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Progressive Multifocal Leukoencephalopathy(PML) info

New research article for May 2005 release describes full recovery of PML after removal of immune suppression. I think immune monitoring can remove PML cases from occurring.


Am J Transplant. 2005 May,5

Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient.

Crowder CD, Gyure KA, Drachenberg CB, Werner J, Morales RE, Hirsch HH, Ramos E.

Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

We report the case of a 47-year-old man who developed progressive multifocal leukoencephalopathy (PML) after receiving immuno-suppressive therapy for renal transplantation. The patient presented with a focal seizure and cognitive changes 5 months post-transplantation. He was found to have enhancing lesions in the parietal lobe and typical findings of PML in a brain biopsy.

Immunosuppression was discontinued and the neurological symptoms gradually resolved over a period of 4 weeks. The patient is free of any neurological symptoms 36 months after the diagnosis of PML and imaging studies demonstrate resolution of the PML lesions. The patient returned to hemodialysis 3 months after immunosuppression was discontinued. We also present a review of the literature on PML in renal transplant recipients.

http://www.ncbi.nlm.nih.gov/entrez/quer ... s=15816900

This sounds good and much like what a lot of us have hoped for. Bring back Tysabri WITH monitoring of the suppression of the immune system. I was told by a person in medical field that for now, it sounded as though Tysabri would come back "black labeled". Meaning not the general MS public would be able to get it and you would be tested, tested, and tested again while on it. No problem. Got a friend right now that has been having his liver "watched closely" because of his Betaseron use. Got a call from DR the other day to STOP the Betaseron and get an appointment with a Gastrologist. It don't sound good for him. But it goes to show that most things we take can be dangerous. And we take them to fight the MS the best way we can.

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Extract from Nature Biotechnology academic articles.

It quotes one of the world experts on PML, Igor Koralnik, who is working together with Biogen and Elan. They seem to buy the COMBO argument.


Nature Biotechnology 23, 397 - 398 (2005)

Tysabri raises alarm bells on drug class.

Cormac Sheridan

What could have triggered Tysabri's adverse events?
Tysabri's mechanism of action, now the focus of intense scrutiny, is thought to involve preventing the migration of circulating inflammatory immune cells into inflamed tissues, such as the central nervous system in the case of MS, by binding the 4 subunit of 41 and 47 integrins. But in blocking damaging immune cells from crossing the blood-brain barrier, could Tysabri, an IgG4 monoclonal antibody (most other marketed antibodies are of the IgG1 isotype), also interfere with the passage into the CNS of immune cells that protect against PML?

The condition, which can occur in highly immunosuppressed individuals, is caused by reactivation of the human polyoma virus JC (JCV), a pathogen normally present in a dormant state in around 85% of healthy individuals.

Last year Igor Koralnik, associate professor of neurology at Harvard Medical School in Boston, Massachusetts, and colleagues detected JCV-specific CD8+ T-cells in 8 out of 11 (73%) healthy volunteers, indicating that circulating cytotoxic T-lymphocytes (CTLs) may be involved in preventing the development of PML in healthy subjects (J. Virol. 78, 10206−10210; 2004). That finding opens up one potential line of inquiry for the expert panel, of which Koralnik is a member. "It's as if the cops are patrolling the streets but they cannot get to the buildings where the drug dealers are," he says.

"It's just not clear if there are additional parts to that we don't understand," says UC neurologist Zamvil. The selection criteria for recruitment to the SENTINEL(COMBO) trial required subjects to be on Avonex therapy for at least one year before being administered Tysabri. The interferon, which has several immunomodulatory effects, influences the expression of over 1,000 genes, he says, including those for matrix metalloproteases that also have a role in lymphocyte trafficking across the blood-brain barrier. "Maybe if you attack the immune system from two different angles, it may be enough to allow the virus to become active," says Koralnik.

The specificity of the adverse events seen in the SENTINEL trial is "very peculiar", says Lawrence Steinman, professor of neurology at Stanford University in Stanford, California. Although Tysabri, in combination with Avonex, may be interfering with immune surveillance functions, he says, why this has not caused other opportunistic infections is not clear.
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Opinion from an neurologist.

"PML risk and combo vs. mono.

A. What can Interferon do by itself. It works at a bunch of levels, but incompletely at any:
1. Decreases MHC class II expression (antigen presentation)
2. Down regulate metalloproteases at BBB
3. Change from TH1 to TH2 cytokines (more IL4/IL5/TGF and less IL2.
4. Decreases some chemokine expression.
5. Increases sVCAM-1 (acts to decrease VLA-4/VCAM-1 interactions).
6. Decreases some co stimulatory surface proteins.
7. Combination of above steps, down regulate microglial activity.

B. What does Tysabri do alone:
1. Binds to VLA-4 which reduces VLA-4/VCAM1 interactions at the blood brain barrier (or VLA-4/MadCAm intereactions in the gut). This reduces immune cell migrations (T cell, B cell and macrophafe).
2. Binds to fibronectin and inhibits the FN/VLA-4 interactions that allow cells to move efficiently once they have crossed into brain (following a chemokine trail).
3. Binds to VCAM-1 on microglial cells in the brain to inhibit some T cell (VLA-4 expressing)/microglial antigen presentation.

C. Combo does everything above plus:
1. Avonex increases Tysabri level by about 50% at steady state, thus A + T is really A + 1.5T

D. JCV specific TH1 cells are required to be in the brain to prevent PML


Av does not equal PML (10 years of experience in 120,000 patients).
T may or may not equal PML (0 cases in 780 MS patients treated > 2 years)
Av + 1.5 T equals PML in some patients (perhaps those that were most inhibited by Tysabri in the first place?


IMHO the keys are:
1. Avonex results in fewer and less effective JCV specific Th1 cells.
2. These cells are relatively excluded from the brain in Avonex plus Tysabri treated patients.
3. This exclusion is even more complete because of prolonged Tysabri half life (leading to 1.5 times level) and because of sVCAM-1 induction by IFN.
4. Azathioprine results in fewer JCV specific TH1 cells but I don't know if it affects Tysabri levels or sVCAM-1

Bottom Line:
With no doubt on my part, combo therapy has more risk than Ty only treatment. However, I think there is some risk with Ty mono. If this risk is in the patients who are most VLA-4 deficient after Ty (recall from McGill study, there was a lot of variability in VLA-4 neutralization by Ty), then a simple test may find this subset of patients and allow dose reductions or increased dosing intervals. Thus, maybe we need to dose like some epilepsy drugs rather than use a one dose fits all mentality. The test for a "level" would be to determine how much VLA-4 is blocked at one month (before next dose). If the value is high, future doses can be at more spaced out intervals. Just my opinion of course. "
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From Prohost research.

TYSABRI LIGHT IN THE MIDDLE OF DARKNESS

Researchers might have stopped the JC virus from causing destruction.
In yesterday’s prohost Fax letter, we brought to subscribers’ attention that in its November 19, 2004 issue,journal Science published a study funded by the NIH aimed at finding a way to stop JC virus from causing PML.

Walter Atwood, Ph.D., professor of biology and medicine at Brown University and colleagues, tested the drug chlorpromazine, which is indicated for psychosis and is also an effective treatment for nausea and vomiting, on PML and found it was able to effectively block JC papoviral transmission to glial cells.

The scientists also tested a second-generation (atypical) anti psychotic, clozapine. They found that it also blocked viral transmission. Since both drugs are known to be serotonin-dopamine inhibitors, the research team hypothesized that the JC papovirus may bind either to serotonin receptors or dopamine receptors to infect glial cells.

As a matter of fact, by testing compounds with similar effect, the scientists learned that the JC papovirus enters the central nervous system by fastening itself to the 5-HT2A serotonin receptor on the surface of glial cells. When this receptor is triggered, it initiates the pathway that allows the virus to enter the cell.

Knowing in fact that the antihistamine cyproheptadine has a very high affinity for 5-HT2A receptor without producing the serious side effects of the two anti psychotic drugs, the researchers were interested in the drug at the time. They believed that it is likely that this drug could prevent the virus from entering the glial cell and, thus, protect from or even treat JC papovirus-caused PML, without subjecting patients to the ti psychotic drugs’ side effects.

This story might open our minds to the fact that what seems impossible to some could become possible with such a simple solution.If Tysabri returns to the market, the bad surprise will hurt those who missed the opportunity to buy the stocks of the two firms at a very low price.

Does this mean that we are optimistic?
Yes, we are by nature. We believe in the power of science, in our scientists’ determination to utilize this power to solve problems of diseases and of drugs, especially those drugs that are breakthroughs that suffering patients badly need.
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PML is NOT invariably fatal!

A new case report of a transplant patient who contracted PML along with a literature review of 13 additional transplant patients with PML has just been published (Am J Transplantation, 5,1151-1158, 2005).
Here are the key findings:

1. Of the 14 patients, 8 died. In all 8 patients, immunosuppressant therapy was continued until death, and PML remained undiagnosed until after death (diagnosed at autopsy).

2. PML was diagnosed in the remaining 6 patients while they were still alive. Major immunosuppressant therapy (azathiopine, cyclosporin, cyclophosphamide, Ara-C etc) was stopped in 5 patients.
All 5 recovered!

3. Major iimmunosuppressant therapy was not stopped in 1 of the patients cited in Item 2, presumably in an effort to save the failing transplanted kidney of the patient. This patient died.

4. Mild immunosuppressants (steroids) were continued in 4 of the 5 patients who survived. Yet, the PML resolved in these patients and they recovered.

It is clear that discontinuation of major immunosuppressant therapy in patients diagnosed with PML permits them to recover and survive. This is contrary to the myth that PML is invariably fatal.
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Does anyone know the current status of the second Tysabri/Avonex combo patient who obtained PML? Apparently the patient had recovered to some degree but that info is about a month old.

Harry

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Question to FDA from an MS patient

Question to FDA
I’ve received Tysabri for my MS. Am I going to develop PML?

FDA reply: Although the risk, if any, of PML in patients receiving Tysabri is not known, it is important to recognize that only two confirmed cases of PML have been identified from among over 8000 patients who have received Tysabri. Patients should, however, discontinue use of Tysabri until further notification.
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Better,



And that, in a nutshell, is the BIG problem!! Until someone comes up with a scientific answer to that problem, MS patients won't likely see Tysabri available.

Harry

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Comments from an Pathologist / Virologist


"I think this type of PML hunt is rather overblown

I think we are on the cusp of new medical literature concerning PML in MS - also there are a few good MS autopsy studies that show that immune suppressed MS patients (especially those with CCR5 mutations) die much sooner than patients with normal immune systems - also from a path point of view MS looks just like PML unless you can find JC virus in the oligodendrocytes - the problem is that the PML diagnosis criteria is pretty fuzzy - (like patient 3 never actually reached the bar for being called a PML case)

Also given that 40% of normal people have JC virus in their brain, and another 10-40% can show JC virus that is PCR amplifiable in their CSF also makes the diagnosis of PML very tricky - my view is that the re-review actually cannot find any new cases unless patients are exhibiting severe neurological decline and those patients would have been reviewed first - so Mullen's comments preclude those from being called PML cases.

Also there have been rumors of PML occurring in MS patients on no MS treatments and if that is true when it hits the news it is going to make PML a much more common diagnostic entity - a few people I have talked to think that many more elderly people develop PML but it is mis-read as a stroke and they are sent to nursing homes where they decline and die and the PML is never diagnosed - you also have to remember that there are more than 10 diagnostic entities associated with demyelination.

Suffice to say PML is about to become a much more common and better understood entity over the next 6 months and this will remove the uncertainty of tysabri association with PML - one thing is quite clear and that is that tysabri cannot cause PML - it may allow immune suppression in some combination therapy and that can be monitored rather easily."
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[quote="better2gether"].
Comments from an Pathologist / Virologist

Better,

This doc sounds a bit scary...


"I THINK this type of PML hunt is rather overblown"

"I THINK we are on the cusp of new medical literature concerning PML in "

"Also there have been RUMORS of PML occurring in MS patients on no MS treatments"

"a few people I have talked to THINK that many more elderly people develop PML but it is mis-read as a stroke "

"one thing is QUITE CLEAR clear and that is that tysabri cannot cause PML -it may allow immune suppression in some combination therapy and that can be monitored rather easily."


Yet another PML expert was quoted at the AAN conference as stating that Tysabri did indeed cause the PML. Probably a good idea to see what comes out of all the current investigation that is being done.

Harry

Better,

This doc sounds a bit scary...


"I THINK this type of PML hunt is rather overblown"

"I THINK we are on the cusp of new medical literature concerning PML in "

"Also there have been RUMORS of PML occurring in MS patients on no MS treatments"

"a few people I have talked to THINK that many more elderly people develop PML but it is mis-read as a stroke "

"one thing is QUITE CLEAR clear and that is that tysabri cannot cause PML -it may allow immune suppression in some combination therapy and that can be monitored rather easily."


Yet another PML expert was quoted at the AAN conference as stating that Tysabri did indeed cause the PML. Probably a good idea to see what comes out of all the current investigation that is being done.

Harry

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New York Times
06/10/05 05:33 am

Doubt Cast on 4th Case of Illness on M.S. Drug

By ANDREW POLLACK
Published: June 10, 2005

A Biogen Idec official has sent an e-mail message to neurologists suggesting that a suspected fourth case of a brain infection in a patient taking the drug Tysabri was a false alarm, according to two doctors who received the message. The e-mail message said the patient was shopping when she heard news reports last week that she had the potentially fatal infection.

http://www.nytimes.com/2005/06/10/busin ... iogen.html
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