Tysabri info

[HarryZ]

Better,

Harry, if Jeff Krasner of the Globe had a very good source before he printed that article, why is he talking about a fourth death ?

Better

You are asking the wrong person! Perhaps you should be e-mailing Jeff and asking him since he wrote the article. I am going to check with my sources and see if I can find out how reliable a reporter he is.

Jeffrey Krasner can be reached at krasner@globe.com. Globe staff writer Diedtra Henderson contributed to this report. She can be reached at dhenderson@globe.com


Harry

[HarryZ]

Better,

I've been told by another person in the news business that Jeff Krasner is considered very reliable in his field. At this point I would therefore have to think his story has credibility.

Harry

[better2gether]

Harry

I found this interesting message on the Elan messageboard:

Recommend this Post - This post has 133 recommendations

Letter to the SEC

by: paul_1149 (54/M/southern NY) 06/02/05 04:05 pm
Msg: 675189 of 675610

To: enforcement@sec.gov

Subject: False and Damaging Journalism


Dear sir or madam:

You are aware of the article in the Boston Globe today which declared that a fourth fatality had occurred connected to the use of Tysabri. The claims of this article are materially false.

This latest possible case has not even been declared PML. Nor has the person died, contrary to the article's headline on Page One. For that matter, the second discovered case of PML has not ended in death, so the headline's count is twice wrong.

This last possible case had only 1 to 3 doses of Tysabri. Tysabri has several linear years and thousands of patient-years of safe use under exhaustive review. Is it suddenly feasible that it has become this lethal a killer?

More likely is that the severe reactions this patient had were due - as in all other Tysabri-related PML cases - to the use of other immunosuppresants.

We do not know the medical history of this patient, including possible use of other immunoregulators.

We do know that news of a non-material event was dug up by the Boston Globe and trumpeted to the public, causing the loss of a billion dollars to investors and perhaps affecting the eventual return of Tysabri by increasing political pressure on the FDA.

This is an unconscionable use of the power of journalism. Exactly what checks and balances are on these recipients of public trust? The potential for abuse of position, including even for personal aggrandizement, is enormous.

Would that the Globe had used its investigative energies to distinguish between the safety of Tysabri for monotherapy, where there have been no severe side effects whatsoever, and the combination therapy which indeed has caused problems.

I truly hope that the entire Tysabri saga, and this latest chapter in particular, is the cause for the SEC to investigate the manipulation of the market through the advancement of false information and the suppression of actual facts. Between the state of financial journalism, the free reign given hedge funds (ELN has been on the Regulation SHO list for over two weeks now), and the legal and political minefield the drug companies must traverse, the small investor, who is the strength of the American economy, is literally being driven out of the stock market.

How many life-changing medications have been delayed or scuttled entirely for these reasons? For the good of the nation, this activity must be reined in.

Sincerely,
Paul ...

cc: ombud@globe.com

Regards

Better

[DenverCO]

On 4/20/05 Art Mellor posted "Press Would Like to Talk to Tysabri Users". The investigative reporter was none other that Jeff Krasner of The Boston Globe. In that post there is a link to Krasner's letter soliciting Tysabri trial participants to interview. The letter refers to the suspension of Tysabri as the "ongoing medical fiasco."

Unbiased journalism? I don't think so.

[HarryZ]

Better,

Jeff Krasner will have to answer to his editor and anyone else who wants to challenge his article. Since editors of newspapers have the final say on any kind of controversial items, I can only assume that the Globe's editor gave approval to Jeff's news item.

If you are concerned with the validity of what he has written, I suggest you e-mail him and voice that concern. (his e-mail address was provided) That article was posted on Brain Talk and Montel Williams' Spotlight on Health MS forums where I saw it this morning.

I don't know Jeff Krasner from Adam and never heard of him before I read this article. Like my previous message stated, I was told he was considered very reliable in his field....whatever that means in journalism.

I'm sure if Jeff did something very wrong the sharks are already circling.

Harry

[HarryZ]

Here is an interesting article by Dr. Scott Gottlieb who is a physician and editor of Forbes/Gottlieb Biotech Investor. He is a fellow at the American Enterprise Institute and is a former senior official at the U.S. Food and Drug Administration and Medicare program.

Harry

_________________________

Dr. Scott Gottlieb, Forbes/Gottlieb Biotech Investor, 06.03.05, 3:32 PM ET

NEW YORK - Reports yesterday that a fourth case of a rare, often fatal, brain disease might be linked to the now-withdrawn drug for multiple sclerosis, Tysabri (developed by Elan and Biogen Idec), has added a new and more difficult wrinkle to the saga of this drug.

Earlier this week, I reported on my weblog www.FDAInsider.com (which focuses on U.S. Food and Drug Administration policy issues that impact investors) that there were at least four principal questions that the FDA needed to answer before it would have enough comfort to allow this drug to be reintroduced. Those questions are listed at the end of this article. But the latest case of the brain disease in a patient using Tysabri probably puts the answers to these questions further out of reach.

The Boston Globe reported in Thursday's edition that Biogen Idec (nasdaq: BIIB - news - people ) has informed the Food and Drug Administration that another patient--a 48-year-old woman with multiple sclerosis--may have contracted the central nervous system disease known as progressive multifocal leukoencephalopathy, or PML.

The patient who contracted the latest case of PML was apparently taking the drug in combination with another multiple sclerosis drug Avonex. There have been rumors that there was a fourth case of PML since the American Academy of Neurology meeting in April.

The Boston Globe apparently got the latest report after filing a Freedom of Information Act request for adverse event reports related to Tysabri. This means the report is old and not part of the ongoing investigation that the companies and the FDA are making into the drug. So other cases could well emerge from that ongoing investigation.

Biogen Idec and Elan (nyse: ELN - news - people ) announced on Feb. 28 that they were suspending sales of Tysabri after two patients were found to have contracted the disease. A review of clinical trial records later identified a third patient. Two of the patients have since died.

Ever since they announced the drug's suspension, the companies have been examining patients' records for other instances of PML. Biogen has said that they will present their findings to the FDA by the end of the summer.

Each new case of PML reduces the chances for a quick return of Tysabri. Also complicating matters is that there is no discernable pattern to which Tysabri users are at highest risk of contracting PML.

At first, it was thought that the risk was apparent only when Tysabri was used in combination with Avonex. Then a case of PML emerged in a Crohn's patient who was not on Avonex (although the patient was reported to be on other immunosuppressive drugs).

Then it was believed that the risk of PML increased with long-term use of Tysabri. But the latest case of PML is rumored to have emerged in a patient who had received only three doses of the drug. That could mean the risk of PML is apparent even with short-term use of Tysabri.

In fact, Tysabri is beginning to fit the profile of the kind of medicine that gives the FDA the most discomfort: a drug for which the factors that increase a risk of suffering a certain side effect cannot be readily identified, and where the side effect is fatal and does not respond to withdrawal of the offending treatment.

Tysabri is a highly effective medicine with a unique mechanism of action. The road to bringing it back on the market, however, is unclear.

The drug is likely to play an important role in very sick MS patients who have not responded to existing therapy, and indeed, the benefits may well outweigh the risk in these patients. But FDA is likely to tread cautiously here: perhaps taking many months to convene expert committees on both the drug and on PML, to see which if any of the four questions I posed can be more readily addressed.

So history should be a guide here as to what the FDA is likely to do:

If the FDA cannot identify reasonable criteria that would help guide doctors and patients as to who may be at risk for PML, and how that risk can be reduced, there is very little advice the agency can offer the drug's users, and very little chance that the agency will soon feel comfortable making the drug available again, except perhaps under the most limited circumstances.

The Pfizer (nyse: PFE - news - people ) antibiotic Trovan and the Johnson & Johnson (nyse: JNJ - news - people ) gut drug Propulsid are perhaps a harbinger of what is next. Both of those drugs were withdrawn from the market for safety concerns, and then reintroduced in very limited circumstances, mostly for extraordinary uses that require those drugs' unique mechanisms. That's hardly the kind of market Elan and Biogen were angling for, but it may be what they and patients need to settle for, at least for the foreseeable future.

Questions the FDA needs to answer to reintroduce Tysabri:

Can those at risk for PML be reliably identified through prospective testing?

Can the FDA determine whether the risk of PML is the same if Tysabri is given alone, without co-administration of other immunosuppressive drugs?

Can the FDA determine whether use of the drug in certain dosages or for certain lengths of time modulate the risk of PML?

Can the FDA identify characteristics that would allow doctors to prospectively identify patients with rapidly progressive disease, unlikely to respond to other medicines, for which the risk of PML is outweighed by the benefits of Tysabri?
____________________

[better2gether]

.
Med journal fans hopes for Tysabri

By Val Brickates Kennedy, MarketWatch
June 9, 2005


BOSTON (MarketWatch) -- In the upcoming edition of the New England Journal of Medicine, several medical experts say that while they see a link between the use of the recalled drug Tysabri and a deadly brain disease, they also see a possibility of the drug still being of use if patients are closely monitored.

Tysabri was developed by Biogen Idec and Elan Corp . Approved by the Food and Drug Administration for the treatment of multiple sclerosis in November 2004, Tysabri was pulled from the market in late February, after two cases of progressive multifocal leukoencephalopathy, or PML, surfaced in patients given the drug during clinical trials.

In an editorial slated to run later this month, the editor-in-chief of NEJM, Dr. Jeffrey Drazen, says that while he sees a link between Tysabri and the onset of PML, further study is needed to determine whether the drug's benefits justify its risks. Tysabri is also known as natalizumab.

"In the case of natalizumab, there is a dilemma. On the one hand, it appears to be a promising therapy for multiple sclerosis and has raised the hopes of patients with this debilitating condition; on the other hand, the complication of PML can be fatal," wrote Drazen.

Drazen made his remarks in an editorial about the formidable risks that clinical trial patients face. The editorial accompanied the analyses of data collected from three clinical trial patients who used Tysabri and subsequently contracted PML. Two of those patients died from the disease.

"Given these data, the association between treatment with natalizumab and the occurrence of PML seems clear. What we do not know is the magnitude of the risk of PML per year of exposure," wrote Drazen.

PML is believed to be caused when a virus called the JC virus is reactivated and attacks the brain. Medical experts have estimated that up to about 80% of the public carry the JC virus, which almost always remains dormant. PML, which is extremely rare, is most often seen in patients who are severely immuno-suppressed, such as those suffering from advanced AIDS. The disease is often fatal.

Another NEJM editorial speculated that PML victims might stand a better chance of recovering if Tysabri was discontinued in the very early stages of the disease.

In a letter that will appear in the same issue as Drazen's editorial, Biogen researchers offered hope that Tysabri could return to the marketplace if patients are strictly monitored for the onset of PML.

"It is possible that testing for the appearance of JC virus in plasma [blood], along with a high degree of clinical suspicion, will permit early diagnosis and discontinuation of natalizumab therapy and allow patients to recover," wrote the Biogen researchers, who included Biogen's executive vice president for development, Dr. Burt Adelman.

"We remain firmly committed to a thorough evaluation of the safety profile of natalizumab so that we may provide physicians and patients with the necessary information to make informed benefit-risk decisions about their multiple sclerosis therapy," the Biogen team added.

Drazen also praised Biogen specifically for its handling of the clinical trial patients.

"We need to be sure that research is carried out in a responsible manner and that patients who volunteer to participate are treated in an open, honest and fair fashion," said Drazen, "from what is currently on the public record, Biogen appears to have honored this trust."

Tysabri had been considered a major breakthrough in the treatment of multiple sclerosis. Biogen and Elan had also been testing the drug for the treatment of Crohn's disease, which like MS, is believed to be caused by the immune system attacking the body. Tysabri appeared to be able mitigate those attacks.

Biogen and Elan suspended all sales and testing of Tysabri in late February after two patients using the drug in a clinical trial were reported to have contracted PML. A third PML victim, also from a clinical trial, was identified in March. A fourth suspected case of the disease was reported to the Food and Drug Administration recently.

Of the three confirmed PML cases, two of the patients have died, while a third survived. The fourth suspected victim is also alive, according to Biogen and the FDA.

Three of the patients, who suffered from multiple sclerosis, used Tysabri along with another Biogen drug, Avonex. A fourth patient, who suffered from Crohn's, had been taking Tysabri, along with a variety of other medications for his condition.

Since the discovery of the first two cases in February, Biogen and Elan have embarked on an exhaustive medical review of the roughly 5,000 patients who took Tysabri, looking for clues on what triggered PML. The companies have said that they hope to have the review completed by late summer, at which time they can discuss whether Tysabri should be put back on the market and in what capacity.


Val Brickates Kennedy is a reporter for MarketWatch in Boston.

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[jaycee]

On May 22, Reed posted in this thread about a gross error on the InteliHealth website. I somehow got caught up in trying to get someone at Harvard Medical School (the supposed editors in charge of content there) to issue a correction. No one at InteliHealth responds except with a automated response. I finally went to Harvard Medical School's website and picked out three big wigs seemingly associated with their relationship with InteliHealth. I got an answer from one of them right away. Here it is:

Thank you for taking the time to contact Aetna InteliHealth about the content. I had not yet received your message through the usual channels.

The original language did not mean to imply that RRMS was more severe than CPMS, but only that the debility of RRMS could be substantial. Based on your comments, I understand how the language could lead to other interpretations. I have made revisions to the column to decrease any possible misunderstanding and will submit them to InteliHealth immediately.

Howard LeWine, MD
Chief Medical Editor, Internet Publishing for the HMS-InteliHealth Collaboration

PS This makes me feel like I did something worthwhile. I get so much from this site and I want to contribute.

[reed]

"Multiple sclerosis can vary in severity, with the relapsing-remitting type being especially debilitating."


I quote the offending language above. My parse would ask "especially, compared to what?" I cannot say what the language "meant to imply." I can only tell, as can anyone who looks, what the language does imply.

Thanks for taking this on, jaycee. I'm willing to forgive and forget....as long as they find us a cure!

Reed

[HarryZ]

Here's a pretty decent summary of an initial report on PML and Tysabri.

Harry

___________________________

By Neil Osterweil, MedPage Today Staff Writer
Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine
June 09, 2005
Also covered by: Forbes

MedPage Today Action Points


Inform patients with MS that Tysabri, which in clinical trials appeared to be highly promising, was withdrawn from the market because of a few cases of a rare but fatal infection, progressive multifocal leukoencephalopathy (PML).


Reassure patients that Avonex (interferon beta-1a) is still available and has not been shown to be linked to progressive multifocal leukoencephalopathy when used as directed.


Review
BOSTON-The multiple sclerosis drug Tysabri (natalizumab), withdrawn from the market following reports linking it to two cases of a rare fatal opportunistic infection, appears to work with other drugs to allow reactivation of an otherwise innocuous latent virus.


That's the consensus of investigators in a special early release of information scheduled for publication in the July 28 New England Journal of Medicine. The drug, launched with great promise for MS patients, was withdrawn on Feb. 28.


That NEJM issue will contain details of three separate case reports of patients who developed progressive multifocal leukoencephalopathy, or PML, during treatment with Tysabri. Two patients were treated for MS and one for Crohn's disease.


One of the patients with MS and the patient with Crohn's died from PML. The other MS patient became quadriplegic and lost the ability to speak. This patient improved after discontinuation of Tysabri, followed by further therapy with Ara-C (cytarabine), which has been shown to be effective in the laboratory against the suspected viral infection.


Last week, the Boston Globe reported that Tysabri's maker, Biogen Idec, had informed the FDA of a possible fourth case of PML, in a woman with MS who had taken it along with the company's other MS drug, Avonex (interferon beta-1a). Her case was not reported in the journal, and her condition could not be ascertained immediately. However, the NEJM said it was the Globe report that triggered the early release of its data.


Although PML was diagnosed in only three (now possibly four) of the 3,000 or so patients who took Tysabri in clinical trials, drug safety monitors were alarmed because the infection is almost always seen only in severely immunocompromised patients. These include AIDS patients or organ transplant recipients who are taking immunosuppressants. Until these case reports, there were no known cases of PML in patients with MS.


PML is caused by reactivation of a clinically latent infection with the JC polyomavirus. These often-fatal opportunistic infections of the central nervous system destroy oligodendrocytes in the brain, resulting in demyelination of multifocal areas and deterioration of various neurologic functions.


The JC virus is acquired by most people during childhood and antibodies against the virus are present in 50% to 86% of adults. The virus remains dormant in the bone marrow, kidney, and spleen, and infection is usually asymptomatic unless the person is immunocompromised.


Tysabri is a humanized monoclonal antibody against α4-integrins, receptor proteins involved in cellular binding and response to extracellular matrix. When used in conjunction or in sequence with other drugs that affect immune function, Tysabri appears to interrupt normal lymphocyte function, allowing the JC virus to grow unchecked, said Igor J. Kralnick, M.D., of Harvard Medical School in an interview.


"In the patients who received natalizumab and also had other medications such as Avonex, it's likely that the prevention of normal migration of the lymphocytes in the tissue allows the virus to replicate without being contained, and finds its way to the brain and causes the disease," said Dr. Kralnick, who co-authored an editorial accompanying the NEJM case reports.


"It is also not entirely ruled out that some people have the virus latent in the brain and in certain circumstances need to have the trafficking of the lymphocytes to prevent the virus from reactivating within the brain."


One patient, a 46-year-old woman who had received 37 monthly doses of Tysabri, plus weekly Avonex injections for relapsing-remitting MS, died about three years after starting on Tysabri. At autopsy, she was found to have multiple large and small PML lesions in tissue sections taken from most areas of both cerebral hemispheres, according to a NEJM report by B.K. Kleinschmidt-DeMasters, M.D., and colleagues at the University of Colorado Health Sciences Center.


The second fatal PML case reported in the NEJM occurred in a 60-year-old Belgian man who had received five doses of Tysabri for Crohn's disease as part of a clinical trial, wrote Paul Rutgeerts, M.D., Ph.D., and colleagues at the University of Leuven Hospitals in Leuven, Belgium.


The patient died five months after reporting to the emergency room with severe confusion and disorientation. Although he was originally thought to have died from an astrocytoma, the investigators took another look at the serum samples and brain lesion tissues taken at biopsy after hearing about two other cases of PML in patients on Tysabri.


The investigators found evidence of the JC polyomavirus in blood samples taken three months after the patient had started on an open-label trial of Tysabri, but before he had exhibited symptoms. The patient had previously taken the immunosuppressant Imuran (azathioprine), but had discontinued it eight months before admission to the hospital.


In the third case reported in the NEJM, researchers reported on a 23-year-old man who had received 28 infusions of Tysabri, in addition to weekly injections of Avonex. He developed a rapidly progressive case of PML that did not respond to treatment with corticosteroids, Vistide (cidofovir) and IV immune globulin. The infection left the patient "quadriplegic, globally aphasic, and minimally responsive."


Three months after stopping Tysabri, his physicians detected widespread inflammation of the CNS, which they attributed to immune-reconstitution inflammatory syndrome. Following a course of Ara-C, the patient had improvement of symptoms, including return of speech and ability to walk, although he still had cognitive and neurologic impairment. The authors reported that the reasons for improvement were unclear as Ara-C has been shown to be effective in vitro, but it failed to show efficacy in a randomized control trial in HIV patients with PML.


"Our case report suggests that some degree of recovery from natalizumab-associated PML is possible," wrote Annette Langer-Gould, M.D., of Stanford and colleagues there and at the University of California San Francisco.

Biogen Idec, the drug-maker, noting the recovery, commented in a letter to the NEJM that accompanied the research papers, “It is possible that testing for the appearance of JC virus in plasma, along with a high degree of clinical suspicion, will permit early diagnosis and discontinuation of natalizumab therapy and allow patients to recover. Similar findings have been reported for BK virus, a related polyomavirus that infects transplant recipients.”

[HarryZ]

Hmmm...just saw this article today from CNN Money which supposedly was reported in the Wall Street Journal as well. Sure hope they start confirming or negating these reports soon. No details other than how this news effects the stock prices of Elan and Biogen!

Harry

__________________________

Drug again said tied to brain infection

Fifth case of a rare brain infection may be linked to multiple sclerosis drug, newspaper reports.
June 13, 2005: 9:45 AM EDT


NEW YORK (Reuters) - A possible fifth case of a rare and often fatal brain infection linked to the multiple sclerosis drug Tysabri has been reported to federal regulators, the Wall Street Journal reported Monday.

The case was reported on May 16 through the Food and Drug Administration's Adverse Event Reporting System, which collects reports of possible drug reactions from physicians and drug makers.

An FDA spokeswoman told the newspaper that these reports do not represent confirmed cases.

The drug's makers, Biogen Idec Inc. (up $0.03 to $35.04, Research) and Elan Corp. (unchanged at $7.13, Research), have reported three confirmed cases of progressive multifocal lukoencephlopathy (PML) in patients taking Tysabri. Two of the patients died, while the third is reported to have shown recent improvement. The companies stopped selling the drug in February.

A possible fourth case was reported to the FDA earlier this month, but the companies said the PML diagnosis has not been confirmed. The fifth possible case concerns a female patient, of an undisclosed age, who has been hospitalized, the report said. No other details of her condition were available.

[better2gether]

Interesting info from another messageboard.

This post has 143 recommendations


"FDA view of Tysabri ?

Biotech analysts here in Boston have had, and continue to have, keen interest in the Tysabri situation. They are "pulsing" every avenue of information.

The following is an amalgum of what some of them think they have learned from Elan, BIIB, and Wash DC sources -possibly elements of FDA itself.

FDA is asking for a protocol for field test for JC virus in blood. FDA is DEMANDING that the field test be READY TO GO IN THIRD QUARTER 2005 AS PART OF THE RE-INTRODUCTION OF TYSABRI. PLEASE NOTE THIS IS AN FDA DEMAND.

The FDA is under such MONSTER POLITICAL PRESSURE TO RETURN TYSABRI TO MARKET that it is not requiring the field test be validated before re-launch of Tysabri.

Where is this political pressure coming from? As you know, about 4 weeks ago Mrs. Romney,an MS sufferer and wife of our Mass. governor expressed sincere regret that Tysabri, that had seemed such a beacon of hope for MSers, was taken off the market. As you know this MS scourge is considered more of a women's disease. Inquiring analysts are being told that the pressure is coming from the wives, mothers, sisters, daughters, and nieces of Congressman and US Senators who have MS, know people with MS, or have friends with MS.

As both BIIB and Elan have said, they have been constantly apprising the FDA on the investigatory details on Tysabri.

While BIIB senior managers are saying that they are blinded to the details, the FDA apparently is not.

The medical science community seems to be very favorably aligned to tysabri's return as indicated by the pre-publication release of data in the NEJM on the tysabri cases. That data indicated that tests could be run to deal with the risk of PML for MSers.

Patients, doctors, and their concerned friends appear to be speaking up forcefully for tysabri's quick return. "
.

[HarryZ]

Better,

It's not surprising that when politicians become involved, it takes a lot less time to get anything done. One only has to look at the effect Nancy Regan has had on stem cell research in the US.

The FDA is between a rock and a hard place. They are getting political pressure applied to them and since they are a government agency, I imagine it is pretty "hot" in their head office.

At the same time they can't re-release Tysabri into the market without having some mechanism to detect PML. The legal ramifications of them doing this without a valid test mechanism would be extreme.

MS is a disease that causes such dispare that many patients are willing to risk serious illness and/or death from a drug in the hope that it may help them. But because of the legal system in the US, allowing a drug to be used without removing the chances of litigation, is a major concern. And you can bet this is going through the minds of the people in the FDA.

Harry

[DenverCO]

Better,
How do congressmen influence the FDA? Should we be contacting our representatives with our opinions?

Harry,
I agree with you that the FDA has to minimize the risk of litigation, but I wish posting a blackbox warning about the possible link to PML would suffice. Hopefully a test for early detection of PML is right around the corner...as in next week!

[better2gether]

Denver,

I think contacting your representatives with your opinions is a good idea.
Don't underestimate the influence from the congressmen on the FDA.

Best regards
Better