fatal flaw in Tysabri

When Anita Louise Smith enrolled in an experimental drug trial in 2002 in Colorado, she had a diagnosis of multiple

sclerosis but, no symptoms and was looking to reduce the chances of being ravaged by the disease. Last year, she

died at the age of 46 from an infection linked to the drug.

This tragedy - recounted in an article in the March 4 issue of The Lancet by two Stanford University School of

Medicine neurologists - serves as a telling case study of what can go wrong in clinical trials. In their article,

Annette Langer-Gould, MD, and Lawrence Steinman, MD, warn of the pitfalls of testing a drug with unknown side

effects in patients who would do fine without the drug.

The drug in question is natalizumab, which has the brand name of Tysabri. In November 2004, the U.S. Food and Drug

Administration fast-tracked its approval for use in multiple sclerosis patients following promising results seen

early in two clinical trials. But within months of the approval, some patients taking the drug had developed a rare

infection - progressive multifocal leukoencephalopathy, or PML - and Smith and one other patient had died.

Langer-Gould, a clinical instructor in neurology, treated a patient who was part of the clinical trial and developed

PML after taking Tysabri; the patient survived. But that experience, coupled with an examination of Smith’s case,

prompted Langer-Gould to approach Steinman about writing an article that would examine the appropriateness of

testing a drug on people with no evidence of the disease and who are not disabled at the time of the trial.

We are arguing that people with no disability should probably not enter into a clinical trial or be

recruited into clinical trials, because where is the potential benefit to them if nothing is wrong?"; said

Steinman, professor of neurology and neurological sciences and of pediatrics.

This situation represents a systemic problem, said Langer-Gould. It is not just one company

being a rogue, doing something out in left field.";

Langer-Gould and Steinman argue that if a drug has a known risk of death, it should only be used on patients who are

likely to suffer severe disability from the targeted disease - and for whom there are no other options. In other

words, those who have tried all the other available therapies. That is almost the reverse of what happened in the

Tysabri trial, which excluded the most severely affected patients.

";A big mistake was made in these trials that, in my opinion, is easily preventable,"; said

Langer-Gould. ";All they need to do is tighten up entry criteria into multiple sclerosis clinical trials and

we could avoid similar types of problems in other trials.";

Multiple sclerosis results when the immune system attacks the protective myelin sheath surrounding nerve cells,

causing them to misfire and leading to loss of motor control and possibly paralysis. Tysabri appeared to block this

effect and, after the first year of the two-year clinical trials, did not appear to cause more infections.

Steinman was involved early on in the development of the drug, publishing on its effects in 1992. Even then, he had

suspicions that the drug’s mechanism of action - blocking the entry of immune cells into the nervous system - might

also make patients more vulnerable to infections. Indeed, PML is an infection that usually affects people whose

immune systems are compromised.

";It was a shocking development that a drug that had so much promise and so many potential benefits ended up

causing two deaths and one very serious injury,"; said Steinman. ";It is kind of a cruel Greek drama,

something that may be more beneficial than anything yet developed for multiple sclerosis, but yet may be far more

dangerous than those other approved drugs.";

The FDA withdrew Tysabri only three months after its approval. The FDA is now considering re-approving the drug. On

March 7 and 8, an FDA advisory panel is meeting about the possibility of bringing back Tysabri as a single therapy

(in the trials, it was combined with another drug).

";I predict it will come back with really hellacious warnings,"; said Steinman. ";I think the

right course would be to have it undergo more testing, but I don’t think that is practical or fair to patients; they

ought to have the opportunity to decide with their physicians if they are willing to take the one in a thousand risk

of dying.";

But Steinman and Langer-Gould expressed reservations about the drug returning to the market. They noted that its

effects, while impressive, are in general not much better than what is seen with other available drugs: The risk of

relapse dropped from an average of two relapses every three years using other approved multiple sclerosis drugs to

one every three years with Tysabri.

";Do you want to expose someone to the risk of death for eliminating one relapse every three years?";

said Steinman. ";I say no.";

";I’m not sure if it is wise to re-approve it,"; added Langer-Gould. ";The question is, will the

FDA rise to the occasion and admit their mistake and try to prevent future mistakes or are they going to ignore

it?";

....

In 1988, Chris Sheridan was diagnosed with Multiple Sclerosis.

By 2005 he was completely housebound.
Today Chris walks, drives, showers and cooks for himself and no longer suffers constant shaking, trembling, chronic fatigue, double vision or slurred speech...

He now works a normal eight hour day and lives with his wife Yvonne and their two kids Jack and Saoirse.

"MS With No Fear, 20 years living With MS" is the story of Chris Sheridan and how he has learnt to control and overcome all the symptoms of MS...

• He was diagnosed with Multiple Sclerosis in 1988.
• Partially blinded in 1993.
• Slurred speech in 1998.
• Wheelchair bound in 2005.
• He made a Full amazing recovery in 2006.
  

He has learnt to counteract all the negative feelings that go with this diagnosis.

Through his own unique ability and a very special process he regained full strength in his legs and learnt to walk again.

In his book "MS With No Fear",Chris details his full story and explains just what he had to do to aid his FULL Recovery.

He hopes to help newly diagnosed people and their loved ones to come to terms with their diagnoses.