call me crazy
by: pinvestment 08/12/05 03:11 pm
Msg: 743066 of 743066
but listen to this argument
the rumored story about a rumored patient involves a commercial combo patient - that means this patient was failing therapy on beta inf then go between one and three doses of tysabri in combination with avonex - upon cessation of ty sales my guess is that this patient would be put on avonex and/or something else
if you remember patient 3 - this person took remicade and AZA after a long course of other treatments - but despite that history after just a few doses of tysabri in the second course he developed PML and it was blamed on tysabri
so if you are going to use that a suitable model for assignging blame - then in this case tysabri has nothing to do with this PML case (if it is real) and this PML case should be blamed on the treatment that was being given prior to developing the disease
the tysabri effect was long gone months before this episode occurred so take the drugs this patient was on in the last three months and write the article about how those MS drugs caused a PML case
so if this patient was on beta interferon - this is now the first confirmed case of PML caused by beta interferon alone - and thus the tysabri blame should be removed - maybe a safety review of all the beta interferon patients that died should be re-reviewed while beta interferon is taken off the market
fair is fair after all
now that would be a shocker to BIIB - that would cause 1.4 billion in yearly sales to disappear
Thank you Bio for your prompt reply. My training was in Chemical Engineering and bio experience is limited to having worked briefly in Pharmaceuticals over 50 years ago and then recently undergone treatment for NHL. Your explanation shows how complex Beta Interferon treatment is. The bottom line is that Biib and Eln now understand how to solve this problem using blood screening of prospective Tysabri patients as you outlined earlier today. Nothing is perfect as far as safety is concerned but I believe that both these companies have behaved well especially in light of what happened earlier to Merck when they pulled Vioxx.
Well, that "new 4th case" (there were already "new 4th" and "new 5th" in the recent past both proven fake ones) has been dissected and analysed by lots of longs with significant available information and consider to be another NEW FAKE pml. It seems to be a case of worsening MS (patient was already a failure on avonex, that is why She got one dose of Ty during the commercial release). Her blindness seems to be optic neuritis (a severe MS complication) and her general status (not hospitalized, "saw her Neurologists last thursday") does not correlate at all with pml. The MRI lesions seems to be worsening MS. Caveat all these information and explanations are from several posters over the Elan ymb, but quite reasonable to me.
The fact that the market sent both stocks higher today seems to be that the market already more than dysregarded the idea that it is pml.
The unfortunate patient probable needs more Ty for her worsening pml. She has been getting lots of steroids (another sign is not pml, her physician should stop steroids on her, if He/She thinks pml is the reason for the season). Or Novantrone, or Betaseron, or Rebiff...
Then one should discard the idea that this is "another pml case", much less attribute a fake pml to Avonex.
The whole data base for Avonex was review and Biib publically said: no pml cases. Probably, Chiron (Betaseron), and Serono (Rebiff) already look on their own databases without publick acknoledgement (or mandated to do so by the FDA). The notion that the Fda would not have look into it is not feasible in my view.
Is it valuable from a more independent source (NIH, Academics, Outside FDA panel, Fda panel)to formally check into ALL the beta-interferons databases, and especially, as pin suggests, into the hundredes of death recorded over 10 plus years of beta-interferons used in more than 200,000 patients, to find few cases of pml (I extremely doubt there will be even a dozen cases, and even fewer related to "pure beta interferons treatment")??? Well, maybe it is worth it, I will say myself GO AHEAD, and find the "cleaning tool for Ty???, I strongly doubt all that. Pml could be missed once (like the CD subject), but eventually a clearcut association (I not talking causality, and I do believ Ty is part of the causality in Combo induced pml) would have been found, a small cluster of 3 to 5 pmls would not have been missed (my view) over more than a decade of extended commercial view, and with the research time 2 decades of observational time, in a group of drug highly scrutinized by the FDA and competitors.
Do you think that Teva will not immediately blame every beta-interferon out there? Their drug is not one of them.
Do you think that Serono will not blame Avonex IF IT COULD ??? ZERO doubt if they could, they already would have done it.
Do you think Chiron will not blame Avonex and Rebiff (boths interferons 1a) and keep its own Betaseron (interferon 1b)out of the circle of pml friendly drugs, and recuperate a market they have been losing seems Avonex, and Rebiff came out???? ZERO doubt Chiron will attack anyone else drug.
A conspiracy among all of them to hide the bunches of pml ??? Beyond believe, not possible. This companies can not hide a trading secret despite the SEC, FBI, IRS, NASA...
I just do not see the beta interferon "pml cases" hiding out there !!!
Question for you or anyone knowledgeable on the following:
Would treatment of immunocompromised patients on Betainterfereons and or steroids have their situation improved with drugs like Amgen's Neulasta 0r Aranesp? I know that both red and white blood cells are depleted during Chemo for cancer teatment and these drugs are great for improving both these bloodcounts. So my question asks whether any significant improvement is possible for MS patients that have been long term on beta or steroids. The Chrons patient no doubt was badly immunosuppressed but I'm not certain at all what the degree or type of Immune system suppression or modulation is with beta.
Thanks in advance for your response.
1. Forgert "Tysabri is inocent", "Tysabri didn't do it", "Ty mono is safe". Yes, all of the above because I am an Elan holder.
BUT, the "PUBLIC" WANTS MORE. Patients, researchers clinicians, wallstreeters, marketeers, class action suit lawyers (and defending lawyers ), the companies, the Fda agents, the journalists, the analysts, investors, mutual fund managers, hedge fund managers.
2. A blood PANEL of tests with the back up of Koralnic, Atwood, and other Pml and MS experts is a reaasurance to all.
3. A blood PANEL of tests will allow a SAFER and BIGGER market for Tysabri.
4. Patients will give their blood samples about each time they go for infusions (monthly to quarterly).
5. That will allow for a massive Phase IV study (and not so expensive) of several dozens of thousands of subjects worldwide.
6. It will allow for COMBO subjects. You will think that COMBO will be gone, just because the drugs will not be given concurrently? WRONG !
If a subject has been for YEARS on beta-interferons and now the drug is stop for 2 months of washout period, is it a true MONO subject ???
If the putative effects on the immune system of the beta-interferons are long lasting, then MONO is a very relative term.
Patients can not way for too long to go on effective treatment when they are failing other drugs, steroids will be given during the "washout" periods, but steroids are a risk on their own!!!
It is even more relevant for CD subjects, AZA, Remicade, Enbrel...other TNF blockers...their actions are persistent for months (years for AZA), but do not come with the argument that the AZA+Tysabri is "not a tysabri" patient, IT IS, IT IS ANOTHER COMBO one (yes, AZA is very well related to JC, and so it seems to be Ty in combo). What about Lupus, Arthritis, Asthma, Heart Disease and many other disorders that will plausibly be target by Ty? They will be RELATIVE COMBOS with many variables, not all the drugs from the past could be simply erase in few weeks or months, patients can not wait for improvements.
The CD AZA+Ty combo was lethal, IF at the time, with current insight and hindsight, the Mad-JC test detected viremia in high specific loads, and low JC specific CD4 and/or CD8 numbers the action would have been: MRI, read MRI with high index of suspiciousness, CSF tap mad-jc test, Stop Ty, Avoid Steroids, give IVIG, give Risperdal (safe alternative to chlorpromazine), give Cytarabine AND the outcome would probably been very different, alive and low dissability from mad-jc-pml if any.
LOok at MS case pml #2, the measures were taken relatively late, survival acchieved, but significant severe dissability is the outcome.
Look at MS case pml#1, no suspiciousness untill very late, steroids ongoing at higher doses, Ty stop at the very end, no other anti-jc measures, resulted in the unfortunate death of the affected woman.
In a couple of years, vaccines and jc-spefic therapeutics will have a more focus approach, more pro-active and effective.
The viral measurement references show that:
1. Measuring Mad-JC dna vs archetypal dna in blood (plasma and cells) is effective for prognosis, both types of predictive value (positive ones will go on to pml, or worse pml)(negative ones will not developed pml, or improve once pml is in).
2. The "high rate" of positive jc dna in blood mentioned in some studies is due to non specific tests, check the 0.9% results (one of the references shown before) for normal blood donors, vs high rates for immunocompromised non pml, and higher for pml subjects. And this 0.9% is ARCHETYPAL JC.
Testing for MAD-JC is the way to specificity and prognosis value.
3. Viral loads numbers actually increases the specificity of a blood test as predictor for pml (development and evolution).
4. Adding jc specific CD4 and CD8 activity (more expense, but not so much, and available) could add to a blood test PANEL.
5. The PANEL will test for Mad-jc in blood (cells and plasma), and Jc specific CD4 and CD8. It will become a powerful, sensitive, specific and predictive tool for evaluation pre-, during and post-therapy, pre-, during and post-pml.
6. EVEN COMBO use could turn to be manageable this way. All of you think that JM is crazy, but He has much more information than all of you.
7. The case for IVIG, 5HT2a blockers, and vaccines will be explore in a next occasion. But vaccines could turn to be the way to handle this cases before/during Tysabri use.
"J Virol. 2000 Mar;74(5):2288-92. JC virus enters human glial cells by clathrin-dependent receptor-mediated endocytosis.
Pho MT, Ashok A, Atwood WJ.
Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA.
The human polyomavirus JC virus (JCV) is the etiologic agent of a fatal central nervous system (CNS) demyelinating disease known as progressive multifocal leukoencephalopathy (PML). PML occurs predominantly in immunosuppressed patients and has increased dramatically as a result of the AIDS pandemic. The major target cell of JCV infection and lytic replication in the CNS is the oligodendrocyte. The mechanisms by which JCV initiates and establishes infection of these glial cells are not understood. The initial interaction between JCV and glial cells involves virus binding to N-linked glycoproteins containing terminal alpha(2-6)-linked sialic acids. The subsequent steps of entry and targeting of the viral genome to the nucleus have not been described. In this report, we compare the kinetics and mechanisms of infectious entry of JCV into human glial cells with that of the related polyomavirus, simian virus 40 (SV40). We demonstrate that JCV, unlike SV40, enters glial cells by receptor-mediated clathrin-dependent endocytosis."
Clathrin is used by sVCAM-1 to bring messages to the nucleus of a cell (block by Tysabri), and is used by Gamma Interferon (decrease levels from Avonex actions). Decrease Gamma interferon is proven as one of the reasons that Aids patients end up with Pml.
Chlorpromazine (and the safer atypicals) could block BOTH the serotonin outer membrane receptors of a cell, and the Chlatrin inner nucleus system. Proven both by Atwood.