Pulling of MS drug calls FDA actions into question
By Raja Mishra and Jeffrey Krasner, Globe Staff | March 6, 2005
Anna Peabody's dreams of motherhood and marriage -- and merely walking upright -- came alive with the arrival of Tysabri.
Multiple sclerosis patients such as she had waited years for the drug, the first promising treatment in nearly a decade. Early last year, Cambridge biotech giant Biogen Idec Inc. said Tysabri warded off MS more powerfully than even the most optimistic predictions. Peabody, 19, thought the drug ''would change everything."
Just one year of data from test patients was enough to wow federal regulators. They approved Tysabri a year ahead of schedule, without public discussion or debate, and before planned clinical tests were completed. But there were concerns: Some scientists thought the drug would leave patients vulnerable to deadly infections.
At the time, Biogen Idec's vice president of medical research, Al Sandrock, declared: ''No multiple sclerosis drug currently on the market has been approved with less than two years worth of data."
But in a tragic flash, it all unraveled. Two test patients contracted a rare infection. One died. Last week, Biogen Idec and its partner, Elan Corp., pulled the drug from the market.
Tysabri's precipitous rise and fall has called into question the FDA's decision to quickly and quietly approve a potentially risky drug, criticism that comes on the heels of recent controversies over its handling of painkillers and antidepressant drugs.
''They should take as much time as they need to make sure the drugs are safe and effective," said Arthur Levin, director of the Center for Medical Consumers, an advocacy group. Quick approval, he said, ''increases the risk that we're going to discover really serious threats to the public health later on after a drug has been approved."
About 5,000 patients around the nation took Tysabri after its approval last November -- and may have been unknowingly exposed to infection risks. Biogen Idec has mounted a wide-ranging reexamination of its test patients to determine the full extent of the drug's risks. But it is an effort fraught with uncertainty: Some neurology specialists question if the drug can ever be declared safe.
The drug's troubles have also jeopardized the fortunes of a local corporate powerhouse, the biggest biotech company in the region, and the country's third largest. Biogen Idec had banked on Tysabri, and its stock surged 33 percent in just two days when early news of Tysabri's efficacy became public.
Tim Hunt, a Biogen Idec spokesman, said the company moved ''swiftly" to protect patients. ''Tysabri has demonstrated a clear benefit to patients," he said. ''Now we need to step back and learn more about any possible risks."
For patients such as Peabody, who fear the day MS will ravage their bodies and lives, the events have been unsettling -- hope delivered, then snatched away.
''It took something I was really looking forward to away from me. I was real disappointed," she said glumly. ''Real. Disappointed."
Peabody, a first-year student at Simmons College in Boston, was 15 when her hand one day went numb and her feet began tingling. An MRI scan confirmed she had multiple sclerosis.
Her illness, like that of many MS sufferers, comes and goes, in episodes she calls ''flares." There were 14 during high school. When they came she couldn't hold a pen or zip a zipper. Her vision sometimes blurred. One morning, she got out of bed and fell over. Her legs didn't work.
All the while, she was on another Biogen Idec drug, Avonex.
''It wasn't doing what it was supposed to be doing," she said.
The immune systems of MS patients such as Peabody, for reasons unknown, attack a fatty protective covering on nerves called myelin. The attacks hamper the nerves' ability to transmit signals, frazzling the body's communication network. Symptoms vary among the 400,000 US patients, ranging from limb weakness and tingling to paralysis and dementia.
Scientists do not understand why Avonex offers some patients relief. Nonetheless, Biogen introduced it in 1996, and sold $1.42 billion of the drug last year, accounting for 64.5 percent of the company's sales.
But Tysabri was different. In 1992, Stanford's Dr. Lawrence Steinman, with colleagues, found a compound that blocked errant MS-driven immune cells as they traveled to the brain to wreak havoc. It worked in animals. It was precise and elegant.
In 2000, Biogen Idec and Elan agreed to work together to bring Tysabri to market.
But Steinman and others already had doubts. Initially, he thought the drug would only block immune cells migrating to the brain, where much of the damage wrought by MS occurs. But if it blocked immune cells elsewhere in the body, that could mean trouble.
''You don't want to stop [immune cell] movement everywhere. An army unable to respond to threats is not good," said Steinman, who has stakes in two companies with other MS drugs in development. ''To me it was a no-brainer that there was a risk for opportunistic infections."
MS researchers came to understand that Tysabri's immune-disabling effects theoretically put patients at risk for bacterial, mycobacterial, and viral infections. The level of risk was unknown.
''The medical community was worried about that," said Dr. Howard L. Weiner, director of the Partners Multiple Sclerosis Center at Brigham and Women's Hospital and author of the recent book, ''Curing MS."
In February 2004, top managers from Elan and Biogen Idec gathered in the boardroom of Biogen's modest Cambridge headquarters. At 2 p.m., a video presentation of the latest Tysabri data began. At about 2:30 p.m., the celebrating began.
Preliminary results from the final stage trial of Tysabri, still not complete, were unveiled at the meeting: The drug reduced MS episode relapses by a staggering 66 percent -- twice as well as any MS drug in history.
''It was beyond what I ever dared to expect," said Dr. Lars Ekman, Elan's head of global research and development.
The trial was supposed to last two years. But the companies shared the impressive one-year data with the FDA, standard procedure in drug trials. The FDA reacted positively. Getting Tysabri quickly to market based on a single year of testing seemed achievable. The company looked as though it had another MS blockbuster on its hands.
At the FDA, scientists pored through thousands of pages of Tysabri data. The clinical tests had monitored all patients for infections, and found nothing troubling over the course of a year.
Often, on controversial and complex experimental drugs, the FDA convenes public advisory panels made up of independent experts who review data. But Tysabri, as far as the agency was concerned, was a hit. FDA officials decided against calling a public committee.
''This drug had very clear efficacy. It had large effects that reduced the number of relapses in patients . . . that's really powerful evidence," said Dr. Douglas Throckmorton, acting deputy director of FDA's Center for Drug Evaluation and Research, which approved the drug.
With every new drug, the FDA must balance risks and benefits. The more serious the illness, the greater the risk from drug side effects the FDA will accept. Most MS patients live long and productive lives, though many eventually deteriorate to a wheelchair-bound state. The FDA decided MS was serious enough to accept Tysabri's risks, which at that point were largely theoretical.
''MS is a devastating, absolutely life-stealing disease," said Throckmorton. ''This was a drug that had a larger effect on preventing relapses than had been reported before."
As the FDA neared its decision, Anna Peabody began college at her dream school, Miami University in Ohio. But within two weeks, MS returned. Peabody grew as sick as she had ever been. She came home. An MRI scan had confirmed that Avonex, which she had taken for years, no longer did her much good. But on Nov. 23, after granting Tysabri ''priority" status, the FDA approved Tysabri. Peabody -- and thousands of others -- started taking the brand-new drug.
''Everyone said it was going to change everything," she said.
On Feb. 18, Biogen Idec scientists told Dr. Burt Adelman, company executive vice president, the bad news: One Tysabri test patient had died of progressive multifocal leukoencephalopathy, or PML, a rare incurable infection mostly associated with AIDS patients with weakened immune systems. A second test patient had also acquired PML, but was still alive.
The news broke to the public last Monday, and Biogen Idec shares were pummeled, losing more than 40 percent of their value.
Peabody, enrolled at Simmons, got the bad news from her father.
''We both cried," she said. ''Of course, thank goodness I'm alive. It could have been me."
Patients all over Massachusetts and the nation -- about 5,000 people -- had started taking Tysabri. Treatment was stopped for all of them.
One MS patient, Lissa Gifford, 45, of Watertown, insists the drug helped her, enabling her to swim again, and even feel her toes for the first time in years. ''To not have Tysabri is devastating," she said. ''I've tried Avonex, I've tried chemo, I've tried bee stings, and this is absolutely the last therapy for me. Nothing else works."
Still, patients like Gifford may have been exposed to unknown risks. Biogen Idec plans to reexamine MRI scans on hundreds of other test patients, looking for early signs of PML or other serious infections. It may be that the patients taking Tysabri alone remain largely problem free; the two PML-infected patients took both Tysabri and Avonex. It may turn out that the PML cases were not at all linked to the drug. In all, about 3,000 patients participated in a variety of trials for Tysabri for both multiple sclerosis and other diseases.
But Dr. Igor J. Koralnik, a neurologist at Beth Israel Deaconess Medical Center and a PML specialist, said, ''The risks of developing PML are almost nil" for patients without immune system problems.
The drug could be reissued with a more strenuous warning label and recommendations for physicians to closely monitor those on it for infections or be reserved only for seriously ailing MS patients.
''The first critical step is to collect as much information as we can get from patients," said the FDA's Throckmorton, who acknowledged that the PML cases may signal that Tysabri may be riskier than once thought. ''Given the data we have now, does that change the risk-benefit ratio? We can't answer that now."
Weiner, who supports the FDA's decisions in the Tysabri case, said he worried that Tysabri could place patients at risk for infection as long as they take it. Tysabri's accelerated approval was based on one year of testing. Most of the patients in that experiment had been on the drug for just over two years before it was pulled last week. But, thus far, no longer-term tests have been planned.
''There's a nagging question: If people are treated for long periods of time, would something else come up?" said Weiner, adding that he would like to see an FDA advisory panel convened to discuss the matter.
Without Tysabri, Biogen Idec faces a much tougher future, with few likely blockbuster drugs in its research portfolio, and a decimated stock price making it harder to acquire other firms with promising drugs. Biogen shares closed Friday at $37.53, a one-week drop of 44 percent.
''Tysabri isn't dead, it has a pulse, but it's in intensive care," said David M. Steinberg, managing director at Deutsche Bank Securities.
Hunt, the Biogen Idec spokesman, said the firm's business fundamentals are ''excellent," as demonstrated by its 19 percent growth in revenues last year.
Anna Peabody is trying to recover from her disappointment. She wants a career and a family and an active life. But MS shadows her. It permanently disables many patients. Peabody is back on Avonex, though it's not clear if the drug works for her. And, with Tysabri's fate uncertain, she waits for the next MS drug, which could be years, even a decade, away.
''I'm sure there will be a cure in my lifetime," she said. ''Or someone else's."
Raja Mishra can be reached at rmishra@globe.com. Jeffrey Krasner can be reached at krasner@globe.com.
© Copyright 2005 The New York Times Company
|
