BioScience Biz

Wisconsin’s $750 million biotech investment could use better vision

In 2004, the nation took notice as California and Wisconsin independently announced major investments in stem cell and biotechnology research. In California, voters approved Proposition 71, a massive $3B commitment over ten years to fund stem cell research. In Wisconsin, Governor Jim Doyle announced a $750 million state investment in biotechnology in order to help the state maintain a leadership position in the life sciences. Four years later, let’s take a look at what is going on inside Wisconsin and around the country to gauge just how well Wisconsin’s biotech leadership is holding up.

Home cooking—Wisconsin’s biotech investment

The cornerstone of Wiscon’s $750M biotech investment is the $150M Wisconsin Institute of Discovery (WID). WID is a partnership between the state, the Wisconsin Alumni Research Foundation (WARF) and a generous donation from John and Tashia Morgridge, each of which contributed $50 million to build a new public/private hybrid research building on the UW-Madison campus. Some of Doyle’s total came from the public sale of Blue Cross Blue Shield of Wisconsin, which had been in the works quite awhile before Doyle’s announcement. The total also includes $134M and $132M for new additions to the UW-Madison School of Medicine and Public health and to the Medical College of Wisconsin, respectively—funds that also had been raised much earlier and that included substantial private contribution.

By my count, of the $750M, $421M comes from non-state sources or is money that already was earmarked for medical school buildings when Doyle made his announcement, leaving about $330 as Wisconsin’s total commitment to life sciences since 2004—a tidy sum to be sure, but not as impressive as it was made to sound. This is about what California will spend on stem cells each year for the next ten years.

More revealing is what this money is buying. A significant portion clearly is going for bricks and mortar in order to expand and modernize the research infrastructure in Madison and Milwaukee. A substantial amount of the money from BCBS sale of BCBS goes for local public health and education efforts across the state. It is disingenuous to add this money into the total of a biotech initiative.

Even though ground has just been broken for the WID and the building won’t be finished until 2010, we can get a glimpse of the research the Institute will support from the $3M recently awarded for Discovery Seed Grants. These Seed Grants will support the following research:

• finding a diagnostic test for a common causes of infertility in women.
• understanding cognition and the effects of Ritalin in the brain.
• more efficient production of embryonic stem cells.
• finding new drugs that inhibit cancer cells from spreading to other locations.
• improved healing of persistent wounds.
• high-tech screening for drug candidates that can dock to critical disease-specific receptors on cells.
• developing micro-optical lenses that can be fine-tuned by environmental factors.
• finally, there also is a project to find improved ways to teach African American children from low income families to speak proper English.

While each of these projects, individually, are certainly very interesting and address important questions, it is hard to see any overarching theme in this disparate collection of projects. Was there any strategy behind selecting these projects other than that these were the ones that rose to the top of the pile of the potpourri of proposals that were received?

Case in point--as important as the research likely is, how teaching minority children to speak proper English fits into a biotech initiative is utterly befuddling. The micro-lens project may not have much life science relevance as well.

The impression from all of this is that the research component of Wisconsin’s biotech initiative lacks a critical focus that a rather small investment cannot afford. When competing with billion dollar initiatives, a smaller contender needs to clearly define its specific strengths, identify important opportunities related to those strengths and proceed in a focused fashion to capitalize on strength and opportunity rather than spread the largesse willy nilly. But, it appears that Wisconsin soon will have a fabulous, brand spanking new research facility staffed by a mish mash of researchers who will have little in common to talk about with each other.

For comparison, let’s take a look at what Wisconsin’s competition has been up to recently.

Looking Westward--California

While Wisconsin’s $3M in Discovery Seed Grants was given to 8 disparate research efforts, not all of which relate to biotechnology, the California Institute for Regenerative Medicine (CIRM) has so far approved 206 grants for more than $554M, all focused on stem cell research and regenerative medicine. These grants include money to support and train 169 new stem cell scientists and clinical fellows, 22 grants to launch the research of new faculty, funds for 73 seed grants to test highly innovative ideas, and awards for 28 comprehensive grants to senior stem cell scientists.

More importantly, on top of their stem cell meta-focus, the California initiative recently finished a round of grant awards strategically concentrated on developing new stem cell lines. The research programs supported by these California awards will go to find better ways to reprogram adult cells into stem cells and to develop clinical-grade stem cell lines that can be used to treat patients. Some of the projects will develop disease-specific stem cell lines in order to model cell development in Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and cardiovascular disease. This represents a beneficial mix of complementary projects so that the whole of California’s research initiative is greater than the sum of the individual projects.

California made 16 of these awards for a total of $23M, which comes to $1.44M/award compared to Wisconsin’s average of $375,000/award--26% of the California average.

Like the first round, the next round of CIRM research awards will also be strategically focused, but on forming disease-specific teams of researchers and clinicians to develop stem cell therapies for human illness. From the preliminary applications that have been accepted, these teams propose to develop stem cell therapies for diabetes, eye disease, osteoarthritis, wound healing, stroke, heart disease, muscular dystrophy, AIDS, Parkinson’s disease and certain blood diseases. CIRM indicates that successful proposals will include a plan for an investigational new drug filing with the FDA at the end of the four or five year project.

Wisconsin should especially take notice that these disease-specific team projects involve cross-functional teams of scientists and physicians, often from multiple California public and private institutions. The teams can also include partnerships with private biotech and pharma companies across the US, as long as the company has an office in California. Clearly, California is creatively leveraging its resources to not only support research, but also to ensure that the research is translated into business and moves into the clinic.

Compare California’s inclusive, collaborative team approach to Wisconsin’s singular focus on UW-Madison with the WID. While Wisconsin’s 8 Discovery Seed Awards do involve research teams, the teams only come from UW-Madison. These awards fail to take advantage of the growing private biotech sector in Southern Wisconsin and the scientific talent that can be found at other institutions across the state such as UW-Milwaukee, the Medical College of Wisconsin and the Marshfield Clinic.

In other words, California has purposefully focused its research efforts, while simultaneously encouraging broad public and private partnerships across the state. Wisconsin has done exactly the opposite by funding a broadly unfocused research portfolio restricted to a single institution.

California has positioned itself to get more “bang for the buck” than Wisconsin will for its investment.

It doesn’t stop there—the competition is getting more intense

In a 2004 press release, Governor Doyle said that California’s $3B stem cell investment, “…will not diminish Wisconsin’s role; if anything, there will be a synergy between our two states." However, time shows that California prefers to synergize elsewhere.

For example, the Canadian Institutes of Health Research announced in a recent press release that it will join forces with California to focus on cancer stem cell research. Toward this end, Canada pledged $100M ($98.9M USD) to the Cancer Stem Cell Consortium, a partnership of academic, business and government agencies, which will work with CIRM.

On top of that, CIRM is actively seeking partnerships with the US federal government as well as with other nations in order to turn their ten-year commitment into a sustainable venture. Indeed the CIRM is working on a deal with the Australian state of Victoria and last year, the Canadian   province of Ontario ponyed up $30M for cancer stem cell research linked to CIRM. 

 Now look Eastward—Maryland, Massachusetts and New Jersey

Wisconsin does not only have to worry about competition from California--Massachusetts,  Maryland and New Jersey have or are planning major financial forays into the biotech field. In mid-June, Maryland Governor, Martin O’Malley announced a plan to provide $1.1B over the next ten years in state incentives in the form of tax credits and grant programs for the state’s biotech industry, while the state’s pension board will invest an additional $500M, bringing the total to $1.6B. The goals are to build a biotech center, finance capital projects and to make equity investments in start-up biotech companies—and intriguing and innovative idea.

It used to be that angel and venture investors covered this earliest and critical stage in biotech development that is euphemistically called the “valley of death”--a nod to the difficulty researchers have commercializing their ideas. But recent trends show that investors are increasingly reluctant to invest in nascent companies—they want to see prototypes and experienced teams in place before plunking down their money. Therefore, equity funding from states promises to meet an increasingly critical need for commercializing emerging biotechnology and this tactic could very well generate a nice return for Maryland —if it is approved by the state legislature.

Not to be outdone in the state bidding war for biotechnology, Massachusetts Governor Deval Patrick recently signed legislation to allocate $1B over ten years to fund the State’s life sciences industry. This includes $250M in tax incentives to support the growth of biotech companies, the same amount to fund research and $500M in infrastructure.

Patrick said it takes "political will and courage to make those long-term commitments" and admitted that his state's funding commitment is, in part, a defensive measure to ensure that Massachusetts’ universities, companies and research institutes retain top scientists and biotech companies.

Patrick’s candid admission underscores the intensity of the competition for science talent and resources in which Wisconsin wants to successfully contend. Further underscoring the high stakes in these biotech funding wars, Patrick claimed that over the next ten years, Massachusetts' support of the biotech industry will create 250,000 new jobs. In this light, it is illustrative that Massachusetts’ commitment to the biotech industry heavily factored into the decision of the regenerative medicine company, Organogenesis, Inc, to expand it operations in the state rather than elsewhere.

Meanwhile, in New Jersey, legislation was introduced in late June to establish an pioneering public-private vehicle for state funding of stem cell research with venture capital. A press release said that the bill will allow private investors to contribute up to $500M over five years to fund such research. To encourage participation, investors would be granted tax credits equal to their investment, but only if a funded research project failed to repay the loan. In order to obtain funding, researchers would submit loan applications to the state’s Economic Development Authority. Both non-profit and academic labs would be able to apply for a stem cell research loan.

What’s a state in fly-over country to do?

Clearly, Wisconsin has a very credible biotechnology research enterprise thanks to the huge bioscience community at UW-Madison. The state’s biotech footprint is even more impressive when private biotech companies and institutions other than the UW-Madison are included. Despite this research muscle and recent infusion of state money, Wisconsin is missing a narrow and critical opportunity to capitalize on its strengths because it lacks the vision and creativity seen in the efforts of other states.

Wisconsin could learn from California and make a much more resolute effort to strategically focus on developing specific biotech strength, be it stem cells or something else. Wisconsin also could learn from California, Massachusetts and New Jersey about creative leveraging of public and private resources to boost, not only academic biotech research, but biotech business as well. After all, the best research, if not translated into successful businesses, does nothing for the people, the state or the economy.

On average, across the country, every new biotech job generates almost 6 additional jobs in the community. Salaries in the biotech industry average a whopping 68% higher than other private sector jobs. This is the return that Wisconsin can expect to realize by wisely investing its resources in biotechnology. However, the latest data show that Wisconsin falls below average in both of these metrics, yet we have an above average per capita infusion of federal research dollars.

Wisconsin clearly has room to realize a better return on its investment.
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© 2008 Steven S. Clark, PhD. Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not 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.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.

Minnesotta gets green light for $300M biomedical research facility

Officials in Minnesota are touting the potential of the planned $300 million Minnesota Biomedical Research Program, a project that already has earned legislative approval for $220 million in state funds. The University of Minnesota says the program will provide space for 100 primary researchers and 500 support staff. And the university believes it can attract $100 million a year in new research funds once the program is up and running. The state has blueprinted 400,000 square feet of research space in four buildings to be completed in 2013. The university will start by expanding the Center for Magnetic Resonance Research and follow up with facilities that will focus on cancer, cardiovascular and infectious diseases.  Read the online StarTribune article here.

In Wisconsin, ground was recently broken at the UW-Madison for the Wisconsin Institute for Discovery, a $150M public/private research facility that will be completed in 2010.

New stem cell database is launched to steer scientists through the stem cell maze

Have you ever wondered where a cardiac muscle stem cell comes from and how it is related to a skeletal muscle stem cell?  Or, can a neural stem cell also differentiate into a glial cell?

If you were to drive from San Francisco to New York without any street signs or a road map, you would spend a lot of time going down wrong paths and may never get to the Big Apple. Similarly, as a stem cell is going from its initial, basic level to a complex ear cell, for example, it needs to be steered through a specific path. This map gives scientists not only the knowledge of where they're going, but key "markers" that need to be crossed along the way. Ultimately this will save stem cell companies time and money. 

Read the news article from the San Jose Mercury News, here.  The new stem cell database can be accessed here, www.embryome.com.

Experts talk about how to make the most of biotech clusters

Many cities and countries view the foundation of a biotech sector as desirable for a high-tech, intellectually driven economy. But a discussion by seasoned, international biotech management and investors suggests that attaining an environment with the right mix of money, management and innovation remains a difficult and long-term challenge.

Location is interwoven with the ability of biotech startups to prosper. Regions with nascent biotech sectors often find attracting the necessary financial and human resources to their area an uphill struggle, which can mean the difference between success or failure for a fledgling life science business. In the following article, a group of experienced biotech executives and investors from around the world discuss the pros and cons of building a business inside or outside a cluster. The article is an abridged transcript of a Bioentrepreneur roundtable discussion held at the Marriott Boston Copley Place.  The article was edited to address the major themes of that discussion and was originally published online in Bioentrepreneur.

The panelists included the following:

Fritz Bühler is Director of the European Center of Pharmaceutical Medicine, University Hospital, Basel, Switzerland, and a partner in Bear Stearns Health Innoventure;

C. Mark Tang is Managing Director and Chairman of World Technology Ventures, LLC, New York, New York;

Pratik Shah is a partner at Thomas, McNerney & Partners, San Francisco, California ;

Mark Leuchtenberger is President and CEO of Targanta Therapeutics, Cambridge, Massachusetts;

Ko-Chung Lin is Chairman and CEO PharmaEssentia, Taipei, Taiwan;

Pedro de Noronha Pissarra is CEO of Biotecnol SA, Oeiras, Portugal;

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How important is location in the success or failure of a biotech enterprise?

Pratik Shah: If I had any advice for an entrepreneur who's looking to start up a biotech not located in a cluster, it would be: "Move to the nearest biotech cluster." There has to be a really compelling reason not to do so. And it has to have something to do with a core competitive advantage that staying in the current location is giving them.

And for governments that are trying to create a nascent biotech sector in their region, the question I have for them is: What are you shooting for? Is the goal to draw sustainable research funding from the US National Institutes of Health [NIH] or the like? Or is it to build companies that are going to create products? If the answer is the former, then there are models that have recently emerged in the United States. For example, Florida has set up the Scripps Research Institute with a significant allocation of government funding to get it up and running, and I presume the goal there is to create sustainable research that will attract NIH dollars. But that's a little bit of a zero-sum game. If the objective is to create products, then there is a fundamental gap, because allocation of dollars is not enough. Without involvement of experienced, professional investors who know exactly what kind of things will get funded down the road, it's hard to create an organization that's really ready for that next level of funding without having an active collaboration or dialog or, in the ultimate sense, a very close partnership with the professional investors who are going to take those companies to the next level.

Pedro de Noronha Pissarra: With clusters, at Biotecnol we personally have a geographical problem. Nobody would invest in Portugal, where we are based. So for that reason, we set up a unit in Maryland, and we started doing our deal-making through the Maryland company, Biotecnol Inc., and the whole thing developed very nicely.

But we're still not quite in the cluster, and attracting top-tier management is a problem. It's not qualified people, because there are many qualified people around that went to Ivy League universities, or went to Oxford and Cambridge in the UK. But it's really hard to find the top-notch manager that will see us to the next stage. So I would say one thing: Don't start the company in a place that is not a cluster!

Portugal is a great place. I love it. I lived, worked, and studied abroad for many years and then went back because of the fantastic lifestyle. But, at the end of the day, you've got to be on a plane every month, going to biotech clusters, delivering your talks, convincing people that while we've got great wines and great food in Portugal, we also do great things in biotech. It was initially a very hard sell, but since we have grown and have created a recognized and successful buisness, perception about us has definitely changed. But we need more examples of success.

Mark Leuchtenberger: When I was recruited to Targanta [in the summer of 2006], they said they had a great drug with two positive phase 3 trials, and said the company is located in Indianapolis. I said, "Well, my geography is here, I've spent twenty years here, and I'm not moving." And they said, No, we're not expecting the CEO to move to Indianapolis. Essentially they were doing this search while acknowledging that Indianapolis might not be like Pedro's description of Portugal. It was going to be a place where you could do R&D, but you might set up a commercial or investment headquarters somewhere else—either San Francisco, or La Jolla, or Baltimore, or Boston, but not Indianapolis. You don't think biotech is regional, but, because of the companies and investors, it's intensely regional. People don't want to have to fly if they don't have to.

Fritz Bühler: I'd like to come back to this two-site company setting. We have never actually been able to work out a company in development with two sites. At some point, you have to move everything to one place. So I think that you may have a problem with Marylan and with Portugal and you'll have to make up your mind.

PNP: We've been asking this question to ourselves for awhile now. What are we going to do now? Are we going to spin-off the products completely to the Maryland subsidiary and Biotecnol Portugal is a shareholder, are we going to raise funds and hire local teams so it actually ends up being a spin-off of the company? I see your point; it's very valid. And it's already creating a lot of questions, so people are saying, "We are investing where? Where are the shareholders, where is the management?"

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Beyond easy access to venture capital and infrastructure, why are clusters so important?

ML: Take the Boston area. I think in the past five or six years or so, Novartis [Basel], Pfizer [New York], Merck [Whitehouse Station, New Jersey], Wyeth [Madison, New Jersey] and Bristol-Myers [Princeton, New Jersey], most recently, have all voted with their feet to come here. I think of it sort of as a casino: the house always wins. By that I mean the house is the resident group of knowledgeable, able managers and scientists. Projects come and go, and sometimes you are out of work for months, but usually you just keep participating and don't have to uproot your family. A lot of people switch jobs in Cambridge and don't even change their commute except for the last 200 feet. There are 50 companies over there!

I think that this is what people are betting their careers on now: serial entrepreneurship, over and over again. I've been doing that for the past five years—some of it works out pretty well and some of it works out pretty badly, but here's the bottom line: you're probably staying in the same location, you're accruing a group of people you trust who you can work with, and hopefully you're accruing the trust of the venture capitalists so that when another good idea comes up, they think of you and hopefully you can participate.

PS: I need you to talk to the CEOs of my companies that have only one product. They're always trying to in-license something for job security, and I say, "Hey you're in a cluster. You're going to be fine."

C. Mark Tang: One thing I would like to mention is the strength and existence of academic institutions that are always related to bioentrepreneurship, because the intellectual property and intellectuals are coming from this area. So I think that's a large part of the reason why big pharma and biotech are here in Boston—because of Harvard, the Massachusetts Institute of Technology, etc.

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In what ways are countries with nascent sectors attempting to foster biotech?

CMT: I'll just explain China as an example of Asia. Typically what China has is the government funding. For example, Ministry of Science and Technology, among other agencies, has grants it can fund research and development of startups with, and the city usually has some fund, and then certain banks do too. The government-owned high tech parks at times provide biotech the incubator space perhaps for free or at a discount for a couple of years and perhaps some seed/grant money for free as well. But there are not many, if any, Western style venture capital [VC] firms or groups for biotech. I once invited a well-known VC firm from the US to China to speak at a conference I organized. The VCs were very excited about the prospect of the industry after seeing a high tech park and want to open an office perhaps in five years. But still, biotech is very new.

PS: I'm curious, are there more examples of countries like Singapore who've said that they're taking a very long-term view and allocating a billion-plus dollars in capital toward biotech? And fundamentally from an infrastructure standpoint, is there really a logical reason that biotech should be there as opposed to some other Asian region? That is a positive example of a government making a long-term financial commitment to try to create a cluster.

CMT: I've been to Singapore a few times and I know a couple of managers of the biomedical fund as well. I think the strategy of Singapore is good. They want to form a biotech cluster. Mainly the money they invested in the beginning had a few strings attached, such as giving them first rights of refusal in Asia. So essentially what they were doing was investing money in technology and products overseas and buying Asian rights, and, in turn they're going to sell those products to the Malaysians, to the Indians and to China.

What's happening in Asia, I believe, is that Singapore is a role model because they have managed to set this up in very powerful way, put the right funds behind it and attract, even buy, top people even a Nobel Prize Laureate, from around the world to work and live there. But in China, as well as other Asian nations, I'm worried whether there are funds available now to do this similar (approach) to Singapore? Of the main Chinese biotech centers, Beijing, Shanghai are very good. The next group is TianJing and Shenzhen. One should not forget that the Western Hemisphere, led by the United State, has an enormous advantage and is ahead by 20 years compared with Asia. I don't think one has to reinvent the wheel. Just take the best from what we have learned in developing biotech regions in the United States and Europe, and then insert that in an orchestrated way in Asia, taking advantages of lost-cost, high quality human resources and emerging large local market there.

Ko-Chung Lin: When I deal with Asian companies, I tell them, "You know, if you want to get money from the US you've got to register yourself in the US." I work with people who are actually registered here, but in reality it's virtual—no one is really based here, everyone is in China. But it appears to be a global company, and this makes US investors feel comfortable. Especially in New York, where there are large funds and they have a percentage that they have to invest internationally, so they're very active in looking overseas. Of course, the key part is you've got to have a good story. You know biotech: you don't have to be making money.

PS: I guess the real question is how many venture dollars are flowing into those regions, and if the answer is not a lot, then I think the writing is on the wall. Because although many countries are vying for life science-oriented venture funds, is biotech really for every region? Is there really a fundamental reason why biotech should be in a particular geography where it already isn't? I would take a really cold, hard look at what the facts are.

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What types of business models and exits can biotechs around the world offer investors?

CMT: Like the US, there are four or five business models in China: reagent, equipment and services; generic drugs; technology platform; R & D products and hybrid of technology and products. Right now, service companies, such as contract research organizations, and generic companies are hot in China. Several of them have raised money through IPOs in US stock exchanges.

FB: Valuations have changed enormously over the past ten years. Obviously once you have an asset you want to let it grow as much as possible, so probably the best point at which to sell or partner is after a proof of concept, and it seems possible to develop any compound up to proof of concept. So I think the time is over for any garden-variety investor; it's now smart money. I believe that the funds have changed greatly in the sense that they are now run by people from the pharmaceutical industry who bring not only the dollars, but smart dollars to the table.

The initial public offering [IPO] situation is another major problem, but one well solved in the United States with the NASDAQ exchange, and poorly solved in Europe or in other parts of the world. There are plenty of stock exchanges, but none really have the right flow or a big enough float, and the situation is so scattered in Europe that it's really difficult to go through a successful IPO. It does still happen, despite this scattering, and one wishes that there would be more concentrated IPOs, but nationalism is a huge problem. Why should you, as a Viennese, invest in Zurich? Or a UK person invest in someplace besides London?

PS: I recently looked at the number of companies that were venture backed that had liquidity events driven by IPOs versus mergers and acquisitions [M&A] in the past three years, with a cut-off of $300 million exit value or greater in biotech, pharmaceuticals and medical devices. The numbers suggested that the two paths led to roughly equal numbers of exit opportunities. So, yes there has been a lot of buzz about M&A because of the recent flurry of activity, but I still think that the other path exists; it's certainly nowhere near the valuations that it used to be and therefore has really created a situation in which the amount of the capital and the pre-money valuations that private investors have to make work is much more constrained. I think the two paths still exist.

FB: I'm not sure that the IPO window is totally closed. There's still some happening, particularly in Europe, although the M&A pathway is the one that is now favored. There again, one should caution the biotech/pharma small companies not to merge or be acquired too early, but really grow their value. Unfortunately, that doesn't always happen because of the enormous pressure being exerted by the pharma world, which is short of good ideas and compounds. There's also an innovation gap and a development gap—so pharma really gets its arms around everything it can find.

PNP: The hybrid model should help with valuations, but it's a very hard sell. To say, Okay, we have excellent development capabilities, we may have worked with Schering-Plough [Kenilworth, New Jersey], with Sanofi-Aventis [Paris] or whomever, but still it doesn't sell because the model is capped. The service company will always be the less attractive thing for the investor. I know Pratik has a service company in his portfolio, but he's one of the very few venture capitalists that I know that has that. So you've got to separate the businesses completely. And this puzzles me because it's a perfect meeting of the two worlds; you can mitigate the risk, you even have nice revenues, you've got granted patents on valuable products and technologies, among great know-how, but when you put the two models together, people don't generally like to invest in such structure. Why? I am not certain, but I am convinced that since we favored a product development oriented strategy we certainly have created a great deal of interest in the investment community.

KCL: I can explain this to you. The problem has two parts. The service guy says, I don't want to do drug development because I'm always losing money; the drug development guy says, I want a high-risk return, and I don't like service. So, when you put them together, very few people want to do it. Another problem is working with partners. Because you are working with big pharma, they give you projects to do services on, and they're scared that you're passing these things on to your idea unit or going around them. So pharma says, Listen, if you want to do drug development, you're not going to get our contract. If you shut down your drug development, then we'll give it to you. Because this product is so important to us, you know we've spent hundreds of millions of dollars, we're not going to give it to you if you have an idea unit.

ML: I've got a Biogen [Cambridge, Massachusetts] analogy from the early nineties. We were going along, scraping by, but we signed this deal, got a little bit of money in, and then all of a sudden the hepatitis B and alpha interferon royalties started to kick in and our royalty revenue went from $60 million to $70 million in 1991 to $135 million in 1992. Suddenly we had money to fund all our own development. Did the investment stock market like it? No, they hated it! It was like it was a service business. It was pure royalty; it was pure profit, but they looked and they said, What are you doing with it? You have boring royalties that are only going to increase a certain amount, and until then you're nothing more than a royalty trust and a boutique and a bunch of airheads walking around talking about things.

PS: But that's actually not as irrational a financial decision as it sounds. Look at Biogen versus Amgen [Thousand Oaks, California]; they were started at roughly the same time, and, if you look at those companies' market caps from when they were started or when they went public to today, you see that there's a long period when Biogen's market cap is basically flat, whereas Amgen was favored by Wall Street. Why is that? Well you could call it brilliance or you could call it just luck. But if you have a specialty product where you can develop a sales force, you're going to make a lot higher margin on a lot lower sales line than a royalty model. That's why the market caps diverged. I think that the fundamental issue of market appreciation comes down to, how much are you really going to be able to derive from the pipeline?

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Biotech drug sales post 12.5% increase in 2007

Pharmaceuticals may be struggling, but biotech drugs are on fire. According to an IMS Health study, global sales of biotech drugs increased 12.5 percent in 2007 to more than $75 billion; that's twice as fast as the pharmaceutical market, which increased 6.4 percent in 2007. The growth is the result of several factors, including additional indications for existing products, recent innovations, and the growth of biologic drug sales outside the U.S. Oncology, auto-immune agents, diabetes drugs and vaccines accounted for most of the growth. Last year, 22 biotech products exceeded $1 billion in sales, compared with just six products in 2002.

The forecast isn't entirely positive, however. Growth was down in 2007 compared to 2006. "Loss of exclusivity and competition from biosimilars, crowded therapy areas with weaker sales growth, payers showing more reluctance to fund innovative drugs without compelling value propositions, and safety concerns for some therapies will all contribute to a more moderate growth environment through 2012," warned Murray Aitken, the study's author. "[C]ompanies with biotech products in their portfolios will succeed only if they meet increasingly demanding regulatory standards, deploy effective commercial models that are accompanied by compelling evidence of their products' value, and develop pricing and market access strategies that ensure that patients have access to the benefits that these new products deliver."

Is drinking red wine the same as going on a diet?

Research says maybe so.

When considering factors that affect health, most people think about fatty diets, sun exposure, smoking, alcohol consumption, etc. But, research clearly indicates that one of the most important factors in quality of health is the simple calorie, which seems to one of the last health factors that people mention.

Everyone knows that obesity is associated with myriad health problems from cardiovascular disease, diabetes and stroke. Recent studies also link obesity to neurological problems such as Alzheimer’s disease. Obesity is caused by several factors including poor diet, sedentary lifestyle as well as genetic and metabolic issues. Certainly, caloric intake is a factor in obesity, but compelling research in rodents has shown that even a diet that does not lead to obesity may play an amazing role in age-related loss of function in the skeletal muscle, brain and especially the heart. When animals are restricted in caloric intake, but allowed normal levels of nutrients, vitamins, etc, their lives are significantly prolonged and their bodies retain a youthful physiology much longer than animals fed a regular diet.

I’ve seen the research data of caloric restriction on the musculature of the heart and the results almost gave me chest pains thinking about what my heart must look like in middle age.

Studies in several labs, including one recently reported by UW-Madison’s Tomas Prolla and Richard Weindruch, show that mice that are fed a component of red wine called reservatrol, along with a regular diet, showed healthier physiologies than mice who were not fed reservatrol. Significantly, the mice fed reservatrol and a regular diet, were as healthy as the mice on the calorie-restricted diet. In other words, feeding reservatrol to mice mimicked the beneficial effects of caloric restriction.

Both, Weindruch and Prolla, admitted to taking reservatrol supplements. But is this a good idea? Read more about this line of research here.

Quintessence moving forward despite discouraging data from competitor

A few weeks ago, I wrote that folks at Madison-based Quintessence Bioscience eagerly anticipated the outcome of a Phase IIIb clinical trial that Alfacell, a major East Coast competitor, would soon release on an anti-cancer therapeutic compound, Onconase™. Quintessence’s lead drug candidate, QBI-139, is very similar to Onconase™ and has not yet been clinically tested.

The results of the Onconase™ trial were just released and Quintessence Chairman and CEO, Ralph Kauten, said that he is “…disappointed that the results of the Onconase™ clinical trial were not an overwhelming success.”

Kauten shared with me a communication that Quintessence sent to its shareholders about the Alfacell trial. In it, they had this to say:

“Alfacell has released data indicating that their first-in-class drug, Onconase, failed to meet the primary endpoint in the Phase IIIb confirmatory trial in malignant mesothelioma. The trial compared the combination of Onconase plus doxorubicin to doxorubicin alone. The primary endpoint was an increase in overall patient survival. Alfacell’s initial analysis of the data showed no statistically significant improvement for evaluable patients receiving the combination of Onconase and doxorubicin.”

In other words, Alfacell tested the combination of Onconase™ plus the standard chemotherapy drug, doxorubicin, to doxorubicin alone in order to test whether Onconase™ would increase the survival of patients with mesothelioma, an extremely difficult to treat cancer that usually is associated with asbestos exposure. After the data were analyzed, there was no consistent difference in the two therapeutic regimens, which means that adding Onconase™ made no significant difference in the survival of the patients.

However, when the data were more closely examined, it appeared that a subset of patients who had failed the standard chemotherapy regimen for mesothelioma, showed a small, but statistically, increase in survival when treated with Onconase™. On this basis, Alfacell plans to submit an application to the FDA for using Onconase™ as a “second-line” therapy for mesothelioma patients who fail the standard chemotherapy. It is unclear how the FDA will respond to this parsing of the data. In the past, they have been averse to such sub-group analysis, but there are indications that this attitude may be changing, so Alfacell is forging ahead with the New Drug Approval process.

As I asked before, should there be cause for concern at Quintessence over these less than encouraging results from a competitor? As before, folks at Quintessence remain very committed to moving QBI-139 into clinical trials, probably sometime this summer. In their communiqué to shareholders, Quintessence went on to explain the following:

“Failing to meet the primary endpoints in the Alfacell Phase IIIb trial certainly makes approval of Onconase more challenging. However, Onconase still has significant potential to be approved as a second line treatment for malignant mesothelioma. While this change would mean a smaller market for the drug, our opinion has been and continues to be that any successful FDA approval of Onconase paves the way for general acceptance of RNases as cancer therapeutics.”

“Quintessence continues to make progress toward filing an IND and initiating a Phase I clinical trial for QBI-139. The majority of the data supporting the IND has been collected and analyzed and GMP manufacturing is underway. We are currently negotiating contracts with the clinical trial site as well as a contract monitoring group. We look forward to demonstrating the clinical benefit of QBI-139 in patients with cancer.”

The FDA’s response to Alfacell will be critical for the future of RNase-based therapies that Alfacell and Quintessence are developing. As I wrote in an earlier article, it is an unfortunate fact that if a drug is tested on the wrong disease and fails, it can be very difficult to resurrect its reputation in order to test it on another, more appropriate, disease. When a drug gets a bad reputation, it becomes much harder to garner enthusiasm from those who would fund the new study—investors and NIH grant reviewers.

Although, it may turn out that that testing Onconase™ on mesothelioma was a bad decision on the part of Alfacell, it was an interesting strategic decision that they made. Mesothelioma was chosen for the initial clinical trials because of its intractability to therapy, which allowed Onconase™ to be granted fast track status and orphan-drug designation by the FDA. This means that Alfacell was able to get Onconase™ into advanced clinical trials much sooner than it would have via conventional investigational drug approval procedures.

Mediocre therapeutic results against a cancer that no other therapy has shown much success against, does not mean that RNase-based therapies will not be effective against other types of cancers. As I pointed out earlier, there is good reason to believe that Quintessence’s lead RNase therapy, QBI-139, is superior to Onconase™.

For these reasons, Quintessence should and will continue to move forward with QBI-139 and focus on more common and easier to treat cancers than mesothelioma.

Madison's stem cell frontier, By Steve Clark

In an earlier column about the recent Stem Cell Symposium held on the Promega Campus, I extolled the exciting frontier of stem cell basic science that was on display; however, it was just as interesting to catch up with local stem cell researchers who attended the Symposium. I caught a glimpse of the current status of stem cell science in the Madison area.

Other health benefits of embryonic stem cells

For instance, I ran into Tim Kamp, an MD in the UW-Madison Department of Cardiology who, along with Professor Jamie Thomson, recently developed a reliable way to derive human heart cells from embryonic stem cells (ESCs).

About four years ago I first met Kamp in his UW-Madison office to learn about his research. At that time, researchers knew that when given the chance, human ESCs haphazardly differentiate in tissue culture into all the different tissue types and Kamp, using a microscope, had been able to find among the clutter of different cells a few well developed heart cells that actually were beating! You can see a short video clip of one of the beating heart cells here.

Using a steady-handed robot, Kamp inserted a very fine probe into a beating heart cell and measured its depolarization or the exchange of ions across its membrane, which constitutes the electric current that causes heart muscle to beat. With this, he recorded an “EKG” on a single human heart cell that changed as expected when he added to the culture, a drug often given to heart patients.

Currently, animal models are the best way to measure pharmacological effects of drugs on the heart—an important but insufficient model since 30% of drug failures are due to cardiotoxicity. Clearly, we need ways to test drugs on human heart cells, but until the advent of ESCs, there was no reliable way to obtain and grow them in the lab. Now, being able to derive functional heart muscle cells from ESCs provides a important option for testing drugs on real human heart tissue, thereby improving the safety and efficacy of new drugs. At least this was Kamp’s goal four years ago when I talked with him in his office.

Things seem to be progressing well. A couple of years ago, Kamp and his co-workers launched the local biotechnology company, Cellular Dynamics International, in order to bring this technology to fruition. In early March, Roche Palo Alto reached an agreement with CDI to begin using their ESC-derived heart cells for testing the cardiotoxicity of candidate drug compounds.

Using ESCs to derive fully functional mature cell types for testing potential drugs and toxins directly on human tissues is an under-appreciated and poorly communicated application for ESCs, but one that will soon be widely employed in the pharmaceutical industry. Thus, human ESCs will likely play an important role in human health, even if they are never used to directly treat human disease.

Kamp indicated that similar screening methods are being developed for other tissue cell types derived from human ESCs.

Treating neurological diseases

A few years ago, I attended a seminar by UW-Madison neuroscientist, Clive Svendson, who showed a video clip of patients with Parkinson’s disease before and after treatment with a nerve cell factor known as GDNF. The result was a dramatic slowing of disease progression in treated patients.

As encouraging as this therapy was, it remains highly experimental since GDNF cannot cross the blood-brain barrier and must be delivered by cannula—a thin tube inserted deep into the brain area affected by Parkinson’s disease—not an attractive long term option.

Furthermore, GDNF therapy only retards the progressive loss of dopamine producing neurons that is characteristic of Parkinson’s disease; it does not reverse the process. Therefore, this will not likely benefit patients with advanced disease who have lost too many of these critical cells. This is where the hope of stem cell therapy merges with the other great therapeutic hope—gene therapy.

For instance, ESCs alone are not likely to be much of a benefit for patients with Parkinson’s, because stem cell-derived dopamine-producing neurons transplanted in the brains of Parkinsonian patients likely will suffer the same fatal fortune as their endogenous predecessors. But, combine stem cell regeneration of the neurons with in situ production of GDNF via gene therapy technology and you just may be able to sustain dopamine-producing cells for the long term. Or so the hope goes.

A similar idea is being tested in Svendsen’s lab for treating amyotrophic lateral sclerosis; also know as ALS or Lou Gehrig’s disease. Like Parkinson’s, ALS is caused by the progressive and irreversible loss of certain critical neural cells in the brain. Svendsen’s lab has developed rat and primate models of ALS and using human fetal-derived neural stem cells, in conjunction with gene transfer technology, have successfully implanted fully functional, GDNF producing neurons in brains of these ALS animals. The results are very encouraging at this point--they see long-term survival of the transplanted cells and sustained production of GDNF, and these correlate with resolution of symptoms.

This is not the first example using ESCs to successfully treat human diseases in animal models, but ESCs have not yet made it into the clinic. Human trials will likely begin in the next year or two and the FDA is now considering how to best monitor them for safety and efficacy--not a trivial undertaking, but, stay tuned.

Moving stem cell science along

At the symposium I also had the chance to connect with Eric Forsberg, the recently appointed Director of WiCell. This is the non-profit spin-off from the Wisconsin Alumni Research Foundation (WARF) that provides support for stem cell researchers at UW-Madison.

According to Forsberg, WiCell, not only maintains the National Stem Cell Bank, it also engages in outreach activities and provides core services for stem cell researchers that are not found elsewhere on the UW-Madison campus. Forsberg pointed out that WiCell is also happy to provide such support and training for private stem cell companies in order to foster the development of cell-based medicine in Wisconsin..

Forsberg hopes to soon partner with the Waissma Center on the UW-Madison campus to begin a trial run to grow clinical-scale batches of ESCs under the cGMP conditions that are required in order to use the cells to treat patients. The Waissman Center has the cGMP facilities to produce biological materials for clinical use.

This will be a proof-of-principle endeavor designed to show that ESCs can be produced in clinically relevant quantities while maintaining their state of differentiation. Unforeseen problems, the bane of any biotechnology research, will be identified and resolved during this trial run so they will be ready when the time comes to quickly move ESCs into clinical trials.

We rapidly approach the day when ESCs will be used in experimental therapies of human diseases. Probably the first trials will use blood or bone marrow products derived from ESCs as a donor source for marrow transplantation or red cell transfusion.
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© 2008 Steven S. Clark, PhD. Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not 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.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit the BioScience Biz Blog.

The stem cell frontier, 2008, on display, By Steve Clark

Cut a flat worm in two, the tail will grow a new head and the head a new tail. Cut it right down the middle, it will grow a mirror image. How does it know what to grow?

Flies can re-grow damaged tissues. Small fish can regenerate heart muscle. Why can’t humans?

In a developing infant, how do human embryonic stem cells know to grow into heart, muscle, liver, neurological and other cell types at the proper time and in the proper place?

These questions are at the center of science’s brave-new-world of stem cell biology and were the topic of the recent 3^rd Annual Stem Cell Symposium. The science was deep and detailed, and enormously enthralling. It was an intellectual playground of exciting ideas and fabulous potential.

The overriding lesson from the conference is that the mechanism by which stem cells regulate how and when they replenish themselves vs develop into different tissues is conserved in species as divergent as worms, flies, fish and mammals. This is fascinating for developmental biologists, but it also has a profound practical impact for eventually using stem cells to treat human disease. Let me explain how.

A primer on stem cell science

Consider for a moment what needs to be accomplished for an immature stem cell to differentiate into, say a beating heart cell. First, there needs to be a stimulus that initiates this program, telling the stem cell to specifically move along the cardiac muscle developmental pathway. The stem cell must then begin expressing heart cell genes while repressing the expression of all other genes that could cause it to become liver, blood, kidney and all other cell types. Quite a tall order!

Once the stem cell develops into a mature beating heart cell, it remains that type of cell. Mature cells, like zebras, cannot change their stripes. We never see a heart cell become a skin cell and vice versa. Cellular development is unidirectional and this has been one of the central tenants of developmental biology.

Then along comes Scottish scientist, Ian Wilmut, who did an experiment in the mid-1990s that no self-respecting developmental biologist would attempt since we all “knew” that cell development only moved in one direction.

What Wilmut did was to remove the nucleus from an egg cell and replace it with the nucleus from a fully mature cell taken from a different animal. Keep in mind that this donor nucleus had already been directed to express only those genes of the tissue it was taken from and to repress the expression of genes from all other tissues.

Wilmut then transferred this engineered egg into the womb of a pseudo-pregnant sheep, where the engineered egg should have died. Instead, a sheep was born that was a genetic twin of the nucleus donor sheep and the world was introduced to the first cloned animal, Dolly.

This is the type of research result that causes a scientific paradigm shift. For the first time, we realized that the genetic program of a fully developed adult cell, when placed in the proper environment, can be reprogrammed to relinquish its adult cell properties and return to its undifferentiated stem cell state, capable of developing into a fully grown sheep. 

Around the same time that Dolly was born, University of Wisconsin-Madison scientist, Jamie Thomson, published his seminal studies demonstrating the ability to grow monkey and human embryonic stem cells (or ESCs). These, of course, are the immature cells derived from five day old embryos that are able to develop into all tissues of the adult body. The way that ESCs are harvested kills these embryos making ESC research highly controversial. It would be great to be able to obtain such embryonic stem cells without having to destroy a functional human embryo.

Fast forward ten years to the conference where Professor Thomson gave an update on his recent report that he can reprogram adult cells to become stem cells without having to transplant cell nuclei. Looking at recent research from different labs, he noted that only a few regulatory genes are needed to maintain cells in their nascent developmental stage. As the research presented at the conference illustrated, these regulatory genes work across different species, so this mechanism is highly conserved in biology.

Thomson used routine gene transfer technology to induce expression of three different regulatory genes in the cells of mature fibroblasts and, amazingly, the mature cells were re-programmed to become stem cells! What Wilmut was able to do by transferring a cell nucleus to an enucleated egg can now be done in a petri dish and without the egg cell.

At the conference, Thompson explained that these “induced pluripotent cells” or iPCs seem to behave exactly like ESCs. Think about the implication of this observation: it means that mature cells from an adult can be re-programmed back to the stem cell state where they are able to generate anew, all tissues of the human body.

What next for stem cells?

UW-Madison stem cell researcher, Clive Svendson, moderator of the conference, believes that the next major advance will be the ability to develop iPCs by simply changing the environment in which adult cells are grown in the lab, which could be accomplished in about a year. This means that we would not have to insert several genes into a cell’s DNA, which has significant risks and is not a trivial procedure. Thus, it soon may be very easy to take cells from your skin, put them into a defined tissue culture environment and develop stem cells that contain your precise genetic makeup. No embryos would be destroyed and no clones would be created in the process, mitigating most of the ethical concerns.

Svendson opined that this could lead to a big boost in the tissue banking business as people store tissues when they are young for making stem cells if they should need them later. This would be necessary because, as Thomson explained, chronologically young cells are more efficient at being reprogrammed than cells from older animals. One can envision that it could become routine at birth to store placental tissue, the youngest tissue readily available that is genetically identical to the newborn baby.

As exciting as the science was at the conference, there remain some problems to deal with before these stem cells are used in the clinic. First, as with ESCs, undifferentiated iPCs form tumors called teratomas. Therefore, we need to develop a fail-safe way to completely separate or incapacitate contaminating stem cells from the functional tissues grown from them before we put them into patients. According to an article I posted here earlier, the FDA recently convened a meeting to grapple with this problem in anticipation that clinical trials will begin in the near future.

Next, even if we can use stem cells to regenerate damaged tissues, we still need to continue research into the causes of degenerative diseases because simply replacing the dying cells without dealing with what causes them to die may only be a short term fix.

Potential ethical issues may still arise

Finally, and potentially an explosive issue, there remains an ethical question regarding iPCs that no one seems to have addressed. When a mature cell is reprogrammed, how far back does it go? Do iPCs only have the potential to develop into different body tissues, or can an iPC, if given the chance, form an embryo? Of course, if the iPC cells are more like fertilized eggs than stem cells, then all bets are off--the ethical issues will arise again.

I asked both Svendson and Thompson about this and both admitted that this idea had not been tested. Svendson even owned up that no one in the field wants to test it. They do not want to know the answer because it could be very inconvenient.

My prediction

Carl Gulbrandsen, Director of the Wisconsin Alumni Foundation, shared with me that reading Thomson’s paper on reprogramming adult cells to derive embryonic iPCs made him “tingle”. Mr. Gulbrandsen does not seem to be the tingly type, but his response to Thomson’s results was not inappropriate—they are that amazing and significant.

As a scientist, I have learned to be cautious about making predictions. However, I venture one prediction here that I believe has a very good chance of being realized: Professor Jamie Thomson will, in the not-to-distant future, be awarded the Nobel prize for his outstanding work that has created a whole new field of stem cell biology and invigorated the practice of regenerative medicine. While I am at it, you can bet that he will share the prize with Ian Wilmut.

Any takers?
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This post was first published in-part by the Wisconsin Technology Network News

 

© 2008 Steven S. Clark, PhD. Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not 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.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.

FDA mulls embryonic stem cell therapy

It is not a matter of if, but of when clinical trials using stem cells to treat human diseases will begin. In anticipation of this, the FDA is considering ahead of time, what kind of oversight they will need to provide when the first clinical trial applications reach their door. Not bad, a government agency thinking proactively! Read on.

Posted on The Scientist NewsBlog by Andrea Gawrylewski

With biotech companies inching up on clinical trials for human embryonic stem cell-based therapies, the US Food and Drug Administration held a meeting yesterday to discuss scientific issues in properly deriving and characterizing the cells, as well as appropriate clinical trial monitoring.

Three biotechs, Geron Corporation, Advanced Cell Technology, and Novocell presented some of their scientific work on spinal cord injury, vision impairment, and diabetes, respectively, at the meeting. Geron and Advanced Cell Technology are hoping to begin testing therapies of cells derived from human embryonic stem cells sometime this year, according to Bloomberg News. Jane Lebkowski, senior vice president of regenerative medicine at Geron Corporation, told The Scientist she could not comment on whether this was true.

"The science was ready to have this kind of discussion, to make sure clinical trials are safe," Celia Witten, spokesperson for the FDA told a group of reporters after the day-long meeting, though she declined to say whether the agency has yet received any Investigational New Drug applications.

The advisory committee, which was made up of 25 independent scientists and FDA researchers, addressed issues of proper animal studies for preclinical testing and how researchers can control the embryonic stem cells for appropriate differentiation -- that is, so they don't form cancerous teratomas.

"There was a lot discussed in the range of things we're already thinking about," Lebkowski told The Scientist. "And several ideas we've been implementing already." Some of the committee's ideas were rather extreme, she added; some of the large animal model studies in non-human primates or pigs that the committee discussed were not very practical and extremely complicated -- the committee mused aloud whether allograft experiments (for example, pig embryonic stem cells transplanted to pig body) should be conducted before transplanting human embryonic stem cells to different species.

Several committee members noted that guidelines and requirements of human embryonic stem cell-based therapies will vary from disease to disease, and cell product to cell product. However, all the members seemed to agree that a common, standardized assay should be developed to determine the tumorigenicity of a specific cell product.

Kenneth Chein, from Harvard Medical School, noted that transplanting cardiomyocites and other types of differentiated embryonic stem cells has yielded mixed efficacy results so far, requiring that more definitive assays need to be developed for efficacy and safety.

The committee also addressed how researchers and clinicians will be able to control and monitor where the cells go once they are administered. While new technologies such as reporter genes may improve researchers' ability to track transplanted cells, some committee members questioned whether new techniques should be used at the same time as therapeutic embryonic stem cells, which itself is a novel type of therapy.

Some members of the committee said they were uneasy about embryonic stem cell therapies, and the committee discussed the potential of developing failsafe mechanisms in the cell products, like suicide genes. But some noted that such approaches may have their own therapeutic complications and risks.
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© 2008 Steven S. Clark, PhD. All Rights Reserved.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not 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.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.