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[Cyberhexe]

3rd Patient had History of Severe Immunosuppression
Previous therapy linked directly to PML

A firestorm has erupted with the revelation on March 29, 2005 that a 3rd patient dosed with Tysabri had been discovered to have Progressive multifocal leukoencephalopathy (PML). PML is a demyelinating disease of the brain caused by the JC virus. This patient had 8 doses of Tysabri over the course of 18 months during a clinical trial for Crohn`s disease, an autoimmune disorder that strikes the bowels. The doses were spaced out as follows: 3 months Tysabri, 9 months placebo, then 5 months Tysabri. The patient passed away in December of 2003, with his death originally attributed to a fatal brain tumor.

The recent revelation of 2 cases of PML found in extended combination therapy of Avonex and Tysabri prompted a reinvestigation of this death. The new conclusion was that the patient had actually died of PML, not a brain tumor. This has been viewed by many as devastating the chances of Tysabri ever returning to market, given that it seems on the surface that Tysabri can cause PML even when used alone (monotherapy).

However, This is MS became suspicious of the link between Tysabri and PML in this case, particularly given the low number of Tysabri doses that the patient had been exposed to, the spacing of those doses, and the mysterious mention of a past history of severe immunosuppresion. If PML were so "easy" to contract when exposed to Tysabri, why would we not see higher numbers of incidents in the multiple sclerosis Tysabri groups, who are more frequently dosed (monthly) over longer periods of time (over three years for the extended trial participants) with higher Tysabri circulation (when combined with Avonex, Tysabri clearance is reduced by ~30%). Something is clearly amiss...

The investigation is enlightening, and we believe, shows that Tysabri cannot easily be considered the critical factor for this case of PML. As you will see, it is not a foregone conclusion that this patient could be considered to have been on Tysabri monotherapy, given the long-term effects of his previous therapies. To preface this article, note that this is an opinion piece based upon information in the public domain and written by non-medical personnel, so all conclusions are meant to serve as discussion points and not definitive answers.

[jojobada]

Um diesen Artikel einzuleiten, merken Sie daß dieses ein Meinung Stück ist, das nach Informationen im public domain gegründet wird und vom nicht-medizinischen Personal geschrieben ist, also werden alle Zusammenfassungen bedeutet um als Diskussion Punkte und nicht endgültige Antworten zu dienen.



3. Patient hatte Geschichte der strengen Immunosuppression vorhergehenden Therapie, die direkt mit PML verbunden wurde Ein Feuersturm hat mit der Enthüllung an März 29, 2005 ausgebrochen, dem ein 3. Patient, der mit Tysabri dosiert wurde, entdeckt worden war, um progressives multifocal leukoencephalopathy zu haben (PML). PML ist eine demyelinating Krankheit des Gehirns, das durch das JC Virus verursacht wird. Dieser Patient hatte 8 Dosen Tysabri über dem Kurs von 18 Monaten während eines klinischen Versuches für Krankheit Crohns, eine autoimmune Störung, die die Därme anschlägt. Die Dosen wurden heraus gesperrt, wie folgt: 3 Monate Tysabri, 9 Monate des Placebos, dann 5 Monate Tysabri. Der Patient überschritt weg im Dezember von 2003, wenn sein Tod ursprünglich zugeschrieben ist, zu einem tödlichen Gehirntumor. Die neue Enthüllung von 2 Fällen von PML fand in ausgedehnter Kombination Therapie von Avonex und Tysabri forderte ein reinvestigation dieses Todes auf. Die neue Zusammenfassung war, daß der Patient wirklich an PML gestorben war, nicht ein Gehirntumor. Dieses ist durch viele als Verwüsten der Wahrscheinlichkeiten von Tysabri überhaupt zurückgehend zum Markt angesehen worden, angenommen, es auf der Oberfläche scheint, daß Tysabri PML verursachen kann, selbst wenn alleine verwendet (Monotherapy). Jedoch ist dieses MS wurde mißtrauisch von der Verbindung zwischen Tysabri und PML in diesem Fall, die niedrige Zahl Tysabri Dosen, daß der Patient, den Abstand jener Dosen und die geheimnisvolle Erwähnung von a hinter Geschichte des strengen immunosuppresion besonders gegeben herausgestellt worden war. Wenn PML so "einfach" Vertrag abzuschließen waren, als herausgestellt Tysabri, warum würden wir nicht die höheren Anzahlen von Ereignissen in den mehrfache Sklerose Tysabri Gruppen sehen, die häufiger (Monatszeitschrift) längere Zeitabschnitte des Überschusses (über drei Jahren für die ausgedehnten Probeteilnehmer) mit höherer Tysabri Zirkulation dosiert werden (wenn Sie mit Avonex kombiniert werden, wird Tysabri Abstand um ~30% verringert). Etwas ist offenbar amiss... Die Untersuchung erleuchtet und wir glauben, zeigen, daß Tysabri nicht leicht gelten kann als den kritischen Faktor für diesen Fall von PML. Da Sie sehen, ist es nicht eine gehen gelassene Zusammenfassung, daß dieser Patient betrachtet werden könnte, auf dem Tysabri Monotherapy gewesen zu sein, die langfristigen Wirksamkeiten seiner vorhergehenden Therapien verliehen worden. Um diesen Artikel einzuleiten, merken Sie daß dieses ein Meinung Stück ist, das nach Informationen im public domain gegründet wird und vom nicht-medizinischen Personal geschrieben ist, also werden alle Zusammenfassungen bedeutet um als Diskussion Punkte und nicht endgültige Antworten zu dienen.

[[KERN]Codex]

Drug Withdrawal a Travesty for MS Sufferers

(Scripps Howard)
Updated: Apr 29th 2005

The yanking from the market of both Vioxx and Bextra, members of a new generation of pain relievers called COX-2 inhibitors, has critics ripping raw flesh off the Food and Drug Administration. Inevitably, the agency and pharmaceutical companies are under intense pressure to over-scrutinize new drugs. But over-caution can also cause tremendous anguish, as multiple sclerosis sufferers using a recently pulled drug called Tysabri can attest.

Tysabri belongs to an incredibly promising new class of biotech drugs called monoclonal antibodies. Monoclonals have repeatedly shown an ability to slow or reverse diseases for which previously there had been nothing available but pain relievers and to be effective against multiple diseases.

Such appears to be the case with Tysabri, produced in partnership by Biogen Idec and Elan Pharmaceuticals and approved for MS in late November. About 400,000 people in this country have MS, in which the immune system attacks both the brain and spinal cord and causes a host of symptoms, including blindness, paralysis, and sometimes death.

There are other MS drugs, but none seems nearly as effective as Tysabri or as well-tolerated. In fact, results released this month of two years of clinical trials showed a stunning 42 percent reduction in the risk of disability progression and an even more amazing 67 percent drop in clinical relapses.

In late clinical trials, Tysabri has also apparently been extremely effective against Crohn`s disease, a severe bowel disorder. Additionally, it was also in human testing for rheumatoid arthritis. So it came as a stunning blow to the approximately 8,000 patients using the drug, as well as a long list of persons waiting to get prescriptions, when the ax fell.

The force behind that ax was a tiny virus that`s extremely common but that the immune system keeps locked up. If unleashed, though, it causes an often-fatal disease of the central nervous system called progressive multifocal leukoencephalopathy. Unfortunately, two MS patients on Tysabri contracted the disease and one died. When the drug makers scoured their databases they found another PML death in a Crohn`s patient. He also died.

It`s possible that in suppressing the immune system`s attack, Tysabri may have let loose the virus. But tremendously complicating matters is that all three patients were also on other immunosuppressive drugs at the time, leaving the real possibility that Tysabri alone is harmless. There are NO known cases of PML in patients using only Tysabri, according to the FDA.

What`s bizarre to Dr. Jeffrey Horstmyer, director of the MS Center at Mercy Hospital in Miami, is that less-effective MS drugs known to kill people have been used for years. "We allow Novantrone," he says, "and yet take Tysabri off the market." Novantrone`s side effects can include heart failure and leukemia.

Likewise, all the drugs that slow the progression of rheumatoid arthritis carry FDA warning labels, and two have been implicated in several deaths. Yet sufferers practically worship the companies that make them.

"Tysabri is a great drug," says Horstmyer. "My patients ... were delighted with the lack of side effects and its effectiveness." He adds they`re "really ticked" that it`s been pulled. In fact, New York Newsday headlined a recent story, "MS Patients Plead for a Recalled Medication," and the drug makers are being deluged with requests from desperate MS sufferers.

Horstmyer thinks the threat of lawsuits was primarily responsible for the drug being withdrawn, while the Competitive Enterprise Institute`s Sam Kazman blames government.

"What we`ve apparently got is FDA reverting to its traditional operating mode of deadly over-caution," he says. "That plays well in both Congress and the press but it`s murder on patients." Yet both agree that but for the COX-2 calamity there would have been no withdrawal and it`s wrong for Vioxx`s tentacles to be reaching out and grabbing other drugs.

"The Biogen and Elan people were trying to demonstrate the highest level of scrutiny" in pulling Tysabri until all patients could be evaluated," says Horstmyer. But, "All the MS drugs have serious side effects," he adds. Moreover, patients with MS "are among the most well-informed," he says, and best able to balance the risks of their disease vs. the rewards and risks of various drugs.

Says Horstmyer, "I really hope they can bring Tysabri back."

(Michael Fumento is author of "BioEvolution: How Biotechnology is Changing Our World" and a senior fellow at the Hudson Institute. E-mail fumento(at)pobox.com.)

© 2004 Scripps Howard News Service.

=>http://www.mentalhelp.net/poc/view_doc.php?type=news&id=7349…

[[KERN]Codex]

Will Tysabri make it back to market? Biogen continues to make drug, in hopes of return
By Val Brickates Kennedy, MarketWatch
Last Update: 7:24 PM ET May 12, 2005


BOSTON -- It`s been nearly three months since Biogen Idec Inc. voluntarily pulled its multiple sclerosis drug Tysabri from the market over safety concerns, but the company holds out hope the treatment will make a comeback.


Not only does Cambridge, Mass.-based Biogen continue to maintain inventories of the drug, it also has retained its nearly 100 Tysabri salespeople along with its marketing team.

And at least for now, Biogen (BIIB: news, chart, profile) still produces Tysabri, albeit at a lower rate. Biogen co-markets Tysabri with Irish drugmaker Elan Corp. Plc. (ELN: news, chart, profile)

"We have a pretty good feeling that it will go back on the market," said Peter Kellogg, Biogen`s chief financial officer. "We had a lot of people lining up for the drug [before the recall] and they`re still inquiring."

While Biogen management continues to be hopeful, one question continues to vex biotechnology investors and medical professionals alike: Can Tysabri, once hailed as a wonder treatment for multiple sclerosis, really make it back to the market?

Tysabri was recalled by Biogen and Elan on Feb. 28 after two members of an MS clinical trial were discovered to have developed progressive multifocal leukoencephalopathy, or PML, an extremely rare but deadly brain infection seen mostly in AIDS patients. One patient died.

A subsequent review of Tysabri patient records revealed a third user also had died of PML, during a clinical trial for the treatment of Crohn`s disease.

As a result, Biogen and Elan have suspended all clinical trials of the drug until it figures out what triggered the PML cases. The companies are engaged in a review of all Tysabri patient files in an effort to solve the puzzle and plan to discuss the results with the Food and Drug Administration later this summer.

Skepticism

Biogen and Elan are trying to get Tysabri back on the market to treat MS as soon as possible, but it`s likely to be greeted with a good measure of skepticism, analysts say.

"Confidence in the drug has been damaged," says Deutsche Bank analyst Jennifer Chao. "It will take time for physicians to regain confidence in the drug."

"I think there`s a high possibility that Tysabri will be relaunched onto the market, but with significant labeling," said Chao, who doesn`t see Tysabri back on the market before 2006. "I think the FDA will likely insist upon long-term, post-marketing clinical trials. They may allow a relaunch contingent upon finishing those trials."


Biogen has continued to make Tysabri largely to keep up its inventories of the drug, which takes months to produce, in case of a relaunch down the road.

The company plans to destroy all returned quantities of the drug, out of safety concerns. Biogen will make a decision as to whether to keep producing the drug sometime next quarter, when it expects the results of its safety review to be completed.

Based on the antibody natalizumab, Tysabri originally was developed by Elan, which saw its potential in treating such autoimmune disorders as MS and Crohn`s disease.

MS, a progressive disease where the immune system attacks the body`s central nervous system, is characterized by lesions on the brain and bouts of physical debilitation. About 400,000 Americans have from the illness.

Biogen buys in

The drug eventually captured the attention of Biogen, which also markets the popular MS therapy Avonex. Together, the companies moved to develop Tysabri first for the MS market, then for Crohn`s.

Clinical data showed the drug to be so effective in treating MS, some hailed Tysabri as a medical breakthrough.

Biogen and Elan won accelerated FDA approval for Tysabri on Nov. 23. Just three months later, it was yanked from the market after the first two PML cases were reported.

PML is fatal in 70% of cases, according to Biogen, and there is no treatment for the disease. So far, only three cases of PML have been reported out of the estimated 5,000 patients who took the drug. Two of those three PML patients have died.

Several shareholder suits have been filed against the company alleging its officers did not properly disclose the PML problem. But Kellogg says no personal injury or product liability cases have been filed to date.


Since the Tysabri recall, Biogen and Elan have reviewed the medical records of Tysabri patients, looking for clues as to why some patients contracted PML. Biogen has been splitting costs of the medical review with Elan, Kellogg said.

The goal is produce a more accurate risk profile of the drug. The companies then hope to hold discussion with the FDA on new labeling and monitoring mechanisms needed to put the drug back on the market.

"I don`t think we can find a way to reduce the risk to zero," said Burt Adelman, Biogen`s executive vice president for development. "But we can find a way to screen to minimize the risk."

The companies should have their review completed by the end of the summer, at which point they would then begin talks with the FDA, who will have final say as to whether the drug should go back onto the market.

Niche drug?

The consensus, however, is that if Tysabri does come back on the market, it would be as a niche drug, at least until enough long-term data can be assembled to prove that the risk of developing PML is highly remote.

"We`re talking about it being looked at as a `salvage` therapy," says Deutsche Bank`s Chao. "Tysabri is a bird that`s had its wings clipped."

One major question is whether physicians would prescribe Tysabri if it were put back on the market. Most analysts and doctors agree the FDA will likely require the product to carry a "black box" warning, the sternest label a drug can carry and still remain on the U.S. market.

"Let`s assume there are no further cases of PML, especially among the monotherapy patients -- then there`s a potential for Tysabri, with proper patient warnings and monitoring," said Dr. Aaron Miller, director of the Corinne Goldsmith Dickinson Center for MS at Mount Sinai Medical School in New York. "The problem is we don`t know the risk of PML with a longer duration of therapy."

"My guess is that a prudent neurologist would only reserve the drug for patients that have failed in other therapies," Miller added. "But before, Tysabri would`ve been the first drug we could`ve gone for."

While neurologists appear to be at least open to the idea of prescribing the drug, most market analysts still believe the drug`s future is gloomy.


Seen as drug of choice

Indeed, the idea of Tysabri being a niche drug was almost unthinkable last November. At that time, market analysts predicted Tysabri would become the drug of choice for MS sufferers, as it didn`t cause the flu-like symptoms associated with Avonex or other leading MS drugs Rebif and Betaseron, all based on the protein interferon.

"Certainly, people with MS are desperate for therapies," says Dr. Patricia O`Looney, director of biomedical research for the National Multiple Sclerosis Society. "There was so much disappointment from people with MS [from the recall]."

As opposed to other medications injected at least once a week, Tysabri was administered just once a month.

"The first-year data for Tysabri showed a stupendous degree of suppression of relapse and [brain] lesions," said David Margolin, an MS specialist at Massachusetts General Hospital. Margolin is also helping to develop a rival MS therapy, currently in Phase II clinical testing, for Genzyme Corp. (GENZ: news, chart, profile)

"The safety data looked pristine," Margolin said.

Not only was Tysabri expected to take market share away from other drugs, many saw it expanding the market nearly 30% by appealing to MS patients who have avoided drug therapy. Some analysts forecasted Tysabri could end up with first-year sales of $400 million and peak sales of $4 billion by the end of the decade.

Some neurologists now think the drug would be prescribed only to patients who are deteriorating and not responding to other drug regimens, such as interferons or Copaxone.

Mt. Sinai`s Miller, for example, says only 5% to 10% of the nation`s estimated 400,000 MS patients would be considered candidates for Tysabri, given the apparent risks.

Deutsche Bank`s Chao says the population is slightly higher, about 10% to 20%, with potential peak sales of about $200 million, four to five years after a relaunch. She adds that despite Tysabri`s woes, Biogen and Elan likely won`t drop the price of the drug, which can cost a patient up to $25,000 a year.

Clearance needed

But for the drug to make it back to the market, it needs FDA clearance.

What`s harder to predict is whether patients are willing to take the risk of developing PML, even if it is remote. While MS can lead to paralysis or blindness in some severe cases, patients generally live normal life spans.

"There are some people who won`t get past that there were people who took the drug and died," said Massachusetts General`s Margolin. "Then there`ll be patients who look at the numbers and want to take the risk anyway."

One reason patients may opt to take the risk is the alternatives for failing patients are also risky. Patients who cannot tolerate or fail to respond to interferons or Copaxone sometimes resort to taking chemotherapy drugs.

"The reason why I think it [Tysabri] will come back is because if you don`t respond to interferon or Copaxone therapy, the alternatives are also very toxic," Margolin said. "When the alternative is chemotherapy or Tysabri, people will probably choose Tysabri."

Meanwhile, because of its strong efficacy in helping slow the progression of the disease, the MS community appears to be receptive of a comeback.

"The MS Society is certainly in favor of new treatments. If the FDA allows Tysabri back on the market, even with a black box, certainly we`d be in favor of it. It would be another option for patients," O`Looney said.


Val Brickates Kennedy is a reporter for MarketWatch in Boston.

GLTAL


=>http://www.marketwatch.com/news/story.asp?guid={33214CB0-F92…

[[KERN]Codex]

The End Of Tsyabri?

http://blog.thesmithlife.com/2005/04/end-of-tysabri.html

(Kommentare von Betroffenen)

[Cyberhexe]

a very interesting statement from an us neurologist written in ymb on may 15th 2005


Face these facts:
1. Tysabri will be back, most likely Sept or Oct, 2005.
2. Most neurologists will welcome its return.
3. These neurologists are most likely to use it in CRAB failures and CRAB patients with significant side effects.
4. Some neurologists will not use Tysabri for a while. They will change as their patients demand it and as their confidence is rebuilt.
5. Just because 90% of neurologists see a role for tysabri does not mean that they feeel the same about the drug as they did pon 2/27/05. It does not mean these 90% will use it as much as they would have used it (if no PML)
6. Tysabris uptake curve will be moved to the right and reduced in amplitude. We were on track to see at least 40000 patients by year end 2005 on Tysabri. When will we get to 40000? It will not be until late 2006 or 2007 now. This is hardly a `niche` drug, and still has an excellent chance to overtake the IFNs. Overtaking the IFNs was guaranteed in the pre-PML era. When you throw in Europe, we will see much higher numbers. Throw in Crohn`s and the numbers are even better.
7. Combo is out. Mono numbers are good enough to recommend switching to many patients.
8. If a patient is clinically and radiologically stable, I would liklely recommend that they stay on current treatmetn (but will gladly switch them if they understand risks)
9. Someday there will be another case of PML.
10. MS patients and doctors are not afraid of risk. They understand nothing is without risk or cost.

[whyso]

New (old )drugs & their doctors (creators) are nearly always shortwinded regarding their acceptance levels from
a dubious but nevertheless "sick community"...

Common sense should always prevail, if we need the drug why object to its usage just because of "The accepted systems rule book?" and its acceptable hurdles and risks?

Wir sollten uns heutzutage gegenseitig helfen dürfen, oder etwa nicht wegen "the written word"-und wer hat das Wort ursprünglich überhaupt geschreiben?

GN8 everybody-tommorow is another day,
Whyso

P.S. Ich freue mich auf Satraplatin