Earlier Natalizumab Trial

A board to discuss the newly-released drug Tysabri, (formerly known as Antegren) as a treatment for Multiple Sclerosis

Earlier Natalizumab Trial

Postby HarryZ » Wed Dec 08, 2004 7:42 pm

I know that some readers may think that I make-up and create "stories" about Tysabri (aka Natalizumab). That, I simply don't do! Today I came across this link that was posted on the Brain Talk MS Forum. It was published by The New England Journal of Medicine which doesn't need an introduction to most people.

This is a short abstract of an earlier Natalizumab trial that shows totally different results than the Tysabri trials. How such a difference exists I simply don't know but is another reason as to why I am so cautious about Tysabri. When the abstract refers to "but this effect was not carried forward in the six months after treatment" I'm not sure if this means after the drug was stopped or 6 months into the trial. Perhaps other readers may know more about this earlier trial.

I am quoting part of another message that a poster on that site wrote:

"I have heard from Serono, Teva and Berlex reps that the data they've seen indicates that Tysabri increases lymphocyte counts (a type of white blood cell) and that as a result, with elevated counts people are being treated for a greater number of infections than those with suppressed immune systems (from Cytoxan, steroids, or Novantrone). I have not seen data yet that supports the statements heard independently from each company.

The Biogen rep told me that without the elevated lymphocytes, the monoclonal antibody has nothing to bond to to get to the antigens that could create an exacerbation. I guess it's all in how one words something."

Again, this is further information that is just starting to come out on Tysabri as other people(including the competitors) are slowly obtaining more data about the drug. Tysabri is going to be a very hot topic in the world of MS medicine for months to come.

http://content.nejm.org/cgi/content/short/348/16/1598

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Postby Observer » Wed Dec 08, 2004 9:05 pm

Harryz

Your referenced link was a Letter to the Editor of NEJM regarding the 6 month Tysabri Phase 2 study that was clearly refuted in the corrspondence by the authors. Unfortunately, one has to be a paying user to obtain the full text of this correspondence.

I think it very unfortunate that you would choose to post half of the information available from NEJM, and I might note that the half you posted seemed to support a negative view of Tysabri. (Of course, upon review it does NOT support a negative view, see below.)

Why not put ALL the information out there to let the reader decide, rather than simply a part which supports one view or the other?

"but this effect was not carried forward in the six months after treatment" I'm not sure if this means after the drug was stopped or 6 months into the trial. Perhaps other readers may know more about this earlier trial.


The trial itself was 6 months, so clearly this means the 6 months AFTER the trial, and AFTER Tysabri administration was stopped. What the authors of that correspondence are saying is that, after Tysabri was stopped, its beneficial effects also stopped. Surprise, Surprise. Tysabri is NOT a cure, it simply reduces relapses, reduces lesions and (after EDSS info in the next several months) may significantly delay disease progression.

Here is the P2 Abstract and Results from the Jan 2003 NEJM (a peer-reviewed journal, I might add):


A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

David H. Miller, M.D., Omar A. Khan, M.D., William A. Sheremata, M.D., Lance D. Blumhardt, M.D., George P.A. Rice, M.D., Michele A. Libonati, M.S., Allison J. Willmer-Hulme, Ph.D., Catherine M. Dalton, M.B., Katherine A. Miszkiel, M.B., Paul W. O'Connor, M.D., for the International Natalizumab Multiple Sclerosis Trial Group

ABSTRACT

Background In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein 4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an 4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.

Methods In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing–remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.

Results There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).

Conclusions In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.



The link is quite long, so go to

http://content.nejm.org/

and search on 'natalizumab' to find the relevant Jan 2003 article. Click on abstract and you can see the above.

We see from the above that, in fact, the Phase 3 results were actually better than the Phase 2: 66% relapse reduction in P3, and something like 50% in P2 (if you do the calculations with the abstract numbers).

Based on the above, to suggest that the P2 trial results were totally different from the P3 results is simply wrong.


And the competition saying that Tysabri patients have increased infections? Uh huh. Relative to placebo, yes, I think it was 2% of Tysabri versus 1% of placebo. Uh, that's 2% of the trial, which means 98% had no such effect. Looks to me like Teva, Serono and Pfizer are trying to misuse basic statistics. Why am I not surprised?

The data have been PUBLISHED in the drug's label. Don't listen to the competition, READ THE LABEL. The competition will do/say anything for their commercial interests (which they clearly place before the interests of the patients) as they have shown time and again from their public comments (for example, Mckinnel of Pfizer discussing a rebound effect from Phase 1 trials on 70 patients, and IGNORING THE PHASE 2 trial on 200+ patients which showed the rebound effect WAS NOT REAL!).

Harryz, it is odd that you would reference the results of a 6-month study, as all along you have been saying that the 1 YEAR RESULTS from Tysabri Phase 3 trials are not long enough. Seems to be a contradiction. 6 months is OK, 1 year is NOT OK, and we now need more data? What gives?


I suggest the best approach is to look at ALL the available data, and make a reasoned evaluation of the facts. I think we have enough information, but I can clearly see that others think otherwise and want more info.


And this information just came out? Oh, really? The original P2 results were published in the Jan 2003 NEJM, almost 2 YEARS AGO. I hardly think that is 'just coming out.'
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Postby HarryZ » Wed Dec 08, 2004 10:50 pm

Why not put ALL the information out there to let the reader decide, rather than simply a part which supports one view or the other?


Because of the point you made...I'm not a paying member and did not have access to the entire article. That is exactly why I asked the question if anybody knew more about this trial.

The trial itself was 6 months, so clearly this means the 6 months AFTER the trial, and AFTER Tysabri administration was stopped. What the authors of that correspondence are saying is that, after Tysabri was stopped, its beneficial effects also stopped.


Any idea then, why the comment was made that long term use of the drug was not of any benefit to the progression of MS?


And the competition saying that Tysabri patients have increased infections? Uh huh. Relative to placebo, yes, I think it was 2% of Tysabri versus 1% of placebo. Uh, that's 2% of the trial, which means 98% had no such effect. Looks to me like Teva, Serono and Pfizer are trying to misuse basic statistics. Why am I not surprised?


This is likely just the beginning of the "war" between the MS big pharmas. I can imagine that the "mud slinging" will become much worse as time goes on...especially with all the $$$ that are at steak.

Harryz, it is odd that you would reference the results of a 6-month study, as all along you have been saying that the 1 YEAR RESULTS from Tysabri Phase 3 trials are not long enough. Seems to be a contradiction. 6 months is OK, 1 year is NOT OK, and we now need more data? What gives?


Well, if you READ my post, I clearly asked the question if anyone knew more about this very short abstract. The information contained in it was minimal to say the least and I did not have the ability to obtain more data. I had not seen this before today and it seemed so very different from what has been posted so far about Tysabri. I further stated that I wasn't sure about the 6 month statement of drug use that was made in the abstract. My original comment about more data being required from the Tysabri trials still stands...I hope this clarifies any misunderstanding you may have!


And this information just came out? Oh, really? The original P2 results were published in the Jan 2003 NEJM, almost 2 YEARS AGO. I hardly think that is 'just coming out.'


The "just coming out" comment was in reference to the competitor's comments and other MS medical people that have recently been made, not to the earlier trial info from April of 2003....that date was clearly visible at the top of the abstract and I presumed most readers would be able to differentiate between the two.

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Postby Observer » Thu Dec 09, 2004 9:04 am

Harryz

For some reason, NEJM has stopped allowing access to the full text of articles over 6 months old. Even if you register (free) you cannot view correspondence (which is the tidbit that you posted). Frustrating but true.

At any rate, I'd reviewed this some time ago and the rebuttal by the Jan 03 authors is complete and convincing. I wish I could access it, perhaps someone here can.


Any idea then, why the comment was made that long term use of the drug was not of any benefit to the progression of MS?



Notwithstanding that neither the P3 tysabri trial nor the drug's label has made any claim regarding 'benefit to the progression of MS', has Tysabri been advertised as a cure? I think not. After quitting therapy, should Tysabri continue to be effective? Oh would that were true, and all could surely rejoice. Tysabri would indeed be a CURE. But it has never been advertised as such, and methinks you expect too much. Unfortunately, like many medications, if you stop taking it, the effect of the medication eventually goes away. That was the conclusion of the April 03 correspondence, which was in response to the Jan 03 NEJM article.

Furthermore, you can read that long-term disability progression was NOT an endpoint of the P2 study (check the NEJM Abstract) nor even of the 1yr P3 Tysabri trial. The P2 trial was only 6 months long, and all know that is insufficient time to generate reliable changes to EDSS. (If I have to obtain citations to this effect, please advise and I can do the homework.)

I am very surprised that you'd only now be aware of this important part of the history of Tysabri. But then again, I know very little about the CRABs, so I probably should not be surprised. Mea culpa.

But I wonder - WHY do you never find ANYTHING positive about Tysabri? All of your information is only negative? Is this truly happenstance, or is there some other agenda? Please let me know. TIA.

Now, regarding your comment about 'different results' for clarity, here is exactly what you said


This is a short abstract of an earlier Natalizumab trial that shows totally different results than the Tysabri trials. How such a difference exists I simply don't know but is another reason as to why I am so cautious about Tysabri. When the abstract refers to "but this effect was not carried forward in the six months after treatment" I'm not sure if this means after the drug was stopped or 6 months into the trial. Perhaps other readers may know more about this earlier trial.



And in spite of the suggestion in your reply to me, I did READ your post but was thoroughly disappointed. How about the courtesy of reading my post, and responding thoroughly and with fact-supported assertions (and please no unamed sources or knowledgable, unreferenced MS researcher contacts)?

In your post (quoted above), you are first flatly stating that the P2 and P3 results are totally different and only THEN asking whether any other readers know more about this trial. Well, much of the trial information is freely available and your statement is proven to be false by the original January 2003 P2 abstract (which I posted) and the P3 trial results.

I'm sorry, but I have to wonder why you wouldn't post the P2 abstract. Why would you make a statement that can easily be verified to be untrue (that the P2 and P3 results are 'totally different')? If, on the other hand, you believe your original statement, perhaps you could indulge me by explaining your reasoning on how they are 'totally different'?

But I go on too long, and I'm tired. I'll just say that there is a reason why it is illegal to cry 'fire' in a crowded movie theatre if the alarm is false. And if one continues to cry 'fire' when there is not any, the call rightfully goes ignored. I guess what I'm saying is that it would be refreshing to see the pluses/minuses, not only the minuses or half the story. Thats IMHO, by the way.

I'll give you the last word, and I hope that my concerns are allayed by your or other's response to my comments. Perhaps I have this all wrong, and if so I apologize. But if I do have it wrong, please lead me thru my error. Thanks in advance.
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Postby OddDuck » Thu Dec 09, 2004 9:52 am

Hi, guys (and/or gals).

I "might" be able to shed a little bit more light on some of this (or maybe not).

Anyway, back in November, I found some abstracts relating to this very subject that got me to questioning some things originally. (One of the findings was from Biogen itself - re: a skew to a TH1 immune system after a period of time, which as we all know in MS, is apparently not desirable in the long run - and so says the abstract I'm about to refer you to.)

Anyway, if you look back at the thread [see link to another thread below], you'll see what I found, posted and speculated (or more accurately) had questions about (which of course cannot be fully answered at this time).

Anyway, maybe this will help?

Deb

EDIT: http://www.thisisms.com/modules.php?nam ... opic&t=564

Ok…..after going to that thread, scroll down to my posts starting on November 6, 2004, that starts out with me saying: “Here is a good website (I thought) describing integrins: http://www.hosppract.com/issues/2000/03/etzioni.htm”..........

Go past that and read the abstract I posted after that and notice that it was dated in 2001 and Biogen itself was involved in the findings (notice my highlights).

The next post I did right after that also contains another abstract talking about the TH1 problem. Then please follow my direct conversation with John regarding this issue. I go on to explain some thoughts of mine a little farther.

Of course, then I go back to the concerns of mine about VLA-4 and fertility, etc., but that is not relevant for this particular subject.

Anyway, maybe those abstracts I posted previously might help? One of them is the abstract referred to as a reference in the NEJM link that Harry posted.

SECOND EDIT: As Observer noted, I have also been unable to get my hands on the complete "letter" referenced in the NEJM link, but DID run across something else.

Here are some interesting exchanges between neurologists regarding Natalizumab (link below). Folks, it’s worth taking a look at, simply because it shows that not only “competitors” are questioning the data, but other neurologists are, also. Which neurologist may be “right or wrong” in the discussion in the link below isn’t the point I’m trying to make. I’m only saying that it appears there ARE neurologists who are questioning the data from the clinical trials (so perhaps what Harry has heard via unsubstantiated “word of mouth”, i.e. that data is being questioned by neurologists, may be true?)

http://www.neurology.org/cgi/eletters/62/11/2038#1678
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Postby HarryZ » Thu Dec 09, 2004 12:35 pm

Notwithstanding that neither the P3 tysabri trial nor the drug's label has made any claim regarding 'benefit to the progression of MS', has Tysabri been advertised as a cure?


I don't believe that I made any mention at all about relating Tysabri to any kind of cure, I was only referring to the comment in the abstract stating that there wasn't any benefit to the progression of MS. That I found kind of perplexing since on the one hand, the trial referred to a 6 month duration and on the other hand, no benefit to MS. It didn't make sense to have that kind of ending comment on such a short trial duration.Again, that's why I asked the question of anyone knowing more about the abstract.


Furthermore, you can read that long-term disability progression
was NOT an endpoint of the P2 study (check the NEJM Abstract) nor even of the 1yr P3 Tysabri trial. The P2 trial was only 6 months long, and all know that is insufficient time to generate reliable changes to EDSS. (If I have to obtain citations to this effect, please advise and I can do the homework.)


That makes it all the stranger that any mention of no long term progression benefit was made in that abstract.

I am very surprised that you'd only now be aware of this important part of the history of Tysabri. But then again, I know very little about the CRABs, so I probably should not be surprised. Mea culpa.


I am aware of some of the history of Tysabri. It was over two years ago that I spoke to one of the neurologists here in London ON who was testing the drug at the large MS Clinic. I asked him about it at the time and he gave me a few of his comments. I know far more about the history of the CRABs and how they evolved over the past 10 years or so. At first I was excited about them and then, after being provided with more accurate information, that excitement turned very quickly to disappointment.

But I wonder - WHY do you never find ANYTHING positive about Tysabri? All of your information is only negative? Is this truly happenstance, or is there some other agenda? Please let me know. TIA.


It's not that I don't find anything positive about Tysabri. I post on many different MS forums and I have stated that the results from Biogen are very good. But at the same time I urge a lot of caution. Why you ask? Perhaps it has to do with the record of the CRABs which were also touted so highly when they first came out, the fact that researchers in the past couple of years have seriously questioned the entire auto-immune theory on MS, the increasing number of incidents by some drug companies of hiding negative data to keep profits up, the internal "dirt" going on inside the FDA and only short-term data being available on Tysabri. That's why I am overly cautious on this drug. But some people equate being cautious to being negative and I don't think that is fair.

I have stated on numerous occasions that I really hope Tysabri does as well as Biogen thinks it will do but until that happens my caution about it is not going to go away. I hope this explains why I feel the way I do. There isn't any "hidden agenda". I know some people won't agree with my thoughts or opinions on this but saying I am negative is certainly not correct. That's all that is needed is a "I don't agree with you, Harry"! Unfortunately some people can't do that and find it necessary to throw in a few personal barbs along the way.

And in spite of the suggestion in your reply to me, I did READ your post but was thoroughly disappointed. How about the courtesy of reading my post, and responding thoroughly and with fact-supported assertions (and please no unamed sources or knowledgeable, unreferenced MS researcher contacts)?


There is obviously some misunderstanding and/or disagreement here and trading barbs back and forth isn't going to solve it. Let's just move on.


In your post (quoted above), you are first flatly stating that the P2 and P3 results are totally different and only THEN asking whether any other readers know more about this trial. Well, much of the trial information is freely available and your statement is proven to be false by the original January 2003 P2 abstract (which I posted) and the P3 trial results.


Going back to my first post, I stated that the abstract in the link gave very different results from what Tysabri gave. I made no such mention of P2 and P3 trial data because I had no idea that the abstract had anything to do with the P2 and P3. Not until you mentioned the relationship between that abstract and the P2 and P3 did that surface. The abstract also made mention of no EDSS improvement and no long term change in the progression of MS. Why do you think that I asked if anyone knew more about the abstract? So how on earth do you get me making false statements about the P2 and P3 when I didn't even know about the correlation? Again, putting words into my mouth, Observer.

I'm sorry, but I have to wonder why you wouldn't post the P2 abstract. Why would you make a statement that can easily be verified to be untrue (that the P2 and P3 results are 'totally different')? If, on the other hand, you believe your original statement, perhaps you could indulge me by explaining your reasoning on how they are 'totally different'?


I'm starting to wonder just what you are reading! You ask me why I didn't post the P2 abstract. How could I post the P2 abstact when 1) I didn't even know the P2 and link abstract were related and 2) I had no way of reading the entire link abstract because I had no access to it and by your very words, it was no longer available anyway!!

But I go on too long, and I'm tired. I'll just say that there is a reason why it is illegal to cry 'fire' in a crowded movie theater if the alarm is false. And if one continues to cry 'fire' when there is not any, the call rightfully goes ignored. I guess what I'm saying is that it would be refreshing to see the pluses/minuses, not only the minuses or half the story. Thats IMHO, by the way.


Maybe that explains some of your questionable comments...that happens to me as well when I become tired :-)) Yes, it's illegal to falsely cry fire in a movie theater but there is nothing wrong with pointing out to the crowd where the fire exists are located prior to the movie starting!! That's all that I am doing....stating caution. I don't know if you have had a chance to read the link that Odd Duck posted re: some neuros questioning some of the Tysabri trial data. They have made some interesting points and again, that is why I preach caution.

I'll give you the last word, and I hope that my concerns are allayed by your or other's response to my comments. Perhaps I have this all wrong, and if so I apologize. But if I do have it wrong, please lead me thru my error. Thanks in advance.


I hear your concerns but I think you have perceived my intentions incorrectly. I hope I've clarified it a bit and let's just say we don't agree with each other on how we view Tysabri. Have a good day.

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Postby optimist » Fri Dec 10, 2004 12:14 pm

Oddduck


Since I'm considering switching from Rebif to Tysabri, I was particularly interested in your post of Dec. 10, 2004 in which you give a link to exchanges between neurolgists regarding Natalizumab(Tysabri). Am I missing something? You say that from your link "it appears there are neurologists who are questioning thr data from the clinical trials". But the only trial I see them referring to is a study of the effect of a SINGLE infusion of Natalizumab on recovery from an ACUTE relapse. How is that in any way relevant to the data from the clinical trials that the FDA reviewed the one year data of before approving Tysabri?
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Postby OddDuck » Fri Dec 10, 2004 2:23 pm

I didn't say which particular clinical trials.

Some people are of the opinion that neurologists just take everything a pharma corp. or another researcher says as "gold", when they obviously don't.

They question each other. That was the only principle I was making. It was just ONE example that it does happen. That's all.

Look at it in a broader sense.

Thanks.

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Postby HarryZ » Fri Dec 10, 2004 8:47 pm

One of the most important aspects of clinical trials is the "peer review" period whereby experienced doctors in the field of the particular trial look at the actual trial data. They "slice and dice" this data and ask many questions to ensure that everything was looked at properly. Most of the time, after drug trials are completed, the company conducting the trial gets a publisher to publish it so this peer review can take place. After that the company will make the decision to obtain FDA approval.

Since the Phase III trials of Tysabri haven't even been completed yet, this proper peer review can't take place. The link that Odd Duck posted simply shows that neuros are doing this peer review for the one "acute trial" and gives us an idea of what kind of questions the docs may ask.

You can be assured that once the Phase III trial data is totally made public, there will be this kind of reviewing taking place, especially by Biogen's competitors. It is going to be some time yet before the MS world of medicine is going to be knowledgeable about this new drug.

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Postby Observer » Sat Dec 11, 2004 2:39 am

The Tysabri Phase 2 trials were 'sliced and diced' and came out very positively reviewed (more on that in my next post). The only reason that the Phase 3 trials were not fully released is that the FDA made the decision to release the drug to the public BEFORE these were completed.

Now, why would they do that? I can tell you why in a very broad context: their view of the data (and they have ALL the data) was that the drug is so good to withhold it from the public is not ethical.

It is disappointing that the totality of the drug trials on Natalizumab that are available are not referred to - only this or that one, depending on who is making the point (me, being postive on Tysabri referencing any postives in the trials, others, being more skeptical, referencing any negatives in the trials). May I suggest that anyone interested read all of the trial data that are published

www.nejm.org

and search on Natalizumab, and make sure you have papers and correspondence ticked on the search form. You could then take this with you to your Neruo and ask him what his view of Tysabri is and ask him for copies of these publications (since the NEJM requirse you to purchase them (at $29.95 each!)). Alternatively, you could probably visit the Library and look at NEJM past issues and fotocopy the trial results. Key results are in Jan 03, Apr 03 (correspondence) for NEJM MS trials. You might also want to look in the journal Neurology for relevant papers on Tysabri.

Here is what I get with a search at NEJM:

Natalizumab for Active Crohn's Disease
Ghosh S., Goldin E., Gordon F. H., Malchow H. A., Rask-Madsen J., Rutgeerts P., Vyhnálek P., Zádorová Z., Palmer T., Donoghue S., the Natalizumab Pan-European Study Group
Abstract | Full Text | PDF
N Engl J Med 2003; 348:24-32, Jan 2, 2003. Original Articles

A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
Miller D. H., Khan O. A., Sheremata W. A., Blumhardt L. D., Rice G. P.A., Libonati M. A., Willmer-Hulme A. J., Dalton C. M., Miszkiel K. A., O'Connor P. W., the International Natalizumab Multiple Sclerosis Trial Group
Abstract | Full Text | PDF
N Engl J Med 2003; 348:15-23, Jan 2, 2003. Original Articles

Natalizumab for Relapsing Multiple Sclerosis
Chaudhuri A., Behan P. O., Miller D. H., O'Connor P. W.
Extract | Full Text | PDF
N Engl J Med 2003; 348:1598-1599, Apr 17, 2003. Correspondence

Natalizumab for Active Crohn's Disease
Lew E. A., Stoffel E. M., Ghosh S., Palmer T.
Extract | Full Text | PDF
N Engl J Med 2003; 348:1599, Apr 17, 2003. Correspondence

4 Integrins as Therapeutic Targets in Autoimmune Disease
von Andrian U. H., Engelhardt B.
Extract | Full Text | PDF
N Engl J Med 2003; 348:68-72, Jan 2, 2003. Editorials

Closing Fistulas in Crohn's Disease — Should the Accent Be on Maintenance or Safety?
Fiocchi C.
Extract | Full Text | PDF
N Engl J Med 2004; 350:934-936, Feb 26, 2004. Editorials


I'll check in Neurology and post whatever I get via search.
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Postby Observer » Sat Dec 11, 2004 2:51 am

Harryz

Upon returning to my office, I can now access the full text of the NEJM Correspondence that you started this thread with. Don't ask me why - from a Singapore hotel room Internet connection, I could not, but from my office internet, I can access it. Strange.

I note that I was in error - the Correspondence that Harryz referred to was about the Phase 1 study, a very small study in (I think) 1999. The Jan 03 Authors (who reported on the P2 study) response is given below, and I believe puts the Correspondence into perspective.

As I think all would agree, we need the full P3 results, particluarly the EDSS results, to fully evaluate Tysabri. Again, I SPECULATE that the EDSS results will be very good, and that is the reason the FDA approved Tysabri (they looked at the data that were available - not ALL of the P3 data since the trials were incomplete - but enough to convince them that Tysabri was beneficial). Lets hope my speculation is correct.

________________________________________

From the April 2003 NEJM Corresondence regarding Natalizumab (Tysabri):

Natalizumab for Relapsing Multiple Sclerosis

To the Editor: As participants in the original exploratory study,1 we did not find that treatment with anti–4 integrin antibody was of clinical benefit. Miller and colleagues ( Jan. 2 issue)2 report that monthly natalizumab infusions in patients with multiple sclerosis significantly reduced relapse rates and enhancing lesions on magnetic resonance imaging (MRI), but this effect was not carried forward in the six months after treatment. The treatment had no effect on the disability score (on the Kurtzke Expanded Disability Status Scale). There was no evidence that long-term natalizumab infusions modify the course of multiple sclerosis.

Epidemiologic studies have shown a biologic dissociation between relapses and progressive disability once a score of 4 to 4.5 on the Expanded Disability Status Scale is reached.3 It may be argued that all patients with multiple sclerosis should start receiving natalizumab at the time of their first clinical presentation; however, the effects of pregnancy in multiple sclerosis clearly indicate that the progression of disability is independent of clinical relapses.4 Longitudinal MRI studies show that perivenous inflammatory changes are associated with local alterations in the blood–brain barrier and are not obligatory events in the evolution of the plaques in multiple sclerosis.5

The results of immunotherapy trials in multiple sclerosis suggest that although such treatments may reduce relapse rates, they do not modify progressive loss of function. In a three-year follow-up of a trial of treatment for acute optic neuritis, a benefit of antiinflammatory treatment was not evident.6 We are not convinced that the effects of natalizumab on relapsing multiple sclerosis are any exception.


Abhijit Chaudhuri, D.M., M.D.
Peter O. Behan, D.Sc.
University of Glasgow
Glasgow G51 4TF, United Kingdom
ac54p@udcf.gla.ac.uk

References


1.Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-alpha4-integrin antibody on brain lesion activity in MS. Neurology 1999;53:466-472.[Abstract/Full Text]
2. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23.[Abstract/Full Text]
3. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.[Abstract/Full Text]
4. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998;339:285-291.[Abstract/Full Text]
5. Narayana PA, Doyle TJ, Lai D, Wolinsky JS. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998;43:56-71.[ISI][Medline]
6. Beck RW. The optic neuritis treatment trial: three-year follow-up results. Arch Ophthalmol 1995;113:136-137.[CrossRef][ISI][Medline]

--------------------------------------------------------------------------------

The authors reply: Chaudhuri and Behan refer to an early exploratory study of natalizumab in multiple sclerosis. This was a study of 72 patients, of whom 37 were randomly assigned to receive two doses of natalizumab, one month apart (and 35 to receive placebo).1 There was a significant decrease in the number of new gadolinium-enhanced lesions on MRI during the 12 weeks after the first dose of natalizumab, as compared with placebo. Given the small size of the study and the limited duration of treatment, however, it is not surprising that no clinical benefit was observed. The positive MRI result did, however, provide us with a reason to undertake our six-month study. Although this study was powered only to investigate the effect of treatment on MRI activity, it showed a significant treatment-associated reduction in relapses. It is not surprising that there was no significant change in disability in either the treated groups or the placebo group over a six-month period.
The mechanisms by which irreversible disability develops in multiple sclerosis are not well understood. Chaudhuri and Behan cite evidence supporting the independence of the progression of disability and relapses,2,3 but these events are not completely unrelated. Incomplete recovery from relapses is one mechanism of permanent disability. The effect of natalizumab on long-term progression of disability can be addressed only by larger, longer-term, phase 3 studies. Two such studies designed to investigate this issue are currently under way.

In our article, we omitted acknowledgment of J. O'Riordan and J. Parratt (Ninewells Hospital, Dundee, United Kingdom), who were investigators in the trial, and Dr. Martin Sanders, who provided helpful comments on the manuscript.



David H. Miller, M.D.
Institute of Neurology
London WC1N 3BG, United Kingdom
d.miller@ion.ucl.ac.uk


Paul W. O'Connor, M.D.
University of Toronto
Toronto, ON M5B 1W8, Canada

Editor's note: Dr. Miller reports having received grant support from Elan, Schering, and Biogen; honorariums for giving expert advice to Biogen, Wyeth, Bristol-Myers Squibb, and Schering; and lecture fees from Serono. Dr. O'Connor reports having received grant support from Elan, Biogen, Athena Neurosciences, Aventis, Berlex, Serono, Teva Neurosciences, Angiotech, and Amgen.

References


1. Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-alpha4-integrin antibody on brain lesion activity in MS. Neurology 1999;53:466-472.[Abstract/Full Text]
2. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998;339:285-291.[Abstract/Full Text]
3. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.[Abstract/Full Text]



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by Miller, D. H.

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This article has been cited by other articles:


Mittelbrunn, M., Molina, A., Escribese, M. M., Yanez-Mo, M., Escudero, E., Ursa, A., Tejedor, R., Mampaso, F., Sanchez-Madrid, F. (2004). VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses. Proc. Natl. Acad. Sci. U. S. A. 101: 11058-11063 [Abstract] [Full Text]

_________________________________________

Here is the link, I'd be interested to know whether anyone else can access it without being a 'paying' customer to NEJM.

http://content.nejm.org/cgi/content/ful ... lcode=nejm
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Postby Observer » Sat Dec 11, 2004 3:03 am

Here is what I get from a search on Natalizumab at

www.neurology.org

You can read the abstracts, but for the full text you must have a subscription.

_____________________________

P. W. O’Connor, A. Goodman, A. J. Willmer-Hulme, M. A. Libonati, L. Metz, R. S. Murray, W. A. Sheremata, T. L. Vollmer, L. A. Stone, and the Natalizumab Multiple Sclerosis Trial Group
Randomized multicenter trial of natalizumab in acute MS relapses: Clinical and MRI effects
Neurology, Jun 2004; 62: 2038 - 2043.
...Natalizumab (Antegren) is a humanized anti-{alpha}4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by...
...Objective: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses....


BRIEF COMMUNICATIONS:
W. A. Sheremata, T. L. Vollmer, L. A. Stone, A. J. Willmer-Hulme, and M. Koller
A safety and pharmacokinetic study of intravenous natalizumab in patients with MS
Neurology, Mar 1999; 52: 1072.
...five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed....
...Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS....


N. Tubridy, P. O. Behan, R. Capildeo, A. Chaudhuri, R. Forbes, C. P. Hawkins, R. A. C. Hughes, J. Palace, B. Sharrack, R. Swingler, C. Young, I. F. Moseley, D. G. MacManus, S. Donoghue, and D. H. Miller
The effect of anti-4 integrin antibody on brain lesion activity in MS
Neurology, Aug 1999; 53: 466.
...Each patient received two IV infusions of anti-{alpha}4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial...
...Antegren (natalizumab; Elan Pharmaceuticals, South San Francisco, CA) is a humanized monoclonal antibody (mAb) derived from a...


CORRESPONDENCE:
Gavin Giovannoni, C. H. Polman, J. Petkau, R. White, A. Thompson, D. H. Miller, F. Dahlke, and L. Kappos
Neutralizing antibodies during treatment of secondary progressive MS with interferon ß-1b
Neurology, Oct 2003; 61: 1025.
...am currently participating in randomized controlled trials of IFN{beta}-1b (Betaferon, Schering), IFN{beta}-1a (Avonex, Biogen), and natalizumab (Antegren, Biogen/Elan) in multiple sclerosis....


Peter A. Calabresi
Considerations in the treatment of relapsing-remitting multiple sclerosis
Neurology, Apr 2002; 58: 10 - 22.
...Of these therapies, anti-VLA4 (natalizumab) may be the first to undergo thorough evaluation in clinical trials....
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Postby OddDuck » Sat Dec 11, 2004 5:30 am

Mittelbrunn, M., Molina, A., Escribese, M. M., Yanez-Mo, M., Escudero, E., Ursa, A., Tejedor, R., Mampaso, F., Sanchez-Madrid, F. (2004). VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses. Proc. Natl. Acad. Sci. U. S. A. 101: 11058-11063 [Abstract] [Full Text]


Observer,

I’m not certain if that’s the abstract you are unable to find or what, but I posted the above back in November. Here that one is again:



Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11058-63. Epub 2004 Jul 19. Related Articles, Links

VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses.

Mittelbrunn M, Molina A, Escribese MM, Yanez-Mo M, Escudero E, Ursa A, Tejedor R, Mampaso F, Sanchez-Madrid F.

Servicio de Inmunologia, Hospital de la Princesa, Universidad Autonoma de Madrid, Madrid 28006, Spain.

The integrin alpha 4 beta 1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of alpha 4 beta 1 during the formation of the immune synapse is currently unknown. Here, we show that alpha 4 beta 1 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-alpha 4 antibodies, VLA-4 colocalizes with the CD3-zeta chain at the center of the synapse. In addition, antibody engagement of alpha 4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4(+) T cell differentiation and naive T cell priming by dendritic cells. The in vivo administration of anti-alpha 4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of alpha 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.

PMID: 15263094 [PubMed - indexed for MEDLINE]



I also had posted the following. Now these next two abstracts were findings that Biogen ITSELF was involved in. My question to Biogen would be: What changed in their research that now discredits their OWN findings in the two abstracts below with regard to anti-VLA4 treatment?

J Clin Invest, April 2001, Volume 107, Number 8, 995-1006

Copyright ©2001 by the American Society for Clinical Investigation

Article

Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

Bradley E. Theien1, Carol L. Vanderlugt1, Todd N. Eagar1, Cheryl Nickerson-Nutter2, Remederios Nazareno3, Vijay K. Kuchroo3 and Stephen D. Miller1

1 Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois, USA
2 Biogen Inc., Cambridge, Massachusetts, USA
3 Center for Neurologic Diseases, Harvard University, Boston, Massachusetts, USA

Address correspondence to: Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611, USA. Phone: (312) 503-7674; Fax: (312) 503-1154; E-mail: s-d-miller@northwestern.edu.

Received for publication November 6, 2000, and accepted in revised form March 13, 2001.

Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing experimental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the 4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti–VLA-4 to regulate proteolipid protein (PLP) 139-151–induced R-EAE when administered either before or after disease onset. Preclinical administration of anti–VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4+ T cells in the CNS. Most significantly, anti–VLA-4 treatment either before or during ongoing R-EAE enhanced Th1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. "


Here with this next research, it appears they attempted to find a way to keep anti-VLA4 treatment from producing the effects (highlighted) in the abstract below. Apparently, they failed with this particular substance. So....again, DID they find ANOTHER substance to put WITH Tysabri that WILL keep the immune system from skewing to a TH1 response (again which we know is bad for MS)? If they did.....great! But I can't find where they did, is all. And remember, this is Biogen's OWN findings. Not a competitor.

Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-03-0974.

Submitted April 8, 2003
Accepted August 18, 2003

Differential effects of treatment with a small molecule anti-VLA-4 antagonist before and after onset of relapsing EAE

Bradley E Theien, Carol L Vanderlugt, Cheryl Nickerson-Nutter, Mark Cornebise, Daniel M Scott, Stuart J Perper, Eric T Whalley, and Stephen D Miller*
Microbiology-Immunology/Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL, USA
Biogen Inc., Boston, MA, USA

* Corresponding author; email: s-d-miller@northwestern.edu.

Interaction of VLA-4 with its ligand VCAM-1 is required for CNS migration of encephalitogenic T cells in relapsing experimental autoimmune encephalomyelitis (R-EAE). Anti-VLA-4 mAb treatment prior to EAE onset inhibits disease induction, however, treatment initiated after the appearance of clinical symptoms increases relapse rates, augments Th1 responses, and enhances epitope spreading perhaps due to the activation of costimulatory signals. To negate the potential costimulatory activity of intact anti-VLA-4, we examined the ability of BIO 5192, a small molecule VLA-4 antagonist, to regulate active PLP139-151-induced R-EAE. BIO 5192 administered one week after peptide priming, i.e. before clinical disease onset, delayed the clinical disease onset, but led to severe disease exacerbation upon treatment removal. BIO 5192 treatment initiated during disease remission moderately enhanced clinical disease while mice were on treatment and also resulted in post-treatment exacerbation. Interestingly, BIO 5192 treatment begun at the peak of acute disease accelerated entrance into disease remission and inhibited relapses, but treatment removal again exacerbated disease. Enhanced disease was caused by the release of encephalitogenic cells from the periphery and the rapid accumulation of T cells in the CNS. Collectively, these results further demonstrate the complexity of VLA-4/VCAM interactions, particularly in a relapsing-remitting autoimmune disease.


Here again is one additional source of some of my original concerns and questions regarding Tysabri, that at some point, I would like Biogen ITSELF to dispute or explain. Until that time, there is no use in “arguing” over it, since it is simply something that I personally have questions about, is all.

Mult Scler. 2004 Oct;10(5):540-8. Related Articles, Links

Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment.

Deloire MS, Touil T, Brochet B, Dousset V, Caille JM, Petry KG.

EA 2966 Neurobiology of Myelin Diseases Laboratory, University Victor Segalen Bordeaux 2, Bordeaux, France.

Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients. In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised. Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observed in vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.

PMID: 15471371 [PubMed - in process]


Here is what I asked (posted) back in early November, and what I would still like to hear Biogen ITSELF answer very specifically and directly someday. I’m not holding my breath, though.

Yea, that's the thing. And that statement is just a general one. Actually, it's a good thing for the rats for THAT disease, but could be a bad thing for MS in many ways.

The thing is, a VLA-4 antagonist stops T-cell migration, but does NOT stop macrophage migration into the brain and/or CNS. For some conditions, that can be a good thing, but in MS, that is NOT always a good thing.

So.....basically, a VLA-4 antagonist can stop the immune system T-cells from entering the brain, but will not stop APCs from entering the brain. So, the probability is that IF any types of MS pathogenesis is from antigens sneaking in and isn't solely an immune system dysfunction, then in the long run, that is a bad thing. (Hence, that may be where and why we are hearing the rumors about Antegren not working for long. Even the findings from Biogen that I posted above indicate the same thing.)

The thing with a VLA-4 antagonist, though, is that when it is used in connection with stem cell research, the very fact that it is so potent and does manipulate what crosses the blood-brain barrier and blocks "certain" other things from crossing COULD be helpful. If you want stem cells to cross over the BBB without interruption from other bodily processes trying to stop them, then it could be great. (Again, though, all this research is in its infancy and a VLA-4 antagonist is nothing to just play around with.)

The other possible problem, though, is the fact that it doesn't allow ANY T-cells to cross. Hence why it says that over time, the body switches to a mainly TH1 immune response. In MS, you want to keep your immune system predominantly TH2. Plus, this allows a HUGE margin for infection, etc. to run rampant should you ever pick something up.

My question also then is...........you DO want the "good" interleukines to do its work in MS (i.e. such as IL10, and other anti-inflammatory cytokines), so if you take Antegren as a monotherapy, how long WILL it take before it stops working? And especially since Antegren only works via ONE mechanism of action, where are the balancing mechanisms that you need to balance out what it's doing?

I think the advice that person got (that I posted above - no wait, maybe it was in another thread - but I won't name names) from her neuro was a good one. Antegren MAY need to be used in combination with something else.

Biogen's OWN research points out many possible difficulties, doesn't it? That's what I found a little disturbing, shall we say. What changed in under a year with their research? Or is getting Antegren on the market more for the goal of supplementing stem cell research in the future?

It's going to get interesting, I'd say.

Deb


Oh.....actually........here's the bottom line of it all, that Biogen ITSELF found:

"...Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. "

I just couldn't find ANYWHERE, from any researchers, that VLA-4 antagonists had yet been "manipulated" or combined with anything to any extent where the above statement may now prove to be false.

That's why I say it'll be interesting to see what research Biogen has been holding back. Actually, I don't think it's research at all. I personally think that the only thing Biogen has been holding back is clinical trial results on humans. Which "might" mean nothing much as far as whether all of the above laboratory findings by them (and many others) has changed at all!

I would just use extreme caution and be VERY prudent before proceeding with Antegren. That's all. Just exercise extreme caution. (Of course, that's just MY personal advice. Take it or leave it.) Maybe I'd suggest that a person pose these very same probing questions to their neuro first, before proceeding with Antegren, also. It never hurts.

Deb


Ok...here's a bit of an explanation regarding myelin degradation in MS. I forgot to mention that a VLA-4 antagonist does not stop B cells from crossing, either. It only stops T cells. So....if some types of MS ARE exacerbated due to B cells, that could pose a problem, also. The following is just an excerpt that helps describe some of the complex problems that happen in MS:

"....This chaos of chemicals causes the inflammation of the blood-brain barrier, thinning it so that T-cells, B-cells and macrophages may enter. Macrophages complete the process by stripping the myelin sheath directly off the nerves. In turn, they release necrosis factor alpha, which is believed to damage oligodendracytes - the cells that produce myelin - making the damage irreparable. (2) The replication of T-cells, the secretion of more and more cytokines, and the eventual destruction caused by the macrophages is cyclic. The myelin can be come inflamed, swollen, or even detached from the nerve fibers. Eventually, it is destroyed and hardened patches of scar tissue form over the fibers (5)."

In any event, another bottom line that I state is that it is important to maintain a "balance" of physiological processes when treating MS.

Oh, and did you know that interferon-1b (Betaseron) has some effect on VLA-4 also, but isn't as potent and does have some other mechanisms of action that balance things out. (And as another plug for my pet project, desipramine also helps strengthen the BBB by minor action on VLA-4.) So..........IFN1b does much of the same thing. Well, there's a positive for a CRAB, huh? I believe you DO want to strengthen the BBB in MS, but just how much? Ya know? I don't think that's the sole answer, is all.

I hope this helps.

Deb


So, in closing, if Tysabri only keeps T cells from crossing the BBB, but does not keep B cells and macrophages from crossing, Tysabri may indeed prove to effect inflammation (and/or even show changes on MRIs), BUT....what will its long-term effects on disability progression and/or in actual patients be? Especially since we know (there can be no dispute about this part) that B cells and macrophages also produce damage in MS, which we see Tysabri apparently does not touch?
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Postby HarryZ » Sat Dec 11, 2004 7:56 am

[]The Tysabri Phase 2 trials were 'sliced and diced' and came out very positively reviewed (more on that in my next post). The only reason that the Phase 3 trials were not fully released is that the FDA made the decision to release the drug to the public BEFORE these were completed.


We know that but it's the Phase III that is the "meat" of clinical trials. That's what most MS docs are interested in seeing.

Now, why would they do that? I can tell you why in a very broad
context: their view of the data (and they have ALL the data) was that the drug is so good to withhold it from the public is not ethical.


How can anyone have ALL the data when the trials haven't been completed yet and the EDSS hasn't been tabulated?

It is disappointing that the totality of the drug trials on Natalizumab that are available are not referred to - only this or that one, depending on who is making the point (me, being postive on Tysabri referencing any postives in the trials, others, being more skeptical, referencing any negatives in the trials). May I suggest that anyone interested read all of the trial data that are published


Like I said above, it's the Phase III info that is the most important and that isn't available yet. Again, why do you use the term "negative" when someone points out a concern in a trial? That happens all the time in "peer review".

I continue to read that although the initial data on Tysabri is very good, many docs continue to state that it is limited data and they are taking a cautious approach.

Harry
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Postby finn » Sat Dec 11, 2004 7:56 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:05 pm, edited 1 time in total.
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