Hi Chris,

This discussion was about the announced 7th case of PML, and the recent death that occurred. It was not intended to center around how effective Tysabri is, or whether some might think it is a risk worth taking ... so that’s why you didn’t run into many comments regarding those points in this thread.

As far as efficacy, although Tysabri claims to be twice as effective in reducing relapses, there has never been a head-to-head trial against the CRABs. It is really impossible to know if it is "more" effective, as results from these trials may be very skewed by any number of factors:

http://www.ncbi.nlm.nih.gov/pubmed/18437041

http://www.ncbi.nlm.nih.gov/pubmed/1...t=AbstractPlus

Tysabri claims to be about twice as effective in reducing relapses, however, IMHO, relapse rates aren’t a significant measurement of “efficacy” with this disease anyway. Even if Tysabri proved twice as effective in reducing relapses in a head-to-head trial, unfortunately that does not mean we are going to be any less disabled in the long-run.

While reducing relapses might be pleasurable, Tysabri proved to be only slightly more effective (in absolute terms) then the CRABs for short-term disease progression. There is no long-term efficacy measure of this drug for disease progression yet, so that is another “unknown” that people need to measure up against the risk, obviously.

http://www.neurology.org/cgi/content...916.38629.43v1

I am glad you are at two years with no problems to report, but that doesn’t mean there haven’t been any with others.

I agree that “the unknown is the long term safety of the using the drug regarding PML and other opportunistic infections”.

However, I disagree that:
- “the unknown is the outcome of PML”
- it was necessarily “assumed that the outcome would be death or severe disability”
- “3 of the 4 PML cases since relaunch of the drug under monitoring have resolutions”

We knew/know the current “potential” outcome of PML, at least at this moment in history. We know that people may die from PML ... since two out of three in the original trials did. We also know that even IF they initially seem to survive the PML (as the recent US patient did), they may succumb in weeks, months, or die from IRIS (used to treat the PML). We don’t have autopsy confirmation on the recent death, but I'm “speculating” that Biogen spokesperson would not be “announcing” her death in the same breath as the fact that she got PML from Tysabri . . . if her death was unlikely to be related to the drug.

We also know/knew patients might live through PML. . . since the third trial patient in the trials did, as have 3 people since. We don’t know precisely “how” disabled that ANY eventually became from PML as much of the details are deemed “patient confidential”. In fact, it was only a few weeks ago that we got “news” that the Florida woman who got PML in Oct, was home and “recovering” under her doctor’s care. Next we know, she’s died.

So, it’s probably going to take time, and perhaps even a court case before we ever find out EXACTLY how disabled ANY of the people who got PML have become, or what the long-term prognosis might be for them.

I don’t know what that sentence means . . . ?

As I said previously on this thread, Tysabri “is at least as effective as our other options, it is much more convenient, and there are less general side-effects.” I get why some people want to use it, and that they may be willing to take a risk . . . just as you would likely understand how others feel the opposite.

Well, you were more wrong then right. . . at least so far. That is the reason we still talk about the risk though, as like you, some people did go on it thinking the risk would be much less then was predicted.

Currently the risk for PML is at about 1:1357, so we are not that far off. While there are many thousands of people on it now, the risk they estimated was 1:1000 for those who’ve been on it for 18+ months. Currently there are 9500 that have been on that long, or longer, and 7 cases of PML . . . so there estimation was pretty close ... SO FAR.

Cherie

As always, very thorough Cherie, and you addressed a few of the points that I too had questions about.

Interesting read thus far

Statistically it would be impossible for confounding factors to have caused the difference in relapse rate. The Tysabri trials had almost 2000 patients which would eliminate any small sample bias. You also conveniently ignore the 6% of Tysabri patients who developed persistent antibodies to the drug effectively rendering the drug ineffective for them. These patients pulled down the reported effectiveness of the drug.



I would hardly use the word "pleasurable" to describe the need to avoid relapses but then again I'm not into inflicting pain on myself and I don't live in a parallel universe. Nothing about this disease is pleasurable.



The 3 original PML cases in the trials and their outcomes can hardly be considered representative since these cases occurred in an environment where PML wasn't even being looked for and these cases were mistreated by applying even more immunnosuppression. In short, they didn't have a chance. In the commercial setting, Doctors are monitoring for PML and removing Tysabri from the bloodstream if detected. Significantly different situations to draw an apples to apples comparison.





Be careful in quoting PML risk rates without all the correct numbers. We know that there have been 4 PML cases, 1 at 14 months, 1 at 14 months, 1 at 17 months and 1 at 26 months. The first 14 month and 17 month cases occurred prior to Sep 31, 2008 where there were 18,000 patients at 1 year, 9500 at 18 months, and 4000 at 2 years of treatment. The next case occurred on Oct 31st, so the number of patients had increased (probably by 1500 per month in each category). The next case occurred on Dec 15th so add another 3000 in each category (2 months of patient treatment). The denominator has definitely increased and I believe you are using the wrong numerator. Including the 3 PML trial cases with the commercial setting cases is apples and oranges as the commercial prescribing restrictions are obviously significantly different from the clinical trial use. The other confounding item is that only 1 PML case has been confirmed under the US TOUCH program with the other 3 PML cases occurring in Europe which doesn't have TOUCH restrictions while the number of Tysabri patients was higher in the US than in Europe. Does TOUCH offer further PML reduction?


Cherie, at the end of the day we're going to disagree on the relative benefits and risks of the drug that I have chosen probably because you've made a different treatment decision. I certainly respect people making different choices for their different circumstances and the last thing I would ever do is try to "sell" someone that my choice was correct or downplay some other choice as being incorrect. That's the line we all have to walk, being informative without our predisposed biases to the choices we have made.



Chris

Cherie,

Before I post retorts to your writings, let me first state that we have both made the treatment decisions we have based on our assessments of the data available and our individual cases of MS. The point of these discussions is to share information to help others in their treatment decisions without the bias we have due to the treatment decisions we've made.

It would be statistically impossible for the Tysabri effectiveness results to be due to confounding factors. The Tysabri trials had almost 2000 patients which would eliminate and small sample bias and there was a Tysabri/Avonex comparison versus Avonex alone arm. The other factor you choose to ignore is that 6% of Tysabri patients developed neutralizing antibodies making the drug ineffective for them. 6% of the TYsabri patients were effectively on placebo and the drug still reduced relapses by 70% relative to placebo.

Avoiding relapses is "pleasurable"? *edit* Avoiding relapses is necessary maybe not sufficient but definitely necessary. Besides nothing about this disease is pleasurable.

Using the PML outcomes from the trials to paint PML outcome expectations is flawed since in the trials, PML wasn't being looked for and was mistreated by adding further immunnosuppression. These patients never had a chance. In the commercial setting, Doctors are watching for PML and trying to remove the immune supression when detected. It certainly doesn't mean that PML won't always remain a serious infection but it does mean that the outcomes won't necessarily be the same.

Please don't quote PML risk numbers that are incorrect. You scare uninformed patients taking the drug and scare away others that are evaluating their treatment decisions. The 3 cases of PML that occurred in the trials don't belong in the PML numerator as we are trying to assess PML incidence in the commercial setting with the commercial restrictions. So we've got 4 PML cases for the numerator. Your patient numbers in the denominator are also incorrect as they are as of Sep 31, 2008. In the 3 months since then more patients (probably 1300 per month) have reached the 1 year, 18 month, 2 years and over treatment threshold. The other confounding items in making this calculation is that 3 of the PML cases occurred between 14 and 17 months and one at 26 months and that only 1 of the cases occurred in the US TOUCH program even though 60% of the patients on the drug are in the US. Do you use the 1 year patient numbers or the 18 month patient numbers given the 14 month cases? Does the TOUCH program provide further PML risk reduction through tighter patient admittance criteria and clooser monitoring? There are a great deal of unanswered questions and certainly a great deal of discussion needed above and beyond a dismissive comment that I'm wrong and the risk is about what the label says.

Chris

Hi again Chris,

*edited*

- we have previously had this conversation about stats & efficacy *edited*, and there are some people here who can become very upset by the re-hashing of this subject

- you don’t need to worry about ME being biased towards any treatment option, as I have had MS for 18+ years and have never even been on any DMD. Either way, it’s not a competition, at least from a patient perspective.

However, since you are missing some of the information you need to make an informed argument, I will provide a very quick synopsis on the numbers . . .

The risk profile of 1:1000 is based on all of the people in the original Tysabri trials, not just those in the MS trials. This included the Crohn’s patients, and it was determined that the risk for PML was 3:3000 (or 1:1000) for those on a mean of 17.9 (18) months.

No matter what other drugs the patients were (or had been) on in the trials, the best go-forward projection Biogen could predict (for PML potential”, while on monotherapy), was 1:1000, over 18+ months. You, and everyone else who’ve been on it, accepted that risk ratio.

Regardless of how you (or I) calculate the current ratio of cases, the stat is lower then was predicted. How could anything that I say (which is still less than Biogen’s prediction of 1:1000) be “scaring” anyone?!?

Virtually all PwMS are all immune compromised, and/or have used prior immuno-modulatory/suppressant drugs. Some suggested that the cases in the trials might have only occurred because of the immunosuppressant qualities of Avonex and Tysabri combined . . . but we now know that people even on monotherapy, i.e. only ONE drug at a time, might be too immune compromised to safely start on Tysabri.

The prescribing criteria for Tysabri states that it is “... recommended for those who have not been helped enough by, or can not tolerate another treatment for MS ...”. That basically ensures that most of us have PREVIOUSLY been on “some” drug that has affected our immune system . . . and would “justify” every case of PML to date. Well all, except one... the European patient who had used NO treatments previously.

The bottom line is that we now know that PML is just going to happen occasionally with Tysabri anyway . . .

TOUCH is in place in the US, to screen out “the most” at risk patients ~ those patients who have used/are using meds that might increase their odds of getting PML. If TOUCH protected people from PML, the Florida patient wouldn’t have gotten it.

Our neuro’s don’t want us to die any more than the makers of Tysabri do. They are making their best judgment call, in the US and in every country that Tysabri is available . . . so your point about “where” people lived when they got the PML is irrelevant. Careful selection and intricate monitoring of patients helps, but it will obviously not stop PML from occurring.

As for the current stat, we can’t count all 35,500 people who’ve been on Tysabri, some who’ve been on for as few as ONE or TWO infusions. While my calculation for a ratio wouldn't be 100% correct, it is as close as we can get and definitely much more accurate then “only four cases of the 35-odd thousand that are on it . . .”.

The 9500 number confirmed in Dec/08 (those who’ve experienced T for 18+ months) includes those 3000 patients who used Tysabri during the trials. Since it seems to take 1 – 3 months to confirm PML, I really don’t think it is necessary to “speculate” how many more (or less) people might be on Tysabri since the last confirmed count.

Nor do we know how many are currently being investigated for PML since the 9500 was confirmed.

If you prefer to take out three patients that got PML in the trials, you will also have to reduce the number from 9500 (- 3000, that were in the trials) to 6500. That would still result in a current “experience” ratio, as best as we can calculate it, of 4:6500 (or 1:1625). . . . which is not THAT far off 1:1357.

There were hundreds of drop-outs in the trials, as there are some % in any trial. Generally those people dropped out because they got too sick (or otherwise didn’t respond well to the treatment during the trials). They are NOT COUNTED in the final statistical analysis for efficacy, so the stats we hear about are based on those who thrived (reasonably well) throughout the duration.

I already spoke to the efficacy comparison between our various drug options, and attached a few links to make my point. And, while it is nice not to have relapses, I (personally) am not going to risk my life to try to avoid them . . . even with the odds as LOW as they currently are.

If you are more comfortable quoting whatever numbers you feel ok with, that is entirely up to you. I will stick (and answer) to the numbers I believe are correct. If reality (from someone else’s perspective, that apparently you don’t agree with anyway) “scares” you . . . perhaps you shouldn’t be have taken the risk associated to this med . . .?

I wish you (and everyone else) well, Chris. I really do hope the odds for getting PML from Tysabri ultimately pan out to be MUCH lower then anticipated, and that Tysabri proves to be a relatively safe (liver function, cancer risk, etc....) and effective treatment option for this disease in the long-run.

Good luck,

Cherie

*edit* You were the one making statements about Tysabri being only about convenience which I believe I appropriately replied to. *edit*

Your PML stats are still wrong even though you continue to take every opportunity to re and repeat them.

*edit*

It shows BiogenIdec data of number of patients on therapy (commercial and clinical) on various dates in 2007. Note that there were 0 (zero) patients at 1 year of therapy until Dec 2007 - The previous trial experience is not quoted in the reported number then or as of Sep 2008. When they say trials they are talking about the active trials they have ongoing. And the 9500 is as of Sep 2008 - they won't update it until they report 4th quarter earnings.

I'm hardly scared by your numbers as I know with certainty that they're wrong. I'm thinking of others who may look at your postings and take them as gospel.

Your PML stats are wrong. Check page 14 of this link:

//library.corporate-ir.net/library/14/148/148682/items/278364/Q4-07%20Earnings%20Slides.pdf

The safety information lists 0 (zero) patients at 1 year of therapy until Dec 2007. The reference to trials does not include the trials for approval but the trials that were started upon Tysabri reintroduction.

You are also misinformed about the us TOUCH program. Part of the program is the screening for putting the proper patients on the drug. The more important part is the monthly pre-infusion checklist to monitor for any new or worsening symptoms. Let's see PML in 1 out of 19500 Tysabri patients in the US (with TOUCH) while there's been PML in 3 out of 16000 Tysabri patients in Europe. Seems like TOUCH could be making a difference.

Clearly you think you know and are correct about everything regarding Tysabri so there isn't much point in discussing this further.

Chris

ok

I have had to do some edits here and need to respectfully request that the guidelines be heeded

http://neurotalk.psychcentral.com/showthread.php?t=1293

perhaps you should both just agree to disagree and let it go, if you cant disagree agreeably

if the back and forth continues in this confrontational way I will need to close this thread

thanks

This is just more for my understanding of where both of you sit, as far as your MS. I've had my disagreements with Cherie before, and maybe I'd be better about her stats if I knew her situation better.

And Chris, maybe you could address this also, so I understand where you come from.

I'll start with me. First symptom I can firmly state with MS was Feb. 2002. Wasn't dx'd until 2006. I was on Avonex a year (2006-2007), had more and enhanced lesions on first follow-up MRI, so went on Rebif for a year(2007-2008). No new lesions on 2nd MRI (I have them every year about March), so Rebif holding things at bay, but I was having trouble with itchiness and general fatigue. Started Ty in April 2008. Other than a half hour of chills after the infusion, rest of the time I'm super! Will have an MRI in March to see how those lesions look after a year on Ty.

I work full-time. I have a tingly left hand, get tired easily, bouts of vertigo off and on, but nothing that a little rest doesn't fix. I'm very busy, and manage to do most everything asked of me. I've learned to let little things go, but if I need to work hard, I can pace myself and get it done over time.

So now, Chris and Cherie, what DMDs have you been on/or not and why, do you work full-time, what kind of disability do you have, etc. Cherie, I know you smoked in the past, but I don't know if that is true now. Maybe the smoking helps MS???

Do you have MRIs yearly, or every two years. I know Cherie says she's had MS for 18 years. Does that mean you were dx'd 18 years ago?

I've been diagnosed for 6 years know. Started with Avonex for a few months and then my Neuro switched me to Rebif. Endured the the flu like side effects for 3 years. My MS was relatively stable (maybe 1 relapse) but I felt like I was in a glider slowly loosing altitude. The continual flu like side effects wore on me mentally. Switched to Tysabri in Jan 2007. I've felt a lot better - less fatigued, more responsive legs, less spasticity. Heat doesn't bother me as much. Not back to running marathons but definitely not in the glider anymore.

I've got some disability with my legs - I walk unaided but definitely labored/not fluently and I have falls infrequently when my legs get stuck on lip, ledges, themselves.


I work part-time since I have a great employer that allows me to work 20+ hours a week and still maintain my health benefits. Helps that I'm an engineer and have a desk job.

Chris