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Tysabri: The Big Multiple Sclerosis Drug That Emerged From "The Hutch
The most effective drug on the market today for patients with multiple sclerosis has roots in a dingy old lab in the 1980s on Seattle's First Hill. It was there that a pair of young scientists at the Fred Hutchinson Cancer Research Center, Bill Carter and Elizabeth Wayner, made key discoveries that paved the way for natalizumab (Tysabri).
The treatment has become the fastest-growing product for Cambridge, MA-based Biogen Idec (NASDAQ: BIIB) and its Irish partner Elan (NYSE: ELN), and it's projected to generate $1.6 billion in sales in 2011. Most people know of its link to a rare, often fatal brain infection called PML, and its dramatic recovery. But few people know where the drug comes from.
So I stopped by Carter's new lab at the South Lake Union campus of "The Hutch" to hear the story.
Carter, 62, didn't seem the least bit self-important about this discovery when I stopped by his office last week. He wore a brown T-shirt and brown sandals. Manila file folders with scientific papers were stacked high on the shelves in his office. He didn't care much to discuss the financial and legal aspects of this story, but when the subject turned to the science, Carter's eyes lit up with boyish enthusiasm.
He got his doctorate at the University of California-Davis in 1974, where he studied how cells bind to each other, or cell adhesion. After a yearlong fellowship in Israel, he joined the Hutch as a postdoc, shortly after it was founded in 1975. Specifically, he wanted to learn more about the adhesion properties of epithelial cells, those that form linings or boundaries between tissues like skin or other organs. He was interested in these cells because they are involved in most adult cancers.
Those cells remain in a non-active state most of the time, but can become highly activated in the case of an injury, Carter says. For example, when a person falls off a bicycle and scrapes a knee, these epithelial cells leap into action. The cells work to close the wound, secrete proteins that trigger an immune system reaction that mop up all the foreign invaders like bacteria. Other cells, platelets, pour in to the area to form clots.
"Everything is moving in that area to cope with disaster," Carter says.
This whole process requires big-time changes in cell adhesion properties. By the early to late 1980s, when Carter was pursuing this work on the third floor of Eklind Hall (an old building on Seattle's First Hill that Xconomy Seattle proudly calls home today), scientists knew very little about this cell adhesion process or the proteins on the surface of cells. "None of the components were known," Carter says.
One way to identify these components was to develop targeted antibodies that would bind with and block receptors ..s. Carter and his colleagues found GP-140, a new type of protein. This was important because it led to the development of methods to identify more adhesion receptors on the surface of cells, and what they interact with. It was the spark that set Carter and his lab partner Elizabeth Wayner off to the races for the next five years. "We said let's hunt for different adhesion receptors" ..s, which could serve as new antibody drug targets.
Wayner was one of the scientists who came into Carter's lab as an immunology postdoc. The biggest step ahead for these two was when they made antibodies that identified a new cell surface receptor called alpha4 beta1. Wayner and Carter, in a paper in 1989 in the Journal of Cell Biology, identified one antibody in particular called P4C2 that they said "completely inhibited" binding to this target. It's now the target—today called an integrin—which is hit by the natalizumab (Tysabri) antibody.
Carter and Wayner's work later veered in different directions.
He looked more at epithelial biology and at triggers that control migration of epithelial cells, which play a role in 80 percent of cancers, Carter says. Wayner focused more on integrins, and blocking killer T cells from binding with them.
This integrin work appears to have more broad application than just with multiple sclerosis. The Biogen and Elan drug is FDA-approved for Crohn's disease, an inflammatory condition of the large intestine, and is in clinical trials for multiple myeloma, a deadly cancer of the bone marrow.
The intellectual property never turned into the basis for a standalone biotech company in Seattle, although it was licensed for a time to a small startup called Oncogen. That company ultimately went out of business and handed the integrin-based intellectual property back to the Hutch, Carter says. Eventually, the IP got into the hands of Elan, which formed a partnership to co-develop and co-market the drug with Biogen in August 2000.
This treatment was approved by the FDA in November 2004 as the first of its kind to stop inflammatory white blood cells from migrating across the blood brain barrier and attacking the fatty coating around nerve cells in the brain. It showed it could reduce the risk of MS flare-ups by two-thirds compared to a placebo—about twice as effective as the standard immune-suppressing interferon beta drugs.
But three months later, Biogen and Elan yanked it off the market after two patients were found to have PML. After protests from patients, the drug was re-introduced in July 2006; the FDA determined the benefit outweighed the risk. The drug generated $343 million in sales last year, and is now being taken by about 35,000 patients worldwide. It is projected to generate $1.6 billion in sales in 2011, according to Christopher Raymond, an analyst with Robert W. Baird in Chicago.
This all means a lot today to "The Hutch." The patent, licensed to Elan, covers methods of using an antibody drug against the alpha4 integrin, a protein on the surface of white blood cells that the drug hits. The patent was issued in March 1998 and lasts until 2015, says Ulrich Mueller, the center's vice president of industry relations and technology transfer. The Hutch isn't saying what percentage royalty it gets on sales because of a confidentiality agreement, although it's common in the industry for such licenses to be worth 1 percent of sales. (If it's truly generating a 1 percent royalty on a $1 billion-a-year drug, that means the Hutch could collect $10 million annually in royalties. Assuming no more PML cases damage the drug, it could be a serious boost for the organization, which generated $3.4 million in total licensing income in fiscal 2006, according to a survey by the Association of University Technology Managers.)
Carter wasn't around for all that development work—it's not the job of a scientist who's trying to explore new frontiers. These days, he's studying integrins for their role in facilitating the spread of cancer cells. If you could shut down this process, you might be able to stop tumors from spreading. That's what gets him excited now. "When you stop creating, you're not a scientist anymore," he says.
Still, Carter follows the news on natalizumab's ups and downs, and is clearly proud to have played a part in making this new medicine.
He's careful not to take too much credit for the years of work that ultimately made it into a marketed product. "I'm glad that a company had the foresight and the commitment to carry this to the market," Carter says. "To take a research tool and turn it into useful pharmaceutical, that's a big gamble." He adds that while in the midst of the work to identify integrins, he never foresaw how this basic science would be translated into such a big new drug. "We were pretty much clueless that it would have any clinical value," he says.