Biogen's Big Picture

Today, Biogen's billion-dollar flagship multiple sclerosis product Avonex (interferon beta-1a) faces stiff competition from Serono's Rebif (interferon beta-1a), launched in the United States in March 2002. Although the two were already competing in Europe, financial analysts and media following the MS market predicted massive market share erosion for Avonex, especially after the announcement that Pfizer had agreed to co-promote Rebif in the United States. Some contend that Biogen is too dependent on the sales of one product and isn't strong enough in the short term to withstand Avonex losses. But as Biogen celebrates its 25th anniversary, Avonex's market share is holding steady at a healthy 50 percent; the company's new complex in Research Triangle Park, North Carolina, puts it on the map as a major manufacturer; and its leaders are confident that the big picture remians regardless of observers' gloom and doom about its product line.

Chairman and CEO Jim Mullen ignores Biogen's "one product company" critics and focuses on long-term growth.

Mullen, along with Burt Adelman, MD, executive vice-president of research and development; Hans Peter Hasler, executive vice-president of commercial operations; and Thomas Bucknum, Esq., executive vice-president and general counsel, tell Pharmaceutical Executive that the drama-tic business and operational changes underway, coupled with sustained small-company enthusiasm and efficiency, ensures Biogen's resilience and long-term growth.

Ready for Two

Jim Mullen's six-foot-four stature belies his gentle manner-although anecdotes reveal him as a leader in a hurry who instills the same sense of urgency in his employees. His management style seems to say that most timelines are made to be shortened, because time is not on the side of today's biotech and pharma companies. It is precisely that urgency that prompted Biogen to launch Avonex within 33 hours of FDA approval. And it got the company where it is today, eagerly waiting, months ahead of schedule, for FDA approval of the second product it will market on its own-Amevive (alefacept), indicated for the treatment of moderate-to-severe chronic plaque psoriasis, an inflammatory skin disease that the American Academy of Dermatology estimates affects more than 100 million people worldwide.

"Whenever we look at a timeline, Mullen throws us up against a wall," says Bucknum about his boss's demand that his team cut their original six-month regulatory application process in half. And for good reason. Amevive represents the first new psoriasis treatment in 20 years, and dermatologists seem receptive, if not outright enthusiastic, about a new option that could offer good results without the toxicity of some oncology products currently used to treat the skin condition.

With FDA approval expected in the first quarter of 2003 and annual sales projected to peak at an estimated $500 million, Biogen began pre-launch professional and consumer education initiatives months ago to prepare the market

for a new entry. Those initiatives include an unbranded insert in dermatology journals that uses sophisticated medical illustrations and excerpts from published scientific literature to explain the immunologic underpinnings of psoriasis and the rationale behind biologic therapies that target T-cells to treat it.

Partnering with the National Psoriasis Foundation and Jerry Mathers, "the Beav" from the classic sitcom "Leave it to Beaver," Biogen aims to raise awareness of the disease and its treatments among patients and their families. Along those lines, the company already launched psoriasissupport.com, a "virtual community" modeled after Biogen's successful multiple sclerosis websites supporting Avonex. (See "Virtual Community Generates Real ROI," PE, March 2002.) If the company repeats its experience with avonex.com and MSActiveSource.com, it will build a membership of tens of thousands of patients who volunteer their personal medical histories and demographic information to help refine the website's content as well as enhance the targeting of Biogen's professional and consumer marketing efforts.

As marketing and medical education efforts were in the works, clinical and regulatory groups expedited Amevive's new drug application process. In yet another demonstration of its sense of urgency, in August Biogen was the first company to submit an application using the then brand-new common technical document (CTD) to FDA and the European Medicines Evaluation Agency (EMEA). Submission for Japan is next.

A few of Biogen's regulatory people were involved in the World Health Organization's International Congress on Harmonization guidelines for global application submissions and felt comfortable going with the new CTD format.

So they didn't hesitate and, to Mullen's satisfaction, the process was successful and efficient. The company plans to continue using the CTD with other compounds as they move through the pipeline. (See "Multi-Product Company in the Making," page 42.)

Building a Portfolio

As promising as the research is, and the market may be, for Amevive, the financial and media worlds are still obsessed with the competition Biogen faces from Rebif. (See "Tug-of-War Waged in Ink," page 40.) And even the company admits that, in the short term, it expects Rebif's sales to affect its bottom line. After all, 93 percent of its 2001 revenue came from Avonex sales.

Biogen's other revenue comes from royalties-the company out-licensed technology to Merck and SmithKline Beecham that eventually led to the development of hepatitis B vaccines and diagnostics. It also licensed alpha-interferon to Schering–Plough more than 20 years ago, and to this day, sales of S-P's Intron A (interferon alfa-2b, recombinant) contribute significantly to that company's $1.4 billion global franchise. Those deals formed the foundation of Biogen's autoimmune franchise and kept the cash flow moving during its early years.

"I think out-licensing was probably the right decision, even though you could say, 'Gee, Burt, if you guys were selling alpha-interferon, beta-interferon, hepatitis B vaccine, and now Amevive, you might be the largest pharmaceutical company in the world," says Adelman. "The reality is that the company did not have the infrastructure at that time to take those products forward. And I'm not sure anybody fully recognized the size of the markets for those two products. The royalty stream, which has been quite significant, enabled the company to grow and build the Avonex franchise, our research organization, and the current pipeline.

If you want to generate cash for critical product development, you have to develop collaborations-research-based relationships-and ultimately that becomes very distracting. I can't think of a better way to get a complex company like Biogen started than with a significant royalty stream that is hands off. We didn't have to do anything except open the envelope and take out the check." Yet, Biogen continues to out-license products, including bivalirudin, an antithrombotic currently marketed as Angiomax by the Medicines Company, also based in Cambridge.

One of the company's most dramatic changes was its move to license more products from others, beginning with Antegren (natalizumab), the first compound in a new class called selective adhesion molecule inhibitors. Discovered by Elan, Antegren may be the next generation MS treatment. The Biogen–Elan collaboration brought Antegren to late-stage clinical research. Two Phase III trials for MS and two for Crohn's disease are currently underway. Other deals, with Icos for LFA-1 antagonists and Celltech for CDP-571, among others, are helping to fill the company's pipeline.

"No matter how good your own science is, there will always be much more science going on outside than inside," says Adelman. "What we've done and should continue to do is use our capabilities and expertise to leverage access to product candidates at reasonable costs. We are not prepared to spend $2 billion for Erbitux, for example. We just don't have the financial wherewithal. We have to bring to the table other assets that a potential partner would recognize as significant in value in lieu of cash. And those attributes are clearly in the biologics manufacturing and commercialization areas."

Long-Term Vision

Coverage of the Avonex–Rebif market-share war has all but eclipsed the news that gives a substantial edge to Avenox, an advantage that no competitor can claim: As of May 2002, Medicare covers Avenox injections. That represents access to the treatment for an additional 30,000–40,000 patients, according to Adelman.

Another edge stems from Biogen's small-company background, which forced integration of business and operations functions. In short, being a big company with small-company cohesion and cameraderie means that employees don't have to be directed to integrate-they already do.

"I came to this company 13 years ago because it had closely aligned its commercial vision with its research vision," says Mullen. "It is one of the competitive advantages and one of the things that allows us to focus on the right things. It's what I call, 'I want to care if we win,' which means that if we get a product all the way through to approval, I want it to be important, not just an approval.

The other way to do that is to have broad interaction of the commercial group all the way back to the R&D group. They've been very strongly connected historically. So it's not as if we're trying to fix something that was broken. What we're trying to do is evolve a system and a structure that still works as we continue to grow. When I first started here, everybody could fit on two floors of this building. So it wasn't all that hard to keep it connected. You wandered around and you had a beer on Friday."

The Friday "happy hour" custom still exists at Biogen headquarters and it's as popular as ever. But communication among headquarters and the other 16 internationally located affiliates is much more of a challenge-less about keeping in touch, and more about cross-training and experiencing different cultures to better drive and manage a global business.

"I don't care how many video conference calls you use," says Mullen, "how much e-mail or voice mail you have. Until individuals have a personal, trusting relationship in which they can conduct business, all those things are a distraction. People have to learn first hand what's going on. So a lot of the senior people need to travel globally. We've put a huge emphasis on international experience and international exposure, so we've moved a lot of people around." (See "International Implementation," page 38.)Mullen lived in Paris for three years as Biogen built its European organization. He says living abroad and working in different disciplines makes for efficient teams. "We have quite a number of people relocating between here and Europe so we're getting a lot of cross-functional experience. We are also trying to avoid the silos that you find in a lot of the big pharma companies, where people have a single job and it takes 20 years before they get experience in anything else. So we have a lot of people who have served in many multifunctional roles."

Lifecycle Advantage

In addition to the unique market leadership opportunity afforded to Biogen by securing Medicare coverage for Avonex, the company has another major ace up its sleeve. It is one of the only biotech companies to get high marks from clinical trial sites in an established survey of 405 principal investigators or study coordinators conducted annually by CenterWatch, a well known clinical trial recruitment website. In June 2001, Biogen ranked within the top tier of sponsor companies that included GlaxoSmithKline, Merck, Pfizer, and Eli Lilly. In fact, Biogen came in third, with 71 percent of the respondents rating it "very good" or "excellent" to work with.

That bodes well for Biogen, in an environment in which companies lose billions of dollars and, even worse, waste valuable time because of stalled clinical trial patient enrollment. That's a problem plaguing many Big Pharma research programs, and it is one of the main causes of the industry's new product dry spell.

So as Biogen works to plump up its autoimmune portfolio with products to treat chronic ailments such as Crohn's disease, it may not experience the delays recruiting patients or negotiating with investigators that other companies often do. That should be true for its second psoriasis treatment LFA-1, and ultimately for cardiovascular patient recruitment, a relatively new therapeutic area for the company, currently in Phase II trials of Adentri (adenosine A1 antagonist) its treatment for congestive heart failure.

Quoted in the CenterWatch survey report, Adelman says that Biogen facilitates sites' relationships with clinical research organizations (CROs). "In the past few years, we have tried to figure out how to best work with CROs so that our sites don't feel they are being managed by an intermediary and not by us directly. Many investigators don't even understand what CROs are and why drug companies use them." He credits the CROs for their high ranking in the CenterWatch survey but admits that he works with CRO senior managers to align their organizations with the Biogen culture and philosophy.

Finding itself in the apple of clinical trial investigators' eyes may prove to be a critical edge in beating competitors to market with secondary and tertiary indications for Biogen's products, potentially extending their lifecycles and contributing to the longevity of its developing autoimmune and inflammation franchises.

Race to the Finish

Hasler, on board for little more than a year after a long career with the international arms of Wyeth, Lederle, and Abbott, thinks about Biogen's global competition with the same sense of urgency as his colleagues and his boss.

"In the multiple sclerosis area, we have more competition today and we know that," he says. "But in the psoriasis area, there are five or six new products expected within a few years. So our speed there is crucial. For Amevive, the labeling negotiations will be crucial for what we'll be able to claim.That's the big theme in the industry today, of course; to bring products quickly to market is number one. And number two is to bring the right product labeling to the market. We are not a generic company. We don't want to get into price competition with others in the market. Our goal is to add value, to differentiate, and to always reach more patients than we have in the past."

As Mullen and his team prepare for the year-long celebration of Biogen's golden anniversary, one thing is true: It's a big deal to go from a one-product company to a two-product company. It's difficult to simultaneously expand and keep the vision and the day-to-day activity aligned on both local and global levels.

But the "campfire culture," as Bucknum calls it, the hallmark of the small company in Cambridge, is still alive and well despite the dramatic changes that will change Biogen from a small research boutique to a large manufacturer ready to hit the ground running in the race to market.