BioScience Biz

Clinical research activity up significantly in 2008

According to a report in FierceBiotech, surprising news came out of the recently completed 45th Annual Meeting of the Drug Information Association (DIA).  Despite cutbacks in the international biopharma industry, clinical trial activity was up in 2008. Overall, 795 new clinical trials were launched in 2008, compared with 662 that were initiated in 2007. There were 5,700 active INDs in 2008, which represents a greater than 20 percent increase over the 4,744 INDs active by the end of 2007—a substantial increase.

Trial activity was also assessed by the number of new FDA form 1572s, which all clinical investigators on FDA-approved trials sign as a promise that he will abide by the federal guidelines set forth in the Code of Federal Regulations for the use of drugs in an investigational setting. The FDA registered 23,827 new 1572s from clinical investigators in 2008, up 5.8 percent from the previous year. However, the number of new 1572s from China-based clinical investigators fell 30 percent due to the long approval process, but Indian-based 1572s rose 14 percent. South Korean investigators submitted 74 percent more 1572s while submissions from Taiwan rose 21 percent. Clinical trial activity is also up in Eastern Europe where the FDA saw significant increases from Russian investigators (20 percent), as well as Romanian (44 percent), Polish (17 percent) and Bulgarian (57 percent) clinical researchers.

It will be interesting to see the data for 2009.

DIA is a professional association of more than 18,000 members worldwide who are involved in the discovery, development, regulation, surveillance, or marketing of pharmaceutical products. The DIA annual meeting is the biopharmaceutical industry's largest, longest running, international event.  

More stem cell trial problems for Osiris Therapeutics

Clinical trials can be vexing, just ask anyone associated with Osiris Therapeutics, a leading stem cell therapeutic company. The company recently announced that their mid-stage, Phase II trials to treat chronic obstructive pulmonary disease (COPD) with adult stem cells (called Prochymal) did a great job reducing inflammation, but failed to improve pulmonary function. The 62 patients enrolled in the trial will be followed for two years in order to assess possible long term effects of the therapy.  Nevertheless, these results reveal how complicated and unpredictable clinical trials can be. 

COPD is really a combination of two maladies, chronic bronchitis and emphysema, rolled into one diagnosis. The disease commonly is caused by smoking, which triggers an abnormal inflammatory response in the lung in some individuals. In the larger airways, this inflammation causes chronic bronchitis, while in the microscopic lung sacks called alveoli, the inflammatory response causes emphysema, which is the destruction of the lung tissues where oxygen and carbon dioxide are exchanged. The result of this double inflammatory whammy is to limit the flow of air to and from the lungs causing shortness of breath. COPD is poorly reversible and usually gets progressively worse over time. In 1990, COPD was the third leading cause of death worldwide.

"...anyone would have predicted a priori that reducing lung inflammation would translate to improved lung function."

Given the central role of inflammation in the pathogenesis of COPD, anyone would have predicted a priori that reducing lung inflammation would translate to improved lung function.  But, this is like believing that the baseball team with the most hits will automatically win the game. It is not uncommon for such surrogate measurements of efficacy to fail to predict the final outcome—the full game must still be played and the clinical trial done before the outcome can be certain. 

Osiris is also testing Prochymal for its ability to treat other inflammatory diseases, so the reduced inflammation seeing in the COPD trial might be a good omen for these other maladies, even if Prochymal is of little benefit to patients with COPD. Unfortunately, however, last month Osiris was forced to discontinue enrollment in a phase III trial to treat the chronic inflammatory bowel condition known as Crohn’s disease. The reason for this, according to the company, is that patients on the placebo arm of the trial were doing unexpectedly well and interim data analysis indicated that this response would make it impossible to show a benefit of the Prochymal therapy. After examining the data with the FDA, it was concluded that  that there was a potential “systematic design flaw” in the trial that “might be related to the fact that patients responding to the initial stem cell therapy were eligible to participate in a second, longer-term trial evaluating Prochymal as a maintenance therapy. Because the current standard for determining response of Crohn's patients to therapy is largely subjective, there may have been response bias to meet the eligibility requirements for continuation of therapy in the longer-term maintenance trial”.

Prochymal is a preparation of mesenchymal stem cells obtained from the bone marrow of healthy donors and specially formulated for intravenous infusion. In addition to Crohn’s disease, Prochymal also is being tested in two other Phase III studies to treat both acute and steroid-refractory graft-vs-host diseases (or GvHD). The FDA granted Prochymal Fast Track status for these and Crohn’s diseases and both the FDA and the European Medicines Agency granted Prochymal Orphan Drug status for GvHD. In addition to the COPD trail, Osiris is also conducting Phase II Prochymal trials for the treatment of acute myocardial infarction and type 1 diabetes.  The therapy also is being developed as a potential treatment for acute radiation syndrome.

"...the company has a lot riding on Prochymal and can ill afford any further
clinical trial snafus." 

Osiris also has another stem cell product in the pipeline, called Chrondrogen, which is being tested for its ability to regenerate cartilage. Last November, Genzyme paid Osiris $130 million upfront and promised up to $1.3 billion more in milestone and other payments to gain commercialization rights to Prochymal and Chondrogen outside the U.S. Osiris retains the rights to market these products in North America.  Clearly, the company has a lot riding on Prochymal and can ill afford any further clinical trial snafus. 
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© 2009 Steven S. Clark, PhD, some rights reserved.  Articles contained herein, are meant to be distributed freely to interested parties. However, any use, including excerpts from any article, must credit Steven S. Clark and provide a link to the original article published in BioScience Biz.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

Slicing and Dicing SBIR Award Data

If you like numbers and acronyms, you will like this article. SSTI (State Science and Technology Institute), a national nonprofit network of practitioners and policymakers dedicated to improving the economy through science and technology, recently published SBIR Phase I proposal and award statistics by state for 2008. They also have similar data going back a few years. Being an Excel addict, I copied and pasted the data into a spreadsheet and was able to parse interesting tidbits from the larger meal of information. For instance, in 2008 the overall success rate for all Phase I SBIRs was just under 17%, somewhat better than research grant success rates at most NIH institutes, with which I am painfully familiar. The percentage of SBIR applications that were awarded ranged from a low of 9.4% at the DoT to a high of 24.1% at the NIH (more than twice the rate of RO1 investigator-initiated research grants in 2008).  Other agencies awarded grants at the following rates: DHS (9.6%), DoD (14.9%), NSF (15.4%), USDA (17.4%), NASA (18.4%), and DoE (18.7%). The raw data can be found on the SSTI web site.

Also interesting is the total number of SBIR grants awarded by the different agencies. In 2008 a grand total of 3555 Phase I awards were made by all participating federal agencies.  By far, the DoD made the most awards at 1825, more than half the total number of awards.  Trailing way behind were NIH (739 awards), DoE (280), NASA (276), NSF (224), USDA (77), DHS (28) and EPA (25).  Other agencies, such as NOAA, are not included here because they awarded so few SBIR grants they had minimal impact on these analyses.

State-by-state data

As I played with the spreadsheet and filtered the data in different ways, I learned a few other things. The top ten states with the most awards are the following in descending order and with the total number of awards in parentheses: California (688), Massachusetts (476), Virginia (224), New York (195), Colorado (182), Maryland (156), Texas (140), Pennsylvania (129), Ohio (120) and Florida (102). Wisconsin came in at a mediocre number 24 with a total of only 37 awards in 2008.

"...SBIR success pretty much follows Big 10 football and basketball success..."

If these data are taken as a measure of the success by which each state translates new technology into business, then Wisconsin (#24) is well behind Michigan (#12), Alabama (#13) and even New Mexico (#14). Illinois comes in at #18 and Minnesota at #22.  Compared to other Big 10 states, Wisconsin is just ahead of Indiana #25.  Iowa trails at #35. If you think about it, SBIR success pretty much follows Big 10 football and basketball success with Michigan and Ohio on top, while Wisconsin is in the second tier with Minnesota, Illinois and Indiana.  A cynical observer might conclude that sports success predicts technology business success. But, that seems to only work in the Big 10, since Massachusetts, with no sports powerhouses, is in the top two of SBIR grant winners from almost all agencies (more on that below).

At face value it may be surprising that states like New Mexico and Alabama are more successful than Wisconsin at winning SBIR grants (ok, so New Mexico also kills my sport’s success analogy).  And these states are consistently more successful than Wisconsin at winning SBIR grants.  From 2005-2008 Alabama won 103, 79, 72 and 73 grants—a declining trend. During the same period, New Mexico SBIR awards were more constant with an uptick in 2008, numbering 57, 60, 56 and 67. In contrast, Wisconsin enjoyed an upward trend from 2005-2007 with a downtick in 2008, with 36, 42, 49 and 37 SBIR awards, respectively. But, the reality that Alabama and New Mexico are more successful than Wisconsin in this regard needs to be tempered by the fact that different states focus on different technologies and may be more competitive in different areas. For instance, in Wisconsin, the number of SBIR awards from each federal agency in 2008, with the success rate in parentheses, is as follows: 1 award from NSF (6.7% success), 1 from USDA—surprising for an ag state,  (8.3%), 10 from DoD (14.7%), 2 from NASA (11.8%), 20 from NIH (29%), 2 from DOE (13.3%). Wisconsin is trending up in NIH supported SBIRs with 13, 19, 22, and 20 grants over the years 2005-2008.  Over the same period, DoD grants were fairly consistent in Wisconsin, numbering 8, 10, 13 and 10. Clearly, Wisconsin is spinning out more life science related tech business than technology business from other industries, with defense-related technology business springing up at about half the rate of biotech business.

Compare Wisconsin’s strong emphasis on life sciences to what is happening in Alabama and New Mexico. Alabama’s 2008 SBIR portfolio is as follows: 2 grants from USDA (40% success rate), 56 from DoD (16.7% success), 4 from NASA (10%), 7 from NIH (18.4%), 4 from DOE (30.8%).  Clearly Alabama focuses on defense and lags behind Wisconsin in biotechnology transfer.

In 2008 New Mexico also focused on defense as well as space and energy related technology transfer. This state won the following SBIR grants: 5 awards from NSF (19.2% success rate), 2 from USDA (40%), 1 from DOT (50%), 24 from DoD (14%), 13 from NASA (32.5%), 5 from NIH (14.7%), 14 from DoE (41.2%).  The state has consistently done well with energy grants since 2005, but the NASA grants awarded in 2008 represents a 2-3 fold jump from previous years.

One take home message from these analyses is that if you are an engineer or chemist, go to New Mexico, if you are a biologist, Wisconsin is a better place to find a job.

Room to improve in Wisconsin

Clearly, in 2008, biotech was the strength of WI SBIR success—with more NIH SBIR awards than awards from all other agencies combined. Wisconsin was 11th in the country in the number of NIH SBIR grants, behind the usual suspects. The top 10 in order were, CA, MA, MD, NY, TX, NC, PA, CO. MI and WA. But after CA (140 biotech SBIR grants) and MA (with 103), which together won 33% of all the NIH SBIR grants, there is a sharp drop in the number of SBIRs awarded by NIH. For, instance, coming in at number three, MD only won 43 SBIR grants from NIH. So, Wisconsin, while ranking near the top 80th percentile for NIH awards with 20 grants, is further behind the leaders than its ranking suggests. 

"...investment in quality research universities pays large dividends
in developing technology businesses..."

Interestingly, CA and MA are also in the top two for NSF, DoD, NASA, and DoE SBIR awards. It is no accident that many of the elite research universities in the US are found in these states and it is these academic elites that feed the new technology pipeline that leads to new business development. Together, these data point to the reality that investment in quality research universities pays large dividends in developing technology businesses—a lesson that Wisconsin cannot afford to forget, but sometimes tries to forget. This state has one elite research university and it pays huge dividends.  Without the UW-Madison, which spins off the lion’s share of biotech and health related (and other) technologies, we would be much farther down the line spinning out new technology businesses.  One question is how can the state get the UW-Milwaukee, Medical College of Wisconsin, Marshfield Clinic and other institutions to move up in R&D status to help make Wisconsin more competitive in generating life science technology businesses? Another question is what would it take to make Wisconsin more successful in translating engineering, energy, defense and agricultural technology into state businesses.

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© 2009 Steven S. Clark, PhD, some rights reserved.  Articles contained herein, are meant to be distributed freely to interested parties. However, any use, including excerpts from any article, must credit Steven S. Clark and provide a link to the original article published in BioScience Biz.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

The Biotech Industry: Promise vs Reality

The Promise

Biotechnology as a business burst on the scene in 1976 when Genentech was launched to commercialize the new discoveries of how to clone and express human genes in bacteria.  This was soon followed by biotech companies commercializing monoclonal antibody technology, combinatorial chemistry and more recently “omics” technology (genomics, proteomics, metabalomics), high throughput screening and other continually emerging and commercializable technologies. 

"The lofty promise of all of this was that through improved technology and enhance understanding of biological activities, the process of drug R&D would become more efficient, faster, less risky and cheaper."

The lofty promise of all of this was that through improved technology and enhance understanding of biological activities, the process of drug R&D would become more efficient, faster, less risky and cheaper. This promise helped foster the perception that, compared to the pharmaceutical giants, smaller biotech companies are more agile, innovative and productive at R&D and, therefore, fill an important gap that the larger, ossified drug companies can not. It has been suggested by more than one industry observer that big pharma should focus on production, marketing and improving current products, leaving the innovative and cutting edge research to the more flexible and adaptable small biotech companies.

The biotech industry has certainly bought into this hope—it is rife with optimism that it can transform the pharmaceutical industry. The expectation has been that the biotech industry would follow a trajectory similar to that of the more mature semiconductor sector where the advent of solid-state technology stimulated fundamental product improvements and reshaped the whole electronics industry.

It is hard to dispute the notion that since genetic engineering technology first appeared in the early 70’s, we have seen the greatest scientific revolution in history.  By all measures—publication rates, patent activity, growth of biological databases—biomedical information has exploded.  This success has greatly increased the number of potential therapeutic targets and new molecular entities (NME) that represent potential new drugs. All of this has bred wide optimism by scientists, investors, Wall Street, policymakers, and others, that this life science revolution would lead to a trove of new drugs and ultimately to enormous financial rewards.

A further, related promise of the biotech revolution is that enhanced understanding of biological processes will allow more intelligent selection of new drug candidates and drug targets, thereby making drug R&D more efficient, less risky and less costly.  

The Financial Reality

Indeed, there have been impressive biotech success stories, such as Amgen, Genentech, Genzyme and a handful of others, but, how has the sector as a whole lived up to this lofty promise?  Thirty years after the launch of the biotech industry, Gary Pisano, a professor at the Harvard Business School, decided to empirically test how well the biotech sector has lived up to its potential.  He collected and dissected financial and productivity data for 293 publicly held biotech companies and from 20 large pharmaceutical companies that existed between 1975 and 2004 and his results, published in the book, Science Business, are sobering.

"...over the years, income has been flat, hovering close to zero..."

Here is what he learned about investment returns on public equity: A hypothetical investor who purchased all 340 biotech IPOs between 1979 and 2000 and held those shares until January 2001, or until company acquisition, would have realized an average annual return of 15%.  Not bad, but not stellar for such a high risk sector.  If the same investor purchased a diversified biotech portfolio in 1981 and sold it at the end of 2003, he would enjoy an 8-fold return, or about a 10% compounded rate of return per year.  Compare this to the more risk-adverse investor who invested in Treasury Bonds; he would have realized a 12-fold total profit and the same investment in the Dow Jones would be worth 21-times more.  Clearly, the return on biotech investment is disappointing when compared to alternative and less risky investments. To be fair, this comparison pits the entire biotech industry against other investment vehicles.  An individual investor who was more selective in the biotech companies he invested in, could have done much better (or worse) depending on his portfolio.

More revealing, however, was Pisano’s analysis of revenue and earnings for the whole biotech sector between 1975-2004. To measure this, he created a yearly aggregate income statement for the entire biotech industry. In other words, he combined the income statements of the 293 companies into one industry-wide income statement. 
   
His analysis showed that over time, total sales for the sector increased exponentially, as one would expect.  However, over the years, income has been flat, hovering close to zero until about 2000, when total sector income actually began to decline.  By 2004, however, the industry showed its first positive income of about 7% of total sales.  But, this is misleading since the most profitable firm, Amgen, heavily skews the results.  Excluding Amgen from the analysis reveals that the remaining biotech sector sustained steady losses throughout its history and never has been profitable. Pisano points out that since this analysis does not include privately held companies, the situation for the biotech sector is even bleaker since almost all privately held biotech companies lose money.

Pisano also noted that positive economic performance is concentrated in only a very few biotech firms—the vast majority of biotech companies have never been profitable.  When considering only those companies with positive cash flows, just fifteen firms account for 93% of the positive income for the sector and two, Amgen and Genentech, accounted for 53% of the total income of these profitable companies.  Some firms have existed for close to 20 years without ever generating positive cash flows.

The Productivity Reality

In simple terms, the raison d'être of the biotech and pharma industries is to turn financial resources into drugs, which in turn should drive profitability.  But, it is no secret that over the last few years, the big pharma R&D productivity has slipped dramatically. Even though R&D spending has increased, the rate at which NMEs are introduced has steadily decreased. Many industry observers argue that biotechnology will be the cure for this malaise and that big pharma companies ought to outsource its novel R&D to the leaner, meaner biotechs. 

Pisano also investigated this promise that the biotech industry is the answer to the productivity crisis in the pharmaceutical industry.  As a measure of productivity, he compared the inflation-adjusted cost per NME between the top 20 pharma companies in the world and the panel of 293 publicly held biotech companies. This analysis was complex with many confounding factors that needed to be accounted for, but these details are beyond the scope of this review. The important thing is that Pisano’s analysis showed no evidence that biotech companies are any more or less productive or innovative than pharmaceutical companies. Productivity and innovation between these two industries has been a dead heat almost since the beginning of the biotech industry.  

"..the biotech R&D productivity and novelty boom that has been
expected has not happened."

In other words, evidence shows that, when it comes to R&D, biotech companies are not more productive or innovative than their larger brethren, which means that the biotech R&D productivity and novelty boom that has been expected has not happened. Pisano writes, “If big pharmaceutical companies are looking to biotech to help them fill their revenue gap, these data would not make one optimistic.”

Conclusions

The malaise of the pharmaceutical industry is no secret, but Pisano’s analysis suggests that, by both financial and operational measures, the biotech sector also has not been healthy during its entire 30 year life. Only very few companies have ever been profitable, and an even smaller number of biotech “elites” have achieved substantial profits. These include Amgen, Genentech, Genzyme, Biogen, Idec and others, which, interestingly, were also among the earliest entrants into the industry. Hence, one might argue that with time, additional companies will rise up to finally realize the biotech promise. But after 30 years, or about 2 product development life cycles according to Pisano, there is nothing to suggest that this will happen in the foreseeable future. In fact, projections that profitability is just around the corner have been made since the earliest days of the biotech industry and have been consistently wrong. The bottom line is that the biotech sector so far has failed to reach its enormous commercial and economic promise.

This begs the question—given this lackluster performance, how has the biotech sector been able to continually attract capital over such a sustained down period from market forces obsessed on quarterly performances? A more important question is whether the industry will continue to be able to attract such capital if it continues to operate in the red. An ominous history lesson might come from the dot-com bubble and burst.  Pisano points out that once it became clear that the vast majority of these internet firms lacked a viable business model, the capital markets quickly pulled the plug. Pisano attributes the remarkable resiliency of the biotech sector to an “irrational exuberance” by investors who hope to invest in the next Amgen, and this is not unlike the exuberance that led to the dot-com bubble. But the sobering reality is that in 2006, only 20% of all publicly held biotechs had any products on the market or earned any royalties from products commercialized by partners. 

Thus, the vast majority of biotechs are simply R&D entities that have nothing to sell, and are not much different than most of the dot-com companies that existed just before the bubble burst.  Sobering indeed.

Fighting back against the high-handed nay-sayers

In a Wall Street Journal op-ed, authors David A. Shaywitz and Thomas P. Stossel take on high-minded academics who relentlessly attack university-pharma associations.  Labeling such critics as "PharmaScolds" they point out that relationships between university researchers and medical product companies are under relentless attack by critics who portray these associations as a morality play in which noble academics struggle to resist the dark, corrupting influence of industry. Then they follow with this question: why are leading disease-research foundations increasingly choosing to partner with industry rather than condemn it?

"The goal of medical research is not to publish papers,
but to develop new treatments..."

The answer is that by prioritizing the needs of patients, medical philanthropies remain keenly aware of something academic critics of industry may have forgotten as they've scaled the ivory tower ladder. The goal of medical research is not to publish papers, but to develop new treatments for people suffering from disease. And translating laboratory research into new therapies, in the words of Robert Beall, president of the Cystic Fibrosis Foundation, is something "academics are really not good at."

Read the full article here.
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Dr. Shaywitz is a management consultant in New Jersey.

Dr. Stossel is a professor of medicine at Harvard and a fellow at the Manhattan Institute.

SBIR (non)Authorization Redux?

The latest word from Washington is that getting the SBIR reauthorization passed before it expires on March 20 is about as unlikely as the Cubs winning the World Series without a shortstop.  In order to keep the program alive until Congress can get around to the reauthorization, a continuing resolution (CR) is needed to temporarily extend its life. In fact, the SBIR program currently lives on via CR life-support since the last Congress did not complete the reauthorization bill.

The SBIR Program, created by the Small Business Innovation Development Act of 1982, periodically comes up for reauthorization every few years.  It was reauthorized in 1986, 1992, and 2000 and was slated again for September 2008; but, instead, congress failed to act and the program was temporarily extended by CR to March 20, 2009.

"You are encouraged to contact your congressional representatives..."

In 2008, Nancy Pelosi’s (D-CA) House made a heavy-handed attempt at the reauthorization, and under pressure from the biotech lobby, a bill (H.R.5819) was strong-armed through the House Small Business Committee. A major point of contention was whether to allow companies that are majority-owned by VCs to be eligible for SBIR funding—currently they are not. In other words, the debate centered on whether to emphasize the “S” vs the “B” in the reauthorization act.  To the consternation of the small business community, which was not allowed any input by the Committee, the bill passed and SBIR eligibility was extended to companies mostly owned by VCs.

Over on Harry Reid’s (D-NV) side of the Capitol, and under the leadership of Senators John Kerry (D-MA) and Olympia Snowe (R-ME), the Senate Small Business and Entrepreneurship Committee recommended a compromise bill (S.3362) that was supported by both the biotech and the small business lobbies.  Despite this broad and bipartisan support, Reid never scheduled a vote on it and the 110th Congress adjourned without completing the SBIR reauthorization.

Both bills are now moribund and the SBIR program is on its last legs unless another CR is passed.  The 111th Congress will have to start from the beginning on a new reauthorization bill, but efforts to reconsider the reauthorization bill have not yet begun.  Even if Congress began work on the bill today, it is unlikely that it would make it to Obama’s desk before the end of this year, several months after the program is scheduled to expire. Hence, another CR is urgently needed in order to avoid interruption in the SBIR program.

You are encouraged to contact your congressional representatives to urge them to take action to ensure that the SBIR program does not die from neglect.  Here is a template of a letter you can send to your Representative and Senators. And If you are worried about that SBIR grant application you plan to soon submit, you might consider sending a letter to those who held up the reauthorization last year, including every member of the House Small Business Committee as well as to Senate Majority Leader Reid.

Tell them what an important “stimulus” the SBIR program is for business development, job creation and the economy.  That ought to get their attention.

Wisconsin task force formed to facilitate tech transfer

This article was originally published on genomeweb.com by Ben Butkus.

On the heels of a Wisconsin Technology Council report released last month examining academic R&D deficiencies in the state, the University of Wisconsin system is organizing a task force to examine how UW system campuses can better parlay their research into industrial partnerships and state-based startup companies.

The task force, called Research to Jobs, will comprise members of the Badger State's tech-transfer, venture-capital, and business communities, and will begin working in early March to develop specific recommendations for Wisconsin universities, research institutions, companies, and government organizations that it expects to release by early summer, task force leader Carl Gulbrandsen said this week.

UW system President Kevin Reilly is convening the task force one month after the WTC, an independent, non-profit organization formed in 2001 to advise the state's governor and legislature on science and technology matters, released its report, entitled "The Economic Value of Academic Research and Development in Wisconsin."

Gulbrandsen, who also heads the Research to Jobs initiative, told BTW this week that the overarching goal of the task force is to unlock the potential in the state's universities to use R&D prowess as a driver of economic development.

"We file a lot of patent applications, but we don’t start the number of companies

that our peer institutions in San Francisco or Boston do."

"We get some criticism because we spend a lot of money on research, particularly at UW-Madison," said Gulbrandsen, who is also managing director of the Wisconsin Alumni Research Foundation, the non-profit patenting and licensing arm of UW-Madison. "We file a lot of patent applications, but we don’t start the number of companies that our peer institutions in San Francisco or Boston do.

"I do think we have some environmental conditions that are quite different from those regions," he added. "We don't have the venture capital money that they have, and we don’t have the number of entrepreneurs that they have. But I still think that we could do a better job."

The report highlights the fact that academic science and engineering research activities in Wisconsin totaled about $1.067 billion and were responsible for creating more than 38,000 jobs in 2007, according to statistics from the National Science Foundation, US Department of Commerce Bureau of Economic Analysis, and other sources.

These figures, which do not include some $42 million in research expenditures by the Marshfield Clinic and the Blood Center of Wisconsin’s Blood Research Institute, place Wisconsin 13th nationally in science and engineering research activity.

However, the report also notes that state support for higher education has been weakening over the past 25 years. In the past decade alone, state appropriations as a percentage of the total UW system annual budget have declined from 33.75 percent in 1997-98, when an $880 million state appropriation was applied to a $2.6 billion UW system budget, to 24.21 percent in 2006-07, when a $1.04 billion state allocation covered less than one-fourth of the $4.3 billion UW system budget, according to the report.

In addition, the $3.8 billion that Wisconsin allocated for all R&D expenditures placed it 23rd among all US states. "If not for Wisconsin’s relatively high ranking in academic R&D, the state would slip out of the top half of all US states in total research and development spending," the report stated.

Also, the report noted that approximately one-fifth of the total $1.04 billion in academic science and engineering research activity was centralized at UW-Madison, the UW system's largest campus, highlighting the need to better tap into R&D activity at the other 12 US campuses. It also noted that despite pocketing the lion’s share of the UW system’s cash for these disciplines, UW-Madison has not taken full advantage of its R&D activity for economic development.

Wisconsin's universities "tend to be underutilized assets from the standpoint of research and development and technology transfer," the report stated. "Without a broader foundation in academic R&D, Wisconsin will find it difficult, if not impossible, to leverage these assets in pursuit of a robust, high-tech and knowledge-based economy for the 21st century."

The UW system has made a concerted effort to spread the wealth from UW-Madison to other campuses in the system. One example is the WiSys Technology Foundation, which WARF established in 2000 to manage intellectual property for all other campuses in the UW system.

This had included four-year campuses at Eau Claire, Green Bay, La Crosse, Milwaukee, Oshkosh, Parkside, Platteville, River Falls, Stevens Point, Stout, Superior, and Whitewater; and a number of two-year campuses. However, in July 2007 UW-Milwaukee said it would manage its own IP in an attempt to contribute more to local economic development (see BTW, 7/30/2007).

Nevertheless, Gulbrandsen said that through WiSys "we've learned that there is a lot of talent at all of the campuses of our university system. We need to work better at linking this talent to the businesses we have in the state. That’s really the focus of this: How can we use the technology that’s being developed in our universities to help improve Wisconsin businesses and start Wisconsin companies?"

As with university tech transfer in general, an overwhelming percentage of the activity is in the life sciences arena, particularly at UW-Madison, which is an internationally recognized leader in areas such as stem cell biology, and which holds multiple key patents that form the basis of commercial research programs in that area.

Gulbrandsen said that "there is good life science research going on at all of the UW campuses. We also have institutions like the Marshfield Clinic, [the UW]-LaCrosse/Gunderson [Lutheran Medical Foundation], and the Medical College of Wisconsin, all of which can be tapped to help with this effort."

Despite the biomedical R&D prowess at UW institutions, Gulbrandsen stressed that it was important not to ignore several other important areas of research within the UW system, such as physical science, nanotechnology, and materials science.

"The newspapers like to write about the life sciences, but we’ve got great physical sciences technologies coming out of Madison, too," he said. "These physical sciences and materials sciences technologies sometimes have a much shorter product development life cycle and time-to-market than the life sciences. We shouldn’t lose sight of those when we’re thinking about economic development."

Gulbrandsen said that Research to Jobs will likely begin its activities in early March, and will make a formal announcement about the various members of the task force sometime before that. However, he did specifically mention the names of a few members who have committed to the task force, including Brian Thompson, president of the UW-Milwaukee Research Foundation; Mark Bugher, director of the University Research Park at UW-Madison; and Tom Still, president of the WTC.

The task force hopes to produce specific recommendations for state economic development players sometime in the early summer. "We're setting aside 10 weeks to do this," he said.

Besides providing proposals to UW system schools and regional corporations, the task force is considering recommendations "with respect to legislation that could help encourage collaborations between companies in Wisconsin and our universities in the area of product development," Gulbrandsen said.

Drug Industry Needs "Open Innovation" Says J&J's Stoffels

The Health Blog just reported on a conversation with J&J's head of drug R&D, Paul Stoffels, on what the drug industry needs to do to survive in a difficult economic and regulatory environment.  Here is what he said as reported by HB.

Drugmakers’ struggle for survival boils down to finding new medicines to replace the old. The key, Stoffels told the Health Blog, is “open innovation,” or looking outside of companies for innovation and then collaborating with biotechs or academics on promising compounds.

 

“All simple diseases have been solved,” Stoffels said. “The next-generation drugs, therapies, are much more complex… You need much more information and science than what you can get out of your own internal labs.”

Stoffels said he learned the value of external partners “the hard way and also the good way.” When his first HIV drugs — developed in-house — were tested in patients, they didn’t work. He realized he didn’t know enough about the clinical complexity of HIV.

He sought the help of hospitals and other institutions working with patients. A 10-year collaboration led to two J&J HIV medicines — Prezista and Intelence — now on the market.

Others in the industry also have acknowledged that external partnerships will be important for developing innovative drugs moving forward. Critics say the drug industry has no choice but to look to biotechs or academic for help, given companies’ weak internal pipelines and stagnant R&D spending.

The future of the drug industry, Stoffels told the Health Blog, is “building networks where together with a number of different groups you come up with solutions to solve different medical needs.”

PRESS RELEASE: First human embryonic stem cell therapy trial approved by FDA

California's Menlo Park-based Geron Corporation announced today that the U.S. Food and Drug Administration (FDA) granted clearance of the company's Investigational New Drug (IND) application for the clinical trial of the world's first human embryonic stem cell (hESC)-based therapy in patients with acute spinal cord injury.

Geron plans to initiate a multi-center Phase I clinical trial that is designed to evaluate the safety of the therapy in patients with spinal cord injuries.

"The FDA's clearance of our...IND is one of Geron's most significant accomplishments to date," said Thomas Okarma, Ph.D., M.D., Geron's president and CEO. "This marks the beginning of what is potentially a new chapter in medical therapeutics - one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells. The ultimate goal for the use of (the stem cell therapy) is to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient's injured spinal cord."

"The neurosurgical community is very excited by this new approach to treating devastating spinal cord injury," said Richard Fessler, M.D., Ph.D., professor of neurological surgery at the Feinberg School of Medicine at Northwestern University. "Demyelination is central to the pathology of the injury, and its reversal by means of injecting oligodendrocyte progenitor cells would be revolutionary for the field. If safe and effective, the therapy would provide a viable treatment option for thousands of patients who suffer severe spinal cord injuries each year."

The Stem Cell Clinical Program

Patients eligible for the Phase I trial must have documented evidence of functionally complete spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have the cells injected into the lesion sites between seven and 14 days after injury. Geron has selected up to seven U.S. medical centers as candidates to participate in this study and in planned protocol extensions. The sites will be identified as they come online and are ready to enroll subjects into the study.

Although the primary endpoint of the trial is safety, the protocol includes secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to enable access to the therapy for as broad a population of severe spinal cord-injured patients as is medically appropriate.

Preclinical Evidence of Safety, Tolerability and Efficacy

Geron submitted evidence of the safety, tolerability and efficacy of its hESC therapy, GRNOPC1, to the FDA in a 21,000-page IND application that described 24 separate animal studies requiring the production of more than five billion GRNOPC1 cells. Included in the safety package were studies that showed no evidence of teratoma formation 12 months after injection of clinical grade GRNOPC1 into the injured spinal cord of rats and mice. Other studies documented the absence of significant migration of the injected cells outside the spinal cord, allodynia induction (increased neuropathic pain due to the injected cells), systemic toxicity or increased mortality in animals receiving GRNOPC1.

In vitro studies have shown that the GRNOPC1 hESC therapy is minimally recognized by the human immune system, which allows a low-dose of immunosuppression drugs.

Also included in the IND application were published studies in animals that showed that administration of the GRNOPC1 hESCs significantly improved movement of animals with spinal cord injuries when injected seven days after the injury (Journal of Neuroscience, Vol. 25, 2005). Histological examination of the injured spinal cords treated with GRNOPC1 showed improved axon survival and extensive remyelination surrounding the rat axons. These effects of GRNOPC1 were present nine months after a single injection of cells. In these nine-month studies, the stem cells were shown to migrate and fill the lesion cavity, with bundles of myelinated axons crossing the injury site.

Production and Qualification of GRNOPC1 hESCs

GRNOPC1 cells are produced using current Good Manufacturing Practices (cGMP) in Geron's manufacturing facilities. Geron's cell production process and clean-room suites have been inspected and licensed by the state of California. The cells are derived from the H1 human embryonic stem cell line, which was created before August 9, 2001 and is on the list of former President Bush's approved human enbryonic stem cells. Studies using this line qualify for U.S. federal research funding, although no federal funding was received for the development of Geron's therapeutic product or to support the upcoming clinical trial.

Induced pluripotent stem cells steal the limelight from embryonic stem cells, by Steven S. Clark

Recent stem cell headlines are all about how adult cells can be reprogrammed into induced pluripotent stem cells (iPS), which was recently hailed as the biggest scientific breakthrough of 2008.  All of this attention to iPS cells and hardly a word about embryonic stem cells (ESCs)—have ESCs lost their luster since scientists figured out how to reprogram adult cells back to the primordial stem cell state?

In reality, iPS cells have been around longer than ES cells.  In cloning the sheep Dolly in 1996, Scottish scientist Ian Wilmut took a single adult cell and injected its nucleus into a sheep egg from which the nucleus had been removed.  The cellular environment of the egg reprogrammed the nucleus of the adult cell so that it was able to give rise to Dolly. 

Last year, the laboratories Jamie Thomson at the University of Wisconsin-Madison and of Shinya Yamanaka, from Kyoto University, reported that this reprogramming could be done by simply expressing only three or four genes in an adult cell.  More recently reprogramming has been used by Harvard professor, Kevin Eggan, to derive iPS cells from patients with ALS (Lou Gehrig’s disease) and by UW-Madison professor, Clive Svendson, to derive iPS cells from patients with another neurodegenerative disease, spinal muscular atrophy (SMA).  Both iPS cell lines were then used to grow the defective neurons in the lab giving the scientists their first access to the very cells that caused the respective neurodegenerative diseases.  This creates a powerful research tool that will enable researchers to study the disease process and find ways to halt it. 

“Clinical trials” using iPS cells

The benefits of iPS cells don’t stop there.  Madison, Wisconsin-based Cellular Dynamics International (CDI) recently produced one of the world’s first commercial stem cell products, ESC-derived cardiomyocytes.  These are functional heart cells that CDI produces and sells to pharma companies for drug and toxicity testing.  But CDI also has a robust research effort to efficiently produce iPS cells, possibly without having to introduce exogenous genes into the adult cells.

“We have a large scale research activity to create a vector-free methodology for no integrated DNA (in the iPS cells),” said Chris Kendrick-Parker, Chief Commercial Officer at CDI.  The company is now filing patents and Kendrick-Parker was not at liberty to say if CDI has developed a DNA-free method for inducing iPS cells.  However, he did say that the company is “looking at all options.”

Kendrick-Parker believes that CDI will soon switch exclusively to using iPS cells to develop heart and other cell types for sale to pharma and researchers.  The advantage of iPS cells he said is that they can be used to produce adult tissues from people representing different ages, ethnic types and sexes as a way to model the human heterogeneity in tissue culture.  This way, “drug companies can actually recapitulate (in tissue culture) what happens in clinical trials,” Kendrick-Parker said.   

For this to happen, Kendrick-Parker says that CDI and other companies will use iPS technology to make a library of iPS cells from a wide range of people in order to reflect the genetic heterogeneity of the population.

Most investigational or even post-market drugs fail due to liver or cardiotoxicity in a subset of people, which is “why pharma is so interested in these (iPS-derived) models,” said Kendrick-Parker.  The cells should allow drug makers to identify organ-specific toxicities before clinical trials begin, thereby saving much time and money bringing a new drug to market, only to have it fail.  For example, having iPS-derived cardiomyocytes from a large patient population might have identified, early on, the cardiotoxicity of Vioxx, saving Merck & Company a great deal of money getting the drug to market and in subsequent litigation fees.

iPS cells in the clinic?

But what about using iPS cells to directly treat disease?  After all, they have been widely touted as the great ethical hope for stem cell therapy since they don’t involve destroying human embryos. 

Currently, iPS cells are made by expressing a few genes in an adult cell, which turns back the cells' developmental clock to an embryonic-like state from which they can become any of the body's 220 different cell types. Yet, the genes used to reprogram adult cells are, themselves, associated with cancer, so iPS cells made this way will not be used clinically.

However, last November, Thomson opined that in about six months, it will be possible to make iPS cells without having to resort to oncogenic gene expression.  While this will eliminate the immediate problem to using the cells clinically, they still face significant hurdles before being used to treat specific diseases.  In fact, Thomson also suggested that there may be problems with iPS cells, saying that there are “dark clouds on the horizon”.

Eric Forsberg, Director of the WiCell Research Institute, explained that reprogramming of adult cells is extremely inefficient, meaning that for some reason, it is only the rare adult cell that can be successfully re-programmed.  This suggests that other unknown factors affect the ability of each cells’ genome to be reset to an embryonic state. 

Researchers also know that reprogramming is incomplete.  The genome clock is not completely reset and this Incomplete reprogramming likely plays a role in the health problems that cloned animals have—Dolly had arthritis and was euthanized due to progressive lung disease.  This raises the possibility that tissues developed from reprogrammed iPS cells might not function normally.

Forsberg pointed out that the extent to which a person’s genome is reset can vary from person to person and this could mean that each person will require an individualized reprogramming regimen in order to create iPS cells for therapeutic use.  But, it is unlikely that the FDA would approve such an individualized protocol—they like uniformity and conformity in therapeutic protocols, not different protocols for different people

Thus, while iPS cells provide enormous potential for learning how human disease develops and progresses and for cost-effective development of new and safer drugs, they are still a long ways from the clinic.  In fact, ESCs will likely find clinical use before iPS cells do.