Fri, Mar. 25, 2005
MS patients angry over loss of drug
BY FRED TASKER
Knight Ridder Newspapers
MIAMI - (KRT) - After five tough years fighting multiple sclerosis with current drugs, Carmen Chediak had just received her first infusion of a new one, Tysabri.
She hoped it would give her more relief with fewer side effects. But in late February, Tysabri was pulled from the market. One person in a 500-patient clinical trial of Tysabri, taken in combination with another drug, had died of a rare disease called PML, which attacks brain cells. Another had contracted the usually fatal disease.
Chediak was angry the drug was pulled.
"It's an overreaction. I know they have to be cautious, but I wish they would hurry up and get it right."
She's far from alone. Tysabri was seen as a significant breakthrough for MS treatment; trials had found it nearly twice as effective in preventing relapses after two years of treatment compared with the current drugs called interferons, doctors said.
Because of that, patients and doctors are clamoring for it to be back on the market soon. "It's perfectly ludicrous," said Dr. William Sheremata, director of the MS Center at the University of Miami Miller School of Medicine, of the drug's removal. "But with product liability attorneys hiding behind every bush, there's no alternative to pulling it."
MS affects 400,000 people in the United States, primarily women between ages 20 and 40. It causes loss of muscle and bladder control, blurred vision, speech and hearing problems and fatigue. Symptoms come and go; relapses sometimes worsen, in dire cases causing death.
"For many years we have used other, more dangerous treatments for MS," said Dr. Jeffrey Horstmyer, director of the MS Center at Mercy Hospital in Miami. "Even if Tysabri has the rare side effect of PML, it's still likely safer than a lot of other things being used to treat it."
Still, Tysabri's problems are significant. The Food and Drug Administration approved Tysabri last November, before the end of its two-year clinical trial, because its benefits seemed so apparent. And 5,000 new patients nationwide were taking Tysabri.
But then a patient who had been taking Tysabri for 37 months in one of the trials died of the brain infection PML, or progressive multifocal leukoencephalopathy. Another, who had been on Tysabri for 28 months, came down with PML. Both patients had been taking Tysabri in combination with Avonex, an interferon made by Biogen Idec.
In multiple sclerosis, the body's immune system attacks the myelin, or insulation, around nerve cells in many parts of the body. When the insulation is damaged, it interferes with the brain's ability to send messages along the nerves.
Interferons, the standard treatment for MS since the 1990s, seek to inhibit the replication of the viruses that attack the myelin sheath. Tysabri was different, developed to prevent the immune system cells from passing from the bloodstream into the brain, where they could attack the myelin sheath.
PML is caused by activation of the JC virus, which exists in latent form in 80 percent of even healthy adults. When it is activated, it attacks the myelin sheath around the nerve cells, making it similar to multiple sclerosis_only more dangerous, often leading to death.
Despite the PML problems, doctors say they support Tysabri.
"Tysabri creates a 66 percent decrease in relapses after two years, compared with about 30 percent for the other drugs on the market," says Sheremata, who took part in early clinical trials of Tysabri.
"Of the 15 patients I gave it to, a significant portion showed an improvement that was unexpected," Horstmyer added. "With Tysabri, after one or two doses patients were saying their bladder function was better, their fatigue was better, their balance improved. One woman who couldn't get up for the past year said she now could stand at her kitchen sink."
Despite the concern over PML, Tysabri's makers, Elan Pharmaceuticals and Biogen didn't pull the plug on the drug altogether. Three weeks ago they announced a "voluntary suspension of marketing" and a "pause in clinical tests."
The FDA concurred. The two drug companies, with help from outside experts, will continue to study patients who took Tysabri in the clinical trials and in the general population. The FDA is doing its own study. Neither will say when a conclusion might be reached.
Nicholas LaRocca, director of policy research with the National Multiple Sclerosis Society, said Tysabri's problems were so unexpected, he was not surprised the drug was suspended.
"We need to know what happened and why," he said. But he added: "Within months they should know enough to gauge the risks and benefits of bringing it back."
One possibility would be to bring it back with a strong label warning limiting its use to the most severe cases, La Rocca said.
"I expect it back on the market in a matter of months unless they find more problems," said Sheremata.
And in a conference call with drug officials, analysts, doctors, Tysabri users and the media, G. Kelly Martin, president of Elan, said that if no further cases of PML are found, he hopes Tysabri sales can resume by fall.
Biogen officials declined to comment on Tysabri's return.
Doctors stress they're not minimizing the dangers of PML.
The two Miami doctors point out that the two patients who contracted PML received both Tysabri and Avonex, an interferon also made by Biogen. And FDA statements say none of the 2,500 patients treated with Tysabri alone in another clinical trial got PML. Avonex, on the market since 1996, also never has been associated with the condition when used alone, and has not been pulled from the market.
"There was no case in which Tysabri alone was associated with PML," Sheremata said.
Paul Lammers, chief medical officer for the North American division of Switzerland's drug giant Serono International, a maker of MS drugs, speculated the combined use of Tysabri and Avonex, both of which affect the body's immune system, might have been too much. For now, Tysabri is in limbo.
"Where we stand today is where we stood before Tysabri," said Horstmyer. "We had three different interferons, plus Copaxone, plus chemotherapy."
The interferons_Avonex, by Biogen; Betaseron, by Schering; and Rebif, by Serono; all brought to the market in the 1990s, have provided significant relief, cutting the number of painful relapses in patients, slowing their progression to disability, the MS doctors say.
Still, interferons have side effects, doctors say. Common ones include flu-like symptoms; rarer ones include liver or thyroid damage, depression, suicide, miscarriages.
"The most serious side effects are fairly rare," said Horstmyer. "The more common happen more at first treatment; eventually, patients become more tolerant."
"With interferons I had horrible side effects," Chediak said. "I had to have my liver checked every couple of months. I got depressed. I had mood changes. Interferons make you feel bad. Copaxone makes you feel bad, but not as much."
Copaxone, by Teva Pharmaceuticals of Israel, is not an interferon, but a combination of amino acids that create proteins that decoy the body's immune system away from attacking the myelin sheath.
Still, Tysabri patients say they won't be satisfied until that drug is back.
"There's a young guy in my MS support group who's taking chemo, and he can barely talk," she says. "He's waiting to go on Tysabri. He says, `Carmen, this is my last hope.' "The clock is ticking," she says.
2005, The Miami Herald.
http://www.fortwayne.com/mld/newssentin ... 228547.htm