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www.bioworld.com

Tracking Biotech’s Original Movers and Shakers

Chasing Bill Gates

The Rising Power of Investors

Presorted Standard

U.S. Postage

PAID AHC Media LLC

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My company, now AHC Media LLC, acquired BioWorld shortly thereafter, and I have been its publisher ever since. For those of us working on these products, we have enjoyed a truly terrific ride. We’ve reached, in 2010, the 20th anniversary of the business. One of the earliest BioWorld publications we have in our archives is a magazine product, BioWorld, the “Premier Issue” as it was dubbed, dated November/December 1990. Preceded by both online and fax variations, the magazine edition would expire after just one further issue. We have since evolved into an almost entirely online enterprise, leaving both the glossy pages and the faxes behind. Returning to our roots, however, we are celebrating our 20th with the magazine publication you see here – a look back at biotechnology through the prism of BioWorld’s two decades and a look ahead at developments to come. I can think of no more appropriate use of this space than to thank a host of people who have contributed to that ride. The thank yous begin with our customers. Our circulation data does not stretch all the way back to 1990, but certainly we have readers who have been with us since the February 1994 acquisition. Thank you for subscribing. Thank you for making us better every day with your insights and comments. Every move we make, every headline we write is with you in mind. Keep your suggestions coming. I want to thank David Bunnell, whose Io Publishing Inc. nurtured BioWorld through its founding three years, and from whom we purchased the BioWorld assets. Cynthia Robbins-Roth, founding editor in chief, invited me to lunch during that first San Mateo visit, although by then she had moved on and her BioVenture View was an indirect competitor. We became great friends and have been so ever since. BioWorld has benefited from the energy and professionalism of a wonderful staff over the 16 years of our management. I can’t name everyone here but I’ll thank the six managing editors who have directed BioWorld’s daily coverage from our Atlanta newsroom with vision, hard work and sound journalistic judgment — Lynn Yoffee, Charles Craig, Jim Shrine, Randy Osborne, Brady Huggett and Glen Harris. Jim Stommen served for a period as executive editor of both BioWorld and our med-tech unit, with its flagship, Medical Device Daily. Plus, we’ve had three remarkable marketing managers getting the

word out: Paige Stanfield, Chris Walker and Jane Cazzorla. Among our reporters, I must single out the late, great David Leff, who wrote colorfully and astutely for us for 12 years about the science that forms the foundation of the biotechnology industry. He certainly elevated our esteem in the sector in the process. I know the reporters themselves would find me remiss if I did not mention their sources over the years — the thousands of company executives, analysts, scientists, attorneys and other industry insiders who have (usually) returned their calls and answered their questions. Many of you are also subscribers, so we double our thanks. We’ve had excellent business relationships with a number of industry partners and players. Special thanks go to Mark Dibner of BioAbility; Robert Kilpatrick and the Technology Vision Group; Alexandra Scott and the International Business Forum; Matthew Chervenak of General Biologics; and Carola Schropp of the EBD Group. BIO, the Biotechnology Industry Organization, has been both a subject of our stories, as well as a source. We’ve been each other’s customer. We’ve exhibited at BIO every year since 1995. We’ve enjoyed, particularly, a relationship of mutual respect with its two longtime presidents, Carl Feldbaum and Jim Greenwood. And thank you, finally, to the biotechnology industry as a whole. Whether sporting a lab coat or a business suit, you are a smart, upbeat, innovative group. Your optimism has been infectious. I can’t imagine a better industry for us to be covering. Keep the news flowing. We’ll continue to cover it as no one else in the industry has: every business day for the last 20 years.

I first visited BioWorld’s offices on the second floor of a commercial building on South B Street in San Mateo, Calif., in January 1994. The business, then about three years old, consisted mainly of a daily, faxed newspaper, BioWorld Today; a weekly look at financial trends in the sector, BioWorld Financial Watch (since renamed BioWorld Insight); and a nascent online news and data service.

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BIOWORLD 2010

ART DIRECTOR

Rachna Batra

BRAND MANAGER

Nicole Cathcart

ILLUSTRATOR

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STAFF WRITERS

Randy Osborne, Trista Morrison, Catherine Hollingsworth, Michael Harris

SCIENCE EDITOR

Anette Breindl

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Opinions expressed are not necessarily those of this publication. Mention of products or services does not constitute endorsement.

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CONTENTSThe Hope and Promise of Biotechnology By James C. Greenwood

Gates Closed: Microsoft’s ‘Boy Wonder’ Grows Up – and Up

Who’s Who: Tracking Biotech’s Movers and Shakers

The Future Is Here: Who Will Shape Biotech Over the Next 20 Years? BioWorld Says…

The Biotech Revolution: 20 Years of Battling Disease

Two Decades Later, Still-‘Broken’ Model Striving to Fix Itself, Keep the Cash Flowing

Activist Shareholders Up the Ante, But Is Innovation at Stake?

The Blog Fog, Social-Media ‘Journalism,’ Twitter Litter: What’s Next?

The New Patient Activism: Taking It to the Streets – and Beyond

From Orphan Drug Act to ARRA: Government’s Impact on Biotech

Here There Still Be Dragons: 20 Years Later, Looking for Heritability in the Details

Breaking News: There’ll Be No Break in News!

Bio-Developments: 1990-2010

As the Biotech Industry Matures, Enter the Hollywood Era By Karl Thiel

Oh, Magic 8-Ball, Will Biotech Prosper? Predictions for the Future

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On behalf of the Biotechnology Industry Organization (BIO), I want to recognize and applaud BioWorld on its 20th Anniversary as one of the most highly regarded and well-recognized trade publications providing insights and vital coverage of our industry. Shortly after BioWorld opened its doors, BIO was formed through the merger of the Association of Biotechnology Companies and the Industrial Biotechnology Association. The goal of our organization was for the entire industry, from young start-ups to established companies, to speak with one voice on important public policy issues at the state and national levels. That continues to be our primary focus at BIO – to bring together the industry and advocate for large and small companies alike with one voice. Similar to BioWorld, one of our association’s goals is to communicate the contributions and promise of biotechnology to address many of the world’s problems. At the 2010 BIO International Convention, we will release a report on the value of biotechnology titled, “Healing, Fueling, Feeding: How Biotechnology Is Enriching Your Life.” The report tells the promising story of biotechnology through data and anecdotes capturing some of the many contributions of our industry, which I’ve highlighted below. We believe this report and this year’s convention are occurring at a defining moment for our industry. We arrive in Chicago during a period of great uncertainty and great hope for our industry. The global economic downturn has hit our industry hard but the

fundamentals — the brilliant promise of our science — remain strong. This event gives us the opportu-nity to celebrate our accomplishments, discuss our common challenges, learn about new technologies and trends, and seek new opportunities for invest-ment and collaboration. It also gives us the opportunity to assess the great achievements of the overall industry, and look to the future for what we hope to accomplish to move innovation for-ward and help better our world. The past 20 years have propelled the biotech industry to contribute to a better and more sustainable way of life. Thanks to modern biotechnology, we live longer and healthier lives, enjoy a more abundant food supply and higher nutritional value, use less and cleaner energy and have safer, more efficient industrial manufacturing. Today, there are more than 250 biotechnology health care products and vaccines available to patients, many for previously untreatable diseases. Our companies continue to innovate at a breathtaking pace, developing medicines that are providing hope where there once was none and new tools to allow for more personalized and effective care. More than 13.3 million farmers around the world use

By James C. GreenwoodPresident and CEO, Biotechnology Industry Organization

BiotechnologyTHE HOPE AND PROMISE OF

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agricultural biotechnology to increase yields, prevent damage from insects and pests and reduce farming’s impact on the environment. And more than 50 biorefineries are being built across North America to test and refine technologies to produce biofuels and chemicals from renewable biomass, which can help reduce greenhouse gas emissions. We have high hopes for the next 20 years. We have a lofty goal — as an industry, we must continue to leverage cutting-edge innovations to address looming challenges and help create a brighter future. Already, we have made significant progress in meeting this goal and have only tapped a small fragment of the many potential uses —and benefits — of biotechnology. Biotechnology helps us answer the world’s most pressing challenges: resource sustainability, environmental stewardship, water scarcity, an aging population and cancer, to name just a few. The biotech industry is an eco-nomic growth engine, providing high-quality jobs for researchers and scien-tists, and generating employment for millions of workers in other industries. Every day, research scientists explore new ways to improve our quality of life using biotechnology applications. In health care, more than 600 new biotechnology medicines are currently being developed and tested for more than 100 diseases that could yield promising results in the near future. Researchers are capitalizing on genetic information to develop promising new cures for cancer, including therapeutic vaccines, and — through personalized medicine —working to help the right patients get the right treatment at the right time. Fulfilling the promise of personalized medicine truly could transform the delivery of health care within the next 20 years. And promising new work on malaria, tuberculosis, and dengue fever may prove the key to developing vaccines for deathly diseases that plague the world.

While great progress has already been made to improve crop yields and the nutritional value of our food sup-ply, we can expect further positive im-pacts in the near future. Through new biotechnological innovations, scien-tists are in the process of developing salt-tolerant, drought-resistant crops and opportunities for leveraging cur-rently non-productive land. Continued advances in the area of genetically en-gineered animals will enable research-ers to enhance food production and expand scientific knowledge. Also promising are applications that would reduce the environmental footprint of our farms. Biotechnology may pave the way for a 21st century industrial revolution that moves our economy away from a petrochemical-based economy to a more green and cleantech focused, bioprocessing-based economy. This could lead to the emergence of a new “home grown” value chain, giving every state the opportunity to sustainably leverage biological resources. And industry scientists are deploying new tools, such as synthetic biology and genetically enhanced microbes that require only sunlight and carbon dioxide, to enable bioprocesses for biofuels and chemicals. As an industry, we must continue our proud tradition of researching and developing breakthrough new products and technologies that address some of the greatest challenges facing our global population and our planet. It is the passionate, committed people in our industry who conduct the vital research and development work that will help treat previously untreatable diseases, grow more crops on available land, prevent pollution and environmental degradation at the source and develop advanced, renewable sources of energy.

Year round, we remain committed to advocating on behalf of the industry to create a policy and regulatory environment to support the important work that is being done every day. The value of biotechnology is often either overlooked or misunderstood by policymakers and the public. They must be made aware of the value that biotechnology brings to society and everyday life in order to make informed decisions that will affect future biotechnological innovation. BIO has the privilege and honor of telling the biotechnology story to the world. We hope that you will take a moment to read the value of biotech report, which you can access at valueofbiotech.com. And feel free to use the information and stories within the report to tell others about the enormous promise and potential of the biotech industry. Again, we applaud the long-standing commitment of BioWorld over the past 20 years to provide accurate and fair reporting of our industry. We stand ready to advocate and support the industry as it continues to deliver on the promise of biotechnology to help heal, fuel and feed the world for years to come.

THE BIOTECH INDUSTRY IS AN ECONOMIC GROWTH ENGINE, PROVIDING HIGH-QUALITY JOBS FOR RESEARCHERS AND SCIENTISTS, AND GENERATING EMPLOYMENT FOR MILLIONS OF WORKERS IN OTHER INDUSTRIES.

James C. Greenwood is President and CEO of BIO in Washington, D.C., which represents more than 1,200 biotechnology

companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products. BIO also produces the annual BIO International Convention, the world’s largest gathering of the biotechnology industry, along with industry-leading investor and partnering meetings held around the world.

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20 years ago, he sat for a BioWorld Q&A. Today, computer genius and biotech investor Bill Gates is busier than ever.

CLOSED

Microsoft’s ‘Boy Wonder’ Grows

Up — and Up

By Randy OsborneStaff Writer W riting in a BioWorld magazine

feature story two decades ago, David Bunnell described hearing news from the editor that his

friend, the famous entrepreneur Bill Gates, was entering biotech. “‘He is?’ I exclaimed somewhat incredulously. ‘How so?’” That year, 1990, Gates become the single largest investor in fledgling ICOS Corp., of Seattle. “BioWorld visits the software boy wonder,” trumpeted the headline in our premier magazine issue. ICOS, to become best known as Eli Lilly and Co.’s partner for the erectile-dysfunction drug Cialis (tadalafil), was bought in 2007 by Indianapolis-based Lilly for $2.1 billion — seemingly major bucks, but hardly enough to make golden Gates exclaim incredulously, even then. The Microsoft chairman’s presence in the biotech industry has only grown with his riches. In 1994, Gates founded the Bill & Melinda Gates Foundation (then known as the William H. Gates

Foundation) to give back by enhancing health care in poverty-stricken areas of the world. Phone calls and email from BioWorld to the foundation requesting an interview with Gates for our 20th anniversary issue drew an encouraging response at first. Then came a follow-up contact from one of Gates’ staffers, who said he would “have to decline the opportunity” because of other commitments. The chase was on. Trying to reach him through the foundation’s bureaucratic strata was probably futile to begin with, we reasoned. So we tried email to www.thegatesnotes.com, the website where Bill shares with fans under categories such as “what I’m thinking,” “what I’m learning about,” and “my travels.” Maybe Bill would take a few minutes from his schedule to tell our readers what he’d been thinking and learning about since the BioWorld magazine article in days of yore. We could ask him a lot of questions about the

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Maybe it was for the best, since Bill has his own, mostly non-biotech

projects going, and he needs to put his efforts there. Maybe he

wouldn’t have had much to say about the industry overall anyhow.

The chat might have been full of awkward silences.

biotech industry, where it’s been and where it’s going. We could ask him what he meant, in that original interview, when he said: “In my industry, we’ve built up a few companies like Microsoft that are going to be there for a long time. Biotech still doesn’t really have that. You can say Genentech sort of surrendered.” Hmm… 1990 was the year Basel, Switzerland-based Roche AG acquired a majority stake in Genentech Inc. Was Bill talking about that? Could we ask him? Nope. Nothing. Next we considered firing off 150 characters on Twitter, where Bill tweets on occasion. Isn’t this how everybody talks to each other now – by way of Twitter and Facebook? Bill listed 685,227 Twitter followers at last count. Cutting through the noise and persuading him to get on the horn for a real-time chitchat ought to be easy, right? Sure. We gave that one up before starting. Continued effort seemed worthwhile. Bill’s original BioWorld interview contained keen-minded insights, including his comparison of biotech with the burgeoning field of computers. Bill reeled off the commonalities: “Smart people; a new industry where nobody really knows the rules and a lot of surprising things can happen; different ways you can look at partnerships and distributing products; situations where you’re friends on one deal and you’re enemies on the next; a small community where you’re always running into each other; an arena in which the courts are totally crazed with the level of ambiguity — is this thing protected or is it not? — are you going to be put out of business with this lawsuit that’s been running for years, where you basically have to assume that you’re going to win?” We assumed we were going to win. We tracked down David Bunnell, the writer of the original Bill article and founder of BioWorld, as well as other important media outlets. It was Bunnell’s friendship with Bill, after all, that won him the first interview; possibly he could pull some strings and get us a second one. We wrote to Bunnell at www.eldr.com, where

he is co-founder and editor in chief. It’s an online publication that offers “an enlightened, entertaining and sometimes edgy approach to aging through its reviews, articles and interviews, dynamic photography and artwork,” according to the website’s self-description. “Bringing back BioWorld memories for you.” This was the cheery, inviting — or so we thought — subject line of an email to Bunnell. “The reason I’m contacting you is that I’m trying to reach Mr. Gates for 15 minutes, and cannot penetrate the wall of his people; I’m hoping you can help,” we wrote. “Can you? Would you? Thank you for anything you might do.” Bunnell declined the opportunity too, apparently. No reply. Could be that he had just as much going on as his longtime friend Bill. We were aging, and getting edgy about it, but no Bill. Other avenues were explored — many other avenues. We contacted friends of friends of Bill. We tried to find people who knew people who had once stood in line somewhere in proximity to Bill. We cajoled public relations people who seemed like they had important connections. One warned about the “tall order,” but vowed: “I will do everything in my power to make it happen.” Didn’t happen. Not through her power, or ever at all. Maybe it was for the best, since Bill has his own, mostly non-biotech projects going, and he needs to put his efforts there. Maybe he wouldn’t have had much to say about the industry overall anyhow. The chat might have been full of awkward silences. Yet we prefer the past, when the world seemed more manageable and people easier to reach, just by picking up the phone and waiting on hold for a few minutes. Bill was talking about computers when he said the following, but it seems to fit: “The industry is now dominated by large companies that are very different from the ones who started it up, and you get people who are still very nostalgic for those old days.” Amen, Bill. Amen.

ABOVE: Bill Gates

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n 1990, a new group of biotech leaders started to emerge. Some held positions within the industry, leaving big pharma to run young biotech companies or rising through the newly established biotech ranks to advance cutting-edge technologies. Others hailed from the financial community, from Washington or from academia. Together, they were poised to take the helm from the biotech industry’s original founders and navigate through uncharted waters, nurturing innovation, building infrastructure and overcoming early challenges along the way. Twenty years ago, the BioWorld staff compiled a list of those people – the ones most likely to shape the future of the biotech industry. Based on a combination of research, interviews and personal opinions, the list served as an early “who’s who” for the industry. What happened to those petri dish pioneers, those leaders of the lab and brainiacs of the boardroom? Let’s take a look at how the members of our original list have fared over the past 20 years…

In the original issue 20 years ago, BioWorld picked the up-and-coming stars expected to shape the future of the biotech industry. Where are they now?

By Trista MorrisonStaff Writer

Tracking Biotech’s Original Movers and Shakers

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Dennis Longstreet

EXECUTIVES

Hollings Renton

THEN: President and chief operating officer of Cetus Corp., a biotech reeling from the FDA’s rejection of cancer drug Proleukin (interleukin-2).

NOW: Founded in 1971, Cetus was one of the original biotech start-ups. Its first claim to fame was scientist Kary Mullis’ work on the polymerase chain reaction (PCR), a DNA amplification technique that earned Mullis a Nobel Prize and provided the nascent biotech industry with a foundation on which to build. But by 1990, Cetus had turned its focus to drugs, namely cancer drug Proleukin and multiple sclerosis drug Betaseron (interferon beta-1b). When the FDA rejected Proleukin, Renton was brought in to get things back on track.

He did just that. Within a year, he had engineered Cetus’ acquisition by Chiron Corp., where he took over as president and chief operating officer. He oversaw Chiron’s approval of Proleukin and Betaseron. Chiron itself later would be acquired by Novartis AG, but Renton didn’t stick around to see that – he was lured to a

little cancer start-up called Onyx Pharmaceuticals Inc. Onyx was the brainchild of Frank McCormick, now director of the UCSF Helen Diller Family Comprehensive

Cancer Center. Back then, McCormick was vice president of research at Cetus and then at Chiron. Shortly after the merger, he got funding from venture investors Brook Byers and Sam Colella to spin out a biotech focused on cancer. Renton joined Onyx as president and CEO in 1993. He quickly inked deals with Warner-Lambert Co. (now Pfizer Inc.) for Onyx’s lead oncolytic virus program and with Bayer AG for an early stage kinase inhibitor program. After going public in 1996, Onyx fell victim to the harsh markets of 2001 and was forced to restructure. Then Pfizer backed away from its partnership, forcing Renton to make what he called a “key strategic decision.” Onyx abandoned its Phase III oncolytic virus program to focus on Nexavar (sorafenib), then in Phase I/II with partner Bayer. “We were probably one of the earlier companies to make a strategic decision to abandon a platform and focus on a single drug,” Renton said. The bet paid off. Nexavar gained approval for kidney and liver cancers, posting global sales of $843.5 million last year and helping thousands of patients. Renton retired in 2008 and now serves as chairman of the board at Affymax Inc., co-chairman of the board at Portola Pharmaceuticals Inc., and board member for Rigel Pharmaceuticals Inc. and Cepheid Inc.

THEN: President of Johnson & Johnson’s Ortho Biotech group, the first standalone biotech subsidiary to come out of big pharma and the only company at the time with a monoclonal antibody on the market (transplant rejection treatment OKT3).

NOW: Ortho laid the groundwork for a string of successful J&J biotech subsidiaries, including Centocor Inc. Longstreet’s influence was critical to building the big pharma’s biotech presence, as was that

of James Utaski, who oversaw J&J’s business development and venture capital efforts during the same time

period. Over the years, Longstreet moved up the big pharma’s ranks, eventually serving as group chairman and managing

four medical device divisions with $4 billion in sales. After retiring in 2005, he joined

private equity firm RoundTable Healthcare Partners in 2006, where he still serves as a

senior advisor and sits on multiple company boards.

“ We were probably one of the earlier companies to make a strategic decision to abandon a platform and focus on a single drug.”

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Michael Riordan

THEN: Founder, president and CEO of antisense start-up Gilead Sciences Inc.

NOW: Drawing on experience from both the medical and venture capital fields, Riordan (left) founded Gilead when he was just 29 years old. In addition to making BioWorld’s original movers-and-shakers list in 1990, he was also named one of BioPeople Magazine’s most eligible bio-bachelors. In 1990, Riordan had been pushing Gilead’s scientists to figure out a way to make antisense work, but to no avail. The programs were sold to Isis Pharmaceuticals Inc., which continues to advance antisense today. Gilead then turned its focus to aptamers, which were later sold to Eyetech Pharmaceuticals Inc., Archemix Inc. and others. But the seeds that would one day grow Gilead into a $7 billion HIV and liver disease powerhouse were already being planted: Riordan recruited John Martin, now chairman and CEO; John Milligan, now president and chief operating officer; and Norbert Bischofberger, now chief scientific officer. That early dream team picked up rights to some antiviral technologies that had fallen through the cracks during the merger of Bristol-Myers Co. and the Squibb Corp. Although only in preclinical, they would one day become HIV drug Viread (tenofovir disoproxil fumarate) and HBV drug Hepsera (adefovir dipivoxil). Riordan left Gilead in 1997 and spent several years traveling in Europe and Asia. He’s working on a nonprofit at the intersection of human rights and digital media, but prefers to keep the project under the radar for the time being. And – attention, ladies – he hasn’t settled down to marriage yet, so you’ve still got a chance to capture this bio-bachelor’s heart.

James Sherblom

THEN: Chairman and CEO of Transgenic Sciences Inc., a pioneer of manufacturing recombinant products in transgenic animals.

NOW: Sherblom hailed from Genzyme Corp., which back then was no stranger to supporting its early stage enzyme research with diverse acquisitions. He employed a similar strategy at TSI, acquiring lab-testing service firms to help fund the transgenic manufacturing programs. TSI was sold to Genzyme,

and Sherblom founded Seaflower Ventures to seed new life science and medical technology start-ups. The firm was involved in funding Geltex Pharmaceuticals Inc., which developed Renagel (sevelamer hydrochloride) and was later bought by partner Genzyme for $1 billion. Seaflower is well-respected in the early stage venture industry, and Sherblom still serves as managing general partner. He also co-founded the Massachusetts Biotechnology Council, which has grown into a powerful regional biotech industry organization representing more than 600 member organizations.

Ron Unterman

THEN: A pioneer in environmental biotechnology, Unterman left General Electric to co-found Envirogen Inc., a start-up focused on bioremediation of hazardous wastes.

NOW: Unterman served as chief scientific officer as Envirogen went public and was sold to engineering and technology firm Shaw Environmental. He later joined the Slater Center for Marine and Environmental Technologies, a Rhode Island venture firm.

Roger Salquist

THEN: Chairman and CEO of Calgene Inc., which held the future of agricultural biotechnology in its hands as the first biotech to pursue approval of a genetically engineered food.

NOW: Salquist got his FDA approval of the Flavr Savr tomato, although it proved too expensive for commercial success. Nevertheless, he negotiated Calgene’s acquisition by Monsanto Co. in 1996 and then founded venture firm Bay City Capital in 2007. Bay City has helped fund dozens of biotechs and still invests actively in the space today. Salquist, however, retired in 2003 to serve as chairman of the Connect entrepreneurship program at the University of California, Davis. He later moved on to a position as chairman of lipid profiling company Lipomics Inc.

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Virginia WalkerTHEN: Vice president of finance at California Biotechnology Inc. and a champion of creative biotechnology financing.

NOW: Walker organized the first conference of the association of biotechnology financial officers. She also helped turn around CalBio, which later became Scios Inc., now a Johnson & Johnson subsidiary focused on marketing heart failure drug Natrecor (nesiritide). But the biotech industry lost her talents as she took senior finance positions with General Electric, semiconductor company Intersil Corp., software developer OSE Systems/Enea and high-tech consulting firm Jamison Group.

Art BenvenutoTHEN: A former Eli Lilly and Co. executive who took the helm of Marrow-Tech Inc., serving as chairman, president and CEO of the regenerative medicine firm.

NOW: Marrow-Tech changed its name to Advanced Tissue Sciences Inc. and won FDA-approval of Dermagraft, a bioen-gineered, cryopreserved tissue used to treat diabetic foot ulcers. But the firm went bankrupt trying to fund its portion of a joint venture with Smith & Nephew. Dermagraft, however, lived on: the tech-nology was sold to Advanced BioHealing Inc., which successfully markets it today.

Benvenuto (right) went on to serve as chairman of the life science group at RA Capital Management LLC, and he served on several biotech boards. Today he is chairman and CEO of Micell Technolo-gies Inc., an early stage firm developing bio-coatings for drug-device combina-tion products. And Benvenuto wasn’t the only ATS alum to impact the indus-try: ATS Chief Medical Officer Ron Cohen became founder, president and CEO of Acorda Therapeutics Inc., which recent-ly won FDA approval of Ampyra (dal-fampridine) to improve walking ability in patients with multiple sclerosis.

John GroomTHEN: A Smith Kline & French Laboratories alum who left big pharma to serve as founding president and CEO of Athena Neurosciences Inc.

NOW: Groom engineered Athena’s $600 million takeover by Elan Corp. plc. in 1996, which gave the big pharma access to soon-to-be-approved muscle spasticity drug Zanaflex (tizanidine hydrochloride) and seizure drug Diastat (diazepam). Elan also took over development of a little multiple sclerosis antibody in Athena’s pipeline: back then it was known as Antegren, but it would one day become a blockbuster under the brand name Tysabri (natalizumab). Groom joined the Elan ranks, eventually serving as president and chief operating officer. Known as a charismatic leader, he retired in 2001 and now serves on several biotech boards.

Alan TimmsTHEN: Traded a high-level position with G.D. Searle & Co. (now part of Pfizer Inc.) to serve as president and CEO of Glycomed Inc.

NOW: Timms had decades of big pharma experience gained first at Sandoz (now part of Novartis AG) and later at Searle, where he served as president of research and development. He left to run his own consulting company, but after just two years he was recruited to the top spot at Glycomed, a biotech founded by Brian Atwood, who later went on to found venture firm Versant Ventures. Glycomed’s carbohydrate chemistry platform proved difficult to advance, however, and Timms left the struggling company during a 1994 restructuring, just prior to its acquisition by Ligand Pharmaceuticals Inc. Timms returned to his consulting firm until he retired in 2001; he also served on several biotech boards.

Glenn FrenchTHEN: President of Applied Immune Sciences Inc.

NOW: Applied ImmuneSciences Inc., an

innovator in cell and gene therapies, sold one-third of itself to Rhone-Poulenc Rorer Inc. in 1993. The big pharma (which would eventually form part of Sanofi-Aventis Group) bought the rest in 1995, at which point French moved

on. Like so many other early biotechs, Applied ImmuneSciences produced more than one future biotech leader: scientific founder Thomas Okarma went on to become president and CEO of stem cell pioneer Geron Corp.

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David Blech

FINANCIAL COMMUNITY

THEN: Founder of at least a dozen biotechs including Genetic Systems Corp., Celgene Corp., Icos Corp. and Neurogen Corp., as well as the head of biotech investment firm Blech & Co., which was seeking to “rescue” struggling companies.

NOW: Blech kept founding biotechs – among them Alexion Pharmaceuticals Inc. and Neurocrine Biosciences Inc. He shook up many traditional venture capitalists with his unorthodox funding approaches and decision-making based on what he referred to as an intuitive sense about people. But Blech’s empire came crashing down when his investment firm got into trouble for buying and selling stocks to and from brokerage accounts that he controlled, which created the illusion of liquidity. His firm failed to open its doors on Sept. 22, 1994 – known on Wall Street as “Blech Thursday” – sending ripples through the entire biotech sector and stranding several biotechs that had depended on his support. Blech later pleaded guilty to criminal securities fraud. But that wasn’t the end for Blech – like so many of the biotech companies he invested in, he would rise again from the ashes. The Seattle Times reported a few years ago that he was consulting for Intellect Neurosciences Inc., an antibody firm working on disease-modifying Alzheimer’s drugs. And the Times also noted that his family owns about $25 million worth of biotech penny-stocks.

Denise Gilbert

THEN: An analyst with County Na-tional Westminster Bank (a.k.a. County NatWest) known for insight-ful, substantive commentary that got beyond the hype.

NOW: As investment banks began to sense biotech’s potential, Gilbert was one of the original financial analysts hired to cover the industry. After advancing through analyst positions with Smith Barney Harris & Upham and Montgomery Securities, she moved to the corporate side as chief financial officer and executive vice president first at Affymax Inc. and later at Incyte Corp. In 2000, she left Incyte to bicycle around the world. She later served as CEO of privately held bioinformatics firm Entigen Corp. before branching off on her own as an independent consultant. Gilbert serves on the boards of Dynavax Technologies Corp., Cytokinetics Inc. and KaloBios Pharmaceuticals Inc.

Yasunori Kaneko

THEN: Head of corporate finance for Paribas Capital Markets Ltd.’s investment banking division, where he was known for pioneering strategic alliances between U.S. and Japanese biotech companies.

NOW: Kaneko (right) left Paribas to serve as chief financial officer and senior vice president at antisense pioneer Isis Pharmaceuticals Inc., which he took public in 1991. He then headed finance and business development at Tularik Inc., a company started by fellow Genentech Inc. alum David Goeddel, now a managing partner with venture firm The Column Group. At Tularik, Kaneko oversaw several big pharma partnerships and took the biotech public in 1999, five years before it would be acquired by Amgen Inc. He left Tularik to join Skyline Ventures, an active health care investment group. According to Skyline’s website, Kaneko “committed to golf several years ago after an unfortunate heading incident at a team reunion for his junior All-Star soccer team.”

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Nancy Olson

THEN: A former general partner at venture firm Sequoia Capital who was independently backing young biotechs.

NOW: In 1993, Olson was recruited to run health care investments for St. Paul Venture Capital. She backed companies like Biopsys Medical Inc.

(bought by Johnson and Johnson), Santarus Inc. (now public) and Pro-metheus Laboratories Inc. (profitable and soon to be public). When St. Paul launched its health care-focused Fog City Fund in 2000, Olson was appoint-ed as the fund’s sole managing partner and continued to provide seed funding for firms like BioLucent Inc. (acquired by Hologic Inc.) and Somaxon Pharma-ceuticals Inc. (now public). She consid-ers herself extremely fortunate to have been investing on behalf of a single limited partner for 17 years, and as Fog City Fund winds down, she has taken an active role in nonprofits including the University of California, Berkeley, the Girl Scouts of the San Francisco Bay Area and the San Francisco Opera.

Joe Lacob

THEN: Partner at venture firm Kleiner, Perkins, Caufield & Byers.

NOW: Lacob is one of the few on this list who, 20 years later, is still with the same company. But don’t let that fool you into thinking he’s been complacent. Lacob has managed investments in more than 50 life science companies, not to mention several internet companies and green-tech/alternative energy companies. He serves on the boards of several biotech and medical device firms as well as nonprofits, and is known within the industry as a prominent venture capitalist.

THEN: As managing director at investment banking firm PaineWebber, Papadopoulos was known for taking risks to finance young biotechs.

NOW: As he rose through the PaineWebber ranks, eventually becoming chairman of the bank’s biotech-focused subsidiary, Papadopoulos became known as the industry’s consummate deal maker and financier. He managed complex acquisitions like Warner-Lambert Co.’s $2.1 billion buyout of Agouron Pharmaceuticals Inc., and he developed innovative mechanisms to help fund research. Among the funding models he popularized were Special Purpose Accelerated Research Corporations, or SPARCs, which were similar to R&D limited partnerships but involved spinning off a product to be funded as a separate publicly traded company rather than a private investment opportunity. He also conceived the tracking stock concept, which helped Genzyme Corp. reorganize its business units. One of Papadopoulos’ most innovative inventions was the use of Regulation D filing exemptions to allow sophisticated private investors to invest in biotech start-ups. The approach, used for both ICOS Corp. and

Athena Neurosciences Inc., “brought venture capital to the masses,” Papadopoulos said. Few of Papado-poulos’ creative financ-ing mechanisms have survived to the pres-

ent day. Symphony Capital’s funding model contains echoes of the old R&D limited partnerships, but for the most part, as tax benefit loopholes were closed, simpler financing approaches like registered direct offerings and PIPEs took precedence. Still, many say the industry couldn’t have matured without Papadopoulos’ help. After PaineWebber, Papadopoulos served as vice chairman of investment bank Cowen & Co. until his retirement in 2006. But his influence extended beyond banking. He doubled as a venture capitalist, pouring his own money into biotechs like Anadys Pharmaceuticals Inc., Cellzome Inc., and Exelixis Inc., which he co-founded and still oversees as chairman. He remains an active investor and board member of several other biotechs, including BG Medicine, Regulus Therapeutics Inc., Joule Biotechnologies Inc. and Biogen Idec Inc. Papadopoulos also gets credit for raising the bar on biotech conferenc-es: The banking conferences he sponsored during the industry’s early years were known for bringing together the top minds in the business and chang-ing the intellectual level at which business was discussed. He still hosts an exclusive biotech conference each year in Greece, which serves as the main funding source for a nonprofit he co-founded with Harvard Medical School’s Spyros Artavanis to provide support and guidance to Greek scientists.

Stelios Papadopoulos

“ [Regulation D filing exemptions] brought venture capital to the masses.”

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Larry Bock

THEN: General partner with Avalon Ventures, a then-young life science and high-tech investment firm that is still active in biotech company formation.

NOW: Bock had biotech in his blood: his father, Richard Bock, was one of the original biotech brokers. With that kind of pedigree, it was no surprise when Larry Bock ditched a job at Genentech Inc. to return to business school and try his hand at venture capital. In the 1980s, Bock was trying to recruit Harvard neurologist Dennis Selkoe to start a biotech company. Kevin Kinsella, founder of Avalon Ventures, was pursuing Selkoe as well. The two “decided to collaborate rather than compete,” Bock said, and the result was Athena Neurosciences Inc., which would later be bought by Elan Corp. plc. Bock and Kinsella worked so well together that they collaborated again on Vertex Pharmaceuticals Inc. and Genpharm International Inc. (now part of Bristol-Myers Squibb Co.) – and then Bock finally joined Avalon full-time. Over the years, Avalon sowed the seeds that would grow into much of the biotech industry as we know it today. It founded Sequana Therapeutics Inc. (now part of Celera Corp.), Pharming Group NV, Neurocrine Biosciences Inc., Ariad Pharmaceuticals Inc., Pharmacopeia Inc. (bought by Ligand Pharmaceuticals Inc.), Onyx Pharmaceuticals Inc., Caliper Life Sciences Inc., Idun Pharmaceuticals Inc. (acquired by Pfizer Inc.), Aurora Biosciences Corp. (acquired by Vertex), Conforma Therapeutics Corp. (bought by Biogen Idec Inc.) and many others. Yet some have noted that Kinsella’s investment in the hugely successful Broadway musical “Jersey Boys” made him more money than his biotech ventures. Around 2003, Bock felt the biotech venture capital business was starting to get crowded, so he moved to the still nascent nanotech field. He joined CW Group, where he founded Illumina Inc., and later moved to Lux Capital Management, where he founded Nanosys Inc. and Genocea Biosciences Inc. But while building nanotech start-ups, Bock noted that it was difficult to recruit American scientists because the next generation was placing its bets on other career paths. Inspired by the science festivals he saw on a family trip to Europe, he started a nonprofit “to get people excited about science again.” His San Diego Science Festival attracted about 250,000 attendees last year and is now gearing up to go nationwide. Bock and his wife also founded Community Cousins, a nonprofit aimed at matching families of different ethnicities to create friendships and destroy racism.

[Bock started a nonprofit] “to get people excited about science again”

Chris Gabrieli

THEN: Launched the healthcare practice at Bessemer Venture Partners.

NOW: Gabrieli led Bessemer’s investments in bio-techs like Affymax Inc., Isis Pharmaceuticals Inc., Sirtris Pharmaceuticals Inc. (now part of GlaxoS-mithKline plc) and others. He shifted his focus to politics and education about a decade ago, running for various offices in Massachusetts and found-ing Massachusetts 2020, an initiative focused on expanding public school hours. He also serves as chairman of the National Center on Time & Learn-ing, and he co-authored a book called Time to Learn: How a New School Schedule is Making Smarter Kids, Happier Parents, and Safer Neighborhoods.

Ken Kelley

THEN: Partner with Institutional Venture Partners.

NOW: Kelley oversaw the funding of 20 biotech and medical device firms during his tenure at IVP. In the mid-1990s he founded IntraBiotics Pharmaceuticals Inc. (now Ardea Biosciences Inc.), taking the company public in 2000. He went on to fund more start-ups as general partner at Latterell Ventures, and he later formed his own consulting firm, K2 Bioventures. Kelley now serves on several boards and holds the CEO spot at PaxVax Inc., a biotech he founded in early 2007.

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Rep. Robert Kastenmeier, D-Wis.

THEN: As chairman of the House Sub-committee on Courts, Intellectual Prop-erty and the Administration of Justice, Kastenmeier was pegged to “make or break” the Boucher bill, an initiative de-signed to protect biotech process pat-ents against foreign competitors.

NOW: The Boucher bill, formally known as the “Biotechnology Patent Protection Act,” made the rounds in Congress for several years before passing as a set of amendments to the patent law. It addressed the fact that while host cells used to produce genetically engineered proteins were patentable, the process of producing the protein within the cell was not. The Boucher bill influenced later legislation such as the 1995 “Biotechnology Patent Process Protection Act.” Back in 1990, the Boucher bill was a controversial topic within the industry, with the Association of Biotechnology Companies speaking out against it while the Industrial Biotechnology Association supported it. The situation was just one of many in which the two industry trade groups found themselves at loggerheads, making it difficult for biotech interests to gain any political traction. That changed in 1993, when the two merged to form the Biotechnology Industry Organization (BIO), which has served as biotech’s political voice ever since. Kastenmeier, meanwhile, lost his 1990 re-election bid to Republican Scott Klug.

Margaret Mellon

THEN: Director of the National Wildlife Federation’s biotechnology policy center.

NOW: As a scientist, Mellon had more credibility than the average gadfly, and her push to get politics out of science at federal agencies was aligned with the biotech industry. But she was no fan of agricultural biotech, having co-authored books like Ecological Risks of Engineered Crops and Hogging It!: Estimates of Antimicrobial Abuse in Livestock. She drew attention to the potential risks of releasing untested genetically modified organisms, and her reasoned voice of opposition was critical in positioning agricultural and environmental biotechnology as real issues that deserved real legislative consideration. Mellon left the NWF to serve as senior scientist and director of the food & environment program at the Union of Concerned Scientists, a science-based nonprofit. She also serves on the U.S. Department of Agriculture's Advisory Committee on Biotechnology and 21st Century Agriculture.

Jeremy Rifkin

THEN: President of the Foundation on Economic Trends and a biotech naysayer who fought access to genetic information, argued about side effects associated with Genentech Inc.’s growth hormone and sued the FDA over quality issues.

NOW: When you see protestors dressed like tomatoes outside of BIO’s annual conference, you have Rifkin to thank for it. He was one of the first anti-biotech activists, making frequent television appearances in which he condemned agricultural biotechnology and genetic engineering. One of his 17 books, The Biotech Century: Harnessing the Gene and Remaking the World, poses such questions as “Will artificial creation…mean the end of nature?” and “What will it mean to live in a world where babies are genetically engineered and customized in the womb?” When it became clear that the U.S. was going to embrace agricultural biotechnology, Rifkin shifted his focus on that front to Europe, and he has had an impact in shaping the anti-biotech sentiment overseas. He still runs the Foundation on Economic Trends, but he’s become somewhat more mainstream over the years, turning his attention to topics like green energy, sustainable development and employment in an automated world.

REGULATORY

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Greg Simon

THEN: As staff director of the investigations and oversight subcommittee of the House Committee on Science, Space and Technology, Simon was trying to strike a compromise between biotech and environmental groups regarding field tests of GMOs.

NOW: Simon was open-minded, listening to the arguments of the agricultural biotech industry and its opponents, such as Jeremy Rifkin and Margaret Mellon. He made sure that key Democrats remained open-minded as well instead of yielding to environmental extremists, and his push for conservative, regulated progress propelled the U.S. to become one of the only countries that supported ag-bio. Simon served as Vice President Al Gore’s chief domestic policy advisor on economic, science and technology issues from 1991 to 1997, overseeing the NIH and the FDA. He and a group of other biotech regulatory experts, known as the “Clone Heads,” influenced

the development of the regulatory framework for biotechnology products. He also played a significant role in the creation of the international space station and revamping the telecommunications industry. Simon made a quick sojourn into the private sector, starting his own consulting firm, before teaming up with Michael Milken in 2003 to fund a nonprofit called FasterCures. The group works to boost funding for disease research organizations; increase patient participation in research; build networks between nonprofits, philanthropists and the industry; and otherwise speed new drugs to market. Simon also served as part of the Obama administration's transition team reviewing the Department of Health and Human Services. Last year, he left FasterCures to serve as senior vice president of public policy for Pfizer Inc.

David BeierTHEN: Vice president of government affairs at Genentech Inc.

NOW: Beier was one of the first lobbyists to work Capitol Hill for the biotech in-dustry, and as such he was instrumental in shaping early legislation, including

successfully lobbying to keep orphan drug exclusivity provisions in the Or-phan Drug Act. In 1998, he became Vice President Al Gore’s chief domes-tic policy advisor. He then served as a partner with the Washington law firm of Hogan and Hartson until 2003, when he accepted the role of senior vice presi-dent, global government affairs for Am-

gen Inc. He continues in that role today, serving as a member of Amgen’s CEO staff and overseeing health care policy, corporate affairs, domestic and inter-national government relations, health economics initiatives, pricing, payor planning, philanthropy and corporate communications. He also serves on the board at Aryx Therapeutics Inc.

Lisa Raines

THEN: Director of government relations for the Industrial Biotechnology Association.

NOW: Like David Beier, Raines (left) was one of the first biotech lobbyists and was instrumental in keeping orphan drug exclusivity provisions in the Orphan Drug Act. She joined Genzyme Corp. as senior vice president for government relations in 1993 and had a hand in just about every piece of biotech legislation to emerge during the 1990s, including the Prescription Drug User Fee Act of 1992, the Biotechnology Patent Protection Act of 1995, the FDA Export Reform and Enhancement Act of 1996 and the FDA Modernization Act of 1997. Raines developed a reputation as an intelligent, hard-working, passionate and loyal figure on Capitol Hill. She always spoke her mind and wasn’t afraid to go head-to-head against big pharma’s deep-pocketed trade associations when necessary. She also took on the biotech industry, convincing cash-strapped CEOs that FDA user fees were the only way to help an underfunded agency keep up with its workload. On Sept. 11, 2001, Raines was aboard American Airlines flight 77 from Washington D.C. to Los Angeles, on her way to a Genzyme sales meeting in Palm Springs, Calif. All 64 people on board the plane – including Raines, then 42 years old – were killed when terrorists hijacked the aircraft and crashed it into the Pentagon, killing another 125 people on the ground.

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Alfred Gilman

THEN: Professor of pharmacology at the University of Texas Southwestern Medical Center and discoverer of G proteins.

NOW: Gilman (right) and other researchers defined the G protein-coupled receptor pathway, one of the most common mechanisms for getting information from the outside of a cell to the inside to regulate the cell’s function. It is estimated that between one-third and one-half of all drugs work in this pathway. Gilman’s discovery earned him the nickname “G-Man” and a Lasker Award in 1989. A few years later he was awarded the Nobel Prize in Physiology or Medicine, which he shared with fellow G-Man Martin Rodbell, now deceased. Gilman was elected as dean of UTSW Medical School in 2005. But for the last few years, he’s left the research world to serve as chief scientific officer of the Cancer Prevention Research Institute of Texas (CPRIT). Modeled on the California Institute for Regenerative Medicine, CPRIT is a state agency empowered to spend $3 billion over 10 years on cancer research in Texas. Gilman also serves on the boards of Regeneron Pharmaceuticals Inc. and Eli Lilly and Co.

SCIENTISTS

Philip Leder

THEN: Founding chairman of Harvard Medical School’s department of genet-ics and one of the first researchers to use transgenic mice to study cancer.

NOW: Leder, like many of the scientists on this list, remains at his post 20 years later. Perhaps this reflects that while investors and entrepreneurs expect rapid returns, scientists understand that making important discoveries and proving them out takes a lifetime. Leder’s genetically engineered “oncomouse” went on to broadly impact the study of cancer, and the concept of mimicking human diseases in mice has become a standard in biotech research. His work was recognized with a Lasker Award and the National Medal of Science. Earlier in his career, he also contributed to the deciphering of the genetic code, figuring out which letters corresponded to which amino acids. He is now the John Emory Andrus Professor of Genetics at Harvard.

Robert Langer

THEN: Professor of chemical and biochemical engineering at the Massachusetts Institute of Technology and a pioneer of controlled-release drugs and biodegradable polymers.

NOW: Langer’s discoveries sin-gle-handedly shaped the drug delivery industry. Over the years his combination of science and business acumen has helped found about two dozen com-panies, including Enzytech Inc. (now part of Alkermes Inc.), Momenta Pharmaceuticals Inc., Pervasis Therapeutics Inc., Bind Bioscienes Inc. and Selecta Bio-sciences Inc. His work has been

recognized with the National Medal of Science, the Millennium Technology Prize and numerous other awards. Langer is known for his creativity and his solutions-based approach to melding material science and pharmaceuticals. In addition to drug delivery, he contributed to early work in angiogenesis and tissue engineering. He now serves in the top post of “Institute Professor” at MIT, where he runs the world’s largest biomedical engineering lab. His research focuses on polymers for the delivery of genetically engineered proteins and nucleic acids, including siRNA, and nanotechnology.

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Catherine Mackey

THEN: Director of plant genetics at DeKalb Genetics Corp. and the first scientist to report solid data on genetically engineered corn.

NOW: Originally a Pfizer Inc. scientist, Mackey moved to DeKalb as part of Pfizer’s divestiture of its genetically modified seed business. After advancing through the DeKalb ranks and launching three products, she played a role in the firm’s $2.5 billion sale to Monsanto Co. Mackey then came full circle by returning to Pfizer to lead its genomics and proteomics programs. By 2001, Mackey had risen to the position of senior vice president of global research and development at Pfizer. She now runs Pfizer’s oncology-focused facility in La Jolla, Calif., and manages the big pharma’s external research networks in the Western U.S. She also serves on the boards of several San Diego nonprofits.

R. Michael Blaese

THEN: Chief of the cellular immunol-ogy section of the NIH’s National Cancer Institute.

NOW: Another gene therapy pioneer, Blaese worked with W. French Anderson on early clinical trials for ADA-SCID. He went on to serve as president and chief scientific officer of the Molecular Pharmaceuticals Division of Kimeragen Inc., a genetic surgery company that merged with ValiGene SA. Blaese has dedicated his life to studying and treating children with rare genetic disorders, and he is currently chief of the Clinical Gene Therapy Branch at the National Human Genome Research Institute. He also is working on gene therapies for cancer and HIV.

Scott Putney

THEN: Vice president of molecular biology and AIDS vaccine specialist at Repligen Corp.

NOW: The development of an AIDS vac-cine has proven more difficult than anyone could have imagined. Encour-aging data emerged from the recent combination of Sanofi-Aventis Group SA's ALVAC HIV vaccine with the AIDS-Vax product from VaxGen Inc., Genen-tech Inc./Roche AG and Global Solu-tions for Infectious Diseases, but much work remains to be done. Repligen eventually dropped its AIDS vaccine program, and Putney went on to run protein and molecular biology for Al-kermes Inc. He led efforts to develop an inhaled human growth hormone, then went to work for Alkermes’ part-ner on the product, Eli Lilly and Co.

W. French Anderson

THEN: Chief of the molecular hema-tology branch at the NIH’s National Heart, Lung and Blood Institute and a pioneer of gene therapy.

NOW: After conducting the first safety test of a gene therapy in humans, An-derson used the approach to replace a defective gene in a young girl with ad-enosine deaminase deficiency-related severe combined immunodeficiency (ADA-SCID), an immune deficiency disorder also known as “bubble boy disease.” ADA-SCID has become one of the more successful endeavors within the troubled gene therapy field. He joined the University of Southern California faculty and later served as director of the Keck School of Medicine’s gene therapy labs. In 2007 he was convicted of sexual abuse of a minor and is currently serving a 14-year sentence. He main-tains his innocence.

Steven Rosenberg

THEN: Chief of surgery at the NIH’s National Cancer Institute.

NOW: He is chief of surgery at the NIH’s National Cancer Institute, and a professor at the Uniformed Services University of Health Sciences and at the George Washington University School of Medicine and Health Sciences. Rosenberg is known for advancing both immunotherapies and gene therapies for cancer. He pioneered the early work on interleukin-2 as a cancer therapy, providing data that were instrumental to Cetus Corp.’s and Chiron Corp.’s development and eventual approval of Proleukin. He was also the first to conduct gene therapy trials in cancer, the indication which has subsequently become among the most advanced and generated the most industry interest in the gene therapy field. He currently is working on a melanoma vaccine.

Special thanks for helping us locate and profile these leaders goes to: Jill Anderson, Brian Atwood, Gil Bashe, David Beier, Art Benvenuto, Jeff Bird, Larry Bock, Lou Bock, Ray Briscuso, Carl Feldbaum, Stephanie Fischer, Alfred Gilman, Robert Langer, Robert More, Nancy Olson, Stelios Papadopoulos, Richard Pops, Hollings Renton, Michael Riordan, Cynthia Robbins-Roth, Greg Simon, Alan Timms, Troy Wilson

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Trying to guess who will emerge as the movers and shakers of the biotech industry

over the next 20 years is akin to trying to find a needle in a giant stack of … needles.

The sector has grown and expanded since its early days thanks to the tireless and

inspiring work of so many. And even more executives, investors and scientists

are stepping up every day, leaving the BioWorld staff with the unenviable task of

narrowing down to a handful the people we think will influence biotech over the

next 20 years. We considered the current trends in deal-making, the changing

financing models and the latest scientific breakthroughs, and we sought some

outside nominations to help us get a sense of the big players in biotech today whose

influences could easily stretch across the next two decades and beyond.

Some on this list will seem no-brainers. Others will raise some eyebrows. Regardless,

this opinionated list is a personal one to BioWorld and is certainly not intended to

be all-inclusive. If you think we’ve left out someone, let us know.

In the meantime, here are, in no particular order, our predictions for the future.

Join us in 2030, and we can see how well we’ve done.

Who Will Shape Biotech Over the Next 20 Years? BioWorld Says…

Severin SchwanHe’s among a new genera-tion of young big pharma CEOs, having risen rapidly through the ranks to take

the helm at Roche AG in 2008, just in time to lead the charge on the largest-ever biotech acquisition with the $46 billion buyout of Genentech Inc. Since taking over, Schwan has garnered a reputation for rattling some of the staid big pharma traditions – even going so far as to cast his lot with BIO instead of the pharma lobbying group – and has demanded continuing innovation even as other pharmas move into the less risky generic space. He’s also known for his collegiate-style management, a sign that he could make good on his pledge to preserve Genentech’s culture of innovation, which bodes well for the industry overall.

John MaraganoreThe CEO of pioneering RNAi firm Alnylam Phar-maceuticals Inc., Mara-ganore is well known

for his science-driven management approach, and he’s been a strong

proponent of innovation over repur-posing or generic drug development. Under his leadership, Alnylam has become a go-to firm for RNAi-based intellectual property and has devel-oped ALN-RSV01, the first RNAi drug to hit clinical proof of concept. And, in an industry currently facing some tough decisions as the R&D failure rate increases, with more money spent and less to show for it, Mara-ganore has been particularly forceful in his belief that solid science must trump marketing-based decisions and such nebulous calculations as net present value.

Peter HechtHecht has been CEO of Ironwood Phar-maceuticals Inc. since its founding in 1998. He gets credit for recognizing the potential of bowel drug linaclotide early on and prioritizing it ahead of more advanced programs – similar to how Amgen Inc. peered through a haze of competing products and saw the early potential in Epogen (epoetin alfa). Linaclotide went on to generate good Phase III data, attract a trio of lucrative partnerships and pave the

way for Ironwood’s $216 million IPO – which some would say opened the cur-rent IPO window. Public investors are learning to love Hecht for his focus on long-term value and his often uncon-ventional, Warren Buffett-esque tech-niques, such as investing his own mon-ey into every financing, incentivizing his board with stock, and hand-picking his IPO investors. Whether Ironwood becomes the next Amgen or Hecht goes on to something else, there’s little doubt he’ll have an impact.

Sol J. BarerThe chairman and CEO of Celgene Corp., Barer has been a driving force behind the firm, which has become one of the top biotech market caps since it merged with partner Pharmion Corp., in a $2.9 billion deal disclosed in late 2007. Bearded, scholarly Barer, with multiple degrees from Rutgers University, continues to lead Celgene to strong earnings, thanks to sales of such products as Revlimid (lenalidomide), Vidaza (azacitidine) and Thalomid (thalidomide), while pushing ever-forward with new programs in inflammation and solid

EXECUTIVES

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tumors. And, throughout Celgene’s considerable growth, he’s been known for maintaining the same culture of entrepreneurship that the company boasted 20 years ago.

David GoeddelHe’s the self-effacing scientist who was among those powering Genen-tech Inc. in its first years. Now he’s a managing partner with The Column Group, a venture capital firm focused on investing in the neglected area of early stage drug development. Known for gene cloning expertise, Goeddel laid the groundwork for a handful of strong-selling Genentech products. He co-founded Tularik and was president and CEO until Amgen Inc. bought the firm in 2004 for $1.3 billion. Now he’s heading up NGM, a start-up focusing on diabetes and skeletal muscle health.

Richard PopsHe’s the high-profile CEO of Alkermes Inc., who retook that position in late 2009, more than two years after he departed. Back in the saddle, his first move was to launch a strong push for growth and innovation in the face of economic hard times, when others were hunkering down. Congenial and widely respected, Pops serves on several biotech boards as well as the Biotechnology Industry Organization and the Pharmaceutical Research and Manufacturers of America. He’s not just a thinker; he’s a doer. And we can’t wait to see what he does next.

Carol GallagherHired as CEO of privately held Calistoga Pharmaceuticals Inc., Gallagher is charged with

building a business development strategy for the small Seattle-based firm working on isoform-selective PI3 kinase inhibitors. After serving in key roles in a handful of big pharma and biotech companies, she perhaps is best known for leading the Rituxan

(rituximab) commercialization team at Biogen Idec Inc., getting that product to the $1 billion mark. As biotech moves away from one-pill-fits-all to a more personalized medicine approach, executives like Gallagher, who have a knack for finding the right patient populations, talking to the right doctors and bringing on board the right partners will be even more crucial to success.

Edwin MosesMoses heads up Ablynx NV, a firm that develops domain antibody-derived therapeutics and has

managed to buck the tough financing trends in Europe. He took over as CEO in 2004, got the firm through an IPO in 2007 and, at the start of 2010, the Ghent, Belgium-based firm had more than two years of cash in its coffers. And his business savvy likely will con-tinue giving a boost to the European biotech industry. To date, Moses has been involved in financing rounds totaling more than €300 million and has led a number of deals, including the £316 million cross-border merger between UK-based Oxford Asymmetry International and Evotec Biosystems, of Germany.

Ron CohenWhen BioWorld’s first biotech all-stars list came out in 1990, it included Art Benvenuto, then Co-

hen’s boss at Advanced Tissue Sci-ences Inc. But Cohen wasn’t destined play second fiddle for long: In 1995, he founded Acorda Therapeutics Inc. His physician’s background gave him the patient-focused outlook he used to tap into advocacy group networks, raise venture money, advance his lead product into Phase III trials for spinal cord injury and multiple sclerosis, take Acorda public, build a niche sales force, bag an ex-U.S. partnership and gain FDA approval of Ampyra (dal-

fampridine) for the improvement of walking ability in multiple sclerosis patients. Moving forward, Cohen’s job will be to silence the skeptics and prove Ampyra’s commercial viability, all while advancing Acorda’s next gen-eration of neuroregenerators.

Chris LeMastersHe’s a company builder who hails from the business development rather than the finance side. He spent six years with Eli Lilly and Co. before jumping to the biotech world to run business de-velopment at Conforma Therapeutics Corp. He oversaw Conforma’s eventual acquisition by Biogen Idec Inc., then co-founded spinout Cabrellis Pharmaceu-ticals Corp. and oversaw its takeover by Pharmion Corp. He and the former Cabrellis team then started Tragara Pharmaceuticals Inc. and in-licensed a cancer and inflammation drug, and LeMasters simultaneously started up Aarden Pharmaceuticals Inc. to de-velop drugs targeting protein tyrosine phosphatases. We have no doubt that this is just the tip of LeMasters’ compa-ny-founding iceberg.

Personalized MedicineMany insiders agree the personalized treatment approach will be the wave of the future. As executive director of the Personalized Medicine Coalition, Edward Abrahams is poised to play a key role. The coalition already has grown from its original 18 founding members in 2004 to more than 160 today. Abrahams previously served as executive director of the Pennsylvania Biotechnology Association, where he spearheaded the successful effort that led to the Commonwealth of Pennsylvania’s investment of $200 million in the state’s biotech industry. Then there’s Mara Aspinall, former president of Genzyme Genetics, who’s hailed as being at the forefront of personalized medicine, and serves on the board of the Personalized Medicine Coalition. She’s now

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president and CEO of diagnostics firm On-Q-ity Inc., which is working on DNA repair biomarkers for predicting treatment response and microfluidic chip technology for monitoring circulating tumor cells, and is an active member of the federal Secretary of Health and Human Services’ Advisory

Commission on Genetics. And Randy Scott, executive chairman of Genomic Health, and Kim Popovits, president and CEO of Genomic Health, are working to improve the quality of cancer treatments through genomic-based treatment decisions. Scott founded Genomic Health after

watching a close friend struggle with cancer and wondering why the molecular make-up of specific tumors had not become the basis for cancer care. The personalized approach could set a new standard for health care if these and other supporters have their way.

Daphne ZoharHer name is synonymous with innovation. Her venture firm, Puretech, bridges the so-called

“valley of death,” meeting with aca-demics to identify promising early stage technologies and funding them to the point of licensing or company creation. She started Solace Pharma-ceuticals Inc., Follica Inc., Satori Phar-maceuticals Inc. and many others, but one of her most ambitious and creative projects to date is Enlight Biosciences LLC. Enlight arose from Puretech’s realization that big phar-ma was intensely interested in new academic technologies that could aid drug discovery, even if venture inves-tors had little appetite for funding such endeavors. Zohar brought to-gether Pfizer Inc., Merck & Co. Inc., Eli Lilly and Co., Johnson and Johnson, Abbott and Novartis AG in a precom-petitive partnership that funds those technologies. Such precompetitive deals are said to be the wave of the future, and Zohar is riding the crest of that wave.

Clarke FutchHe’s the co-founder and managing director at Cowen Healthcare Royalty Partners. He previously

served as a partner at Paul Capital Partners, where he led royalty-related investments for the Paul Royalty Funds. He helped pioneer the use of securitization with pharmaceutical royalties as a means of alternative —

and flexible — biotech financing and, over the past two years, has helped raise nearly $2 billion dedicated to the royalty finance market. He joined CHRP along with co-founder Todd Davis and Gregory Brown, all of whom were lured to Cowen from Paul Capital and had worked as a team on royalty-based investments.

Francesco De RubertisHe’s a partner at Index Ventures, a UK- and European-based VC firm that has been breaking the mold for biotech investing and dealmaking for the past several years. De Rubertis helped secure the impressive $190 million Phase I-stage deal between private Dutch biotech PanGenetics BV and Abbott, and is a fan of asset-centric investment models, which are designed to get new compounds into the industry without having to fund whole companies. He’s also focused on funding much-needed early stage investments and public equities, and his name is sure to be a staple in the European venture community for years to come.

Robert (Bob) MoreThough you’d never know it from his humble persona, More is one of the venture guys every biotech wants to have on its board. Prior to joining Frazier Healthcare Ventures two years ago, More spent 12 years with Domain Associates. He was involved with investments in ESP Pharma Inc. (acquired by PDL BioPharma Inc.), Esprit Pharma Inc.

(acquired by Allergan Inc.), Novalar Pharmaceuticals Inc. (gained FDA approval) and many others. But plenty of VCs offer experience — what More adds is an uncommon dose of common sense. Biotechs report that he’s one of the few investors who starts a company by asking why it deserves to exist rather than just whether or not he can make money off of it. And while More doesn’t shy away from giving portfolio companies a reality check, he’s a true believer in biotech’s potential. We can’t wait to see what he funds next.

Activist ShareholdersThey are already leaving an imprint on biotech. Billionaire investor Carl Icahn has pushed through some of the biggest acquisition deals of the past few years, such as ImClone Systems Inc.’s $6.5 billion buyout by Eli Lilly and Co. and MedImmune Inc.’s $15.2 billion takeout by AstraZeneca plc, and he continues to push companies via not-so-subtle approaches (i.e., proxy fights and aggressive grabs for board seats) to do what’s best for shareholders. Whether that pushing is good or bad for the industry is debatable; but, if there’s money to be made in biotech, Icahn’s not going away any time soon. Also raising the profile of activist investors is Biotechnology Value Fund. Partners Mark Lampert, Oleg Nodelman and Matthew Perry have been putting the pressure on portfolio firms that fail to act quickly after clinical failures and waste cash reserves rather than returning money

FINANCIERS

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SCIENTISTS

to shareholders. After all, they say, more money returned to shareholders means more money to invest in a new, promising biotech venture.

Bill GatesHe and his wife started the Bill & Melinda Gates Foun-dation, which has provid-ed a substantial amount of

funding — $22.6 billion, in fact – over the years for translational research. In biotech circles, the Gates Foundation is best known for supporting research on HIV/AIDS, malaria, polio, childhood vaccines and neglected diseases. Now, there are even biotechs being founded specifically with the aim of targeting those diseases. Among its many initia-tives is the Grand Challenges Explo-

rations award, launched in 2008 to provide initial grants of $100,000 two times a year for research in the area of global health, with successful proj-ects given the opportunity to receive follow-on grants of up to $1 million. With those kinds of programs and a globe-spanning approach, the Gates Foundation’s impact on world health is just beginning.

Robert LanzaLet’s face it, Lanza is one of our biotech celebri-ties. He’s even been in-terviewed by Barbara

Walters. He’s the chief scientific offi-cer at Advanced Cell Technology Inc., adjunct professor at the Institute for Regenerative Medicine at Wake For-est School of Medicine and a stem cell pioneer whose discoveries range from animal cloning to generating induced pluripotent stem cells. At ACT, Lanza heads a team that has been able to grow stem cells into ret-inal cells to potentially treat macular degeneration and Stargardt disease. He’s authored more than 20 scientif-ic books, holds a number of patents and, in the years ahead, he’s certain to hold a key role in the burgeoning field of regenerative medicine.

Christoph WestphalA biologist and serial entrepreneur, Westphal had a hand in establishing (among others) Alnylam Pharmaceu-ticals Inc., Momenta Pharmaceuti-cals Inc. and Acceleron Pharma Inc., as well as Sirtris Pharmaceuticals, which was founded in 2004 and sold to GlaxoSmithKline plc for $720 mil-lion in 2008. These days, Westphal heads up the GSK Center of Excel-lence for External Drug Discovery in Boston, targeting age-related dis-eases, which will no doubt grow in importance as the baby boomers age over the next 20 years.

Craig VenterA biologist-entrepreneur and presi-dent of the nonprofit J. Craig Venter Institute, Venter has been called one of the 21st century’s leading scien-tists, but he is best known for mapping the human genome. Venter and his team at Rockville, Md.-based Celera Genomics in 2000 announced they had developed a rough draft of the human genome using the whole shot-gun sequence technique, which was different than the approach used by the National Institutes of Health in its parallel Human Genome Project. Ven-ter’s genome research work appeared in the February 2001 issue of Science, while the NIH’s published that month in Nature. Venter’s current work is dedicated to human, microbial, plant and environmental genomic research and seeking alternative energy solu-tions through genomics.

Larry NortonThe deputy physician-in-chief for breast cancer programs at Memorial Sloane-Kettering Cancer Center, Norton is a medical oncologist best known for folding mathematics into the biotech mix. His work as a “biomathematician” has included the development of the dose density therapeutic approach that employs a math-based model to deliver cancer drugs for maximizing the killing of cancer cells while minimizing toxicity. It’s an approach that defied traditional dosing methods,

but Norton’s tenacity was able to overcome the industry’s initial skepticism. He also serves as the principal investigator of a program project grant from the National Cancer Institute aimed at better understanding breast cancer in the lab to create new treatment approaches.

Marc Tessier-LavigneHe made an industry name for himself as vice president of research drug discovery at Genentech Inc., and became chief scientific officer after the merger with Roche AG in 2009. Before Genentech, Tessier-Lavigne – who discovered the role of netrins in 1994 – was well known in academia, and his jump from Stanford University to Genentech raised a few eyebrows. Genentech, though, created a position that let him oversee a broad spectrum of research. It’s just the right slot for a person with the energies and acumen of Tessier-Lavigne, who also co-founded the neurology firm Renovis Inc. in 2000.

Eric Lander Lander is a biology professor at the Massachusetts Institute of Technology, co-chair of President Obama’s Council of Advisors on Science and Technology and a founding director of the Broad Institute. He was a leading contributor to the international Human Genome Project and under his leadership,

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the Whitehead/MIT Center for Genome Research (which formed the core of the Broad Institute) was responsible for developing many of the key tools of modern mammalian genomics. Lander also is known for his development of a molecular taxonomy for cancers, grouping them according to gene expression and information, such as their response to chemotherapy treatment.

Susan Desmond-Hellman She’s the former head of Genentech Inc.’s oncol-ogy division and a pioneer

in cancer research. She joined the big biotech as a clinical scientist in 1995 and, during her more than 13 years at Genentech, some of the company’s big-gest drugs gained approval, including Avastin (bevacizumab), Lucentis (ra-

nibizumab) and Herceptin (trastuzum-ab). She left Genentech after the Roche acquisition and took a job as chancel-lor at the University of California, San Francisco, an institution that’s hardly a slacker in the world of biotech research. She was selected by Forbes as one of the seven most powerful innovators in 2009, and if she returns to the corpo-rate fold at some point, it seems likely that good things will follow.

Francis CollinsA physician-geneticist and director of the Na-tional Institutes of Health, Collins is best

known for spearheading the Hu-man Genome Project – the U.S.-led international effort to map and se-quence all human DNA. His team in 2000 revealed a working draft of the human genome sequence, with the reference sequence completed in 2003. Before being named NIH chief, Collins served as the director of the agency’s National Human Ge-nome Research Institute, where he oversaw the discoveries of several genes, including those responsible for cystic fibrosis, neurofibromato-sis, Huntington’s disease, a familial endocrine cancer syndrome, genes for Type II diabetes and the gene that causes Hutchinson-Gilford progeria syndrome. As NIH head, Collins will be instrumental in securing funding for government-sponsored research and setting priorities for what could become the next generation of bio-tech products.

Richard PazdurThe director of the FDA’s Office of Oncology Drug Products has been called the cancer drug czar critics love to hate. Pazdur, who left his faculty job at the University of

Texas MD Anderson Cancer Center in Houston in 1999 to join the FDA, is known for reiterating at agency advisory committee meetings that the approval process is “not merely a screening process for drug activity” – always remaining insistent that cancer medicines must show clinical benefit. He has authored more than 160 peer-reviewed papers about oncology, has written chapters for more than 30 oncology textbooks and is the editor of two standard reference oncology texts.

Steven NissenHe’s the chairman of the depart-ment of cardiovascular medicine at the Cleveland Clinic Foundation in Ohio and has been known in recent years for raising drug safety issues with medications such as Merck & Co. Inc.’s no-longer marketed COX-2 inhibitor Vioxx (rofecoxib), GlaxoS-mithKline plc’s diabetes drug Avan-dia (rosiglitazone) and stimulants used to treat attention deficit hy-peractivity disorder. Nissen, who has served on various FDA advisory committees and has testified before Congress about drug safety, was the co-author of a June 2007 meta-anal-yses published in The New England Journal of Medicine, which reported there was a significant increase in the risk of heart attacks and car-

diovascular-related deaths linked to Avandia. Nissen’s main research focus has been on the use of intra-vascular ultrasound imaging in as-sessing progression and regression of coronary atherosclerosis. Some in the industry respect him, others call him a gadfly. But he’s influencing the safety standards to which all drugs are held.

President Barack ObamaThe 44th U.S. president not only solidified his place in history as the

first African-American elected commander-in-chief but also as the first president to get a major piece of health care legislation enacted since Lyndon Johnson signed Medicare into law in July 1965, achieving the victory of ensuring health insurance coverage for nearly all Americans that many of his predecessors, including Bill Clinton, Harry Truman and Theodore Roosevelt, had failed to do. The health reform law also for the first time provides a pathway for regulatory approval of follow-on biologics. It’s too early to say how much of an impact the new law will have on biotech, but we’re certain to see some repercussions – good and bad – over the next 20 years and beyond.

REGULATORY/LEGISLATIVE

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Since the first biotech drug – Genentech Inc.’s genetically engineered human insulin product Humulin – gained approval in 1982, the industry’s impact on human health continues to grow. During the past two decades alone, more than 200 biotech drugs have hit the market. We’ve seen the promise of monoclonal antibodies, kinase inhibitors and other

biologically targeted drugs become reality, often providing the best – and, sometimes, the first – treatment options to millions of patients around the globe. These drugs have extended lives and improved the quality of lives for people afflicted with disease. And biotech is far from stopping. What will see in the next 20 years? Will we have a host of RNAi-based drugs on the shelves? Will embryonic stem cell therapy live up to its potential? Will nanotechnology prove the wave of the future? Based on these examples of the industry’s success so far, we can’t wait to find out.

The Right ‘Time’GLEEVEC’S APPROVAL MAKES HISTORY

The FDA’s 2001 fast-track nod made Novartis AG’s Gleevec (imatinib) the first in a new generation of cancer chemotherapy agents. The Bcr/Abl-tar-geted drug even made the cover of Time in May of that year, hailed as a magic bul-let for curing cancer. Thanks to Gleevec, several cancers, including chronic myeloid leukemia, transformed from fatal diseases into chronic illnesses. Before Gleevec, roughly 30 percent of pa-tients died within five years of being diagnosed with CML. Gleevec lowered that rate to 10 percent. Besides earn-ing scientists Brian Druker, Nicholas Lydon and Charles Sawyers the Lask-er award in 2009, the introduction of Gleevec opened the door for a host of other drugs designed to go after cancer on a molecular level. It also validated the then-emerging rational drug de-sign approach.

20 Years of

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A Vast ImprovementAVASTIN SETS THE BAR IN CANCER TREATMENT

It’s hard to believe there was ever a time when the idea of attacking cancer by starving tumor cells would be met with derision. But that’s what Harvard researcher Judah Folkman faced nearly 40 years ago when he proposed an anti-angiogenic approach to treating the disease. Fortunately, Folkman persevered, and his work led to the development of VEGF-inhibitor Avastin (bevacizumab, Genentech/Roche), approved in 2004 in colorectal cancer. Since then, Avastin has gained the FDA’s nod in lung and breast cancers. While the drug does have its drawbacks, its introduction helped re-energize the oncology space, and it set a high standard for other drugs to beat.

Making MiraclesRARE, GENETIC DISEASE PATIENTS FIND HOPE

The 2010 Hollywood release “Extraordinary Measures” told the story of researchers working on the first drug for Pompe disease, an inherited disorder that disables the heart and

muscles. Prior to the first enzyme replacement therapy, Myozyme (aglucosidase alfa, Genzyme), babies born with infantile onset Pompe disease often died before reaching their first birthday. But biotech didn’t stop there. Genzyme and Shire plc have gotten ERTs approved for other lyso-somal storage disorders, Gaucher and Fabry dis-eases, and those early successes have prompted other firms to focus on other rare, genetic indica-tions. BioMarin Pharmaceutical Inc., for example, developed much-needed treatments for muco-

polysaccharidosis VI (Naglazyme, galsulfase), MPS I (Aldura-zyme, laronidase) and phenylketonuria (Kuvan, sapropterin dihydrochloride). And in 2007, Alexion Pharmaceuticals Inc. gained approval for Soliris (eculizumab), the first drug for paroxysmal nocturnal hemoglobinuria. A host of other candidates is in development, and we may soon see the first drugs approved in indications like Duchenne’s muscular dys-trophy, Friedreich’s ataxia and other genetic diseases.

Biotech’s Vision QuestFIRST DRUGS HIT THE MARKET FOR WET AMD

Before QLT Inc.’s photodynamic therapy Visudyne (verteporfin) gained approval in 2000, there were no available therapeutic treatments for wet age-related macular degeneration. The leading cause of blindness in people over the age of 50, the “wet,” or advanced form, of AMD devastates the lives of patients, who

find themselves unable to do everyday tasks such as reading, driving and recognizing faces. Though it only accounts for about 15 percent of all AMD cases, wet AMD is responsible for 90 percent of severe vision loss. Biotech is helping to improve those numbers. Five years after Visudyne hit the market, Eyetech Pharmaceuticals Inc. and Pfizer Inc. won approval for the first VEGF-targeted AMD drug, Macugen (pegaptanib sodium injection), followed in 2006 by the superior Lucentis (ranibizumab) from Genentech Inc. (now part of Roche AG). More than 30 drugs currently are in clinical testing.

1990: Reverse transcriptase inhibitor AZT was the only

approved HIV therapy

JULY 1991: FDA approved ddL (dideoxyinosine, Bristol-Myers Squibb), viral replication inhibitor

APRIL 1994: The Inter-Company Collaboration on

AIDS Drug Development agreed on a protocol to speed up evaluation of

triple-drug combos

JUNE 1994: Antiretroviral Zerit (stavudine,

Bristol-Myers Squibb) was approved

NOVEMBER 1995: FDA cleared 3TC (lamivudine, BioChem Pharma,

Glaxo Wellcome) in combination with AZT as a first-line treatment

DECEMBER 1995: The first

protease inhibitor, Invirase (saquinavir, Roche)

gained approval

MARCH 1996: Two more protease inhibitors — Norvir (ritonavir, Abbott) and Crixivan (indinavir sulfat, Merck) — cleared the approval process (Merck’s drug after a record 42-day review)

JULY 1996: Viramune (nevirapine, Boehringer Ingelheim) gained approval as the first non-nucleoside reverse transcriptase inhibitor

JULY 1996: First dual-protease inhibitor trial – Norvir plus Invirase – reduced HIV RNA by an impressive 99 percent at six weeks in 120-patient study

SEPTEMBER 1997: Combivir, a single-tablet formulation of 3TC and AZT, gained approval

JUNE 1992: FDA approved ddC (dideoxyctidine, Roche), viral replication inhibitor

OCTOBER 1998: NNRTI Sustiva (evavirenz, Bristol-Myers Squibb) was approved

Biotech’s Contributions to HIV: 1990-Present

A Matching SetHERCEPTIN’S APPROVAL SETS PERSONALIZED MEDICINE GOAL

Among its other accomplishments in health care, the biotech industry heralded the shift away from the one-drug-fits-all style of big pharma to a personalized medicine approach. The combination of targeted drugs aimed at subset populations plus diagnostic tests to identify likely responders is expected not only to improve the chances of a patient’s successful treatment but also to help reduce treatment costs per patient. The first and best example of the drug-diagnostic marriage came in 1998 when Genentech Inc. (now part of Roche) gained approval of breast cancer drug Herceptin (trastuzumab), a monoclonal antibody against the growth factor receptor HER2, in parallel with an immunohistochemical test kit produced by Dako Corp. and designed to pinpoint patients with HER2-positive tumors.

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FEBRUARY 2002: FDA approved Procleix (Gen-Probe Inc. and Chiron Corp.) for the amplified nucleic acid test for use by blood banks to detect HIV viral genes

MARCH 2003: Fusion inhibitor Fuzeon (enfuvirtide, Trimeris and Roche) was approved

JULY 2003: Gilead Sciences Inc.’s NRTI Emtriva (emtricitabine) was approved

OCTOBER 2003: ‘Flexible’ protease inhibitor Lexiva (fosampranavir calcium, Vertex and GlaxoSmithKline) got an FDA nod

OCTOBER 2001: FDA cleared

Viread (tenofovir disoproxil fumarate,

Gilead Sciences), a nucleotide

analogue reverse transcriptase

inhibitor

AUGUST 2004: Truvada, a combination Emtriva/Viread (Gilead) drug, won approval

JUNE 2006: Prezista (darunavir, Tibotec), another protease inhibitor, entered the market

JULY 2006: The first once-daily, triple-drug regimen, Atripla, was approved. (Atripla combines Gilead’s Viread and Emtriva with BMS’ Sustiva)

JANUARY 2009: FDA gave accelerated approval to a second-generation NNRTI, Intelence (etravirine,

Tibotec)

APRIL 2009: Pharma giants Pfizer and Merck pooled their HIV portfolios into a joint venture, ViiV Healthcare,

to create new molecules and more convenient formulations of existing drugs

SEPTEMBER 2009: For the first time, an HIV vaccine successfully – albeit modestly – reduced the risk of HIV

infection in humans. The 16,000-patient Thailand study tested ALVAC HIV (Sanofi) and AIDSVAX B/E (VaxGen)

You Are HereMAPPING THE HUMAN GENOME

This international research project kicked off in 1990 and became a 13-year endeavor to identify all the genes in human DNA and determine sequences of about 3 billion chemical base pairs. The project finished up in 2003, though analysis of the data is expected to have continued impact on biotech for years to come. It already has spawned offshoots, including the 2006-initiated Cancer Genome Atlas, a coordinated effort to understand cancer using genome analysis technologies and large-scale sequencing. Recent technological advancements also have brought genome sequencing down to the company level, with Complete Genomics detailing in a Science article in late 2009 that it had been able to complete a human genomic sequence for as little as $1,700. Further discoveries and more efficient sequencing are sure to come.

Going Beyond the LabTECHNOLOGY REVOLUTIONIZES DRUG DISCOVERY

In the 1980s, the discovery of polymerase chain reaction set the molecular biology space on its head, and advancements over the past 20 years have continued to make basic drug dis-covery and target research more and more efficient. In 1997, a new DNA technique emerged that combined PCR, DNA chips and a computer program and offered researchers a vital tool in the search for disease-causing genes. And the technology is only getting better. We’ve seen breakthroughs in high-throughput screening, in silico testing and fragment-based platform technologies, and further discoveries and inventions could one day turn drug dis-covery into a highly efficient engine to sustain development efforts far into the future.

Of Cells and CytopeniasFIRST DRUGS FOR MDS

Before 2004, patients suffering from myelodysplastic syndromes could undergo a stem cell transplant, at least if they were healthy enough. But patients not eligible for the risky procedure finally gained an effective treatment option with the approval of Vidaza (azacitadine) from Pharmion Corp. (now Celgene Corp.) MDS, described as a collection of dis-orders in which bone marrow does not func-tion normally and not enough blood vessels are made, can cause anemia, neutropenia (putting patients at high risks for infec-tions) and thrombo-cytopenia (increasing the chances of a severe bleeding episode). Roughly one-third of MDS cases progresses to acute my-elogenous leukemia, though most pa-tients die as a result of infection. Fol-lowing Vidaza, two other drugs hit the

market for MDS: Dacogen (decitabine, SuperGen Inc. and Eisai Co. Ltd.) and Rev-limid (lenalidomide, Cel-gene). In addition to giv-ing patients an alternative treatment option, those

first drug approvals also helped to draw greater attention to this often-underdiagnosed disease.

Prognosis ImprovingHIV GOES FROM DEATH SENTENCE TO CHRONIC ILLNESS

It’s hard to believe that only 20 years ago, patients diagnosed with HIV/AIDS had only one treatment option – AZT – and, often, a poor prognosis. When basketball great Magic Johnson was diagnosed with HIV in 1991, for instance, people still considered the disease a death sentence. But today there are 30-plus drugs and drug regimens available, and HIV has become a manageable illness in the developed world. True, patients would like fewer drugs (and fewer side effects) and the successful development of a preventive vaccine has so far proved elusive, but the HIV space is one of the most striking examples of how the biotech and pharma industry has stepped up to the challenge during the past two decades. Even now, companies continue working to discover better therapies and vaccines, make dosing regimens more convenient and get the latest treatments to HIV-infected patients in developing nations. (See timeline below.)

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C ynthia Robbins-Roth is tired of hearing about how “the biotech business model is broken” – and she’s been tired of it for a long time. A few years ago, the industry veteran and founding editor of BioWorld got

so fed up with the buzz phrase that she bailed out altogether to become a parent advocate at the Turning Point Program, a nonprofit agency that helps families with mentally ill children. “I was exasperated,” she said. “I felt like I was writing the same editorial for BioWorld over and over.” This was half the reason she left biotech; the other half related to a small-plane crash in 2001 which left her severely injured, and one of her children mentally traumatized. At Turning Point, “I felt like I could do something that mattered,” Robbins-Roth said. Biotech is as impressive as ever in the scientific realm, but “still using the same, infrastructure-heavy approach that was developed by big pharma,” while complaining about the broken model, she said. “As soon as you put capitalism as the driver, you start making dumb mistakes and overcharging blind old ladies on Medicare,” added Robbins-Roth, who still writes a column for BioWorld Today. “Double-digit net earnings growth year over year, that’s [the demand that] all the big biotechs and pharmas ran into. How do you grow by double digits when you’re throwing off $12 billion in profits?” Robbins-Roth answered her own question. The problem of boosting Pfizer-sized profits by that margin is solved less by

smart work in the lab than by desperation. “We fool ourselves into thinking we’re making life-saving medicines but actually we’re not, a lot of the time,” but instead are trying to come up with new versions of existing therapies, she said. “Once enough people in the company are driving Porsches, you’re in trouble.” She doesn’t accept the notion of overpaying scientific talent in order to keep it. “[Companies say,] ‘We have to give them bonuses or they won’t stay.’ Then let them go! I was really shocked to find out that a vice president of research can make a million dollars, and that’s without all the bonuses. Where did all the innovation come from? From the companies that weren’t paying their VPs a million bucks. And what have they done? They’ve tried to make third-generation versions of erythropoietin.” Reasonable returns and satisfying pay for staffers could fix the “broken” model, Robbins-Roth said. “I cannot believe that we cannot be creative about finding a business model that isn’t based on maximized return but on a pretty damn good return, in which people are rewarded well for doing great work. Are they going to end up being like the Oakland A’s, where they’ve got an incredible eye for talent and a great farm system, and then the Yankees come along and steal everybody? That’s a possibility, but it’s still a heck of a way to keep fresh blood coming into the place.” Anyway, in Robbins-Roth’s view, “it’s really clear that

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everyone is expendable.” She uses an example from her nonprofit work with parents and children, where counselors used dialectical behavior therapy, which combines cognitive therapy with mindfulness. “There’s a vaguely Zen-like balance between staying the same and changing – you may not have created all of your problems, but you still have to solve them,” she said. “Biotech is stuck outside the dialectic, still in the mode of, ‘I want everything to stay the same.’ When you poke the industry, people get hysterical. But change happens if it’s needed, with or without you.” From Robbins-Roth’s 50,000-ft. perspective, “the more things changed, the more they stayed the same” over the past couple of decades, but closer-to-the-ground opinions of other industry leaders highlight some stark contrasts. Stelios Papadopoulos, the widely known chairman and founder of Exelixis Inc., former vice chairman of Cowen & Co., noted that in 1990 “we were naïve about the future, some of the risks and how big the successes would be. If you asked me then if there would be multi-billion-dollar biotech companies in 20 years, I would have said, I doubt it.’’ He would not have believed that most of the top-selling products would be biologics, either, he said. As for the years ahead, Papadopoulos said, getting funding will remain a problem. “We are now in a place where what biotech does is practiced by pharma, too,” he said. “Back in the 1980s, pharma did organic chemistry, not biology. [And] the stock market is not patient enough to wait through years of losses,” especially not in a research area beset by binary risk, he added. “It isn’t only a structural funding problem,” Papadopoulos said. “Biotech is a feeder for pharma, but pharma [itself] is in deeper trouble,” as patents expire, patient groups crusade against high prices and the pharma giants face an overall public-relations crisis. Hollings Renton, former CEO of Onyx Pharmaceuticals Inc. and current chairman of Affymax Inc. and Portola Pharmaceuticals Inc., points – like Papadopoulos and Robbins-Roth – to business models and financing, and how the former have become “tougher” as the latter has grown more restrictive. “In the 1990s, biotechs could go public with just preclinical data,” he recalled, whereas now the market wants Phase II proof-of-concept results. “[Venture-capital firms] are looking at companies that are later-stage, and have to fund them longer,” which means “some exciting breakthrough science may not be getting funded” at all. As pharma continues to cut back on research and development, opting instead for in-licensing deals, biotech is up against the demand for more efficient business models that can survive the continued squeeze in access to capital. Though the economic situation seemed to be improving as 2010 wore on, the struggle remains uphill, particularly for fledgling biotechs

trying to stay on their feet with enough cash to reach the magic Phase II zone. Even then, of course, the fight isn’t over. “One challenge that’s the same is getting [drugs] to market,” Renton said, thanks to an ever more wary FDA. “The odds haven’t improved even as the science has gotten better.” Bob More, general partner with Frazier Healthcare Ventures, said biotech is doing what’s necessary to adapt on the clinical side in order to keep the financial coffers stocked for the projects that matter most. “The big movement today is to kill bad ideas faster,” More said. “[Twenty years ago,] the model was to keep all ideas alive as long as possible. But this industry isn’t going to survive if we fund everything.” Larry Bock, formerly with Avalon Ventures and now director of the USA Science and Engineering Festival, said biotech has gone through “a number of iterations” regarding the types of firms that have been able to gain funding over the past 20 years. First the clichéd “low-hanging fruit” was popular, whereby companies sought to make a therapy such as human growth hormone and become a fully integrated pharma outfit by that path, Bock said. Next came a focus on small molecules that could interfere with a biological pathway and draw money to let the firm become a solidly grounded development shop. High-throughput experiments followed, along with the charm of genomics – the “pay for information” model. In-licensing of de-risked compounds was the next paradigm to become popular. “Now, unfortunately, I don’t see a lot of the early new biology things getting done,” Bock said, and further pharma consolidation means even fewer available partners to pay for it, while phrma’s discovery and development outsourcing has moved overseas, leaving domestic biotech in the lurch. What’s next? “If the markets turn around – which they will – I think we’ll look back and say this was the best time for biotech investing,” Bock said. “Kevin [Kinsella, of Avalon Partners] and I were most successful starting companies in 1990 to 1993, [which] people called the nuclear winter of biotech. Because when the money came back in 1995, we were the ones who had companies.” Although not as many start-ups are in evidence these days, Bock said, there is “still a ton of money going into academic labs,” which means plenty of licensing opportunities. “A lot of awesome technologies will come out,” he predicted. “Start-ups will be like a kid in a candy store.”

“ The big movement today is to kill bad ideas faster. [Twenty years ago,] the model was to keep all ideas alive as long as possible. But this industry isn’t going to survive if we fund everything.”Bob More, Frazier Healthcare Ventures

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IIf investing in the biotech industry were like a high stakes game of Texas Hold’em, billionaire investor Carl Icahn would be the veteran player sitting at the table, a pile of chips in front of him, surreptitiously eyeing his short-stacked opponents to figure out which one he’ll target next.

He went after ImClone Systems Inc. in 2002, shortly after the now-infamous insider trading scandal involving the CEO (and a certain home-decorating maven) crushed the New York-based firm’s credibility. Through a series of negotiations, he managed to attain the position of chairman and in 2008 succeeded in selling ImClone to Eli Lilly and Co. for $6.5 billion. In 2007, Icahn added momentum to a group of disgruntled shareholders at Gaithersburg, Md.-based MedImmune Inc., prompting that firm to put itself on the selling block. A few months later it went to AstraZeneca plc for $15.2 billion, a price that surprised even the most hardened industry observers. Following Biogen Idec Inc.’s stock slide a few years ago on troubles with multiple sclerosis drug Tysabri (natalizumab), Icahn tried a similar maneuver but was unable to find anyone to pay the rumored $25 billion asking price. He has not lost interest in Biogen, though, and, in recent months, has turned his attention to the firm’s Cambridge, Mass.-based neighbor, Genzyme Corp., faced with a series of manufacturing calamities starting in mid-2009. But, while Icahn’s name might garner the most headlines – and strike the most fear into the hearts of corporate management teams – he’s hardly the only activist shareholder to move into the world of biotech. Last year investment firm Biotechnology Value Fund (BVF) urged the board of Redwood City, Calif.-based Facet Biotech Corp. (which, ironically, was spun out of PDL BioPharma Inc. in a 2008 effort to appease shareholder concerns) to resist the proposed buyout by Biogen for $17.50 per share. That turned out to be a good call, as Abbott swooped in with a whopping $27-per-share offer earlier this year, a major boon for investors, including BVF, which, with a nearly 16 percent stake, stood to net roughly $100 million. In many ways, the rise of shareholder activism is not

surprising. It’s a trend that traditionally increases as revenues, cash balances and management compensation packages climb. If nothing else, the emergence of Icahn and his ilk is a clear sign that the former grassroots industry officially has become big business. As to whether that’s good or bad, it depends on whom you ask. Activist shareholders like Icahn insist that some companies would be better under different management or with different R&D priorities. Icahn was even quoted in a 2007 CNBC interview stating that a lot of biotechs would work more efficiently if they were part of well-capitalized big pharma firms. There’s also the argument that biotech has wasted money over the years, paying for large-scale studies with me-too products in already-crowded fields — for instance, how many TNF-alpha blockers does the rheumatoid arthritis space really need? — or dumping money into trying to revive programs that have failed. And don’t forget the well-worn “seeking strategic options” line, which some companies have managed to turn into a long-term business plan to keep management salaries coming, a trend that has proved particularly irksome to shareholders in the current economic downturn. Outspoken investment firms like BVF, in fact, have begun calling out those idle firms and demanding a return of money to shareholders. In perhaps one of its most drawn-out skirmishes, BVF spent a year trying to spur action at Avigen Inc. After its multiple sclerosis drug blew up in the clinic, the Alameda, Calif.-based firm spent several months looking at strategic options – which included an offer by 30-percent shareholder BVF to buy out the company – before agreeing to merge with MediciNova Inc. According to BVF, that lengthy struggle came with a cost. In an April 2009 interview with BioWorld, BVF alleged that Agiven’s management team had spent more than 50 cents per share during the first six months following the disappointing MS data. Activist hedge funds and investment firms, which previously eschewed public battles with their portfolio companies, are continuing to become more forceful. Besides

Activist Shareholders

Up the Ante...But Is Innovation at Stake?

By Jennifer BoggsAssistant Managing Editor

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BVF, other investors with recent activist roles have included Third Point LLC, Eastborne Capital Management and DellaCamera Capital Management. Those investors may be leery of talking on the record – and possibly damaging relationships with current or future biotechs – but their actions of late have been loud and clear. DellaCamera put the pressure on Enzon Pharmaceuticals Inc., of Bridgewater, N.J., to remove then-CEO and Chairman Jeffrey Buchalter, citing compensation issues and Enzon’s failure to monetize certain assets. In July 2008, Buchalter agreed to step down as chairman – he was replaced by top Icahn lieutenant Alexander J. Denner – and DellaCamera dropped its consent solicitation to boot Buchalter as CEO. (Buchalter resigned as Enzon CEO earlier this year and took the top spot at Archimedes Pharma Ltd.) Sometimes, though, activist shareholders don’t know best. Tang Capital Partners LP lobbied for the board of Vanda Pharmaceuticals Inc. to liquidate the company in 2009 following the FDA’s rejection of antipsychotic drug Fanapt (iloperidone). At that time, Vanda’s cash balance totaled about $42 million, while Fanapt’s future looked cloudy, at best, and Tang was wary of “further erosion of stockholder value.”

The Rockville, Md.-based firm’s board, however, objected, a decision that was vindicated three months later when the agency surprised investors with a Fanapt approval. That news sent the shares soaring 626 percent and helped Vanda secure a potential $465 million Novartis AG partnership. But the Vanda case is just one reason biotechs are wary of activist shareholders. The threat to innovation – and the innovative spirit – could have far bigger ramifications. Biologics and drug development are by no means quick plays. Getting a drug from the lab to the market is estimated to take 12 to 15 years and more than $350 million. And both those figures are likely to grow, especially since past safety debacles have prompted greater FDA scrutiny. So it’s reasonable that a company should fear those investors who seek a quick profit. They could end up hurting the industry’s ability to fund the kind of long-term R&D work and innovation that has fueled biotech for the past 30 years. And what about getting pressured by investors who are unfamiliar with the nuts and bolts of biotech, who don’t re-ally understand the science and technology of their portfolio firms? A 2009 report commissioned by the Biotechnology Industry Organization and conducted by Thomson Reuters quoted an anonymous hedge fund investor who referred to bio-

techCEOs as “kids in the candy store that want to just spend and do a lot of science projects,” but added that shareholders often aren’t experienced enough in the field to tell the com-pany which programs look more viable than others. Activist moves can also get in the way of day-to-day operations. When asked about the ongoing proxy fight with Icahn Capital during a March investor call, Genzyme CEO Henri Termeer said the firm’s focus was on recovery after a tough 2009, rather than “a great set of distractions.” Genzyme managed to settle disagreements with another unhappy shareholder last year. It agreed to name activist investor Ralph Whitworth to its board in November in return for his investment firm’s support in advancing the company’s own slate of directors and proposals. The agreement also calls for Whitworth’s Relational Investors LLC to refrain from takeover efforts or management changes. Biogen employed a similar strategy to avoid a further proxy fight with Icahn. In March, the company agreed to appoint one of Icahn’s nominations to its board, giving him a total of three, plus one company nomination, with the understanding that Icahn Partners would vote its shares at the company’s 2010 annual meeting. And there may be other methods of striking a balance between the needs of shareholders and the needs of companies. BVF, for instance, has proposed a new model, a way of providing biotech shareholders a little protection in an inherently risky business. In February, Capstone Therapeutics proposed a put option to protect investors in case its Phase II proof-of-concept data for lead drug AZX100 came back negative. That way, shareholders are guaranteed to get some of their cash back, avoiding the drawn-out seeking-strategic-options bit that affected Avigen. As CEO Jock Holliman said at the time, Capstone is “putting our money where our mouth is,” and giving shareholders the “ultimate vote regarding how their assets are deployed.” A payout would be similar to a liquidating dividend, but shareholders also would have the option to keep their stock in Capstone in case the company does land a solid strategic transaction. BVF is hoping the Capstone deal will set a precedent. If so, that kind of strategy could prove a win-win, taking some of the risk out of biotech investing without compromising development of a promising drug, and allowing everyone to walk away from the poker table happy.

Activist hedge funds and investment firms, which previously eschewed public battles with their portfolio companies, are continuing to become more forceful.

ecord – and current or futureen loud and clear.n Pharmaceuticals

CEO and Chairmansues and Enzon’s y 2008, Buchalter as replaced by top

and DellaCamera

techCEOs as “kids in the candy store that want to just spend and do a lot ofscience projects,” but added that shareholdersoften aren’t experienced enough in the field to tell the com-pany which programs look more viable than others.

Activist moves can also get in the way of day-to-day

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By Randy OsborneStaff Writer

y first story for BioWorld Today about 13 years ago – in September 1997 – was about DepoTech Corp. raising more than $14 million through a stock sale for the launch of DepoCyt, a sustained-release form of cytarabine. The amount seemed like a big deal, and in those days, it was. San Diego-based DepoTech’s was the only

money story of the day, and the financing closely followed DepoCyt’s new drug application filing. The next year, London-based SkyePharma plc bought DepoTech in a deal valued at up to $56 million – also considered major bucks at the time. Not only have the size and structure of deals changed since 1997 (and even more during the past 20 years). So also has the way they are reported, and these developments have had big consequences, especially for publicly traded firms. Methods of media are changing still, and the speed is continuing to accelerate. When I started as a staff writer at BioWorld Today, the morning of the average news day was simple but laborious. A thick pile of faxed press releases arrived during the overnight hours. More faxes pumped out first thing in the morning. Or maybe the machine had run out of toner before the office opened. Someone would refill and start up the machine again so the faxes could catch up. Then, a senior staff member would be assigned to sift through press releases for potential stories. The online wires distributed releases, too, but we could never be certain whether news taken from online had also been faxed and vice versa. So we sorted through all of them, printing out the online releases that were unique and adding them to the pile of faxed paperwork. Then, staffers gathered in a meeting to decide which releases would provide the grist for the stories du jour. Today not much except staff meetings is the same, mechanically or otherwise, for BioWorld Today or its would-be competitors. Our fax machine has been all but retired. News leads are plucked almost entirely from online sources (or, in the case of pure science stories, from journals. Even those often issue press releases and are sourced online). What’s been the strongest influence, and even more troubling to many companies, is social media. In a Facebooked, Twitterized, fully networked world – one full of blogs, many of which are specialized to various industries including biotech – the meaning and context of news are often garbled, if not disregarded altogether. “Endpoint Hit, Stock Walloped: Wall Street, Media Missing the Point?” was the headline on a BioWorld Insight story in February 2010. Poniard Pharmaceuticals Inc. had reported positive Phase II data with its colorectal drug picoplatin. The compound hit its primary safety endpoint, but analysts found clues in the data to sub-par efficacy and the stock toppled by more than 25 percent. This was hardly for the first time, nor was South San

Francisco-based Poniard the first victim – nor, arguably, the most egregious. Arena Pharmaceuticals Inc., of San Diego, less than a year earlier reported results from its first Phase III trial with the obesity drug lorcaserin and met all three co-primary endpoints. The firm’s shares plummeted by 28 percent. Another San Diego-based firm, Anadys Pharmaceuticals Inc., the previous year unveiled positive data with its hepatitic C non-nucleoside polymerase inhibitor ANA598 and saw its shares punished 40 percent, as investors apparently confused results from one trial with another and fled the stock. What’s going on? Gil Bashe, a consultant in New York, told me for BioWorld Insight that the “tweet is more powerful than the read.” And, to an extent as never before, analysts become part of news stories immediately, as in the unfortunate case of Poniard and others. What he talked about that didn’t get into the article because of space was just as interesting — and also pretty unnerving for biotech companies facing the next 20 years. Not only can a 150-character tweet on Twitter make risk-fearing stockholders sell off and run away, so can a posting by some unidentified person (maybe someone from a competing firm) on a bulletin board associated with Yahoo or another stock-watching outfit, Bashe said. The influence of blogs is another factor, he said. Often poorly informed and slapped together at practically no cost by people with scant understanding of the industry, many blogs seem devoted mainly to snarky language and show-offishness. They’ve become a way for inept, angry writers who otherwise would lack an audience to find one. It’s getting worse, Bashe said. As the Internet revs the pace at which everything happens, particularly the pace at which consumers demand news, online outlets are scrambling to provide it. And as the competition in that venue increases, more and more news outlets seek to “add value” by inserting opinion, garbling stories with too much material while trying to adopt – deliberately or not – the conversationally nasty tone of many blogs. Objectivity, if it ever purely existed, gets lost, and truth along with it, as well as plain old accuracy. What’s ahead? A backlash, maybe, and return to traditional journalism (even if almost no hard-copy newspapers remain to publish it?) Will blogs take over everything? Bashe would not predict. The two worlds may be able to keep coexisting a while longer. Frequently incorrect and sound-bite blog “journalism” operates just ahead of scientific veracity, dry and dull. Intelligent, patient investors rely on the latter. Knee-jerk decision makers – frantic to protect money that may have been poorly placed to begin with – depend on the former. But the tides have turned on old-school coverage, and the industry is likely to be hurting more because of it. The changes are enough to make traditional reporters fret as much as industry CEOs, all in hopes of a return to a media world that might make sense again. Just the fax, ma’am.

The Blog Fog, Social-Media ‘Journalism,’ Twitter Litter: WHAT’S NEXT?

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treet protests by AIDS advocates aren’t something you hear much about these days. AIDS activists, like other patient groups, have become more sophisticated in their approach to advocacy. Since the early days of AIDS activism, the

movement has largely shifted focus from headline-grabbing demonstrations aimed at corporations and government to less raucous campaigns that take the form of legislative lobbying, testifying before Congress, exposing drug pricing and, in some cases, helping to fund research. The adversarial relationship between the drug industry and HIV/AIDS activists has dissipated over time. A movement that once pitted patients against drug companies and the government has given rise to a less confrontational movement. An article in the premier magazine issue of BioWorld admonished drug companies not to ignore AIDS activists no matter how strident their message. “They can envelop your company in a storm of bad publicity. But they can also help you find a cure,” Karen Southwick wrote, pointing to the influence that protesters had in creating and designing parallel track trials at Bristol-Myers Squibb Co. for antiviral compound dideoxyinosine. Sage words, indeed. “In some ways, the more hardscrabble activism is not as prevalent,” Gerard Kenslea, spokesman for the AIDS

Healthcare Foundation (AHF), said in a recent interview. “The activism that many people know from the early days of AIDS really is not in widespread use today. I would say that sort of activism is more the exception than the rule.” Street protests still occur, as seen each year at the International AIDS Conference. But overall, Kenslea sees “a degree more of collaboration” between AIDS patient activists, government and corporations. He noted that his organization uses “a full range of advocacy,” including lobbying for legislative changes, running print ads about drug pricing, filing lawsuits and, on occasion, organizing street protests. Much of AHF’s work now focuses on providing HIV-AIDS patients with access to treatment through the state-administered AIDS drug assistance programs, available in all 50 states. The foundation successfully lobbied to get new treatments added to California’s formulary within 90 days, a process that previously took up to a year. Kenslea and other activists credit the early AIDS activists with changing the way the FDA approves new medicines and setting a model for government interaction with patient groups. “The epidemic really turned the page for a totally new type of advocacy and activism for access to drugs,” he said. “I saw the paradigm shift,” recalled Margaret Anderson, executive director of Faster Cures, who ran support groups for HIV-infected patients during the late 1980s as a

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volunteer for the Whitman-Walker Clinic in Washington. She remembered how young men were dying from AIDS before there was any approved therapy, and their fate was seen as unacceptable to patients and their advocates. Protesters worked to become part of the decision-making at the FDA and the National Institutes of Health, and their efforts, she said, “really changed how some of the federal agencies do business and look at patient groups.” Rather than “taking to the streets,” she said, many disease foundations are working to speed the pace of medical research by providing direct funding. Faster Cures, a nonprofit think tank that works to improve the efficiency of drug research, has created a network of member foundations that fund drug research, from breast cancer to Parkinson’s disease. “These groups have money to put on the table, and they are not just funding academic researchers; they are also funding company research,” Anderson said. The nonprofit International AIDS Vaccine Initiative has a scientific team that has worked with more than 40 academic, biotechnology, pharmaceutical, and government institutions to bring six vaccine candidates into human trials in 11 countries. In addition, the organization started an Innovation Fund for companies, which is supported in part by the Bill & Melinda Gates Foundation. The Cystic Fibrosis Foundation for years has funded medical research and currently is supporting more than 30 potential new treatments being developed by biotech firms and big pharma. The Maryland-based foundation, considered the pioneer in venture philanthropy for drug development, has provided key support in the development and FDA approval of five therapies that are now part of standard treatment regimens for many patients with cystic fibrosis. Founded in 2000, the Michael J. Fox Foundation for Parkinson’s Research has stepped up its outreach to industry in recent years to encourage more grant applications from companies. The Virginia-based Epilepsy Therapy Project has been opening its coffers to industry since 2006. “Clearly, ... AIDS activism set the model” in terms of advocating for research and a faster regulatory process, said Ellen Sigal, chairwoman and founder of Friends of Cancer Research. The breast cancer community became “just as vigilant,” she said, and soon other cancer groups followed

in their pursuit of federal research dollars. “All disease groups fight for money for NIH,” said Sigal, who also serves as chairwoman of the NIH Foundation’s public-private partnerships. The NIH budget doubled between 1999-2003 before falling flat. Last year it received a $10 billion boost, but that pot of money, part of the American Recovery and Reinvestment Act of 2009, is due to be spent this year. For nearly a decade, the congressionally directed medical research program at the Department of Defense has funded significant research for breast, prostate, and ovarian cancers, and other noncancer research areas. Last year, the program supplied more than $600 million in research funding. In February, the NIH, FDA and the Department of Health and Human Services announced an initiative to accelerate getting scientific breakthroughs to patients. Some $6.75 million will be made available over three years through the FDA and NIH for work on regulatory science. The research supported through this initiative will focus on new methods, models and technologies for evaluating safety and efficacy of medical product development. “We need more boundaries broken to solve these problems,” Sigal said, emphasizing the role of public-private and interagency collaborations to advance drug research. During the early days of AIDS activism in the late 1980s, the focus of the grassroots movement immediately turned to drug development, specifically allowing patients access to experimental drugs. Spearheading the movement was the AIDS Coalition to Unleash Power, or ACT-UP. The group demanded a faster FDA drug approval process and health care coverage of experimental treatments. And as HIV/AIDS drugs came to market, patient activists were outraged by the high cost of life-saving therapies, the first of which was GlaxoSmithKline plc’s AZT. To this day, the high cost of HIV/AIDS therapies continues to be a major focus of groups like the AIDS Treatment Activist Coalition (ATAC) and the AIDS Healthcare Foundation. In its most recent industry report card last year, ATAC gave several drug companies poor grades in areas like HIV/AIDS drug innovation and drug pricing. Among the exceptions were biotech firms Gilead Sciences Inc. and Tibotec Therapeutics Ltd and pharma giant Merck & Co Inc.

“ AIDS activism set the model.”ELLEN SIGAL, Chairwoman and Founder, Friends of Cancer Research

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WASHINGTON — Few laws have had greater impact on the growth of the biotechnology industry than the Orphan Drug Act. The law, enacted Jan. 4, 1983, provides drugmakers federal grants for clinical trials, tax credits of 50 percent on study costs, exclusion from user fees, seven years of marketing exclusivity and other incentives to develop treatments for rare diseases or genetic conditions. Before passage of the act, only a handful of rare disease treatments had been approved by the FDA, mostly because pharmaceutical companies had few incentives to pursue those drugs, explained Timothy Cote, director of the FDA's Office of Orphan Products Development. He noted that the nearly $1 billion it typically costs to develop a medication far exceeds the expected profits for a medicine to treat rare diseases, which generally affect small populations. But while rare diseases are individually infrequent, they are collectively common—something recognized by Abbey Meyers, a self-described Connecticut housewife, who founded the National Organization for Rare Disorders. Meyers knew that if she could get advocates of the more than 7,000 rare diseases together, they could be a formidable political force, Cote said. "I don't think there is a human being more motivated than one with a sick child and the possibility of finding a cure for that child." Meyers' strategy paid off when her group caught the attention of Rep. Henry Waxman (D-Calif.), whose interest in the topic quickly turned to the pursuit of legislation. The Orphan Drug Act, Cote said, has been heralded as "one of the most important" pieces of drug development legislation. "Congress saw a problem, enacted a remedy, and what was hoped for is exactly what happened." The incentives provided under the law quickly "changed the whole algebra of whether or not it made any economic sense to develop a drug for rare diseases," Cote said. While orphan drug development is "not a charity endeavor," it has been a "beneficent endeavor," and one that has "worked out amazingly well." Nearly three decades after Waxman first introduced his legislation in 1981, about 2,160 products have received

orphan designation, with nearly 360 of those gaining U.S. approval, Cote said. While some of the medications granted orphan status initially had received FDA approval for other conditions, most approved orphan drugs are new molecular entities that have been developed exclusively to treat a rare disease, Cote noted. Additionally, about one-third to one-half of all new molecule entities approved by the FDA are orphan products, he said. The biotech industry by far has supported most of the orphan drug development in the U.S., Cote acknowledged. "A whole host of companies," including Novato, Calif.-based BioMarin Pharmaceutical Inc., Gaithersburg, Md.-based Sigma-Tau Pharmaceuticals Inc. and Cambridge, Mass.-based Genzyme Corp., have established orphan drug development models. But growth in the biotech industry has triggered questions from lawmakers about whether the Orphan Drug Act should be revisited, Cote said. An amendment to the FDA 2010 appropriations bill included a requirement for the agency to establish two committees to evaluate how the FDA reviews medications to treat rare conditions and neglected tropical diseases, with a report due from each panel to Congress next year. Additionally, the Institute of Medicine has embarked on its own review of the nation's rare disease policies, with a report due from that body in late September. While most orphan drug-related incentives have been successful, the priority review voucher, which initially was expected to be a "Golden Ticket," so far has received "underwhelming" attention from drugmakers, Cote said. Under the program, created by Congress as part of the FDA Amendments Act of 2007, a drug developer with a treatment for a neglected disease could receive a voucher from the FDA for the expedited review of a second treatment of the firm's choice. The voucher can be sold or bartered to another company or acquired as part of a buyout of its owner. Neglected diseases are those that are infectious or parasitic and typically affect larger populations in poor nations. However, they also can affect small populations in the U.S., which is why many meet the orphan drug designation criteria, Cote explained. Although economists have valued the vouchers at

By Donna YoungWashington Editor

Government’s Impact on Biotech

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between $50 million to $600 million, so far only Novartis AG has won one, he said. But Cote remained optimistic for the future of the vouchers, arguing that the program is an "experiment" that may take 10 to 20 years before its success is known.

A New Era for Stems CellsOne drug development area that is expected to soon rapidly expand – potentially providing many new medicines for genetic and rare diseases – is stem cell-based therapies. Cote noted that the FDA has granted orphan drug designation to more than 20 investigational stem cell-based therapies, including those based on human embryonic stem cells (hESCs). The number of hESC lines approved for federal research dollars has more than doubled within the first year of President Barack Obama's March 9, 2009, executive order revoking former President George W. Bush's limitations on federal funding to 21 existing cell lines. While Bush's orders did not make hESC research in the U.S. illegal, it resulted in companies and academic institutions having to go to great lengths to ensure no federal dollars were used for anything, such as equipment or personnel hours, involving research outside the 21 approved lines – essentially putting the "kibosh" on a lot of work, said William Caldwell, CEO of Worcester, Mass.-based Advanced Cell Technology Inc. Bush's actions, which also included vetoes in July 2006 and June 2007 of stem cell bills passed by the House and the Senate, also created an "overhang" on venture capitalist and other investment in firms involved in hESC research, due to fears of getting caught in a political storm, Caldwell said. VCs and other investors can understand and contemplate scientific, development and commercialization risks, he said. "But what they don't understand, and what they won't take on, is the political risk. It is not quantifiable for them, and they just won't take it on," Caldwell said. After Bush's orders, companies involved in the hESC space essentially had three options: self-funding their research; cannibalizing other parts of their company to continue their work; or dropping out of the business altogether, said Caldwell, whose own firm ended up selling its animal segment to stay alive. "While we were going back and forth, the rest of the world was moving forward," said James C. Greenwood, CEO of the Biotechnology Industry Organization, who noted that there was a "serious fear" in the early 2000s that hESC research scientists would leave the U.S. for Europe and Asia to continue their work. But in November 2004, the tide began to turn in the U.S. when California voters passed Proposition 71, which provided $3 billion for stem cell funding. "It showed there was support in the country for funding," Caldwell said. Greenwood predicted that with Obama's order and new guidelines by the National Institutes of Health, the U.S. no longer is in jeopardy of experiencing further hESC funding restrictions like those imposed during Bush's tenure. Now that all of the "obstacles" from the past decade are behind them, companies like ACT and Menlo Park, Calif.-

based Geron Corp. — both of which hold FDA-approved investigational new drug applications for Phase I studies, albeit on clinical hold – are at the doorstep of testing their hESC products in humans, Caldwell said. "That will be a major, major accomplishment, given the fact that it has taken 12 years of development, research and work to get to this point," he added. While the success of the hESC story "has yet to be totally written," Caldwell said he expected VC funding to pick up for the space once there is validation of a therapy.

Awaiting a Story EndingAnother unknown story ending for biotech is the impact to the industry of the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of 2010 – health care reform. But now that the laws, signed by Obama on March 23 and March 30, respectively, are in place, BIO's Greenwood said he expected venture capitalists to be less spooked by political uncertainty and more willing to invest in biotech. The big win for biotech in health reform was, of course, the 12 years of data exclusivity protection against follow-on biologics (FOBs) – although BIO would have preferred 14 years. But with the FOBs victory behind it, BIO now is putting its efforts into ensuring biotech's concerns are addressed in patent reform and bills reauthorizing the Small Business Innovation Research (SBIR) program and the Prescription Drug User Fee Act (PDUFA), Greenwood said. The SBIR program, created in 1982 under the Small Business Innovation Development Act, provides U.S. small businesses with competitive grants intended to encourage exploration of new technologies. The program was up for reauthorization in September 2008, but has been operating under a series of resolution extensions since then due to differing demands within the House and the Senate. BIO has been working on getting Congress to overturn eligibility restrictions imposed in 2003 by the Small Business Administration, which disqualified from the SBIR grants firms that are majority VC-backed. "We think that is inconsistent with the intent of Congress, and we are trying to change that," Greenwood said. BIO also is working to "bend the curve" to make PDUFA more fair for drugmakers. PDUFA, which is up for reauthorization in 2012, gives the FDA the authority to collect fees from drug companies submitting marketing applications. The user fees are intended to provide additional revenues for the hiring of more staff, improving systems and establishing a better managed drug-review process to get therapies approved quicker. Within the first year after PDUFA's initial enactment in 1992, 7 percent of the FDA's budget for human drug approval came from user fees. But now, drugmakers pay about 66 percent toward the agency's budget, Greenwood noted. "We should try to get it down to at least 50 percent, so that it is a 50-50" split between user fees and congressional appropriations.

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Twenty years ago, BioWorld highlighted rational drug discovery as the scientific method of the future. But if there is a scientific method that came of age over the past two decades, it would

have to be genomics. When BioWorld published its premier magazine issue in 1990, the human genome project was just going from a gleam in the eye of Francis Collins to a bonafide sequencing effort. Two separate drafts of the human genome sequence were published a decade later, in 2000, in back-to-back papers by the publicly funded Human Genome Project and a private competitor it had acquired along the way, Celera Genomics. This year thus marks the 20th anniversary of the start of the Human Genome Project, and the 10th anniversary of its completion. Since then, its pace has become faster as its provenance has grown. While the first human genome took 10 years to sequence, the same feat can now be accomplished in a matter of weeks. Now, as genomics analysis enters its second decade, it also is entering a new phase: If the ‘90s were characterized by producing the original draft sequences, and the ‘00s by genome-wide association analysis, in the ‘10s it’s the technology. And, like any teen, that technology is finding its individual side. Genomewide association studies (GWAS) have found multiple genetic contributors to the most common disorders and many uncommon disorders. Naming human genetic variation as its Breakthrough of the Year in 2007, Scienceincluded heart disease, diabetes, breast cancer, restless leg syndrome, atrial fibrillation, glaucoma, amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, colorectal cancer, ankylosing spondylitis and autoimmune diseases as

ailments for which gene associations have been identified. But therapeutic benefit from those findings has been slow in coming – and there is an increasing realization that this is not just the natural time lag and attrition from scientific finding to marketed therapeutic, but partly due to the nature of the enterprise itself. Francis Collins, who is now director of the National Institutes of Health, told BioWorld that in his opinion much of the disappointment with GWAS stems from what he termed “an intellectual disconnect”: the relationship between risk prediction and therapeutics development is “regularly muddied up.” Specifically, he said, because the common variants that have been identified do not contribute particularly strongly to the risk of developing the associated diseases, many people conclude that the corresponding genes do not make particularly interesting drug targets. But that conclusion, Collins said, is false. To see what common variants might bring to the table, he said, one only has to look at diabetes. There are 18 common variants that impact a person’s risk of developing diabetes. None of them, Collins said, are particularly strong predictors, making them disappointing by the logic that equates effect size with pharmacological utility. But two of those weakly risk-conferring genes are within the major target genes of current diabetes treatments. Drugs targeting PPAR-gamma and KCNJ11 “are the two major orally available diabetes treatments today,” Collins said, showing that a gene that confers a modest risk can nevertheless be a drug target of blockbuster proportions. And given the track record of the two genes with drugs available to target them, “don’t you think the other 16 [common variants] are interesting, too?”

By Anette BreindlScience Editor

DragonsHERE THERE STILL BE

20 YEARS LATER, LOOKING FOR HERITABILITY IN THE DETAILS

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Nevertheless, genomewide association studies suffer from two major limitations. First, they can detect mainly single-nucleo-tide polymorphisms, or SNPs — single-letter changes to the genetic code. But the past few years have shown repeatedly that other types of genomic changes also can contribute to ill-ness, most notably, copy number variations and deletions. Furthermore, genomewide association studies are able to detect only common variants – those where even the less frequent variant occurs in at least 5 percent of the population – because rarer variants cannot be validated statistically. In fact, a much-noted study published in 2007, which reported 10 new genetic risk factors for diabetes, also missed several risk genes that had been identified by other methods. The probability values of those associations were not strong enough. Together, those limitations mean that heritability is not that much less mysterious than it was in 1990. At last year’s annual meeting of the American Society for Human Genetics, Alan Guttmacher, acting director of the National Institute on Child Health and Human Development, summed it up succinctly, if perhaps a bit depressingly: “We, at this point, in 2009, do not understand where most human heritability comes from.” Collins agreed that “there clearly is missing heritability.” Family studies indicate that the genetic contribution to the risk for most common diseases is around 30 to 50 percent, and GWAS studies have not uncovered nearly all of that 30 to 50 percent. But hope springs eternal, and many in the genomics community are pinning their hopes on advances in genome sequencing technology. Such advances have made it easier to move beyond SNPs and identify harder-to-find genomic variations like deletions and copy number variations. Collins says that such rare variants will turn out to contain “a fair amount” of the currently missing heritability, either in additional risk genes or in those already identified. But perhaps the most important change is not that sequencing is getting fancier, but that it is getting cheaper: Following its own version of Moore’s law, sequencing the

whole genomes of individuals has now come within the reach of individual labs rather than being the sort of massive “it-takes-a-village-to-sequence-a-genome” undertaking that was the Human Genome Project. In his talk at the ASHG annual meeting, Guttmacher predicted that genomic variations ultimately would become part of individual medical records – a sort of family history on steroids. Perhaps. But if and when the personal genome as part of the medical record comes to pass, future privacy concerns will likely also dwarf anything that is addressed by HIPPA forms. Jay Bamshad is a University of Seattle researcher whose team has identified the cause of several rare monogenic disorders by sequencing the genome’s protein-coding parts, otherwise known as the exome. At the ASHG conference, he told reporters that exome sequencing studies “generate a tremendous amount of data about variation that people have [in parts of the genome] where we are not asking questions.” Study subjects that are having their exomes sequenced to find the genetic cause of a rare disease do not know whether they are carriers for cystic fibrosis, or have mutations in their BRCA genes. “Are those things that we should be looking at? The data are available. If we should be looking at them, is that information that we should be returning to them? And if so, in what context?” And beyond the landscape of currently known medically relevant genes, he added, are those whose significance will be determined in the future. “The information we generate. . . is static, but what the meaning of that information is, is going to change over time.” For an update on what they mean by then, check back with BioWorld’s 40th anniversary issue.

FAMILY STUDIES INDICATE THAT THE GENETIC CONTRIBUTION TO THE RISK FOR MOST COMMON DISEASES IS AROUND 30 TO 50 PERCENT, AND

GWAS STUDIES HAVE NOT UNCOVERED NEARLY ALL OF THAT 30 TO 50 PERCENT.

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There was plenty of activity to glean news from in 1990 that has somehow managed to transcend time and remain relevant in 2010. Health care spending accounted for 11.5 percent of the U.S. GDP and represented a $714 billion market with a booming 7.2 percent growth rate in 1990,

as Americans clamored for health care reform to address the increasing prevalence of diseases such as HIV/AIDS, diabetes and cancer. Back then, the average citizen spent $2,734 on health care annually and the majority supported more spending to pursue advancements in drug development and the creation of more health care jobs to prepare for the graying Greatest Generation’s final assault … this time on Medicare. Flash forward to a 2010 report published by the Centers for Medicare & Medicaid Services (CMS) that says national health care spending, bolstered by the proliferation of equally expensive and efficacious biotech drugs, is now a record-setting $2.4 trillion market that accounts for 18.3 percent of GDP, with a 4.4 percent growth rate, ironically its lowest rate of increase in nearly 50 years. Americans, spending $7,214 per person annually on drugs and care, are now split evenly on the health care reform (HCR) issue and fighting it out in Civil War II: The Health Care Free-for-All Over Free-for-Some Health Care. But biotech advocates, do not despair! The present Econozilla that is devouring companies and trampling markets will not claim biotech; nor will the full-metal jacket HCR offensive render the death of its innovation. Biotech is the junior drug market, but is hardly a recession virgin, as it has weathered four previous official recessions before this one. And the HCR issue has been volleying back and forth across the political tennis net longer than even the pharmaceutical industry has been around — when Teddy Roosevelt received so much flak in 1912 that he lost his first presidential election bid. If the anti-reformists are victorious, the inscription on

By Michael HarrisStaff Writer

NEWS FLASH: BioWorld Will Cover It All

There’ll Be No Break in News!

Lady Liberty will likely be changed to “Give me your tired. Your poor. Your huddled masses … just make sure they already have health insurance!” Whichever side emerges victorious still will likely fall under the offensive of Boomsday, when ailing, aging baby boomers — the largest demographic battalion ever born — storm the health care system with a blitzkrieg of sheer numbers that will overpower health care’s infrastructure with a saturation bombing of red ink that will make the recession of 2009’s impact look like a mere flesh wound. That looming scenario currently is being evaluated and played out in war-game fashion all across the world in think tanks, government sessions and drugmaker boardroom soirees, even as disease marches on. But as you already know, BioWorld will keep you informed. Of the many things that began, existed or ended in 1990, some are permanently defunct, some are in decline and limping along, some have come and gone and attempted comebacks, and some you just wish would go away. The negative aspects of some events linger and worsen, and some deserve to be commemorated. Use the list below to match your own responses. In case you were so fascinated and engrossed in 1990 by the prospect of getting daily biotechnology news delivered to you while you drank morning coffee in the clinic, or swigged Maalox in your boardroom, or babysat your VC’s kids before school, here is what you missed in popular culture that year:

“ The Simpsons” TV series began

The fi rst web page on the World Wide Web was published by Tim Berners-Lee

The fi rst in-vehicle GPS Satellite Navigation System was sold by Pioneer

Operation Desert Shield deployment began

The Communist Party relinquished sole power in Soviet government, thus dissolving the USSR

The Jackson 5 music group disbanded

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The Saturn vehicle line was launched by General Motors

The 1990 recession began

Alternative rock band Pearl Jam formed

The Three Tenors formed

Nelson Mandela was released from prison

East and West Germany united

The Americans with Disabilities Act was signed into law

The Channel Tunnel was connected

Exxon Valdez Alaskan oil spill occurred

The Hubble Space Telescope was placed in orbit

Microsoft Corp. released Windows 3.0

Milli Vanilli lip-synched its way to Grammy fame, then shame

Depletion of the ozone layer was discovered over the North Pole

In 1990, you did biotech to stand out; now you do it to blend in. For the first half of the past 20 years, biotech was the rebel technology; in the 21st century, it is the drug market du jour, accounting for 40 percent of new drug approvals and primed to supplant pharma in dominating the blockbuster drug list in this decade, for the first time in history. As for BioWorld? Well, we’ve pub-lished more than 5,220 issues over 7,300 days, reporting on billions in fi-nancial transactions and earnings, con-veying news on thousands of compa-nies, deals, personnel changes, clinical trials and more. And we’ve done it all in 24-hours time, day after day, year after year, decade aft … wait a minute, when do I get a vacation around here? Looking for a big difference? In 1990, some companies wanted to be called anything but biotechs in the press, for fear of being associated with the ominous ick-factor or ambiguity of left-field perceptions of “FrankenFoods,” first-of-a-kind drugs borne of living organisms and “Invasion of the Body Snatchers”-like clones that are genetically birthed in the lab, rather than born of the womb. Now, it’s difficult to find a pharmaceutical company that doesn’t want biotech credibility in its name, mission or pipeline. All signs are pointing to the likelihood of our 40th anniversary edition commemorating biotech’s role as the world’s biggest therapeutics market.

1990

The Human Genome project, an international effort to map the human genome, is launched.

A 4-year-old girl with an immune disorder receives the first experimental gene therapy treatment.

The first transgenic daily cow is created to produce human milk proteins for infant formula.

The first field test of a genetically modified vertebrate is conducted, on a trout.

1992

Scientists from the U.S. and UK reveal a method for testing embryos in vitro for genetic abnormalities, including cystic fibrosis and hemophilia.

1993

Two smaller trade groups are merged, forming the Biotechnology Industry Organization.

1994

The first breast cancer gene is discovered.

1995

Immune system modulation, gene therapy and recombinately produced antibodies enter the clinic.

Scientists complete the first full gene sequence of a living organism other than a virus, for the bacterium Hemophilus Influenzae.

1996

Scientists discover a gene associated with Parkinson’s disease.

1997

Dolly the sheep becomes the first animal cloned from an adult cell.

1998

Human embryonic stem cell lines are established.

The C. elegans worm is sequenced, becoming the first complete animal genome.

A preliminary draft of the human genome shows the whereabouts of thousands of genes.

2000

A preliminary draft of the human genome sequence is released.

2002

An international group of scientists sequences the genomes of the parasite that causes malaria and the mosquito that spreads the disease.

A draft of the complete map of the human genome is published, ahead of schedule and under budget.

Scientists identify more than 200 genes involved in differentiation of stem cells.

Successful results of a vaccine against cervical cancer marks the first time preventive measures have been shown against cancer.

Scientists discover how small pieces of RNA control many cell functions.

Security and ethical questions arise when scientists make a synthetic polio virus using genome sequence information.

2003

Discovery of a gene for depression offers new hope for treating schizophrenia and bipolar disorder.

GloFish, the first biotech pet, is introduced to detect water pollution.

The first endangered species – the banteng – is cloned.

Dolly, the first cloned sheep, is euthanized after she develops lung disease.

Gendicine gains the first regulatory gene therapy approval, in China.

2004

Avastin, the first anti-angiogenic drug for cancer, is approved.

The first RNA-interference product, for wet macular degeneration, enters the clinic.

The first cloned pet, a kitten, is delivered.

California voters approved Proposition 71, allocating $3 billion for embryonic stem cell research.

The first drug for a specific race — BiDil — is approved for blacks with congestive heart failure.

Centers for Disease Control and Prevention researchers sequence the virus that killed 20 million people in 1919-1920.

Harvard researchers convert skin cells into embryonic stem cells.

2005

Researchers at the University of Wisconsin differentiate human blastocyst stem cells into neural stem cells, and then into spinal motor neuron cells.

2006

Scientists develop biotech pigs with high levels of helpful omega-3 fatty acids.

Scientists determine the 3-D structure of the human immunodeficiency virus which causes AIDS.

2008

Japanese chemists create the first DNA molecule made almost entirely of artificial parts, which is useful in gene therapy.

Craig Venter and his team replicate a bacterium’s genetic structure entirely from laboratory chemicals, moving a step closer toward creating the world’s first living artificial organism.

2009

Geron Corp. gets the go-ahead from the FDA to start a Phase I trial of human embryonic stem cell-derived oligodendrocytes in patients with spinal cord injury.

President Obama signs an executive order lifting a restriction on federal funding for human embryonic stem cells.

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Biotech’s relatively short commercial history might be rather easily divided into three chapters, each corresponding roughly with the calendar decades of the ‘80s, ’90s, and ‘00s. The first chapter we might call “Discovery,” as it chronicles the key inventions and innovations that made the modern industry possible and highlights the first few approved products – insulin, interferon alpha and tissue plasminogen activator. The second chapter, which might aptly be titled “Commercialization,” begins in mid-1989 with the market approval of Amgen’s Epogen, biotech’s first blockbuster, followed in short order by a relative flood of new products and companies, peaking in the late 1990s as monoclonal antibodies finally came into their own. But what should we call the third chapter, corresponding with the decade we just completed? Ten years ago, it seemed clear that our entry into the “Post-Genomic” era would guide the opening decade of the 21st century. The Human Genome Project and investment darling Celera Corp. raced to the finish line with their respective genomic sequencing projects in 2000, just as the dot.com bubble of the Nasdaq Composite reached its apogee and a seemingly inexhaustible supply of capital flowed into technology. This wasn’t just going to be a biotech decade; it was going to be The Biotech Century.

TEN YEARS AFTER

Things look a little different on the other side of the decade. By many

measures, the last 10 years have been less productive than the 1990s, despite incredible advances in science. Certainly there’s been no appreciable uptick in the approval of biologics by the Food and Drug Administration – which is remarkable, considering that biotechs can now count essentially every major pharma company as direct competitors in this regard, as well as partners and collaborators. From an investment perspective, the past decade has been a stark disappointment – an experience not limited to biotech, although it certainly includes it. The Nasdaq Biotech Index has plummeted over the past decade. From the peak of the bubble on March 10, 2000, over the following 10 years, the index underperformed even the lousy showing of the S&P 500 over that period (although it has done somewhat better than the Nasdaq Composite itself). And when it comes to the big ideas, we’ve seen less than we hoped for. If the 1980s brought us the first recombinant proteins, and the 1990s brought us monoclonal antibodies, what was the new treatment modality of the 2000s? Ten years ago, many of us would have predicted that gene therapy would play a commercial role by now, or that RNA-targeted therapeutics would have seen more commercial success, or that stem cell therapy would have advanced further. By this sort of quantum-leap view, progress in biotech seems to have slowed considerably. And when it comes to the creation of new companies, we’ve again seen productivity drop drastically in the 2000s.

ENTER THE HOLLYWOAs the Biotech Industry Matures,

By Karl ThielBioWorld Today Columnist

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BETTER THAN EVER

Yet for all that, the past 10 years have been incredibly positive ones for the industry, and the next 10 are going to be even better. Consider the investment angle. Biotech, writ large, has been a lousy investment over the past decade, sure, but then it has often been a lousy investment when one views the industry as a whole. In contrast, you could have bought a common-sense basket of biotech stocks even at the peak of the market in 2000 and be sitting on some huge gains today. And it didn’t require huge risks or even great insights – all you had to do was limit yourself to the well-recognized names that already had approved products 10 years ago. Celgene Corp. and Gilead Sciences Inc. were two of the best performing stocks of the decade in any industry, and creating that kind of wealth for shareholders is what keeps money flowing to the sector – and gives biotech the ability to invest further in itself. This has always been an industry of haves and have-nots, and that trend accelerated in the 2000s – big companies generally got bigger, while newcomers found it hard to find a place. When it comes to technology, the real lesson of the past decade is that biotech has so thoroughly won the game that its victory is in some ways hard to recognize. Remember the talk of “rational drug design” that was part of the lingua franca 10 years ago? We have a new term for it now: R&D. It’s a matter of course that the many tools that came largely out of the biotech industry have become a standard part of the

discovery and development process. Chance observations will always play a role in the lab, but trial-and-error as the infrastructure of discovery is pretty much out the window. Remember all those so-called “tool” companies being furiously formed at the end of the last decade? There were bio-informatics companies, database com-panies, makers of chemistry libraries, medicinal chemistry specialists, func-tional genomics companies, proteomics companies, gene expression companies, structural biology companies, and so on. Many of these failed or were absorbed, often at a loss to early shareholders, while a lucky few with sufficient resourc-es reinvented themselves as integrated drug discovery firms. As businesses, the track record of this group was spotty at best. As technology, it was incredibly successful – these tool companies failed by and large because everybody needed access to what they did, they needed it on the cheap, and they often needed it in-house... so they duplicated or commoditized it. The industry has become much more “integrated” if only in the sense that many technologies once sufficient as the basis for a standalone business are now just part of basic competence for any discovery lab.

GENIE GOES TO HOLLYWOOD

What’s more exciting is the decade ahead. The number of novel biologics approved by the FDA has been steadily increasing over the past three years (albeit from a pathetically low number), and 2009 looked like a bit of a breakout, with seven of 26 novel products approved being biologics. So far, 2010 looks like it’s shaping up to be even stronger. If there’s one thing that seems constant across the decades, it’s that bringing novel products to market always takes longer than expected, but a huge number of biotech products in late

development suggests that the industry could start to dominate approvals in a few years. And with an industry-friendly new law just passed on follow-on biologics, companies that successfully create a product franchise will be able to hold onto it for a long while. So maybe we’ll label the chapter of the last decade “Integration.” And what about the next 10 years? A tentative title might be “Hollywood.” From the outside, biotech – if we continue to define it as we do today, as either small-cap drug discovery or pure-play biologics companies –may continue to look like a perpetual outsider, always scrambling for cash and tilting against long odds. When we look at the biggest names in biotech 10 years from now, they’re likely to look very similar to the biggest names we see around us today – we’re simply not building an industry where every new start-up can have ambitions of becoming the next Merck or Genentech. Big pharma will try to maintain lean structures for the foreseeable future, which means they will accelerate down the path they’ve already been on, which is toward a Hollywood model of drug development. This isn’t really new; a shrinking number of big pharma companies increasingly act as major studios that look to biotech for scripts and production talent. But continuing evolution of collaboration models – witness the growth of “option” deals over the past few years, something straight out of Tinseltown – will help cement this relationship. It leaves biotech as a place where successful companies can thrive and grow, but new upstarts always have a chance to find a place ... which makes it a very exciting place to be. Here’s to the 2010s.

Karl Thiel, an analyst for the Motley Fool, is a BioWorld Today columnist. His opinions do not necessarily reflect those of BioWorld.

CHANCE OBSERVATIONS WILL ALWAYS PLAY A ROLE IN THE LAB, BUT TRIAL-AND-ERROR AS THE INFRASTRUCTURE OF DISCOVERY IS PRETTY MUCH OUT THE WINDOW.

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A merican writer and economist Peter Drucker once said that trying to predict the future is like “trying to drive down a

country road at night with no lights while looking out the back window.” Nevertheless, being the intrepid industry observers that we are, we have pondered where the biotech industry might be in that sci-fi-sounding year of 2030. Will we gather together that year at the annual BIO meeting (perhaps in Beijing or Bangalore) to

Oh, Magic 8-Ball, Will Biotech Prosper?

regale one another with tales of drug approvals, record profits and the stamping out of disease, hunger and pollution worldwide? Or will we still be lamenting the shortage of early stage venture capital and the so-called “broken model”? Where do you think biotech will be in another 20 years? We posed the question to our staff and a handful of industry leaders and got a number of interesting responses – some serious, others less so – in return.

Biotech’s core will have moved from the West (U.S., Europe) to the East (Korea, Japan, Singapore).

We’ll have low-cost, orally available individualized medicines.

Individual gene sequencing will be included as the standard of care for every patient.

We will have cured a lot more diseases.

Gene therapy will fi nally work.

Regenerative medicine efforts will lead to off-the-shelf replacement organs.

There will be no more blockbuster drugs.

Drug pricing constraints will limit funding for internal R&D.

Contract research organizations will be bigger than drug companies.

Big pharma will be distributors relying solely on biotech for R&D.

The traditional biotech company will no longer exist.

Big pharma conglomerates will have disassembled into small companies.

Biotechs will have discovered an alternative to founding a company around every new project.

Venture capitalists will have exited biotech.

Partnerships will still be key.

The biotech and pharma industries will be a branch of the federal government.

The diagnostics industry will be bigger than the drug industry.

We’ll be profi table.

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