The story of Biogen Idec's (BIIB) drug Tysabri, the multiple sclerosis treatment that was just withdrawn from the market, is a cautionary tale in the benefits and perils of tinkering with the human immune system.
That system is a biological wonder. Its foot soldiers ceaselessly patrol the body, looking for invaders like bacteria or viruses, as well as for cells that might turn cancerous. It then mounts assaults on all these threats and aids in the healing of injuries.
But for reasons that still aren't well understood, the whole system can misfire, attacking the very body that it's supposed to defend. In rheumatoid arthritis, for instance, the immune system assaults the lining covering various joints in the body, causing pain, swelling, and stiffness. In type 1 diabetes, immune cells destroy insulin-producing cells in the pancreas. And in multiple sclerosis (MS), the immune system attacks the brain.
T-CELLS GONE BAD. Obviously, one way to fight autoimmune diseases is by putting a brake on misguided attacks. In MS, for example, the culprits are T-cells. Normally, T-cells are the immune system's assassins, killing invading microbes and the cells they infect. But in MS, the T-cells go bad. They travel to the brain and mount an assault on a substance called myelin, which acts as a protective sheath around nerve fibers.
The T-cells also attack oligodendrocytes, the cells that make the myelin. Once this crucial insulation is damaged or removed, electrical signals can no longer travel normally between nerve cells. The result: a whole host of symptoms, from loss of balance and muscle coordination to slurred speech and tremors.
The clever idea behind Tysabri was to collar those T-cells and keep them from mounting their deadly assault. So scientists created a molecule, known as a monoclonal antibody, that specifically targets and gloms onto those T-cells that are mobalized to attack myelin. The drug attaches to docking ports -- or receptors -- on the cells' surfaces. "The drug binds to the receptors that are 'upregulated' on active T-cells and prevents them from interacting with inflamed tissue," explains Walter Atwood, professor of biology and medicine atrown University. "That prevents the T-cell from recognizing and destroying the myelin sheath."
"HOPES DASHED." Clinical trials with Tysabri showed that the approach worked well. The drug reduced the rate of clinical relapses in MS patients by up to 66% and was slowing the development of brain lesions. But from the very beginning, the notion of blocking T-cells was troubling. If Tysabri prevents T-cells from doing their normal job, would that lead to an increase in infections? Possibly. "One of the concerns about the drug was that infection in general could be a significant side effect," says Dr. John Richert, an immunologist at Georgetown University.
That's why Biogen and the Food & Drug Administration kept a close eye on all the people getting the drug. And for a long time, the news was good. Trials showed "borderline increases in infection in the treatment group," says Richert. "But they were minuscule differences -- not enough to jump at." Adds Dr. Aaron Miller, medical director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai School of Medicine and chief medical officer of the National MS Society: "When we saw the data, we thought [infections] were not materializing as a problem."
Until recently. On Feb. 18, Biogen Idec told the FDA that one patient on Tysabri has died of a disease called progressive multifocal leukoencephalopathy (PML) and that another patient may have the same disease, which is always fatal. A few days later, the drug was withdrawn from the market. "This is horrible," says Miller. "Many, many people were eagerly awaiting the drug. Now they will have their hopes dashed. Quite possibly, the drug might never be used again."
USUALLY HARMLESS. Does Tysabri cause this terrible disease? The answer won't be known for sure until more research is done. But to experts in PML, the idea is biologically plausible. "It is too soon to blame this particular drug," says Brown University's Atwood. "But [this mechanism] is probably what is going on."
To understand why, consider what researchers know about PML, a brain-eating disorder caused by the so-called JC virus. It's so common that JC "is ubiquitous," explains Eugene O. Major, senior investigator at the National Institute of Neurological Disorders and Stroke. More than 80% of the people in the world have been infected with it.
Many, perhaps most, people never completely fight off the infection. "The general thought is that you are infected for life," says Atwood. The JC virus lurks in kidneys, lymph nodes, and bone marrow, and possibly, in the brain. No matter where it is, the virus normally does no harm.
DEADLY MULTIPLIER. But when the immune system is suppressed, bad things can happen. If it's not there already, the virus manages to get into the brain. How? It can hop a ride inside immune system cells, Major has found. "But there's no reason why it can't just freely pass into the brain in the blood," he says. In the more unlikely event that the virus is already in the brain, the suppression of the immune system allows it to become active.
Once the JC virus is in the brain and active, things turn deadly. The virus is uniquely adapted to infect one type of cell -- human oligodendrocytes. Once infected, an oligodendrocyte makes lots of copies of the virus. Then it dies, releasing those viral copies. The new viruses infect neighboring cells, which die as well. That creates dead areas -- or lesions -- in the brain, which can be seen on MRI scans.
These lesions have devastating effects. As the oligodendrocytes die, neurons lose their protective myelin. The first symptoms are mild cognitive impairments, movement disorders, visual problems, and seizures. As PML progresses, it leads to paralysis, comas, and death.
BEWILDERING TURN. The emergence of AIDS, which suppresses the immune system, has made this rare disease a little less rare. In 1979, the incidence of PML was 1 in 10 million people. By 1992, it was 1 in 100,000 to 500,000 people. Clearly, suppressing the immune system can unleash the virus and the disease. In particular, scientists have learned that high levels of antibodies against the JC virus can be found even in people who succumb to PML.
That's crucial to the Tysabri story. The immune system has two main modes of attack. It produces antibodies, which bind to invaders and neutralizes them. It also makes T-cells, which gobble up threats.
The discovery that antibodies alone don't protect against the JC virus means the cellular response of the immune system -- the T-cell part -- is vital to keeping this deadly microbe in check. Explains Major: "It's the suppression of cell-mediated immunity which allows the virus to reactivate from the sites of latency, move to the brain, and infect the oligodendrocytes." In other words, clamping down on the T-cells unleashes the deadly JC microbe.
And suppressing the T-cells is precisely what Tysabri was designed to do. So in a tragic irony, the same mechanism of action that is so beneficial in MS could be allowing a normally harmless virus to turn deadly.
"INCREDIBLY TRICKY." The connection remains to be proved, and Biogen Idec is now taking all the right steps, scientists say. "The company has been very responsible," says Georgetown's Richert. Executives immediately withdrew the drug and are putting together a panel of experts on PML to study the data.
Even if there is a link between Tysabri and the disease, it may still be possible to bring the drug back on the market. One hope is that scientists will be able to identify patients who are at risk for the PML and thus be able to target those who can take Tysabri safely. "But I'm still somewhat pessimistic," says Miller.
Either way, the overall lesson is still a sobering one. The human immune system is "incredibly tricky," says Miller. Trying to alter its action to produce a beneficial effect may have unforeseen and dangerous consequences. And the challenge for drugmakers and doctors is always to figure out how to make the benefits exceed the harm. By John Carey in Washington