13th Case of PM from Tysabri posted today; June 26th [Archive]

Lady

06-27-2009, 02:40 AM

This is EX-US, but they do have a protocol program for Tysabri use, just like the US does. I don't understand why so many are getting PML.

Tysabri Outreach Unified Commitment to Health (TOUCH) in the United States

and Tysabri Global Observational Program in Safety (TYGRIS) for the global cohort.

They probably use the same methods as we do. Were these people unconfirmed and being tested?--or has the length of time on TY starting to matter?

Article by Dr Lily Jung

Careful Patient Selection

Asked for comment on this latest development, Lily Jung, MD, a neurologist specializing in MS at the Swedish Neuroscience Institute, in Seattle, Washington, speaking on behalf of the American Academy of Neurology, pointed out that natalizumab is a very effective drug. "Risks are present with any medication, and for each patient we should think about the risks and indications for the drug," Dr. Jung told Medscape Neurology & Neurosurgery.

"These new cases of PML emphasize the importance of carefully identifying patients with active relapsing disease who would most benefit from the drug and in whom the risks are therefore considered worthwhile," she said. "It has made all of us think more carefully and discuss with each patient the potential risks of PML with Tysabri."

She added that drug holidays have not been proven as useful with natalizumab. In patients who resumed treatment after the drug was rereleased, she noted, the development of neutralizing antibodies was more common than among those who did not go on and off the drug.

Dr. Jung reports speaking on behalf of Biogen and Teva and consulting with Seronon over the past year.
Lady

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komokazi

06-27-2009, 09:17 AM

Tysabri Global Observational Program in Safety (TYGRIS), I believe is primarily a formal data collection mechanism unlike TOUCH which is a formal drug control process (both for initial and subsequent dosing). TYGRIS is also voluntary where TOUCH is mandatory. In the detailed PML patient summaries, EU patients received more Tysabri after new or worsening symptoms which wouldn't occur under TOUCH. Some of the EU patients also received steroids prior to ruling out PML which also is a no no but not necessarily driven by TOUCH.

calcal

06-27-2009, 12:13 PM

In the detailed PML patient summaries, EU patients received more Tysabri after new or worsening symptoms which wouldn't occur under TOUCH. Some of the EU patients also received steroids prior to ruling out PML which also is a no no but not necessarily driven by TOUCH.

But these differences wouldn't have anything to do with these patients developing PML since both of those events (receiving more Tysabri after worsening symptoms or receiving steroids prior to ruling out PML) only could occur AFTER the patient already had PML.

So that information doesn't shed any light in figuring out why patients outside of the US might be more susceptible to PML than those in the US.

I wonder if the risk of PML outside of the US then is much higher than 1:1000.

komokazi

06-27-2009, 01:50 PM

Not suggesting that the steriods caused the PML, just that they worsen the potential outcome and EU docs are still giving them before ruling out PML.

Not sure why 4 EU patients with similar drug exposure developed PML at around the same time

Apr 15, 2009 - 31 months started Sep 06
Jun 10, 2009 - ~32 months started Nov 06
Jun 19, 2009 - ~31 months started Oct 06
Jun 23, 2009 - 30 months started Jan 07

Odd given that there have been 0 US cases in the exposure timeframe even though there are more US patients in this treatment window. Certainly suggests that it is something unique to the EU. The clustering of patients could provide some clues as to what triggers the JC virus in the first place. Did they all have weakened immune systems from similar reasons - flus, other illnesses? Did they all take similar drugs which reduced the clearance of Tysabri?

Just a heads up that I'm in the 31 month Tysabri exposure time.

calcal

06-27-2009, 02:07 PM

Not suggesting that the steriods caused the PML, just that they worsen the potential outcome and EU docs are still giving them before ruling out PML.

No, I'm not saying that that is what you were saying at all. But those two factors couldn't have anything do to with susceptibility to PML outside the US since both of those actions (continuing Tysabri or giving steroids) would occur AFTER the person is already demonstrating symptoms of PML, i.e., after they already had developed it and implemented in RESPONSE to symptoms of PML. Those actions may exacerbate PML, but they didn't influence whether the patient developed it or not.

So they can't be risk factors in why there are more cases suddenly outside of the US since they don't shed any light on how or why the person developed PML in the first place, only what the response is to symptoms of PML once it's already developed.

The clustering of patients could provide some clues as to what triggers the JC virus in the first place. Did they all have weakened immune systems from similar reasons - flus, other illnesses? Did they all take similar drugs which reduced the clearance of Tysabri?

I didn't think having the flu predisposed a person with the JC virus to develop PML. That would be pretty scary if that were the case and I would imagine that flu vaccinations would be mandatory for Ty-users if that were true.

I don't think the answer to predisposing factors is going to be as easy as any of the reasons you've given. I'm sure their backgrounds, etc. have all been looked at pretty closely, so I think those questions would have been the first ones that were asked of the very first group of people who developed PML before the results of the fast track application was completed. All they had come up with is some of those people had had prior exposure to immune-suppressing treatments. Now others have developed it without any prior exposure to immune-suppressing treatments. And steroids are even permitted to deal with relapses during Tysabri treatments.

It doesn't look like there have been any commonalities at all between ALL of those who have developed PML. Except if more people are developing it the longer they are on Ty, then it could well be that your risk of developing PML goes up significantly the longer you are on it - obviously Tysabri would be the culprit and the causal connection. I don't see the TOUCH program influencing the risks of developing PML since it is mostly it seems just a monitoring program, not any kind of program that would prevent PML from occurring since people have developed PML with no prior exposure to immune-suppressing drugs. The TOUCH program seems to be trying to have a proactive approach to try to identify PML as quickly as possible, but I don't see the program preventing it from happening.

mmcc53

06-27-2009, 02:45 PM

In the US, the dose of Tysabri is set, not a fluctuating issue - PML, worsening MS, or not. That is clearly stated in the TOUCH program and CANNOT be overridden by a doctor.

Worsening MS is NOT the same thing as PML, BTW, even in Europe.

Also when cases as so closely clustered and ALL in the non-US population, you certainly do have the ask why.

Does anyone know if these people who developed PML were given a larger than standard Tysabri dose?

Steroids to deal with a relapse are permitted under the touch program, so that is probably not the answer.

lady_express_44

06-27-2009, 03:16 PM

Awesome post, Calcal.

Lady, the purpose of TYGRIS was detailed in Biogen's Risk Plan, but I'm not sure if this ended up being the final goal of the Study:

TYSABRI Observational Cohort Study Purpose: Evaluation of TYSABRI long-term safety in clinical practice setting

♦ Subset of patients in TYSABRI Registry will enroll into this voluntary observational cohort study
♦ 5000 MS patients worldwide (3000 in US) followed for 5 years
♦ Powered to detect rare events with incidence of 0.06%
♦ Collects all serious adverse events and concomitant immunomodulatory and immunosuppressant therapies
♦ Assess risk of serious infections and malignancies
♦ Investigate potential signals of unanticipated adverse events

http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4208S1-01-04-%20Biogen-Bozic.pdf

Last I heard, it included patients from the EU, Canada and the US, with Germany having the largest number of enrolled patients to date:

http://www.neura.net/channels/1.asp?id=942

I know Canada has "CARE" (similar to TOUCH), which I was told was something that Biogen set up here (as well as the infusion centers), so I would be surprised if the EU doesn't have adequate monitoring as well. But, as you pointed out Calcal, that isn't going to change the # of cases, just the potential outcome of them.

I haven't seen any evidence that people in the EU are getting a different dosage than Americans/Canadians ... and why would any country circumvent the manufacturer recommended dosage anyway, given the risks? :eek:

"The recommended dose of TYSABRIÒ is 300 mg IV infusion every four weeks. Dilute TYSABRIÒ concentrate 300 mg/15 mL in 100 mL 0.9% Sodium Chloride Injection, USP, and infuse over approximately one hour. Do not administer TYSABRIÒ as an IV push or bolus injection (see Preparation Instructions) .

Observe patients during the infusion and for 1 hour after the infusion is complete. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction (see WARNINGS, Hypersensitivity)."

http://www.rxlist.com/tysabri-drug.htm#ad

I think there is detailed information available on the net about the first few EU cases ... so maybe I'll have a look and see if it provides dosage information for them anyway...

Cherie

mmcc53

06-28-2009, 04:26 PM

There is a big difference betweem Tygris and Touch, as someone pointed out.

Curious. LE44, that you ASSUME Canada is doing the same thing as TOUCH. You live in Canada. Why don't you find out what the program is. And how many Canadians have gotten PML?

You yourself talked about "varying doseages." In the US that is forbidden, not left to a doctor's discretion. That is a MASSIVE difference.

What is the percent of PML cases among US Tysabri users since Tysabri came back on the market with requirements to ensure it is a mono-use drug and that there must be a washout time???? What is it for non-US users? How do you explain that difference. The evidence points to the TOUCH program being very effective in substantially reducing the PML cases in the US, to way below the stated risk of 1 in 1,000. Fact is that so far it isn't even close to that level of risk.

Instead on continue the anti-Tysabri tirades backed up largely, but "I assume," "I think," etc. Why don't you look into the huge difference in PML by those in the US who are required to follow TOUCH and the other countries where that is not so?

Trying to force all counties to follow TOUCH may be more effective in reducing the risk of PML than anything else.

marcstck

06-28-2009, 05:53 PM

The TOUCH program does nothing to prevent people from getting PML. It is designed to catch cases of PML early on, potentially before they turn lethal. I think that is one of the biggest misunderstandings people have about the whole Tysabri issue. TOUCH does not prevent the contraction of PML. It is strictly a monitoring program, not a preventive one...

My neurologist routinely does six-month spinal taps on all of his Tysabri patients, in an attempt to find activated JC virus. If such a find is made, the patient is pulled off the drug immediately. His is the most proactive protocol I've heard of in attempting to prevent PML in Tysabri patients. Here's a link to information regarding a clinical study he did in this regard...

http://www.msrcny.org/pdfs/JC-BK_virus_in_MS_4-08.pdf

As a matter of disclosure, I did six doses of Tysabri back in the fall of 2006. It didn't help me at all, but then again I have progressive disease. It is still entirely at the doctors discretion as to which patients they put on Tysabri...

I am now on Rituxan, which also carries with it the risk of PML. Again, this drug has done nothing for me...

As for the discrepancy between the US and foreign PML cases, the cynic in me has a hunch that there have been US PML cases that have not been officially reported. There have been anecdotal reports of "suspected PML cases", but there have been no follow-ups on those reports. As I said, this is just a hunch, I'm not stating it is a fact, and have no evidence to back it up. I just offered it up as a possible explanation for the discrepancy in the incidence of PML seen between European and US Tysabri patients...

Whatever the case, it does appear clear that the risk of PML rises with the duration of treatment...

I expect we'll also see cases of PML in some of the oral agents that are now nearing approval, such as FTY 720 and cladribine. Many drugs that significantly suppress the immune system leave us open to opportunistic infections such as PML...

Ikoiko

06-28-2009, 06:32 PM

lady_express_44

06-28-2009, 08:31 PM

I am going to disagree here. I think TOUCH is designed to prevent PML. Before each monthly infusion, you are asked a series of questions, including, are you sick now, and in the last month have you taken any immunosuppressive drugs (they have a list). If you answer "yes," they will not go ahead with the infusion.

That would be like saying "if a person has an abortion, miscarriage, or stillborn child ... they were never really pregnant".

Asking questions isn’t going to PREVENT PML. The best that could be hoped for by asking these question is that the PML is going to be caught early.

By the time the neuro is told “yes, I am having difficulty thinking”, “aphasia”, or “sudden left side weakness”, the PML is already underway. At that point the neuro would (if he followed Biogen’s advice) take the person off of Tysabri, PERHAPS do a MRI, and PERHAPS give them PLEX as a safety precaution. Some neuro’s might also do CSF testing, which quite often shows “negative” for PML/JC the first time or two anyway ... so it is very possible that some people will carry on none the wiser that the PML is there.

A patient might never know that they actually have a PML lesion, because a PML lesion can often be mistaken for MS one ... and any new activity is likely to be “assumed” to be from the MS, not from the PML progressing.

I agree with Marc that there are likely a number of people in the US (and maybe even elsewhere) that are in this situation, because who has ultimate accountability for following up to ensure the person had/didn’t have PML; the doctor, the patient, the infusion center, Biogen, ANYONE?

We had this discussion in depth a few months ago actually:

http://brain.hastypastry.net/forums/showthread.php?t=53623&highlight=tysabri

As far as the TOUCH program being any more foolproof than the protocol elsewhere in the world, I can't speak specifically for Europe because I don’t know what happens there. What I do know about the Canadian monitoring system, "CARE", it is a Biogen-managed program like TOUCH (as are apparently our infusion centers), and CARE provides for:

- 1-800 Customer Service line
- Manufacturer recommended dosages, scheduling, and administration protocol for the drug
- Questions asked at every infusion
- Generally recommended wash-out periods, with neuro discretion (JUST like the US)
- Regular MS Specialist checks (monthly, in the case of my MS Specialist)
- Immediate requirement to take a patient off Tysabri when there are problems
- Treatment with PLEX (or other established methods)
- PML testing; CSF, MRI, etc.

I went over all of that in the following thread already, http://brain.hastypastry.net/forums/showthread.php?t=59778&page=2 and what we are waiting on is for mmcc to prove there was something more to the US program. Not sure why she doesnt just “request this information from the FDA or her neuro”, like she told me to ... but for some reason she has opted to wait till her next appointment to obtain a copy of the 'FDA established and unnegotiable requirements for TOUCH wash-out period for each drug'.

In the meantime, if there is something "special" going on with TOUCH in the US, beyond what I've listed (above), just let me know and I will follow up here in Canada to see what is happening in that regard.

I do not recall ever having considered that they might be administering different dosages of Tysabri in other countries. Provide a link to anything that I may have said that may have given anyone the impression that I was seriously concerned about that ...

All countries are using Tysabri are using it as a monotherapy, UNLESS perhaps the patient is part of a trial that is combining therapies (for the purposes of a trial).

Regardless, every person that has come down with PML since the trials has been on monotherapy. There have been various means used to try to manage the PML/relapse symptoms that the patient presented with (mirtazapine, steroids, PLEX, etc) .... but those treatments have NO BEARING WHAT-SO-EVER on whether the person actually had PML to begin with . . . just perhaps whether the PML patient absolutely needs know that they do.

Cherie

Ikoiko

06-28-2009, 08:36 PM

calcal

06-28-2009, 08:53 PM

Thanks Ikoiko for that info!

lady_express_44

06-28-2009, 09:48 PM

Some of the questions ARE to prevent PLM: example, if you have taken any immunosuppressive drugs in the past month you ARE more at risk for PML. Also, you may be more at risk if your immune system is down with the flu, etc. So if you answer "Yes," they don't do the infusion.

Theoretically, I suppose.

They don't know what causes PML with Tysabri yet. It may be that some people are going to get it with this drug no matter what they do or don't do ... just like allergic reactions don't happen for everyone.

8:8,200 (1,400 from the trials, and 6,800 post-marketing) who have been on Tysabri for longer than 24 months have come down with PML. It may simply be that the longer a person is on, the more risk there is.

It was initially implied that it could have been because of the Avonex/Tysabri combination (which is the reason that combo-therapy is not generally permitted) ... until someone got PML with monotherapy.

Then it was suggested it was due to the use of prior immunosuppressants ... until someone got it and was drug naive.

I'm glad that they suggest most people don't take Tysabri when they are sick ... but I have heard of several people who couldn't get a straight answer in that regard too. In one case where a lady was unwell, her neuro, the infusion center, and Biogen all opted out of recommending what she should do at infusion time.

When people are sick, the infusion center apparently recommends the patient contact their neuro, then the decision is up to him/her. Some have continued on with infusions as scheduled, but in most cases that I've heard of, even when the neuro said it was a go, the patients have chosen not to anyway.

At least one (if not two) of the EU patients that came down with PML were in TYGRIS, and two were in the Biogen's STRATA extention study. These people must be being monitored too.

I just read a full summary on all (but the last) of the 13 PML patients to date; including prior drugs used, symptoms they presented with, drugs they were treated with, tests that were done ... In that summary (that is intended for doctor use only), they STILL feel they do not have enough information to understand why some have come down with PML.

Cherie

(Those same 4 questions are asked her in Canada, and very likely in the EU as well).

Ikoiko

06-28-2009, 10:37 PM

They DO know that PML is more common in immunosuppressed people. HIV+ patients, for example. Those on other immunosuppressive drugs, for another example. And *of course* Tysabri is a risk factor for PML.

lady_express_44

06-28-2009, 10:47 PM

They DO know that PML is more common in immunosuppressed people. HIV+ patients, for example. Those on other immunosuppressive drugs, for another example. And of course Tysabri is a risk factor for PML.

True enough ... but it may simply b that Tysabri that will cause PML, in spite of any prior drugs, wash-out periods, etc. That seems apparent by the fact that the one guy was drug naive.

But I agree that any extra precautions in this regard can only be a good thing.

Cherie

Ikoiko

06-28-2009, 10:52 PM

Yes! Tysabri is a risk factor for PML!

No one is disputing that.

marcstck

06-29-2009, 02:44 AM

Lady

06-29-2009, 02:52 AM

Trying to get my head around all this late night reading. Almost 3 am here.

We know Tysabri is a risk factor for PML, that is definitely agreed upon.

I was reading the general information on how Tysabri works.

"Natalizumab is a monoclonal antibody directed against the 4-integrin chain of the very late activation antigen 4 (VLA-4) dimer on lymphocytes thus preventing entry into the central nervous system and other end organs."

So it seems that it targets the very cells which are there to keep latent viruses in check. That is why JCV can also reactivate, to cause PML in patients using the drug, IMO.

So if Tysabri targets VLA4, and VLA4 is extremely important because it mediates T cell migration into the brain when there is a need for those T cells in the brain to fight infection, there you go. :)

What if there is an active infection going on in the brain? Suppressing VLA4 leaves us open to the risk of a CNS infection turning lethal, and also of other viruses that lay latent in the brain becoming active.

This is why IMO, why PML is a problem with the use of Tysabri. Ty attacks the very cells we need to fight infection.

I hope some people can be detected early, for let's say JCV, or tested for it before and while on Tysabri, with a LP. Or Tysabri is stopped at the very first symptom of an abnormality. Not waiting, thinking it is a relapse as a first thought, and perhaps feeding the JCV steroids which would compromise the immune system even further.
Lady

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Lady

06-29-2009, 03:03 AM

Marc, you typed a nice quick answer, while I was typing my heart out on here thinking the same thing about the T-cells being suppressed.

Posting 8 minutes after you. :)

I didn't know how long the T-cells were suppressed for. You said 6 months after the drug is stopped? That sure doesn't help in the recovery efforts for these people who get PML.
Thanks for that information. Were you tested for that?
Lady

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komokazi

06-29-2009, 07:43 AM

Since Tysabri suppresses T cell surveillance of the immune system for about six months after a patient ceases taking it (as it did when I stopped taking it), skipping a dose because a patient has "taken an immunosuppressive drug", or has the flu, will not likely prevent the onset of PML.

Though there may be some ancillary preventative aspects of the program, at its core, TOUCH is meant to detect PML, not prevent it...

Marc,

Beg to differ. If Tysabri's effect was 6 months, they wouldn't be performing PLEX to reduce Tysabri in the system. Further evidence that the immune system recovers quickly - Immune Reconstitution Inflamatory System IRIS occurs weeks after PLEX as the immune system mounts its attack.

Chris

mmcc53

06-29-2009, 10:12 AM

The TOUCH program does nothing to prevent people from getting PML. It is designed to catch cases of PML early on, potentially before they turn lethal. I think that is one of the biggest misunderstandings people have about the whole Tysabri issue. TOUCH does not prevent the contraction of PML. It is strictly a monitoring program, not a preventive one... This is NOT correct. Yes, it is designed to catch potential cases of PML early. but it is also designed to reduce the chances of contracting PML in the first place. Nothing can PREVENT catching PML as the TOUCH program makes clear, but some of the features of TOUCH appear to be working when it comes to REDUCING the chances. Check the data - US PML cases vs. non-US.

As a matter of disclosure, I did six doses of Tysabri back in the fall of 2006. It didn't help me at all, but then again I have progressive disease. It is still entirely at the doctors discretion as to which patients they put on Tysabri... Tysabri is for people with "relapsing MS." Lots of doctors keep patients listed in their records as RR so they can try the various drugs on them, but it is approved for "relapsing," not ALL MS.

As for the discrepancy between the US and foreign PML cases, the cynic in me has a hunch that there have been US PML cases that have not been officially reported. There have been anecdotal reports of "suspected PML cases", but there have been no follow-ups on those reports. As I said, this is just a hunch, I'm not stating it is a fact, and have no evidence to back it up. I just offered it up as a possible explanation for the discrepancy in the incidence of PML seen between European and US Tysabri patients... C'mon. an internet rumor with ABSOLUTELY NO EVIDENCE is an absurd theory. Why do you think this would happen here and not in Europe???? Are our doctors part of a vast conspiracy that the European doctors are not.

If you are going to repeat these paranoid theories, how about ONE SINGLE BIT of back up information - a patient name, a doctor name, etc.

There are reports of alien sitings in the US, too. - they at least frequently come with "photos."

mmcc53

06-29-2009, 10:25 AM

Theoretically, I suppose.

They don't know what causes PML with Tysabri yet. It may be that some people are going to get it with this drug no matter what they do or don't do ... just like allergic reactions don't happen for everyone. Sure they know - impaired immune systems. That is one reason that AIDs patients are so prone to it

It was initially implied that it could have been because of the Avonex/Tysabri combination (which is the reason that combo-therapy is not generally permitted) ... until someone got PML with monotherapy. Not quite. Based on the best scientific evidence - an oversuppressed immune system makes PML more likely. Therefore IN THE US you CANNOT take Tysabri until other immunosuppressant drugs are washed out of your system. Will this PREVENT PML? No. Will it reduce the chances of getting - it appears that it does.

I'm glad that they suggest most people don't take Tysabri when they are sick ... but I have heard of several people who couldn't get a straight answer in that regard too. In one case where a lady was unwell, her neuro, the infusion center, and Biogen all opted out of recommending what she should do at infusion time. That cannot be the case, if this happened in the US. When the time for the infusion came up, SOMEONE had to say yes or no. If you READ the TOUCH material - it is REQUIRED that the doctor make that determination. It is not a choice left to the patient, unless the partient does not want Tysabri. In other words the doctor must make a determination that the infusion will or will not be permitted. As with any drug, the patient can always decline. The patient cannot decide to go ahead if the doc says no.

At least one (if not two) of the EU patients that came down with PML were in TYGRIS, and two were in the Biogen's STRATA extention study. These people must be being monitored too. In the US EVERY patient is in TOUCH. You have just made it crystal clear what one big difference is.

The other is that TYGRIS is a monitorring, not preventative program. TYGRIS is used to gather data.

mmcc53

06-29-2009, 10:44 AM

...and what we are waiting on is for mmcc to prove there was something more to the US program. Not sure why she doesnt just “request this information from the FDA or her neuro”, like she told me to ... but for some reason she has opted to wait till her next appointment to obtain a copy of the 'FDA established and unnegotiable requirements for TOUCH wash-out period for each drug'. The reasons are pretty clear:

1. Unless YOU find it yourself, you do not believe ANY information which contradicts your paranoid view when it comes to Tysabri. Even then, it is reported by you as "alleged,", etc. I took Tysabri for 18 months, was enrolled in the TOUCH program, and was in the US. I saw the washout list which was shown me as part of the TOUCH review. You live in Canada, have never taken Tysabri and have never been enrolled in the TOUCH program.

You will NEVER believe it consider Tysabri, so I really don't care what your opinion of my truthfullness is. I care what information people who are seriously considering a drug with potentially serious side effects receive.

Anyone who is considering Tysabri now is very aware that they should ask about washout times for other drugs.

2. You are the one alleging that this is not true - YOU email and ask for. it in writing. The fact is the last thing you want is to confirm it is accurate or you would have gotten the info yourself a long time ago.

3. ANYONE considering Tysabri should and can get this information from their neuro before committing to take the drug and not rely on ANY information posted about Tysabri on these WEB sites without confirming it with an MS Specialist. Anyone interested can also just ask their neuro whether they are getting Tysabri or not.

4. LE 44, when you post "alleged," information or wrong information I tend to challenge it because your blind anti-Tysabri view may effect people who are trying to make a decision which can effect the course of MS and their health. YOU are not considering Tysabri, but many people are and they should not base that information on allegation and innuendo.

Lady

06-29-2009, 03:59 PM

mmcc, why are you so adamant to challenge everyone who has an opinion other than yours? You are the one who fought to get this drug back on the market, going to the FDA's, Tysabri Medical Conference, writing letters and doing everything in your power to force the FDA to allow Tysabri back on the market. Are you feeling any guilt, since you yourself then went off the drug?

You seem to be the only one, tearing apart this pleasant :rolleyes: discussion on Tysabri. Don't you think we all have a right to our ideas and opinions, just like you do? Everything is fight, fight, fight, with you. Why? Maybe an anger management course might help you define your problems. Just a suggestion.

Btw, people may be considered Progressive, but if they have Relapses, they can receive Tysabri, you should know that. Relapsing Progressive MS people, were in the case files as well as RRMS people were. It isn't only for Relapsing /Remitting MS.

So if you want, you can rip apart my opinion below too, but not the people who post it. That is not allowed.

We are here to support people with MS and help with questions from people in Limo or Newbies, not fight with them if their doctors tell them something, or they read an article and post it, or their opinion differs from yours.
Please refrain from your attacks on the people who post here.
Lady

.
Trying to get my head around all this late night reading. Almost 3 am here.

We know Tysabri is a risk factor for PML, that is definitely agreed upon.

I was reading the general information on how Tysabri works.

"Natalizumab is a monoclonal antibody directed against the 4-integrin chain of the very late activation antigen 4 (VLA-4) dimer on lymphocytes thus preventing entry into the central nervous system and other end organs."

So it seems that it targets the very cells which are there to keep latent viruses in check. That is why JCV can also reactivate, to cause PML in patients using the drug, IMO.

So if Tysabri targets VLA4, and VLA4 is extremely important because it mediates T cell migration into the brain when there is a need for those T cells in the brain to fight infection, there you go. :)

What if there is an active infection going on in the brain? Suppressing VLA4 leaves us open to the risk of a CNS infection turning lethal, and also of other viruses that lay latent in the brain becoming active.

This is why IMO, why PML is a problem with the use of Tysabri. Ty attacks the very cells we need to fight infection.

I hope some people can be detected early, for let's say JCV, or tested for it before and while on Tysabri, with a LP. Or Tysabri is stopped at the very first symptom of an abnormality. Not waiting, thinking it is a relapse as a first thought, and perhaps feeding the JCV steroids which would compromise the immune system even further.
Lady

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komokazi

06-29-2009, 05:05 PM

Lady,

I happen to agree with MMCC. It's important to get accurate information to MS patients which is why we are posting replies to writing which we believe is innaccurate or subjective in nature. We've all made different treatment decisions for our MS and those decisions color our discussions on other treatments sometimes to the detriment of those who haven't already decided.

I didn't choose to take LDN like you and Cherie did. The last thing I would do is pop in on the LDN board spouting my reasons why I didn't chose it and using every new piece of information to rationalize that decision.

Chris

snack

06-29-2009, 05:52 PM

Mam lady express you must be trying desparately to short Elan og Biogen, your news regularly comes from free business sites like yahoo. MM great, oh you are not on Tysabri and your interest is getting a little suspect. Disclaimer I do a lot of investing, don't own any MS pharma cos. not the place to be in these days with Obama. The money on Biogen was made years ago when they introduced Avonex.

MMCC53 admirable trying to defend Tysabri, though the ex lady will not give up trying to trash Tysabry and she has too much time on her hand to do this on multiple forums. I should think her credibility is shot by now with lack of information ranting. If not shorting I wonder what her agenda is.

lady_express_44

06-29-2009, 06:30 PM

lady_express_44

06-29-2009, 06:44 PM

Marc,

Beg to differ. If Tysabri's effect was 6 months, they wouldn't be performing PLEX to reduce Tysabri in the system. Further evidence that the immune system recovers quickly - Immune Reconstitution Inflamatory System IRIS occurs weeks after PLEX as the immune system mounts its attack.

Chris

I don’t understand what your point is, Chris?

I don't think most ex-Tysabri patients use PLEX, or end up with IRIS after stopping Tysabri ... only those who have PML (or who are thought to have PML).

As far as I know, PLEX is used to quickly neutralize (lack of a better word at the moment) the effects of Tysabri on the immune system, which will hopefully lead to arresting the advancement of PML in a patient. Then, IRIS develops, because of the “reconstitution” effect of the immune system.

I don’t know how long Tysabri would normally stay in one’s system, but it would seem that under normal (non-PML) circumstances, people would still have to wait to start another immune suppressing drug, like (perhaps) Novantrone, Cellcept, Rituxan ... maybe even the interferons. :confused:

I've heard of some people who’ve gone onto the interferons off Tysabri (remember Victor, Chris?), and I would think that he had to wait some period of time .... but I'll try to find out from him.

Anyone else here have to move to another drug after Tysabri? Was there a Tysabri wash-out discussed, considering we all agree that suppresses the immune system?

I didn't choose to take LDN like you and Cherie did. The last thing I would do is pop in on the LDN board spouting my reasons why I didn't chose it and using every new piece of information to rationalize that decision.

Chris

What drug any of us takes should not cause us lose our ability to be objective. Or is that another side-effect of Tysabri? :rolleyes:

Cherie

Lady

06-29-2009, 06:50 PM

Lady,

We've all made different treatment decisions for our MS and those decisions color our discussions on other treatments sometimes to the detriment of those who haven't already decided.

So I have noticed. :)

I didn't choose to take LDN like you and Cherie did. The last thing I would do is pop in on the LDN board spouting my reasons why I didn't chose it and using every new piece of information to rationalize that decision.

Chris

This is not a Tysabri Board, in case you haven't noticed. :rolleyes:

I used to be a naysayer on LDN years ago. I asked questions and gave my opinion on LDN right here on this board when they had a sticky for LDN'ers. But I did it without attacking others who made that choice to take it.

I gave reports and information, known to me at that time, while I researched it. I might have been injecting Avonex or Copaxone when that BOARD was on the old forum.

I speak of the drug only, I did not personally criticize the person for his/her opinions and reasons for their choice, or views on their drug of choice. I never tell people what to take or what not to take.

Chris, you can go on any BOARD you wish, to ask questions, to take notes, or discuss drugs. Just don't pick on people who make that choice or tear apart information YOU THINK is incorrect.

Discussions can be handled with a little finesse. Do not attack. It's not allowed. You are being monitored.
Lady

komokazi

06-29-2009, 07:30 PM

I don’t understand what your point is, Chris?

Simple. Marc claimed that the effects of Tysabri on T-cells lasted 6 months. I tried to provide examples to show this was incorrect. My body can attest to the fact that the major effects subside for me after about 3 weeks (decrease in benefit) due to the drop in the level of drug in my body. PLEX speeds this process and IRIS is proof that the immune system recovers quickly.

What drug any of us takes should not cause us lose our ability to be objective. Or is that another side-effect of Tysabri? :rolleyes:

Cherie

Perception is always in the eyes of the beholder. Rolleyes back at you for your claim of being objective.

Chris

marcstck

06-29-2009, 10:37 PM

Marc,

Beg to differ. If Tysabri's effect was 6 months, they wouldn't be performing PLEX to reduce Tysabri in the system. Further evidence that the immune system recovers quickly - Immune Reconstitution Inflamatory System IRIS occurs weeks after PLEX as the immune system mounts its attack.

Chris

You may beg to differ, but you are simply wrong. There are clinical studies that show that CNS immune surveillance is suppressed for a least six months after cessation of Tysabri therapy.

http://www.ncbi.nlm.nih.gov/pubmed/16634029

Six months after cessation of natalizumab therapy, low lymphocyte counts in the CSF persisted.

I don't think it can be stated any more clearly than that...

As I stated before, I am not an anti-Tysabri person. I took the drug for six months. It does wonderful things for some people. Along with its proven benefits, it carries an as yet unknown risk of PML infection with its use.

Only time will tell what how high this risk really is. Despite what others have argued here, TOUCH is not designed to prevent PML, but to detect it early after onset.

As the above study notes, after a patient stops taking Tysabri (and if they don't undergo plasmapheresis) the effects of Tysabri persist for at least six months. Skipping a dose if a patient has the flu, or has taken a suspect drug, would therefore not have much impact on the patients chances of contracting PML.

In fact, the reason patients are asked if they have signs of the flu is that Tysabri's immunosuppressive effects can exacerbate an influenza infection. The above study notes that immune system reconstitution occurs more quickly in the bloodstream than in the CSF of patients who cease taking Tysabri. Thus, skipping a dose could help a patient fight off a flu bug...

Ikoiko

06-30-2009, 12:27 AM

In fact, the reason patients are asked if they have signs of the flu is that Tysabri's immunosuppressive effects can exacerbate an influenza infection.

Yes this is correct. I misspoke earlier.

As for being asked if you have taken an immunosuppressive drug, I guess if you had, you would skip more than one dose of Ty, depending on the drug.

komokazi

06-30-2009, 07:34 AM

Marc,

This study suggests 3 months (97 days at the bottom) based on drug clearance levels.

CLEVELAND, Feb. 2 -- Plasmapheresis can rapidly clear natalizumab (Tysabri) from circulation, potentially offering a way to mitigate progressive multifocal leukoencephalopathy (PML), the rare, often-fatal condition triggered by the drug, researchers here said.
Action Points

* Explain to interested patients that natalizumab (Tysabri) can cause a rare but often fatal condition called progressive multifocal leukoencephalopathy.

* Point out that study participants did not have PML, meaning that the procedure's effectiveness in reducing PML severity was not directly tested.

In clinical trials, about 0.1% of patients treated with natalizumab -- approved for multiple sclerosis and Crohn's disease -- developed PML. The condition is apparently triggered by the drug's reactivation of latent infection by the JC virus. (See: DDW: No New Leukoencephalopathy Cases Seen With Natalizumab (Tysabri))

Three sessions with a plasmapheresis technology accelerated natalizumab clearance by three-fold in 12 patients with multiple sclerosis, reported Robert J. Fox, M.D., of the Cleveland Clinic, and colleagues in the Feb. 3 issue of Neurology.

After the three sessions, given over five to eight days, mean serum natalizumab levels declined to a mean of 3.2 mcg/mL. Earlier testing in the same patients showed that, in the absence of plasmapheresis, mean serum levels of the drug fell to about 19 mcg/mL during the same interval (P=0.002).

A subset of three patients -- those with natalizumab levels declining to less than 1 mcg/mL -- also showed reduced blockade of alpha-4 integrin, natalizumab's functional target, the researchers said.

Reducing the alpha-4 integrin blockade is believed to be important in restoring normal immune function and trafficking of immune sells into the CNS and, presumably, the body's ability to fight the JC virus and reduce PML severity.

Accordingly, decreased alpha-4-integrin saturation is a desired target to restore trafficking of immune cells into the CNS, which would be desired in the case of a CNS-based infection such as PML.

In the other 75% of patients, no consistent effect on alpha-4 integrin saturation was seen during the two weeks following plasmapheresis.

But all patients showed increases in transmigration of leukocytes in response to CCL-2 in vitro, a marker of immune function, suggesting that patients' immune responses were enhanced, the researchers found.

Consequently, Dr. Fox and colleagues said the findings offered a way to reduce the risk associated with natalizumab treatment.

"The results of this study suggest that plasma exchange may be effective in rapidly restoring central nervous system immune effector responses in natalizumab-treated patients, which may benefit patients with serious opportunistic infections such as PML," they wrote.

On the other hand, they noted that none of the patients in their study had PML. The study also did not address the longer-term consequences of the procedure.

The 12 MS patients were 18 to 50 years old (mean 41) and had been given at least three doses of natalizumab.

Beginning 10 to 14 days after their most recent infusion, patients underwent three sessions of plasmapheresis involving 1.5 plasma volumes each.

Natalizumab levels in serum declined by a mean of 82% (SD 8.1%) immediately after the first session, rebounding slightly during the next 24 hours to a net reduction from baseline of 65% (SD 8.3%).

In vitro studies of patients' white blood cells before and after plasmapheresis indicated that leukocyte transmigration was increased by a mean of 120% (P=0.006).

Using the data from this study, Dr. Fox and colleagues calculated that five plasmapheresis sessions would be sufficient to reduce natalizumab concentrations to less than 1 mcg/mL in 95% of patients.

Without plasmapheresis, this level of natalizumab clearance would take 97 days after drug infusion with a normal dose.

The study was funded by Biogen Idec, Elan Pharmaceuticals, and the National Institutes of Health.

lady_express_44

06-30-2009, 11:12 AM

Chris, Marc's point was that "skipping a dose because a patient has taken an immunsuppressive drug or has the flu will not likely prevent the onset of PML".

His other point was that "the reason patients are asked if they have signs of the flu is that Tysabri's immunosuppressive effects can exacerbate an influenza infection."

Your thoughts were that:

Simple. Marc claimed that the effects of Tysabri on T-cells lasted 6 months. I tried to provide examples to show this was incorrect. My body can attest to the fact that the major effects subside for me after about 3 weeks (decrease in benefit) due to the drop in the level of drug in my body. PLEX speeds this process and IRIS is proof that the immune system recovers quickly.

The study participants you linked to had used PLEX, whereas most people do not ... unless they are suspected of PML.

Either way ... 97 days or 6 months, it seems Tysabri does not STOP affecting the immune system for a some time after a person stops using it, and especially without the use of PLEX.

Cherie

marcstck

06-30-2009, 03:21 PM

Chris, the study you cite looked specifically at serum lymphocyte levels, which the study I linked to acknowledged reconstitutes faster than CNS lymphocyte levels.

In the absence of plasmapheresis treatment, after cessation of Tysabri therapy, serum lymphocyte levels appear to return to normal in about three months, but were still deficient at six months in CSF.

Since PML is an infection of the nervous system, CSF immune surveillance is more pertinent in discussions regarding it. Doubtless, plasmapheresis will hasten the return to normal lymphocyte levels in the CSF.

Most patients ceasing Tysabri, unless they are suspected of having PML, do not undergo plasmapheresis, which is a very unpleasant procedure (I did five sessions in 2006 as an attempt to beat back the progression of my disease). I think it's important for patients to realize that, after stopping Tysabri, a considerable length of time passes before their immune systems return to normal.

Here's my description of my experiences with plasmapheresis, taken from my blog:

Plasmapheresis: Now, this one was more fun than a barrel of demented, sadistic, bloodsucking monkeys. Since Multiple Sclerosis is thought to be the result of a misguided immune system, in theory, at least, stripping some of the components of the immune system from a patient's blood should result in some relief from the disease. The one thing you quickly learn when dealing with Multiple Sclerosis, though, is that "theory", and "reality" are often two entirely different things.

When I underwent plasmapheresis, blood was continuously drawn out of my left arm via an intravenous tube, fed through a machine that looked like it came straight out of a 1950s science-fiction movie, and then returned back into my body through a tube attached to my right arm. The science fiction machine stripped the blood of plasma, which contains antibodies and other immune system components, and replaced it with sterilized plasma from a blood bank.

It sounds neat and simple, but undergoing plasmapheresis was actually kind of horrific. Because a large volume of blood is needed to move through the science fiction machine, the needles stuck into my arms were the size of garden hoses, and, naturally, the nurses had trouble getting them in. This led to my having several fainting spells, and I had to go through this procedure five times in a two-week period. During one of the treatment sessions, a tube came loose, and blood, my blood, started squirting all over the room. I remember sitting there and watching the hijinks, thinking, "this would be really really funny if it wasn't MY BLOOD! MY BLOOD SQUIRTING ALL OVER THE FREAKING ROOM!” The nurses did a nice job of surreptitiously wiping the splattered blood off of the walls, as if seeing them wipe the blood off the walls would be any more upsetting to me than watching the blood get onto the walls...

After each treatment, I was hit with a fatigue more intense than any I've ever experienced before or since. It felt like it was either sleep or die.

When all was said and done, plasmapheresis did absolutely zilch for me, other than give me the unique opportunity to feel like a victim of Count Dracula. Of all the treatments I've been through, plasmapheresis was definitely the worst.

Lady

06-30-2009, 07:47 PM

Marc, that sounds awful. What a horrifying experience that must have been. Like your worst nightmare, only you are awake. :eek:

Komokazi,
You left out some information on that last post. Especially, the last few lines, which are indeed important information, and some in between also.

You ended it with this:
Without plasmapheresis, this level of natalizumab clearance would take 97 days after drug infusion with a normal dose.

To be added:
But Dr. Fox and colleagues did not address the risk of immune reconstitution inflammatory syndrome (IRIS), which can occur following plasmapheresis and is nearly as deadly as PML.

One of the most recent patients to develop PML on natalizumab therapy died in December following plasmapheresis treatment, according to a press report.

The timing suggests the death may have resulted from IRIS, the report said.

Also this was written in February 2009 before more PML deaths have occurred.
Lady

http://www.medpagetoday.com/Neurology/MultipleSclerosis/12704

.

mmcc53

06-30-2009, 08:11 PM

mmcc, why are you so adamant to challenge everyone who has an opinion other than yours? You are the one who fought to get this drug back on the market, going to the FDA's, Tysabri Medical Conference, writing letters and doing everything in your power to force the FDA to allow Tysabri back on the market. Are you feeling any guilt, since you yourself then went off the drug? No, none at all. I wanted the option to decide to take and I wanted other MSers to have that option.

Let me be clear - I took it for 18 months, and for 12 of those months it worked. The only reason I stopped was that Tysabri stopped working for me. Why wouldn't I want others to have that choice???

Btw, people may be considered Progressive, but if they have Relapses, they can receive Tysabri, you should know that. Relapsing Progressive MS people, were in the case files as well as RRMS people were. It isn't only for Relapsing /Remitting MS. You just answered your own question - because I think decisions should be based on ACCURATE information.

The truth is what I said - Tysabri is for "relapsing" forms of MS. It is not approved for "progressive." Many docs keep MSers listed as RR so they can try drugs. Someone who is progressive does not have relapses.

RR and Relapsing Progressive MSers are both considered "Relapsing," which is why the type of MS has "relapsing" in the name. Only a very small number of MSers are relapsing progressive.

Those who are Primary Progressive, or Secondary Progressive are not eligible for Tysabri - READ THE TOUCH LITERATURE. It is clear.

We are here to support people with MS and help with questions from people in Limo or Newbies, not fight with them if their doctors tell them something, or they read an article and post it, or their opinion differs from yours. This is an MS Board. While limbo landers can join and post, this Board was created for MSers (including newbies), Many of us look for answers, opinions, and information from each other. Newbies tend to look for more information, of course, but all those who read here, ESPECIALLY newbies deserve to have accurate information provided.

I look for people to give me additional information and correct factual errors when I am considering an action dealing with my MS. I don't feel the need for pats on the back, if that is what you consider supportive, I have been a member here for 10 years, and I come here for information

[QUOTE=Lady;363476]Please refrain from your attacks on the people who post here. [QUOTE] I'm sorry if you consider my answers to be attacks on people. If you look back, I think you will find that one poster here is consistent in her personal attacks on me. I think telling someone that information they posted is wrong is not a personal attack.

If you look at other Tysabri posts I think you will find that I have responded when a poster asks a Tysabri question. Otherwise my responses are to correct incorrect information.

I think you would also find that that is true for other subjects as well.

mmcc53

06-30-2009, 08:32 PM

Anyone else here have to move to another drug after Tysabri? Was there a Tysabri wash-out discussed, considering we all agree that suppresses the immune system? Yes I stopped Tysabri because it was failing to work for me. I had a couple of days of IV steroids right after that. Taking a few days of IV steroids to deal with a relapse while on Tysabri is permitted, so having them after I had stopped was reasonable.

I am now on zenepax which is another form of monoclonal antibody currently in Stage 3 (?) testing so that it can be labled for MS use. Unlike Tysabri it was not developed for MS - it has been in use for 10 years as a kidney anti-rejection drug. The MS-label testing is extremely promising, though, and the drug is working very well for me - much better than Tysabri in fact.

It does not carry the PML risk because it suppress a different set of cells. There are other side effects, like with all drugs, but PML is not one of them.

I started it (estimate) 6-8 months after Tysabri. However, this was partly because it took a lot of insurance company fighting. As far as I know there is not a "post-Tysabri" washout period in the TOUCH program, but it is now known that the biggest post-Tysabri probem is that those who quit before taking Tysabri for a certain length of time can have a bad rebound effect.

What drug any of us takes should not cause us lose our ability to be objective. Or is that another side-effect of Tysabri? :rolleyes: Lady, you mentioned "personal attacks?" This is pretty personal, I think. And adding cutesy emoticons afterward is not only annoying but another form of personal attack.

Annie1234

06-30-2009, 11:25 PM

Wow. This is becoming too hard to follow.

Tit for tat, this for that. I would not recommend this thread to anyone with Tysabri/PML questions -- instead, I would refer them to their neurologist.

Perhaps there will be less disagreement discussing a new model for MS -- CCSVI (Chronic Cerebrospinal Venous Insufficiency) . . .

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19060024#id379895

http://www.thisisms.com/forum-40.html

http://www.thisisms.com/ftopict-7374.html

lady_express_44

07-01-2009, 12:31 AM

Sure they know - impaired immune systems. That is one reason that AIDs patients are so prone to it

Not quite. Based on the best scientific evidence - an oversuppressed immune system makes PML more likely. Therefore IN THE US you CANNOT take Tysabri until other immunosuppressant drugs are washed out of your system. Will this PREVENT PML? No. Will it reduce the chances of getting - it appears that it does.

That cannot be the case, if this happened in the US. When the time for the infusion came up, SOMEONE had to say yes or no. If you READ the TOUCH material - it is REQUIRED that the doctor make that determination. It is not a choice left to the patient, unless the partient does not want Tysabri. In other words the doctor must make a determination that the infusion will or will not be permitted. As with any drug, the patient can always decline. The patient cannot decide to go ahead if the doc says no.

In the US EVERY patient is in TOUCH. You have just made it crystal clear what one big difference is.

The other is that TYGRIS is a monitorring, not preventative program. TYGRIS is used to gather data.

The reasons are pretty clear:

1. Unless YOU find it yourself, you do not believe ANY information which contradicts your paranoid view when it comes to Tysabri. Even then, it is reported by you as "alleged,", etc. I took Tysabri for 18 months, was enrolled in the TOUCH program, and was in the US. I saw the washout list which was shown me as part of the TOUCH review. You live in Canada, have never taken Tysabri and have never been enrolled in the TOUCH program.

You will NEVER believe it consider Tysabri, so I really don't care what your opinion of my truthfullness is. I care what information people who are seriously considering a drug with potentially serious side effects receive.

Anyone who is considering Tysabri now is very aware that they should ask about washout times for other drugs.

2. You are the one alleging that this is not true - YOU email and ask for. it in writing. The fact is the last thing you want is to confirm it is accurate or you would have gotten the info yourself a long time ago.

3. ANYONE considering Tysabri should and can get this information from their neuro before committing to take the drug and not rely on ANY information posted about Tysabri on these WEB sites without confirming it with an MS Specialist. Anyone interested can also just ask their neuro whether they are getting Tysabri or not.

4. LE 44, when you post "alleged," information or wrong information I tend to challenge it because your blind anti-Tysabri view may effect people who are trying to make a decision which can effect the course of MS and their health. YOU are not considering Tysabri, but many people are and they should not base that information on allegation and innuendo.

Lady, you mentioned "personal attacks?" This is pretty personal, I think. And adding cutesy emoticons afterward is not only annoying but another form of personal attack.

Mmcc, your recollections, reasoning and arguments are not worth my effort to respond to. (insert preferred cutesy emoticon)

Cherie