Whether taking an over-the-counter medication for an allergy or receiving chemotherapy to combat cancer, for most of us the question of where the drugs we take come from rarely arises. But it is a fascinating one. Indeed, the tale of Bexxar provides a remarkable case study of the process. Bexxar (tositumomab and iodine I131 tositumomab) a radioactive monoclonal antibody treatment for low-grade or follicular non-HodgkinÕs lymphoma (NHL), received FDA approval on June 30, 2003. Simply put, Bexxar began at the U-M Cancer Center with an idea, which was tested, proven, accepted, produced and is now available. But of course, no story is that simple in science, medicine, government or business.

The notion of attacking a cancerous cell with a man-made or 'monoclonal' antibody (see How Does Bexxar Work?) was not new in the late 1980s, when U-M doctors Mark Kaminski (now co-director of the Leukemia/Lymphoma/Bone Marrow Transplant Program at the Cancer Center) and Richard Wahl (now chair of nuclear medicine at Johns Hopkins University Medical Center), began to apply this approach to lymphoma. Many scientists had been experimenting with monoclonal antibodies since the mid 1970s. The method showed potential to treat cancer because, unlike chemotherapy, it was more discriminatory in the cells it attacked, thus promising fewer side effects. For several years, trials had been ongoing in various cancers including lymphoma, but the outcomes had been disappointing. By the close of the decade, this avenue of research was felt to be less fruitful than other approaches.

"Perhaps we were na•ve," says Kaminski in retrospect, "but we didn't want to give up on monoclonal antibodies. We persisted in trying different approaches. "We treated our first patient in April, 1990," remembers Kaminski. "The trial was designed to determine potential safe doses and to further explore the best ways to deliver the antibody, as well as to assess potential side effects. But because of the skepticism about antibody treatments in general -- let alone one containing a radiolabel too -- accruing patients to the trial was very slow. Doctors -- even our own colleagues -- were difficult to convince. What drove our progress were the patients -- those who had run out of options and had heard about our trial."

Although word of mouth helped spread the news about the trial, it wasn't until preliminary findings were published in the New England Journal of Medicine in 1993 that the floodgates opened. Those early outcomes, based on only 10 patients, were promising beyond any expectations. Perhaps science had closed the book too soon on monoclonal antibody research.

Recalling that first trial, Kaminski tells of the astonishing results -- including a complete response in 4 of the 10 patients -- and of how it felt to experience this alongside his fellow scientists and the patients. "We were absolutely delighted, of course. I remember standing in the lab with Dr. Wahl looking at a CT scan of Patient #4. This gentleman had a 1-kilogram mass in his abdomen. That's bigger than a 48-ounce steak -- and it had disappeared. We had never seen anything like that. We just sort of looked at each other and nodded; we knew we were seeing something very special. It was just so . . . cool . . . and so exciting!"

To keep going meant accruing more patients to the study, and making further refinements in the dosing. But the initial idea remained unchanged, and the results from the initial patients were sufficient for the filing of a patent by Drs. Kaminski and Wahl, the U-M, and Coulter Corporation. The pharmaceutical companies Corixa and GlaxoSmithKline have since acquired Bexxar for commercial launch.

To determine the optimal regimen and which patients would gain the most benefit from Bexxar, the team now needed a trial at multiple cancer centers. That wouldn't happen until 1996.

To produce enough Bexxar of a therapeutic grade to conduct such a large trial, the story becomes one not only of science and medicine, but of business and finance. Venture capital, factory specifications, quality assurance, every aspect had to come together to give the U-M team the "critical mass" to proceed to a multi-center trial. That pivotal trial, completed in 1998, showed that 50% of patients no longer responding to chemotherapy were helped by Bexxar, with 20% of those patients showing complete remission. At last, with time, patience and reams of data, it was proven that what was accomplished in Ann Arbor could be replicated elsewhere.

Throughout the process, the U-M/pharmaceutical company partnership had been interacting with the Food and Drug Administration (FDA) who would ultimately hold the key to Bexxar's public availability. Detailed reporting, clinical trial design and oversight were essential to ensure that the treatment would eventually be accepted for marketing to the thousands stricken with low-grade NHL [see How Many Patients will be Helped?].

Still more trials followed, along with considerable delays at the FDA. As a result, Bexxar became a lightning rod for patient advocates lobbying the FDA for more streamlined processes to bring cancer-fighting drugs to market faster. To hear Mark Kaminski recount the story, it's clear that the final years were not without frustration. But it is equally obvious that he can find positives even when describing the most wearisome stages of the journey. "All along, the satisfaction of working with this treatment has been in helping those that no one has been able to help previously. All of the patients who participated in the trials are truly heroes. But some went above and beyond to advocate for getting the drug approved -- even traveling at their own expense to Washington to testify before an FDA committee. What a tremendous sacrifice on top of what cancer had already taken from them."

For Kaminski and the lymphoma team at the U-M Cancer Center, shepherding Bexxar from an infant idea "out of the nest" is something to celebrate, but only for a moment.

"U-M has now shown a track record of getting a drug all the way down the line. It can be done and we're one of the leaders, but we're not standing still." When it comes to Bexxar, trials are ongoing -- with very promising indications -- to assess Bexxar's usefulness as a first-line treatment (beyond its current approval as a treatment only after other alternatives have failed). And numerous other approaches follow in its path.

"The great thing is that Bexxar isn't the end of the story," says Kaminski. "The future is looking incredibly bright. When a lymphoma patient comes to me and says 'my doctor just told me that I have an incurable disease,' I tell them 'don't give up. A new treatment available may actually cure them and we don't yet know it because it takes a long time. Along the way there are lots of new treatments that are extremely promising.'" Based on his experience with Bexxar, Kaminski's enthusiasm about what clinical trials at the U-M Cancer Center provide patients is clear. "They're offered hope beyond what they've ever expected. Never say never."

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