduction. If a colorectal cancer patient had the mutation, entire groups of therapies, called “anti-EFGRs,” were no longer recommended. This is not a rare mutation, as an estimated 40% of patients have the mutation. 

The result? Profound, immediate changes in market share potential for pharma companies offering the anti-EFGR monoclonal antibody therapies cetuximab and panitumumab.

In terms of pharmaceutical revenue, this is a very big deal. Each therapy carries a price tag that reflects the critical nature of the cancer indication, generally over $2000 per month. There are 150,000 new cases diagnosed in the US every year (resulting in 50,000 deaths). So just a simple calculation of the market shows that about $1.5 billion annual new business disappeared for makers of anti-EGFRs (40% of patients x $2,000 per month per patient x 12 months x 150,000 new patients per year), which of course excludes revenues from the estimated 400,000 current colorectal cancer patients.

And in terms of fighting this nasty scourge, the ASCO announcement was a very big deal. It personalized the treatment for 60,000 new patients annually (40% x 150,000) who would have otherwise placed their hopes for survival on a therapy that simply wouldn’t work for them.

The trade name for Cetuximab is Erbitux(FDA approval 2004), which is marketed in the US by ImClone & BMS, and in the rest of the world by Merck. Panitumumab is marketed by Amgen globally as Vectibix (FDA approval 2006).

Based on the stock market dip over the last 18 months (called the “Global Financial Crisis”), it is hard to discern definitively what effect the ASCO recommendation had on the stock prices of the companies involved.

But the bigger change will likely be observed internally at these companies, as they continue to commit resources to biomarker discovery and qualification. Biomarker activities around KRAS might have identified the lack of efficacy in the mutant form, which corresponds to not being effective in 40% of patients.

When it comes to post-hoc personalized medicine for blockbuster drugs, the pharma industry clearly doesn’t like surprises. Biomarker activities and translating those activities into clinical trials push those surprises into the research phase, where they belong.

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