Tysabri article from today's WSJ

A board to discuss the newly-released drug Tysabri, (formerly known as Antegren) as a treatment for Multiple Sclerosis

Tysabri article from today's WSJ

Postby Brownsfan » Fri Feb 24, 2006 7:06 am

Tricky FDA Debate:
Should a Risky Drug
Be Approved Again?

By ANNA WILDE MATHEWS and SYLVIA PAGÁN WESTPHAL
February 24, 2006; Page B1

Next month, Food and Drug Administration advisers will take up one of the most difficult questions the agency ever faces: Should a promising drug that carries a known and deadly side effect still be allowed on the market?

Tysabri was seen as a life-changing drug for the nation's 400,000 multiple-sclerosis patients and a potential blockbuster for its makers, Biogen Idec Inc. and Elan Corp. But last February, it was abruptly withdrawn after being linked to a rare but often fatal brain infection called progressive multifocal leukoencephalopathy, or PML. Two patients died of the condition, while a third survived but was significantly impaired and no longer able to work.

Now the companies hope to convince an FDA advisory committee, and the agency itself, that Tysabri should be back on the market. A two-day meeting set for March 7 and 8 will focus on whether the drug should return -- and what limits should be set on its use if it does.


The meeting also will provide the latest setting for debate over how the FDA should balance medicines' efficacy and safety. On one side, the FDA generally weighs the seriousness of the condition involved, the effectiveness of the drug and whether there are alternative medications. On the other side, the agency evaluates the frequency and severity of side effects and whether they can be easily detected, prevented or cured. The FDA also considers whether a drug's label warnings are sufficient, or whether other restrictions are needed, a tack that has become increasingly common during the past several years.

Sometimes, "a considerable toxicity is acceptable because the benefit of the drug is great, and you try to minimize the harm to people," says Robert Temple, director of the FDA's office of medical policy. The agency last week signaled that it believes Tysabri holds value for at least some patients by ending a freeze on Biogen's clinical trials of the drug. "We consider MS a very serious disease, and people might take risks to get an effective treatment," Dr. Temple says.

Dr. Temple says that "every case is different." In treatments for certain conditions, such as cancer, possible deadly side effects are accepted. "You have to use those kinds of remedies to get any effect at all," he says. By contrast, the arthritis pain treated by Merck & Co.'s withdrawn Vioxx isn't seen as a life-threatening condition for most people.

The FDA is believed to have allowed only one drug -- GlaxoSmithKline PLC's Lotronex -- back on the market after being withdrawn for safety reasons. The medication, a treatment for irritable bowel syndrome, was reintroduced in 2002 after being recalled in 2000 after reports of intestinal problems that led to a few deaths. Some patients pushed hard for the drug's return because they felt they had no alternative treatments. The FDA imposed significant restrictions: Lotronex can be prescribed only by doctors enrolled in a special program, and patients must sign consent forms.

Because it showed powerful effectiveness in treating MS, Tysabri also has strong backing from a vocal group of MS patients. "Frankly, I'm willing to take the chance," says Marcy Canavan, an Accokeek, Md., retiree who plans to speak at the FDA committee meeting. Ms. Canavan, who says she has no ties to Biogen or Elan, was scheduled to start on Tysabri before it was withdrawn. She believes the drug will help ease worsening MS symptoms that include walking difficulties. Other symptoms of MS can include vision problems and numbness, but most people with the disease have a normal or almost-normal life expectancy.

Tysabri won accelerated approval from the FDA in November 2004. One trial had shown that the drug reduced the rate of MS relapses, or flare-ups, by 66%. Just three months later, however, the companies suspended sales of Tysabri. All three cases of PML occurred in clinical trials -- two in MS patients and a third in a patient with Crohn's disease, an intestinal illness. About 3,000 people had taken Tysabri through studies.

James Mullen, chief executive of Biogen, says if the drug comes back the company will "strongly warn" about the brain infection, although he declined to provide specifics because he says those details likely would be worked out with the FDA next month. "We are not telling people that we think we solved it and that we are not going to see it," he says.

Among the issues confronting the FDA: Is Tysabri appropriate for all MS patients or should it be limited to those who haven't gotten results from other treatments? Should people get it only when their MS is advanced? Biogen says Tysabri should be available for a broad spectrum of patients. Some neurologists have told the company that they may still prescribe it for newly diagnosed MS patients, because of the drug's superior efficacy.

Other doctors say they would use it only for advanced MS. "The risk is not acceptable" for MS patients with mild forms of the disease, says Annette Langer-Gould, a neurologist at Stanford University who treated one of the Tysabri PML patients.

Another question will be whether Tysabri poses a danger only when combined with other medicines that damp the immune system. Mr. Mullen says Biogen will likely "caution against" using Tysabri with other such drugs. Two of the cases of PML occurred in people taking another immune-suppressive drug, while the third had previously taken such medicines.

Though doctors can't tell in advance which patients may be prone to developing PML, Biogen is likely to argue that the condition's worst effects can be headed off. If doctors intervene early to treat signs of PML, "the outcomes can be pretty good," Mr. Mullen says.

But committee members may question how much of PML's impact can truly be prevented, and whether physicians will be able to easily separate its early symptoms from those of MS itself. "Maybe you can slow or partially arrest the disease," says Jerry Wolinsky, a professor at the University of Texas in Houston, but "once it's active in your brain, you're probably in trouble." Dr. Wolinsky has consulted for Elan and Biogen.

The committee and the FDA also will focus on whether, if Tysabri is allowed back on the market, its use should be restricted beyond the warnings on the label. Two drugs that cause birth defects, acne treatment Accutane and thalidomide, or Thalomid, approved for use in leprosy, have very tough restrictions. For example, women taking Accutane must take a pregnancy test each month, with a negative result, and use two forms of birth control. The FDA has said that in both cases the serious risks merited the stiff restrictions.

Write to Anna Wilde Mathews at anna.mathews@wsj.com
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Re: Tysabri article from today's WSJ

Postby HarryZ » Fri Feb 24, 2006 12:06 pm

Because it showed powerful effectiveness in treating MS, Tysabri also has strong backing from a vocal group of MS patients.


In reading another MS Forum, this info was taken from the Affirm Trial...

"In addition, natalizumab reduced disability progression as measured by change from baseline in MSFC (P<0.0001), the percentage of patients who reached an EDSS of 4.0 (5% vs. 13%; P<0.0001) or an EDSS of 6.0 (2% vs. 6%; P=0.002), and mean (standard deviation) change in EDSS (0.04 +- 0.86 vs. 0.41 +- 1.09; P<0.0001). "

Sifting through all the numbers and using the EDSS numbers in this trial (EDSS being the holy grail of measuring the effectiveness of a MS medication) the difference between Tysabri patients and placebo users was .1, (4.0 - 4.1) hardly what I would call "powerful effectiveness"

There is simply too much unknown about this drug to have it used in mass by MS patients. I sure hope that great care is taken by everyone when Tysabri gets re-approved.

Harry
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Postby Bucks » Fri Feb 24, 2006 2:05 pm

Sifting through all the numbers and using the EDSS numbers in this trial (EDSS being the holy grail of measuring the effectiveness of a MS medication) the difference between Tysabri patients and placebo users was .1, (4.0 - 4.1) hardly what I would call "powerful effectiveness"


How are you coming up with 0.1? Your quote shows after 2 years the average EDSS progression score increase for Tysabri users was 0.04 and 0.41 for placebo users. That's a 90% improvement.[/quote]
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Postby HarryZ » Fri Feb 24, 2006 9:48 pm

How are you coming up with 0.1? Your quote shows after 2 years the average EDSS progression score increase for Tysabri users was 0.04 and 0.41 for placebo users. That's a 90% improvement.


Oops...that's what happens when you rush to complete a message and place the decimal point in the wrong place....the standard deviation between the Tysabri users and placebo group was .040 to .041. The writer in the other MS Forum correctly stated that the statistical difference in these two groups was minimally better as trials go.

Although Tysabri shows a better efficacy than the CRABs, the overall perception that Tysabri is far superior to those drugs is not correct....at least not at this point in time. Don't forget that Tysabri was used on MS patients who had mild levels of the disease and thus when compared to the placebo group in the EDSS levels, there wasn't much difference in this area. Biogen/Elan have continued to highlight the reduction in lesions and reduction in risk of progression, but that doesn't mean much if the EDSS level changes compared to placebo was so small.

Harry
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Postby HarryZ » Sat Feb 25, 2006 10:01 pm

Bucks,

After reading this latest article, I think I would be far more concerned about long term Tysabri use than EDSS differentials!

Harry

___________________


S32.001] Immune Surveillance in Multiple Sclerosis Patients Treated with Natalizumab

Olaf Stuve, Christina Marra, Keith R. Jerome, Linda Cook, Seattle, WA, Petra D. Cravens, Sabine Cepok, Elliot Frohman, Ted Phillips, Gabriele Arendt, Dusseldorf, Germany, Bernhard Hemmer, Marburg, Germany, Nancy Monson, Michael K. Racke, Dallas, TX

OBJECTIVE: To test whether treatment of multiple sclerosis (MS) with natalizumab, an antibody against VLA-4, interferes with central nervous system immune surveillance, leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood (PB).

BACKGROUND: Natalizumab was recently associated with development of progressive multifocal leukoencephalopathy (PML), a demyelinating disorder of the CNS caused by JC virus (JCV) infection.

DESIGN/METHODS: Cell numbers and cellular phenotypes in CSF and blood were analyzed in MS patients treated with natalizumab, untreated MS patients, patients with other neurological disease (OND), and HIV-infected patients. JCV DNA in the CSF and PB of these patient cohorts was quantified by kinetic PCR.

RESULTS: CSF total leukocyte counts, CD4+ and CD8+ T cells, CD19+ B cells and CD138+ plasma cells were significantly lower in natalizumab-treated MS patients compared with OND patients and untreated MS patients.

Natalizumab therapy decreased the CD4:CD8 ratio in the CSF to levels similar to that of HIV-infected patients.

JCV DNA was not detected in natalizumab-treated patients. Six months after cessation of therapy, low lymphocyte counts in the CSF persisted, whereas the CD4:CD8 ratio normalized. The patient with the highest total leukocyte, CD4+ and CD8+T cell counts in the CSF experienced a clinical relapse.

CONCLUSIONS/RELEVANCE: These data suggest that a low CSF CD4:CD8 ratio in natalizumab-treated patients may confer an increased risk of developing PML in these patients.
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Postby Bucks » Sun Feb 26, 2006 3:42 pm

Thanks for posting that Harry. I saw this abstract also on the AAN website. We already know that Tysabri contributed to PML deaths. I don't know what new information this reveals to cause additional concern. Do you?

The low counts 6 months after stopping therapy sounds negative but that contrasts with the fact that the person with the highest raise in counts had a relapse. Also, if the CD4:CD8 ratio was similar to that of HIV-infected patients can it be inferred that the incidence of PML would be similar? Being able to quantify the risk would be a good thing.

I guess I need to have this explained to me in laymen’s terms. I am glad to see more detailed analysis being released.
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Postby HarryZ » Sun Feb 26, 2006 6:07 pm

Bucks,

Bucks wrote:Thanks for posting that Harry. I saw this abstract also on the AAN website. We already know that Tysabri contributed to PML deaths. I don't know what new information this reveals to cause additional concern. Do you?


Well, the docs figure that Tysabri contributed to the PML but nobody seems to know yet as to just what extent and what mechanism is responsible. This is the first study that I have read where they have actually looked into the blood analysis of the Tysabri patients with regard as to what may be happening.

The low counts 6 months after stopping therapy sounds negative but that contrasts with the fact that the person with the highest raise in counts had a relapse. Also, if the CD4:CD8 ratio was similar to that of HIV-infected patients can it be inferred that the incidence of PML would be similar? Being able to quantify the risk would be a good thing.


That's a good question without an answer as yet. I doubt that the incidence of PML would be that high but nobody really knows for sure. That's my main concern with Biogen/Elan....how they rushed this drug into the market with all its potential dangers and little time spent on looking at this in detail

I guess I need to have this explained to me in laymen’s terms. I am glad to see more detailed analysis being released.


I think what they are saying is that they know the CD4:CD8 ratio is what they see in HIV patients and it's similar to what they found with Tysabri users in this study. That would lead them to the conclusion that there is a very distinct possibility of Tysabri opening up the possibility of MS patients developing PML. But until they can scientifically prove that kind of correlation, no researcher on earth would write that in stone. You will see words like "may" and "perhaps"and "possibly" being used. At least they are learning a lot more about Tysabri and PML and hopefully in the not too distant future will be able to tell MS patients the risks involved with using the drug.

Harry
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Postby bromley » Mon Feb 27, 2006 3:42 am

Harry Z,

Thanks for your Tysabri posts.

As I have noted before, one of the MS neuros I am in contact with considers that Tysabri is better than the current DMDs but the risks have not been fully defined. His advice was to wait. He wasn't too impressed with the paper produced by Dr Chaudri on Tysabri. It does look like opportunistic publishing given what's going on at the moment.

One question - what would you do if you came across material showing that Tysabri was very effective and that the risk were low? Would you post?

A number of us have clubbed together and have raised enough money to send you on a cruise next week. The catch - the ship has no TV, internet or telephone. You'd miss the FDA conference - what do you do?

Ian

PS you know I am only joking!
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Postby HarryZ » Mon Feb 27, 2006 6:36 am

Ian,

He wasn't too impressed with the paper produced by Dr Chaudri on Tysabri. It does look like opportunistic publishing given what's going on at the moment.


That paper by Chaudri doesn't surprise me. He has long been an opponent of the current thinking on MS along with the approved medications used to treat it. He is more or less partners with Dr. P.O. Behan who wrote that Pathogenesis of MS paper which attacks the years of abysmal results in MS research.

One question - what would you do if you came across material showing that Tysabri was very effective and that the risk were low? Would you post?


I wouldn't have to because there would be about 1/2 dozen other readers on this and other forums who would be doing this long before me and ensuring that I was aware of their post :)

A number of us have clubbed together and have raised enough money to send you on a cruise next week. The catch - the ship has no TV, internet or telephone. You'd miss the FDA conference - what do you do?


Likely take along a crate of carrier pigeons capable of long distance flying that would be trained to deliver me only messages that dealt with Tysabri :D

Harry
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Postby bromley » Mon Feb 27, 2006 9:16 am

Harry,

With the bird flu sweeping across Asia and Europe, your pigeons won't survive long.

Biogen are after healthy volunteers to test a more potent version of Tysabri and I've put your name forward.

I think you're one of those drug taking LSD type hippies from the 1970s and your desperate to get on Tysabri to re-live your old days.

Ian
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Postby HarryZ » Mon Feb 27, 2006 6:29 pm

Ian,

With the bird flu sweeping across Asia and Europe, your pigeons won't survive long.


The cruise is in the Caribbean and the bird flu hasn't reached there yet!

Biogen are after healthy volunteers to test a more potent version of Tysabri and I've put your name forward.


Gee...it's really nice to have friends in this world...who would offer to give you a medication that could place you into the "next" world :)

I think you're one of those drug taking LSD type hippies from the 1970s and your desperate to get on Tysabri to re-live your old days.


Heh, heh, heh....I just love that dry British humour :D

Harry
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