Earlier Natalizumab Trial

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

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.
Yes, I hope that the EDSS numbers of the Phase III trials are as good as Biogen hopes they will be. But, how can we say that the FDA approved Tysabri based on good EDSS Phase III scores when we have been told all along that there wasn't any Phase III EDSS info available in the one year data? Or perhaps there was some EDSS data that Biogen gave to the FDA but chose not to make public for reasons unknown at this time.

After reading the remainder of the info you posted I am still left with the impression that there is a lot we don't know about Tysabri and that comments made by various MD docs so far is based on limited data.

My position still hasn't changed on this medication....good initial data but until everything can be properly reviewed....caution. And please don't equate caution to negativity.

Harry
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Post by Observer »

Harryz - perhaps I should have said 'skeptical' or 'reserving judgment' rather than negative. I'm glad to see that you are favorably impressed with the data that you have seen. This is the first time I have seen you say something to that affect with regard to Tysabri. Hope I'm not misquoting you on this.

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

'and'

Yes, I hope that the EDSS numbers of the Phase III trials are as good as Biogen hopes they will be. But, how can we say that the FDA approved Tysabri based on good EDSS Phase III scores when we have been told all along that there wasn't any Phase III EDSS info available in the one year data? Or perhaps there was some EDSS data that Biogen gave to the FDA but chose not to make public for reasons unknown at this time.

I clearly said I was speculating on the basis of the FDA decision, even putting 'SPECULATING' in caps.

I am quite sure that the EDSS data have indeed been collected throughout the trial, from day one onwards. That they have NOT been publicly reported is a completely different matter. And indeed, by the 23 Nov 04 approval date many of the AFFIRM and SENTINEL patients had completed the 2+yr trial and their EDSS results are available. The FDA would have (I'm speculating again) looked at these data. The fact that they are not released to the public is just good science - they have a trial design and agreed protocol, and they want to complete it per good and ethical practice. Then the data will be made public.

Look at the downside. ASSUME there are good EDSS data (improvement)at 1 yr, 15 months, or with only part of the total trial patients but that these data somehow turn bad (no improvement) at 24 months. If the companies have published EDSS data at 1 yr, and many patients have switched in hopes of a result that was not sustained at 2 years in the trial, what would these patients now say/do? No way would the FDA or the Companies release the EDSS data unless they have previously agreed to it with the trial protocol, IMHO.

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.
Agree 100%. That is why I am surprised to see references to perceived problems with the 1999 P1 trials, and not looking at the more recent trials. Why disregard a larger P2 trial in preference to the 1/3 size (in terms of patients) P1 trial? Yet the correspondence that started this thread referred to the P1 trials. Admittedly, Harryz did not know that. But it seems to me that the skeptical view support provided by the comments about the P1 trial have been undermined completely.

And I might add that a focus on earlier trials can be misleading, in that new trials are often designed to resolve issues arising from previous trials. For example, comments regarding 'rebound effect.' a phenonmenon suggested by the P1 trial was clearly disproven by the P2 trials. I suspect that even when the P3 results are out, some will continue to look back at P1 or P2 results for something of interest.


OddDuck

The abstracts I could not access were in the NEJM Correspondence. For some reason I can access them from my office.

You make some good points about the original animal model studies and actual animal experiments with Biogen Idec's alpha 4 work. I don't pretend to know, but I'd speculate that the animal models/experiments were not borne-out in later work. Why wasn't this later work released - perhaps competitive reasons.

Have you asked Biogen Idec any of your questions, and if so what was their reply?
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Post by HarryZ »

Observer,
Perhaps I should have said 'skeptical' or 'reserving judgment'
rather than negative. I'm glad to see that you are favorably impressed with the data that you have seen. This is the first time I have seen you say something to that affect with regard to Tysabri. Hope I'm not misquoting you on this.
Now we are making progress :) As for the data part, I don't think that I would say that I am "favorably impressed" with it. I have stated a number of times (more on other less detailed MS forums) that Biogen has given us good data on Tysabri. But you likely would ask why I am not impressed with this data? The answer lies in not trusting everything that drug companies tell us and Biogen is part of this business. I've expressed my reasons for this in previous posts and knowing how Avonex got approved certainly doesn't help the cause either. Hopefully all of my doubt and fears about Tysabari will be gone in time but at the moment they still remain.
I am quite sure that the EDSS data have indeed been collected
throughout the trial, from day one onwards. That they have NOT been publicly reported is a completely different matter. And indeed, by the 23 Nov 04 approval date many of the AFFIRM and SENTINEL patients had completed the 2+yr trial and their EDSS results are available. The FDA would have (I'm speculating again) looked at these data. The fact that they are not released to the public is just good science - they have a trial design and agreed protocol, and they want to complete it per good and ethical practice. Then the data will be made public.
Part of the "good science" on the Phase III trials was the initial plan. That got turned upside down when the schedule changed, only one year data was used and the FDA approved the drug. The comments coming from a number of MS docs who are used to the established protocol were asking how and why this happened. Two year trial data is the minimum standard for Phase III trials so it is not surprising that these docs are questioning the use of one year data as well as not being given the standard "peer review " time. Next week there is a com cast originating from John Hopkins University that is going to be about Tysabri. Several MS docs will be taking part in this web cast and one of my contacts is going to let us know what takes place in this "mini conference". Could be interesting.
Look at the downside. ASSUME there are good EDSS data (improvement)at 1 yr, 15 months, or with only part of the total trial patients but that these data somehow turn bad (no improvement) at 24 months. If the companies have published EDSS data at 1 yr, and many patients have switched in hopes of a result that was not sustained at 2 years in the trial, what would these patients now say/do? No way would the FDA or the Companies release the EDSS data unless they have previously agreed to it with the trial protocol, IMHO.
Certainly not being an expert on EDSS methodology, I do believe that it takes a number of months for the EDSS scores to show change. If the EDSS scores show positive results at 18 months, then they SHOULD continue that trend. If, however, like you said they go bad in the last 6 months, then that would be a severe blow to Tysabri.

Agree 100%. That is why I am surprised to see references to perceived problems with the 1999 P1 trials, and not looking at the more recent trials. Why disregard a larger P2 trial in preference to the 1/3 size (in terms of patients) P1 trial? Yet the correspondence that started this thread referred to the P1 trials. Admittedly, Harryz did not know that. But it seems to me that the skeptical view support provided by the comments about the P1 trial have been undermined completely.
I don't think that I have seen any "peer review" reports done on the P2 trials. This isn't done until the docs have the actual trials in their hand and can read what really happened. I don't know if the actual P2 trials (not Biogen published releases) have been made available to the docs as yet.
And I might add that a focus on earlier trials can be misleading, in that new trials are often designed to resolve issues arising from previous trials. For example, comments regarding 'rebound effect.' a phenonmenon suggested by the P1 trial was clearly disproven by the P2 trials. I suspect that even when the P3 results are out, some will continue to look back at P1 or P2 results for something of interest.
Yes, I will agree with your comments on focus here and that is another reason why the MS docs want to get their hands on the P3 trials. Again, that is why some of them are stating caution because they simply don't know and can't find out for themselves as yet.

I said it before and I'll say it again...it's going to be a number of months yet until Tysabri has had the normal attention given to it that is required to satisfy the MS world of medicine. And until that happens, I will remain cautious, skeptical or guarded...whichever word you prefer to use :D

Harry
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Post by OddDuck »

Have you asked Biogen Idec any of your questions, and if so what was their reply?
First of all, why didn't Biogen just publish on their own any new and/or corrections of the findings I just posted? They knew what they had found and published in the recent past. They aren't stupid. If they ran further studies that showed different or better results, why would they withhold that at all? Or did they NOT find different or better results? Or did they not run further tests at all, and that's why we can find no "corrective" abstracts?

To "ask" them something so simple as that, to me, would be an insult to them, wouldn't it? Or did they just think people wouldn't read enough or dig deep enough, and therefore they didn't NEED to fully publish clarification or subsequent findings? OR....did they ever do any further studies into those exact areas? I mean, I don't know what or why they felt no need to follow up on or to correct their previous findings. But why should ANYONE have to "ask"? They published the original studies that I referred to. They apparently decided to take the chance that not many would make comparisons or ask questions. And besides me, I don't believe many (if ANY) HAVE seen those and wondered about the whole thing. Am I close to perhaps ascertaining the situation correctly? Plus, why do I think that Biogen already knows what the public is questioning? (Remember, I worked behind the scenes in the medical field, and one of my responsibilities was scouring the web, including message boards pertaining to our particular sector of medicine, and reporting back on prevailing sentiments and/or questions out there, shall we say. I'm sure that wasn't the only corporation that does that. That's just a small part of monitoring the market, prevailing attitudes, and competitor moves.)

Come on, as if they are going to answer any of my questions anyway? No offense, but let's be realistic here. For example, Elan supposedly offered to thisisms.com through Arron to answer questions people wanted to propose to them, and so far, to my knowledge anyway, there hasn't been a peep out of them in response to anyone's questions.

And Finn............good point, except that (for example) even when I posted just the links, etc., (even links to prior postings in other threads), it is obvious from the type of comments, etc., that unless some things are posted clearly, succinctly and in full, many people don't read them, misunderstand, tend to "assume" and/or make accusations to the poster.

I personally apologize for the length of my posts and for feeling that I have to repeat myself so often. If you notice, I do not feel the need to speak to folks such as Harry or Robin in such detail or at such length.

But, I certainly do agree with you, Finn. I wish it could be otherwise myself.

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Post by Observer »

Harryz

Slowly but surely we'll get there. 8)


That got turned upside down when the schedule changed, only one year data was used and the FDA approved the drug. The comments coming from a number of MS docs who are used to the established protocol were asking how and why this happened. Two year trial data is the minimum standard for Phase III trials so it is not surprising that these docs are questioning the use of one year data as well as not being given the standard "peer review " time. Next week there is a com cast originating from John Hopkins University that is going to be about Tysabri. Several MS docs will be taking part in this web cast and one of my contacts is going to let us know what takes place in this "mini conference". Could be interesting.
I disagree that anything got turned upside down. As has been posted numerous times before, there were 1-yr endpoints in the P3 trial protocol from the start. Further, the FDA had said PRE-PHASE 3 Trial that if these endpoints were met, they would accept a filing on 1-yr data. Indeed, the endpoints were met or exceeded, and the FDA encouraged the companies to file on the basis of the 1yr data.

Will be very interesting to hear the John Hopkin's webcast. I'll also report what I hear (if anything) from my sources.

I don't think that I have seen any "peer review" reports done on the P2 trials. This isn't done until the docs have the actual trials in their hand and can read what really happened. I don't know if the actual P2 trials (not Biogen published releases) have been made available to the docs as yet.
The P2 trials have indeed been published in the NEJM (Jan, 2003), a peer-reviewed journal. All the data are available and there has been little (if any) negative comment resulting from this trial.

See the links I previously posted for the citation.

As for satisfying the MS World, a lot of patients who have no options now have something they can try. I'm sure we certainly hope Tysabri works for a large percentage of them. I believe this is the initial target population, and one of the major reasons that the FDA approved the drug based on 1 yr data. I suspect (and this is speculation) that many CRAB users will also switch based on the apparently superior performance and minimal side effect profile of Tysabri. When the EDSS results are presented, if they are as expected (by me and many others), I think there will be a wholesale shift to Tysabri.
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Post by HarryZ »

I disagree that anything got turned upside down. As has been posted numerous times before, there were 1-yr endpoints in the P3 trial protocol from the start. Further, the FDA had said PRE-PHASE 3 Trial that if these endpoints were met, they would accept a filing on 1-yr data. Indeed, the endpoints were met or exceeded, and the FDA encouraged the companies to file on the basis of the 1yr data.
I meant the normal process got turned around, that being the completion of the Phase III trials. To my knowledge and not that I spend any time following this, I have not heard of any Phase III trials being cut in 1/2 and a drug being that quickly approved. I wondering why this was done with the FDA behind it. Is it the fact that up to now, MS research results have been so abysmal that the FDA was looking for anything that showed better data than what we have seen. I don't know.
The P2 trials have indeed been published in the NEJM (Jan, 2003), a peer-reviewed journal. All the data are available and there has been little (if any) negative comment resulting from this trial.
I haven't seen any comment on it, period. That is unusual.

As for satisfying the MS World, a lot of patients who have no options now have something they can try. I'm sure we certainly hope Tysabri works for a large percentage of them. I believe this is the initial target population, and one of the major reasons that the FDA approved the drug based on 1 yr data. I suspect (and this is speculation) that many CRAB users will also switch based on the apparently superior performance and minimal side effect profile of Tysabri. When the EDSS results are presented, if they are as expected (by me and many others), I think there will be a wholesale shift to Tysabri.
I read a comment on the MS Foundation board that a patient was talking to a Serono rep about Tysabri. The Serono rep told her that the current thought about Tysabri was that it would be used only for newly diagnosed patients who had very minimal symptoms and disease progression. I've also read on other forums that many insurance companies were balking at the cost and even if there was an 80/20 split cost with the patient, most patients simply couldn't afford even that. Time will tell.

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Post by Observer »

OddDuck, I'm sure you and we all are trying to get at the truth. I don't know why we should NOT ask Biogen Idec. I'll send them your questions (if you don't mind) but will not refer to you in any way, and I'll repost whatever they reply with. What do we have to lose?

As for Finn and posting 'hotlinks' I'm not sure how to do that. I only copied the NEJM link from the address bar in IE.

I prefer to post links or citations, and I do that purposely. I think 'trusted source,' 'knowledgable MS researcher,' etc as support for statements may have a place here, but they should take a distant 2nd to citations which readers can trace, read, and interpret for themselves.

And I am particularly concerned when there is only half the story presented (and especially, it seems to me, that the negative half story gets unusual prominence). I mean, for example, the following innocuous question:

Antegren supposedly causes NABs in approx 6% of the users and they must come off the drug if this takes place. I've also heard that coming off the drug can cause some kind of "rebound" effect with the patient suffering exacerbations. What do you know about this situation? Thanks.
The NABs have been reported in the drug's label, but where has anyone 'heard' of a "rebound" effect - why isn't this elaborated upon? I believe Phase 1 suggested a possible rebound effect. This was disproven by Phase 2. Why would anyone ignore the results of the Tysabri Phase 2 trial which disproved the rebound effect? I cannot understand posting something which ignores information already in the public domain, information that is readily accessible and has been reported on multiple times in this Forum. Is there some reason for this type of post, continually asking questions that have already been answered?

Finn, it is a good suggestion to shorten posts but I think we must post complete, traceable information - negative AND postive. And the post which started this thread referred to a snippet from NEJM corrspondence which contains (surprise, surprise) a negative, but when the entire Correspondence link is posted we see that the negative point is moot. Again, half the information - in a supposedly innocent post. But where are the innocent posts on the positive side? None seem to appear, methinks. At least that's IMHO.
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Post by Observer »

Harryz
I've also read on other forums that many insurance companies were balking at the cost and even if there was an 80/20 split cost with the patient, most patients simply couldn't afford even that. Time will tell.
I've heard that MOST insurance companies have already agreed to cover Tysabri. I can post some citations, if required, but in the interests of brevity I'll post just one. Check out the MS World Message board, for example:

http://msworldboards.org/vbulletin/show ... ht=Tysabri

ALL of the posters making such an indication here indicated their insurance companies were covering Tysabri. Hmmm.

It makes simple sense - you have the CRABS that offer efficacy less than half of Tysabri, do not apparently improve EDSS, and ARE being paid for. But insurers are NOT going to pay for Tysabri. Yeah, right.

Agree 100%, time will tell. I'll be watching and will refer back to this post in several months.
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Post by Observer »

Sorry to keep posting, but just a general comment on FDA approvals.

I meant the normal process got turned around, that being the completion of the Phase III trials. To my knowledge and not that I spend any time following this, I have not heard of any Phase III trials being cut in 1/2 and a drug being that quickly approved. I wondering why this was done with the FDA behind it. Is it the fact that up to now, MS research results have been so abysmal that the FDA was looking for anything that showed better data than what we have seen. I don't know.
I don't think the process got turned around at all (and this obviously is a matter of opinion, and I think we should agree to disagree). The FDA sometimes approves drugs quickly for unmet medical needs in serious and life threatening illnesses. Erbitux was approved on the basis of Phase 2 trials, and was fast tracked (6-month approval cycle) to boot. Velcade was approved fast track on Phase 2 results. I guess it depends on the data quality and the unmet medical need.

Apparently Tysabri qualified in this regard. I believe a large number of MS Docs agree, and certainly the patients who have no other option are probably happy.

Now this is definitely my last word on this.
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Post by HarryZ »

Ovserver,
I've heard that MOST insurance companies have already agreed to cover Tysabri.
Looks like we are reading in different areas. In the MS Foundation forum there have been posts from patients who say that their docs have checked with the applicable company and they are not going to pay. Then again, insurance companies often initially say no and when pressed hard enough, change their minds. Whether this happens with Tysabri remains to be seen.

It makes simple sense - you have the CRABS that offer efficacy less than half of Tysabri, do not apparently improve EDSS, and ARE being paid for. But insurers are NOT going to pay for Tysabri. Yeah, right.
Insurance companies, like drug companies, have little or no interest in the patient's health. It's all about money and the bottom line. That's why they are in business. I would imagine that some insurance companies may just wait a bit before committing to pay for Tysabri....they would want to ensure that the drug is as good as Biogen says it is before putting out that kind of money.

Harry
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Post by OddDuck »

OddDuck, I'm sure you and we all are trying to get at the truth. I don't know why we should NOT ask Biogen Idec.
Well, no offense, but due to my personal feelings about Biogen's "reputation" (which I posted and explained before), and I truly apologize to Biogen for this, .......I just don't trust them to tell the whole truth. And that's not because of any one specific item that you can point at. It is as I mentioned before, it's PURELY my personal "feeling" about them based on their own record, etc., as shown in their SECs, etc. I won't beleaguer the point any farther, though. That's just my opinion, and is neither here nor there in the big scheme of things. I just don't trust them, nor am I trying to influence anyone else's opinion of the company. Not at all.

Besides, I still believe they have read all my posts anyway. All of OUR posts. Hey......all of my questions are right here on a public board. Just refer them here to thisisms.com! That way, they can see both pros and cons from everybody.

Some people on MSWorld.org have some questions, also, that they are asking about Tysabri. (Actually, I was totally surprised!) And believe it or not (I swear - I never even posted over there or got involved in Tysabri discussions at all over there), some women noticed what I did (and they only read the product label, apparently) and the younger women of child-bearing age are questioning the "fertility" and pregnancy related issues with Tysabri. Hey......don't blame me! I only noticed it first, is all. I didn't figure I'd be the only one OR the last one, though.

:wink:

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Post by HarryZ »

Observer,
The NABs have been reported in the drug's label, but where has anyone 'heard' of a "rebound" effect - why isn't this elaborated upon? I believe Phase 1 suggested a possible rebound effect. This was disproven by Phase 2. Why would anyone ignore the results of the Tysabri Phase 2 trial which disproved the rebound effect? I cannot understand posting something which ignores information already in the public domain, information that is readily accessible and has been reported on multiple times in this Forum. Is there some reason for this type of post, continually asking questions that have already been answered?
The "rebound" item got started when a reader from another MS forum discovered a website that involved discussion between drug company sales reps. After searching around this morning I was finally able to find this link http://www.cafepharma.com/ubbthreads/sh ... art=2&vc=1

It supposedly is a forum that is used by sales reps to discuss their various business situations. It certainly isn't known to the public and how the reader in The MS Foundation found it I don't know. I draw your attention to message #311883. Is this comment true, fiction or sour grapes? Who knows! But you can see how information like this starts to spread quickly through various MS forums.

Harry
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Post by HarryZ »

Observer,

For likely different reasons I, like OddDuck, don't trust Biogen. I suppose this mistrust always sits in the background when I state my opinions about Tysabri and shows my feelings towards them. Is it justified? For me it is and the only way it will go away is if Tysabri comes out "smelling like a rose" and does everything that Biogen says it will do for MS patients. Until now I have come accross too many indicators that suggest otherwise. Maybe I will be wrong in my feelings about Biogen and Tysabri but until the drug can prove itself, I remain "cautiously yours".

Harry
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Post by Observer »

Harryz

I would not place a lot of faith in an anonymous post on the Cafepharma boards, especially when it has no data to support it. Further, please refer to #312357 for a rebuttal of the 18-month effectiveness nonsense. There just is nothing to support such a statement.

Ineed, the mean treatment time in the AFFIRM trial so far reported was 20 months (if I recall correctly) yet no reduction in efficacy was noted or reported. So why should we believe an anonymous poster on the Cafepharma board, who presents no support of his claim? Me, I choose to look at the data and facts. I suspect we all do.

So should we perpetuate unsubstantiated rumours? Of course not.

And I might add that the post you reference does not discuss rebound effect, but rather a loss in effectiveness at 18 months. At any rate, both of these rumours have been disproven by the data. A simple check of those data would indicate this, so why perpetuate them?

OddDuck, I understand your and Harryz's skepticism about Biogen Idec. In spite of that, I'll ask the questions and see what we get back.

Certainly the response will be at least as credible as posts on the Cafepharma message board.
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Post by HarryZ »

Observer,
And I might add that the post you reference does not discuss rebound effect, but rather a loss in effectiveness at 18 months. At any rate, both of these rumours have been disproven by the data. A simple check of those data would indicate this, so why perpetuate them?
I realize this quote was in reference to the 18 month effectiveness but I was only trying to show some of the info that was floating around and how it got started. Should we believe any of it?....in time Observer, in time!

Harry
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