I don't think we have an answer to that question yet Rex, but the following is an interesting current abstract from Archives of Neurology, October 2006:

Vol. 63 No. 10, October 2006
Arch Neurol. 2006;63:1383-1387.


Background Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an 41 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.

Objective: To test the effect of natalizumab treatment on the CD4+/CD8+ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.

Design Prospective longitudinal study.

Setting Academic and private multiple sclerosis centers.

Patients Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus–infected patients.

Main Outcome Measures CD4+ and CD8+ T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound 4 integrin on peripheral blood CD4+ and CD8+ T cells was analyzed before and after natalizumab therapy.

Results: Natalizumab therapy decreased the CSF CD4+/CD8+ ratio of patients with MS to levels similar to those of human immunodeficiency virus–infected patients. CD4+/CD8+ ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4+/CD8+ ratios normalized. The expression of unbound 4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4+ vs CD8+ T cells.

Conclusions Natalizumab treatment alters the CSF CD4+/CD8+ ratio. Lower expression of unbound 4 integrin on CD4+ T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

http://tinyurl.com/fel85

Cherie,

Results: Natalizumab therapy decreased the CSF CD4+/CD8+ ratio of patients with MS to levels similar to those of human immunodeficiency virus–infected patients.

Hmmm....not exactly what a MS patient needs!! If nothing else the PML and Tysabri association has accelerated research into this previously unknown area.

Harry

Strange, though...that Tysabri alone doesn't seem to cause PML, judging by the thousands of patients/infusions in monotherapy. The Crohn's case is rife with speculation and questionable assumptions, but based upon the huge number of safe infusions, I couldn't say that, on its own, Tysabri will "give" anyone PML. Perhaps if enough ill-advised practices are followed, PML will occur, but there seems to be little evidence (if any) that Tysabri is unsafe as a monotherapy, and I doubt the Elan/Biogen execs are gnashing their teeth and waiting for PML to resurface. A lot of good scientists signed-off on Tysabri this go-around.

JMO...

That's the problem...nobody knows what Tysabri will or won't do in the long run. Given that many MS patients have had some kind of immune altering/modulating medication in the past, using Tysabri as well appears to increase the risk of immune system complications.

This information is not new and the inventors of the drug have cautioned this problem from the beginning. Initially Tysabri was supposed to be used for new and mild cases of MS. Now it is being recommended for those patients who have not responded to the CRAB's .....the very people that would possibly be at greater risk of PML because of already using immune altering/modulating drugs.

As long as the docs monitor their Tysabri patients closely, then they hopefully will be able to avoid serious problems should PML surface.

Harry

There used to be an article on the NMSS website (can't find it at the moment) that defined their involvement in the development of Tysabri, in conjunction with Dr Larry Steinman. Dr Steinman predicted that Tysabri would run into problems many years ago, and reiterated this several times (to medical authorities) before it's release.

The following is one article I've read, in regards to his opinion:


Mar9, 2005

The news last week that the federal Food and Drug Administration was pulling the multiple sclerosis drug Tysabri from the market stunned many in the medical profession, but neurology professor Larry Steinman, MD, who developed the drug, wasn't among them.

....

Steinman said he predicted early in the drug's development that patients might suffer immunological side effects from Tysabri, which works by preventing lymphocytes, white blood cells of the immune system, from entering the brain and damaging the sheath that protects nerve cells. As the nerve cells misfire, patients suffer progressive loss of motor control and ultimately, paralysis.

Steinman and collaborators at Athena Neuroscience (later bought by Elan, the maker of the drug) had first described this novel approach in a 1992 paper in the journal Nature. They soon learned, however, that the drug was not as specific as they had hoped; it not only prevented migration of lymphocytes to the brain, but to other organs as well, such as the gut and the pancreas. With an immobilized immune system, the body would be unable to fight off disease, Steinman said.

"I was right there at the beginning, and I had a worry then because we learned that the molecule we were targeting was not a unique zip code to gain entry to the brain," said Steinman, who heads the doctoral program in immunology.

He said his biggest concern was that patients would become vulnerable to opportunistic infections. Indeed, PML is an opportunistic infection that most often affects AIDS patients, whose immune systems are compromised.

....

Steinman said he was thrilled with the trial results and began to question his own predictive powers regarding the drug's potential side effects. Nonetheless, he continued to voice his concerns at medical meetings and in scientific journals.

In June 2004 review article in Science magazine, he wrote that this approach to treatment carried "at least a theoretical concern that recipients of the therapy would become generally compromised in their ability to fight infection."

Still, the FDA was so impressed with the trial results that it approved the drug in November 2004 under an accelerated process. Analysts predicted the drug—the first new drug for M.S. in eight years—would have a $2 billion market within two years.

At the time of the drug's approval, it had only been tested in a few thousand patients, Steinman noted.

"I worried that when it becomes the blockbuster everyone expected, what would happen when we had 50,000 patient-years of experience?" he asked. "And sure enough, after only a few thousand patient-years of experience, the drug gets pulled because it causes two people to develop a horrendous disease, and one is already dead."

http://news-service.stanford.edu/new...an-030905.html

http://news-service.stanford.edu/new...is-030806.html

Cherie

I think that everyone would be well advised to to take a wait and see approach to Tysabri. I applaud the pioneers, who are on Tysabri now and pray that the long term effects are not detrimental to their health.

Let us all stay informed and proactive with our health concerns and the Drugs that Big Pharma pushes our Docs to push us PwMS to take. Let's not be to quick to jump on the band wagon, untill we're sure it's safe.

There are risks with all Meds, and we must weigh the risks against the benefits and act accordingly. What is best for us, is our first priority.

Hugs,

Not stated is the fact that Steinman had founded two companies (Neurocrine Bioscience in San Diego and Bayhill Therapeutics in Palo Alto), for which he secured millions of dollars of investor capital. Both companies are working on competitive MS drugs.

Amen......

Same thing with Crestor and Coreg - both of which I take. There is no long-term data because they're new. Still, we actually DO know what Tysabri, Crestor and Coreg will do - they will all improve the lives of those who take them.

There are now 4,500 patients enrolled in TOUCH, and 1,700 have received at least one infusion. As we get into calendar year 2007, the perceived odds of contracting PML (based upon the 3 deaths which occurred before the combo-effect was identified) will have dropped significantly.

IMO, patients should be allowed to evaluate the risks themselves. Those who, for whatever reason, would like to see Tysabri fail will predictably capitalize upon the "uncertainty" angle. Those with a real choice to make will look at tangible evidence, and they'll evaluate their own status with regard to the risk of an alternative (and less effective) treatment. Then they will make a choice, with only their own circumstances in mind...and that, IMO, is how it should be.

A lot of people thought going to the moon was too dangerous. Others determined that the risks were manageable and that they could be overcome. Three guys died early on in the program, and as with Tysabri, the program was stopped while NASA determined what measures needed to be instituted, in order to make the capsule safe. NASA then resumed the program - and the rest is history.

And then a whole shipload were lost and that's the history.

But on Tysabri, I do agree that the PwMS should be the one to make the decision after being given ALL the risks and not just the hype.

Does that statement mean that by taking Tysabri for your MS, there is a guarantee that it will help you?

Another "perceived" guarantee?

I totally agree with you in that most MS patients will make their own choice based on what they know about Tysabri or any medication. I can't imagine, though, that ANY reader here or any MS forum would like to see Tysabri fail miserably because that would only create far more suffering for the patient. And MS patients suffer enough on any one given day.

I somehow think the NASA engineers had a better idea and handle on the risks than what the docs have on Tysabri at the moment.

Harry

Don't confuse the Apollo program with the Space Shuttle. The Apollo outcome was the parallel I was drawing, and that was indeed a success.

Very little in this life is guaranteed; that doesn't mean we live underground or deny ourselves the opportunity to be well. And we both know that there certainly are those who would like to see Tysabri fail.

Certainly not anyone in this forum would rejoice in the failure of Tysabri. I hope it turns out to be a big success for us. But at this time, I still recommend caution.

I cannot imagine anyone would want Tysabri to fail, except investors who are doing stock options, and investors in competitive companies perhaps.

And the reverse is true too. That investors, and Directors of a Pharma will downplay (or even hide) information that detracts from the perception of their drug as Safe and as Effective.

Investors yes; Directors...not really. They do not hide information about drug safety - what would be the point? If a drug is unsafe, people will find out eventually, and failure to disclose adverse effects is very actionable.

In a fair world, one would think so. But look at what happened to me. Biogen was very sneaky about how they handled the recalled Avonex. And I became deathly ill from it. And attorneys told me it is not "actionable". They said it is so costly to sue a Pharma that I would have to have died or been permanently extremely damaged (like the PML patients). My damaged lungs and heart were not bad enough to warrant an atty spending money to sue Biogen. And Biogen was dishonorable and refused to pay me -- all I asked for was my lost wages. They refused.

Go back and see how Biogen handled the recall. It was a beautiful example of a company (not investors, the heads of the company) hiding information and downplaying it.

Sorry to hear about your troubles...but I don't think your experience proves that companies will withhold information about serious side-effects, especially since the trial results are disclosed in public. What CAN happen is that insiders sell their shares prior to the bad news coming out (paging Martha Stewart and Imclone!).

BTW...the attorneys don't spend the money suing Big Pharma - you do...and I think they were telling you that YOU couldn't afford the fees. Class Action suits are what usually get filed against these companies, but yours was apparently an isolated case, correct?

Anyway, best of luck.

Didn't some of the big wigs at Biogen dump some Tysabri stock, before they announced the PML deaths and stopped the sale of TY? They played it down as business as usual, but it didn't smell right.:rolleyes:

That is classic insider trading, Sally, and it's illegal. That's why Martha Stewart went to jail. If they're not in jail, then it didn't happen. Sounds like a message board legend. :)

Insiders have to register in advance to sell shares...they can't just decide on the fly to dump shares today before tomorrow's bad news comes out. I think it's 30 days.

It was all over the news at the time and they were investigating, but we never heard the outcome of the investigations. The big wigs said that it was a planned sale, but didn't have the evidence to back that up.

I guess it was swept under the rug. :confused: That rug at Biogen is starting to fray around the edges.:rolleyes:

Kingrex, your credibility is slipping!

It was big news about inside trading when the Tysabri thing happened. General Counsel of Biogen was found to have dumped his stock after hearing about the deaths, but before alerting the public. He is in trouble with the SEC and was fired becuz of his SEC problem.

In addition, SEC determined there was a large amount of stock option trading (i.e. predicting BIogen's stock would fall-- cant recall if they call that a put or a call) after the deaths and before the public was alerted to the deaths.

This is not board legend. This was all in the newspapers.

Lastly, Kingrex, it is not MY MONEY that the attys woud spend. Attys take personal injury cases like mine on a "free" basis. They fund all of the litigation up front, and then take a hefty amount of the award if they win.If they lose, they absorb the losses, not the client.

They told me that it would require large amounts of money to hire experts to examine me, examine my files, testify, and large amounts of money to combat a Pharma because Pharmas have fleets of attorneys that have tactics that make the litigation extrememly expensive. Surely you have read the book, A Civil Action, which is a similar type of lawsuit but againts W. Grace & Co. in the BOston area (their chemical company dumped the chemicals into the ground which affected the drinking water and caused cancers in young children-- I think John Travolta starred in the movie).

LOL. Biogen has a very large and very thick rug-- like any Pharma. They sure "pulled the rug out from under me". I'm hoping other Pharmas are more ethical than Biogen, but not so naive to believe it.

Kingrex,

The trial results "that the company wants you to see" are disclosed in the public. Just look at Vioxx and how Merck conveniently hid the problems that are now associated with this drug.

If I can recall something I read a couple of years ago, the FDA created some rules that insisted that drug companies publish ALL the information about their drug trials. Problem is, there is no enforcement or penalty associated with lack of compliance.

Harry

And the FDA does not have a big enough budget to monitor post marketing problems with approved meds.

I don't base my credibility on whether or not Biogen or Elan was sued...I'm neither a muckraker nor a newsman. Anyway, somehow, we got on this subject. If you say there was a story there, then I believe it. But it really has nothing to do with Tysabri as a treatment, IMO.

What was the disposition of the case...was anyone prosecuted and convicted of insider trading? If it was all over the news, then it could hardly have been swept under the rug after the story became public knowledge. I'd be interested in knowing what happened, absent the conspiracy talk. Either they were prosecuted or they were not.

Curious how you arrived at this...what is their budget, and how is it distributed?

Ex Biogen exec fined $3 million dollars to settle insider trading charges

http://www1.cchwallstreet.com/ws-por...sp?fn=01-17-06

Ex-Biogen Exec Fined $3M in Insider Trading Case By Jennifer McCandless
January 17, 2006

Thomas Bucknum, former general counsel for Biogen Idec, will pay $3 million to settle insider trading charges filed by the Securities and Exchange Commission.

According to the SEC, Bucknum sold thousands of company shares in the two weeks before the company’s multiple sclerosis drug, Tysabri, was withdrawn from the market in February 2005 because of safety concerns.

In settling with the SEC, Bucknum agreed to disgorge $1.9 million in stock gains from the trade, as well as a civil penalty of $969,000 and interest of $102,000. Bucknum is also barred from serving as an officer or director of a publicly traded company for five years.

Bucknum sold 89,700 shares before information became public that two patients taking its multiple sclerosis drug Tysabri had developed a rare brain disease. Once the information was released and the drug was pulled from the market, Biogen’s stock plunged 42%, according to the complaint released by the SEC.

On the morning of Feb. 18, 2005, Bucknum told his broker he wanted to exercise 89,700 stock options and sell the shares. At about noon, Bucknum attended a meeting in which he and other senior Biogen officers learned that a patient taking Tysabri had been diagnosed with a rare and fatal brain disease and that another patient may have contracted the illness.

Following the meeting, Bucknum called his broker's associate, who told him he had received legal clearance from Biogen for the stock sale, and Mr. Bucknum told the associate to sell the shares. Shortly after 2 p.m., the 87,900 shares were sold for an average price of $67.12 and a profit of $1.9 million.

On February 28, Biogen and Elan Corp., the company’s partner in marketing the drug, suspended Tysabri sales and Biogen’s stock price dropped to $38.65 from $67.28 the day before.

Bucknum resigned as general counsel of the Cambridge-based drug maker last March. In settling with the SEC, Bucknum neither admitted nor denied any wrongdoing.

FDA to create board to monitor drug safety
By Diedtra Henderson, Globe Staff |
February 16, 2005

ROCKVILLE, Md. -- The Food and Drug Administration said yesterday it will create an independent drug safety board -- as critics have demanded -- that would quickly direct the agency how to respond to drugs on the market that are suspected to be unsafe.

The board reflects a major shift in the FDA's approach. To date, most of the agency's focus has been on testing a drug's effectiveness and safety prior to its approval. But once a drug was on the market, the agency relied primarily on the drug industry to alert it to problems. Now the agency is pledging to look for safety problems on its own.

The new safety panel would be made up of agency experts who were not involved in approving the drug and other scientists inside and outside of government. While the drug would remain on the market during deliberations, the panel could act within days, instead of the weeks or months that the FDA has taken to respond to the recent spate of problems first with antidepressants and then with Vioxx, Celebrex, and other painkillers.

The launch of the safety board received both praise and criticism from Congress. It comes as the agency begins three days of hearings today on the risks and benefits of the painkillers, a session triggered by the withdrawal of Vioxx from the market last fall. Agency critics say the FDA is too closely tied to the drug industry it regulates. There also have been internal conflicts, with FDA employees who approve drugs having more clout than the side of the agency that reviews potential problems with the same products.

Meanwhile, the New England Journal of Medicine yesterday published studies showing Vioxx and Celebrex triggered heart problems much more quickly than previously known. One study, a completed review of the trial that led to the withdrawal of Vioxx, indicates that small doses of that drug began to harm hearts within just six months.

Another study indicates that larger doses of Celebrex caused excess deaths due to heart attack and stroke in as little as 12 months. The lead author of the study said the heart risk may actually be greater.

''Had we had more people, it's very possible we would have seen a risk earlier," said Dr. Scott Solomon, director of non-invasive cardiology at Brigham and Women's Hospital. ''So, to conclude from this that there is no risk before one year would be wrong."

Celebrex, Vioxx, and similar drugs in their class, called cox-2 inhibitors, were introduced with much fanfare at a time when drug advertising rules were relaxed. As safety concerns grew, prescriptions steadily dropped.

Solomon said his results do not suggest Celebrex should be withdrawn from the market, as the FDA has been pressured to do. He said that within several months, studies pointing to Celebrex's potential benefit in shrinking tumors are expected to be complete. For now, what's clear is that high doses of the painkiller more than tripled the risk of serious cardiovascular events.


more at: http://www.boston.com/business/globe...528539/?page=2

Thanks Pantos....Johnny on the spot..:D

Hi Rex,

It is unfortunate that we no longer have instant access to this information, but most of us here (at NT) have beat these issues to death previously on threads at OBT. I have links to it all, but the links don't work any more. :rolleyes: :(

My MAIN concern, all the way through this Tysabri fiasco, has been whether the AVERAGE PwMS (not us computer/MS board savy people) are fully aware of what the potential risks are. I'm fairly confident now that the TOUCH program is ensuring that, so I'm not nearly as concerned as I used to be.

Ultimately, the conversation always seems to end up at us:

- having additional "choices"
- what "risks" we are willing to take to have another option available
- the potential for Tysabri to prove to be effective and safe for us in the long run.

It seems apparent that many people and Neuros are still continuing to proceed with caution, and given what we know/don't know at this point, I think that is prudent. However, I sincerely hope that Tysabri proves effective and safe in the long run, and I am very thankful there are people who are willing to step up to the plate to help prove it.

Cherie

http://www.latimes.com/news/nationwo...a-story-footer

Try this article kingrex. It isnt the one I had read before, but it looks like it has the info on FDA not having enough money to monitor drugs after marketing.

And thanks Pantos for providing the links about misbehavior amongst the Avonex folks. Luckily on this board, we can post links. Unlike other boards that do not allow posting links, this board allows us to back up assertions and talk on the basis of real data, and not just conjecture. That is a real strength to this board.

I think it was Maya Angelou that said "Believe someone when they tell you something the first time". This thread seems so full of doubting Thomas'.

I am one of the 75% that will not be resuming Tysabri at this time. I received my one and only infusion Feb. 19th of 2005, appearantly one day after the execs of Biogen sold off their stock. Remembering back to the story at the time, the company was actually alerted by a clinical trial neurologist around Feb. 9th that PML was a factor, but follow up pathology was needed on the deceased patient.

I received a rather lengthy email from Biogen/Elan asking my participation in a survery. It was obvious to me that the survey was talking about Tysabri because 1/ Tysabri was off the market at the time and 2/ Asked numerous questions about what number of deaths are acceptable if a drug could reduce relapses by such and such rate/frequency.

Obviously the survey was longer than what I mentioned but my response included a little extra note to the manufacturers about my distrust of this company. I discontinued Novantrone for a shot at Tysabri. I defended it tooth and nail at the time. Frankly I still feel betrayed by the companies and angry that the cost was $4900 ($4300 for the drug) instead of $2300 as had been announced by the CEO of Biogen in Oct. 2004.

I'm back on Novantrone and to quote my neurologist: "No chance of putting you back on Tysabri, you're not sick enough to take the risk"!! Now as you may know Novantrone is a chemotherapy drug and places the user at a higher risk of heart valve damage even after discontinuing the drug. I suppose repairing a heart valve is less risky of a venture than developing PML. Under her advice, Tysabri will be off my list until there is further data, I have exhausted my lifetime dosage of Novantrone and there are no other viable alternatives.

Laurel

I sort of recall that story but can't actually find the news item quoting the doc. By chance, can you (or any other reader) have a link to that? Thanks.

Harry

I remember it well, Harry,so it was printed, but some of those old links are gone. I think it was in a newspaper article, though.

Welcome, Laurel.:)

Sally,

I think you are very right on it being a newspaper article....I just wish I had the name of the doc and the actual date he said that he advised Biogen.

Harry

I've searched and searched, Harry...Notta!

I do recall, however, that it was one of the Trial Docs, who reported it, but the name excapes me.

That does stink out loud that you took an infusion after the company already knew about the death. Shame on them.

I have a hard copy of the BMJ article, but can't access it on their website because you need a membership to do so.

The article was called "Lessons for clinical trials from natalizumab in multiple sclerosis", written by Abhijit Chaundhuri:

http://www.bmj.com/cgi/content/citation/332/7538/416

The hard copy reads "On 18 February 2005, 10 days before the public announcement, the FDA received information from Biogen Idec of one confirmed death and one possible case of progressive multifocal leucoencephalopathy in patients receiving natalizumab for Multiple Sclerosis".

Cherie

Cherie,

I guess one can always count on you to come up with the goods:) Do you have the capability of scanning the hard copy of that article and sending it to me as an attachment? Many thanks.

Harry