Tysabri Clinical Trial - Woman Misdiagnosed With MS Dies

It's always about money. Despite an annual cost of $23,500, initial sales of Tysabri were booming. As a once-a-month drug administered by a doctor, it received fast-track approval in late 2004. When it was withdrawn from the market 3 months later, 5,000 patients were on it and 15,000 more were awaiting insurance verification for the first dose.

Biogen Idec, of Cambridge, MA, and Elan, in Dublin, Ireland, viewed their new product as a potential blockbuster. The companies needed just 20,000 patients to break even, according to the February 18, 2006 LA Times.

And Wall Street projected yearly sales to one day reach $3 billion.

However, the rosy financial projections went up in smoke in February 2005, when the drug makers suddenly withdrew Tysabri from the market after 5 patients contracted a rare brain disease called PML, short for Progressive Multifocal Leukoencephalophy.

In reaction to the news, Biogen stock dropped 43% and Elan shares plunged 70%, according to the LA Times. The drug makers are currently awaiting a decision by the FDA on their request to allow Tysabri back on the market which is expected to come after hearings are held in March 2006.

The most frequently reported other adverse events in the Tysabri clinical trials, overshadowed by the reports of PML, are listed by the FDA to include infections, severe or life threatening allergic reactions, depression (including thoughts of suicide), and gallbladder problems.

"These events occurred at rates ranging from 0.8% to 2.1%," the agency said.

MS is a brain disease which can lead to muscle weakness, difficulty concentrating, slurred speech and paralysis. About 400,000 Americans and 2.5 million people worldwide are believed to be affected by MS. It is more common in women than men and usually strikes between the ages of 20 and 50, according to the Multiple Sclerosis Society, The disease causes the body's immune system to rebel, by attacking, inflaming and damaging its own nerve tissue.

Anita Smith, a patient enrolled in the Tysabri study for treatment of MS, died from PML, and another patient taking Tysabri for Crohn's disease also died of PML.

According to WebMD Medical News, "PML is a progressive disease of the brain and spinal cord that primarily affects people with weakened immune systems."

"The condition is caused by a virus that destroys the sheath that covers the nerves," it said. "Symptoms include mental deterioration, vision loss, speech disturbances, and movement abnormities or paralysis," WebMD reports.

A March 2, 2005, article by Forbes.com titled, "The Virus That Took Down Tysabri," explains how a specific virus causes the development of PML.

The JC virus discovered in 1971, was named with the initials of the patient in whom it was found. The virus is present in almost everyone, according to the article, but only destroys the brain when something damages the immune system and allows the virus to run rampant.

By suppressing the immune system, Forbes says, Tysabri allows the JC virus, ordinarily latent in a patient's kidney, to travel to the brain via the bloodstream, where it begins uncontrolled replication.

"Since the first description of the disease in 1958, it had remained a rare occurrence," Forbes said, "seen mostly in organ transplant patients whose immune systems were suppressed by drugs." About 5% of people with full-blown AIDS also develop PML

On February 25, 2006, in a new development, News Infirno.com announced a major court ruling in Massachusetts in a wrongful death action filed on behalf of the estate of the 46-year-old wife and mother of two, Anita Smith, that ordered Biogen to produce all medical records on Ms Smith immediately.

It seems that although she had been diagnosed and treated for MS, an autopsy revealed that Ms Smith never had MS, thereby making her enrollment in the trial problematic at best, News Inferno reported.

The allegations in the lawsuit complaint contain a number of interesting facts. In February 2000, Anita Smith was diagnosed with MS and her neurologist began treating her with Avonex, another MS drug manufactured by Biogen.

In April 2002, she was enrolled in a clinical trial and began receiving Tysabri in addition to Avonex. During her treatment with Trysabri, she received thirty IV infusions beginning on April 12, 2002 and ending in January 2005.

Tysabri received fast-track FDA approval in November 2004, the same month that Ms Smith began to suffer severe neurological problems.

She was hospitalized on February 12, 2005, when diagnosed with PML, and died on February 24, 2005. Sales of Tysabri were suspended on February 28, 2005.

An autopsy confirmed that Anita Smith died of PML.

Based on animal and other studies, some of the scientists who developed Tysabri concluded as far back as 1992, that it was far too dangerous for use in humans. Dr Lawrence Steinman, a professor of neurology at Stanford University who participated in an animal study that led to the development of Tysabri, told the New York Times on March 1, 2005, that the FDA should not have approved the drug based on one year's data.

He said the risk of serious infections like PML was "unfortunately logical" given that Tysabri works by interfering with the immune system.

"I'm shocked that it happened so soon," he told he Times, "but I knew it was going to happen sooner or later."

Critic say the Anita Smith case highlights the problems with the way MS drugs are being tested.

"In recent years," the February 18, 2006 LA Times said, "drug companies have been trying out medicines on people with mild symptoms or none at all at the time of treatment, several experts say, including some who, like Smith, might not have the disease."

Ms Smith was diagnosed with MS after a bout of weakness in her right leg, followed by blurred vision. "Although the symptoms disappeared," the LA Times said, "she started taking injections of Avonex."

In fact, most of the 1,171 patients in Ms Smith's trial suffered no disabilities, according to FDA documents reviewed by the Times.

These trials broadened the market for MS drugs but, critics say, put patients who don't need powerful new medicines at risk.

Dr Steinman and another Stanford neurologist, Dr Annette Langer-Gould, have urged the FDA to tighten criteria for selecting patients for MS drug trials.

Dr Langer-Gould explained how Biogen lead the push toward earlier treatment of MS with a study on Avonex 6 years ago in patients who did not meet the clinical definition of MS in effect at the time.

"Although the trial, which showed that Avonex could delay relapses, benefited patients because it led to earlier treatment," she told the Times, "it also benefited Biogen Idec by expanding the market for Avonex."

Dr Langer-Gould said the study did not raise concerns because the drug was already on the market and considered safe. But she told the Times that she worries that patients with mild cases of MS face greater risks from experimental drugs than from their illness.

"What was the rush to treat these patients?" she asked.

Dr Abhijit Chaudhuri a London neurologist, shares her concern. "Patients with mild MS and who are fairly stable generally don't get that bad," he told the Times. "Why on Earth would you go into a treatment trial with the possibility of side effects and complications when you don't expect to get much worse?"

Dr Steinman agreed. "People with no active disease - in other words, people who are doing fine - shouldn't be given an experimental drug with unknown risks," he told the Times.

In addition to the unnecessary risks associated with the MS drugs, they are extremely expensive and patients who believe they need the drugs are in effect being bribed into recruitment for the clinical trials.

Although Ms Smith's insurance covered some of the cost of the drugs she was led to believe she needed, the couple still had to pay about $1,000 a month, her husband told the Times.

He said the motivation for entering the Tysabri trial was largely financial, because the neurologist told the couple that as a trial participant, Ms Smith could receive the Avonex for free.

If true, the revelation of the money trail involved in this trade-off may turn out to be the show stopper in the eyes of the jury.

According to the lawsuit's complaint, when Ms Smith's neurologist misdiagnosed her with MS, and recruited her for the study, the doctor was being paid for serving as an "Investigator" in the Tysabri clinical trial.