Earlier Natalizumab Trial

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

Postby Ptwo » Thu Dec 16, 2004 6:17 am


BTW, in the Multiple Sclerosis Sucks forum, the MS professional who answers a number of questions for readers over there stated that she spoke to about 18-20 MS docs in her circle of work and all of them stated that they would not be rushing into the use of Tysabri until far more data was made available and the drug proved itself in general usage.



Harry, I just took a look at the thread you talking about ( I think) and she say's 9-10 ms docs not 18-20. It's not surprising that people are being cautious with this new drug or any new drug for that matter. The idea of injecting yourself with a bit of biotec is not very appealing to most folks and I think it's a good idea for Doc's to not swallow the drug companies results, hook line and sinker.

Really what's going to happen now is the trial is going to expand to another 75,000-100,000 paying customers and we will get a better idea of how effective it is.

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Postby HarryZ » Thu Dec 16, 2004 11:41 am

Peter,

BTW, in the Multiple Sclerosis Sucks forum, the MS professional who answers a number of questions for readers over there stated that she spoke to about 18-20 MS docs in her circle of work and all of them stated that they would not be rushing into the use of Tysabri until far more data was made available and the drug proved itself in general usage.


That's not the same thread that I got the 18-20 number from and now that you pointed it out to me, it may have been the Brain Talk MS Forum where I saw the info. It was a thread where one of the readers was really questioning Clinical 1 about some comments she made on Tysabri and she came back with the reply. I'll do some searching later today (too busy at the moment).

I was also at the MS Clinic here today, helping a friend who had to see the neuro because of a problem she was having. I spoke to the doc, who just happens to be my wife's neuro as well. They have been doing trials on Tysabri there for 3 years and I came out and asked him what he candidly thought about the drug. I will post his comments later today.

Really what's going to happen now is the trial is going to expand to another 75,000-100,000 paying customers and we will get a better idea of how effective it is.


You've got that right!!

Harry
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Postby HarryZ » Thu Dec 16, 2004 6:29 pm

Peter,

I've just spent over 30 mins looking over 3 MS forums for the "18-20 doc comment that I made earlier....and finally found it. It was on the MS Sucks website and here is part of the message.....

"Physicians with whom I have contact (at least 18-20 who are treating MS) say they will NOT use it in patients who are doing well on another med. They will also not use it on anyone who has an active form of the disease as in needing steroids more than a couple of times a year for relapses. In fact, it is recommended that if there are two relapses in a year on Tysabri requiring steroids, the patient be taken off the med and placed on other therapy(s)."

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Postby finn » Sun Dec 19, 2004 7:08 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:07 pm, edited 3 times in total.
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Postby HarryZ » Sun Dec 19, 2004 9:31 am

Finn,

Nice to see you again.

1. Accordind to this article the early approval process of Tysabri was started by Biogen, not the FDA:


A friend of mine who has gone through the clinical trial exercise and has dealt with the FDA, told me point blank that the FDA simply does not approach any drug company and solicit them to submit for approval. But some MS forum readers insist that the FDA approached Biogen and not the other way around as your article indicates. I guess it all depends on how you want to believe what really happened.

Hope you continue to post more often.

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Postby Observer » Sun Dec 19, 2004 8:29 pm

Finn, on the rebound effect I note that your 2nd citation suggesting this problem was published in MAY 2002 as conference coverage of the 2002 AAN Conference. Yet the Phase 2 trial was NOT published in a peer-reviewed journal until JANUARY 2003. The NJEM paper on the Phase 2 trial is at:

[url]
http://content.nejm.org/cgi/content/ful ... lcode=nejm
[/url]

(sorry, I don't know how the link thing works).

Here is an excerpt from the paper at the above link.
___________________________

Study Design and Randomization

Patients were randomly assigned to one of three treatments — 3 mg of natalizumab per kilogram of body weight, 6 mg of natalizumab per kilogram, or placebo — with use of a computer-generated block randomization schedule. Randomization was performed centrally by PPD Development. Patients received an intravenous infusion every 28 days for 6 months and were then monitored for an additional 6 months for adverse effects. Neither the study personnel nor the patients were aware of the blinded treatment assignments.

Post-Treatment Follow-up

When the values obtained at month 9 and month 12 were combined, the number of new enhancing lesions and scans showing activity were similar in all three groups (Table 2). After treatment, there was no significant difference among the three groups either in the total number of relapses or in those objectively confirmed (Table 3).

_________________________________

In other words, NO rebound effect was noted. Speculation by some after the P1 trials suggested possible rebound was one of the purposes of the P2 trial. I wonder why no one has suggested rebound affect after the P2 trial was published in January 2003. If you have some more recent data on a possible 'rebound effect', or comments thereon, I'd certainly like to see it. TIA.

So I don't know where Dr. Freedman comes up with his comments:


A similar loss of relapse benefit was noted, but with a slightly higher relapse rate seen in the higher-dose group.

This agent presumably works by stemming the flow of lymphocyte traffic across the blood brain barrier. Given alone, it would appear that the cells capable of causing disease simply pile up and enter the brain upon drug cessation. This raises concern over a possible "rebound" effect when the drug is stopped, and speaks for the need to use a concurrent immunomodulatory agent, such as an IFN, to act upon potential disease-causing cells in the periphery.



but it appears that Dr. Freedman is merely speculating on the basis of data that are not statistically significant ('slightly higher relapse rate'). And no others have echoed this speculation, even after the paper was published. Hmmm. But what do I know? Let the reader decide.

And just a further note, from an interview with Dr. Freedman

http://www.medscape.com/viewarticle/491641

Disclosure: Mark S. Freedman, MD, has disclosed that he has received grants for educational activities and clinical research from Serono. He has served as an advisor for Serono, Berlex/Schering, Biogen Idec, and Teva.


This disclosure information does NOT invalidate his concerns published in May, 2002, nor suggest any impropriety. It is simply worth noting and being aware of.

___________________________________________

As for the FDA request for 1 yr filing, I must be reading something differently than you, as here is the excerpt from the article you reference from page 3:


“It wasn’t a sure thing that [Antegren] would affect relapses to a similar degree that it affected lesions,” he says. “When we saw the results we got very excited. Then we went down to the FDA, and they broke their prior
Phase III trial precedent of requiring two years of data, allowing us to file with one year of data—that was an exciting moment.”



So does this indicate that Biogen initiated the filing process? Not IMHO. The trials had pre-approved one-year endpoints, and the companies were obliged to report this to the FDA in the normal course of the trial. Are you suggesting that in this reporting, the companies asked to file on 1yr data? Maybe they did, but where does the article you posted say that? Does the phrase 'allowing us' indicate that Biogen Idec initiated the process? Open to interpretation.

But substantially more details of the pre-NDA process are outlined in several statements at Investment Conferences where Dr. Lars Eckman, Elan's President of R&D, said the FDA encouraged Biogen Idec and Elan to file. Here is one quote from Dr. Eckman, speaking at the Lehman Brothers 3 March 2004 Global Healthcare conference

http://www.tixx.com/lehman.htm

"So, why is the Agency excited about Antegren? Well, there were two reasons. When we presented the Phase II data two years ago, we presented two things or three things. One was that the galinieum enhanced lesions, the new lesions, were reduced by 90%. We did prove that we could reduce the number of relapses with 50% to 60 % in the two categories. And we had excellent safety data. Safety data that did not reveal any difference between placebo and control in any aspect. At the time the Agency said: “If you can provide exceptional data,” and by that they said “in this space” then they would consider a one-year filing.

Since then, we have delivered 2, 200 patients in two trials, one is a monotherapy trial, the Affirm trial. The other one is a combination [trial] with Avonex, [the Sentinel trial]. It’s Avenex vs. Antegren plus Avenex in partial failures. This data has now been presented to the Agency. The Agency came back to me or to us as a team and said, “We want to meet you. We want to have a pre-NDA meeting.” We had the meeting. It was a very constructive meeting and they encouraged us to file. "


There are other references to the FDA guiding the process, but they say basically the same thing: the FDA encouraged the filing. I'll let the readers decide whether to believe Dr. Eckman, but I'd ask why would he make such a statement in a public forum if it were not true? Wouldn't he think the FDA might be a bit upset about him 'putting words in the FDA's mouth' if they were untrue?
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Postby finn » Mon Dec 20, 2004 2:08 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:08 pm, edited 1 time in total.
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Postby Observer » Mon Dec 20, 2004 3:02 am

Finn

Thanks for the tip on how to post links.

I was aware that Dr. Freedman's comments were about the Natalizumab P2 trial, and indeed I quoted the P2 trial NEJM paper which contradicted Dr. Freedman's comments. Again, it 'appears' that Dr. Freedman is drawing a conclusion on data that were NOT statistically significant, which of course is a 'no-no' and may be the reason that no other researchers have echoed his comments (at least, none that I am aware of in print).

Dr. Freedman goes on to suggest that the bad guys are just queuing up outside the BB barrier, waiting for the 'door' to open. To me that seems a big stretch, and the P2 data do not support this contention. Why he stated it is anyone's guess, but the theory does not seem to have resurfaced. But I want to be clear: this is simply a reader's observation, as I am not technically qualified to comment on such matters.

As for the P2 trial itself, I believe the purpose of the post-natalizumab (Tysabri) administration monitoring (months 7-12) in the P2 trial was to determine whether there was a rebound effect. (This is what I was trying to say in a rather awkward way.) Again, the P2 trial data said there was not.

Interestingly, in the link you provided to the 2001 ECTRIMs Abstract of the P2 study, we see the P2 patients had relatively high EDSS scores and some were SPMS:

Results: The patients in the three treatment groups were balanced for baseline demographic parameters; the mean age was 43.5 years, mean EDSS was 4.3 and 68% were relapsing-remitting and 32% secondary progressive. The mean number of new Gd-lesions was reduced by over 88% with Antegren compared to placebo; (p<0.0001). The reduction in Gd-lesions was apparent within 4 weeks of treatment. The proportion of relapse-free subjects was significantly higher in both Antegren treatment groups (p=0.03). Antegren was well tolerated with a similar number of subjects experiencing treatment-emergent adverse events in each of the treatment groups. On a global measure of patient well-being, Antegren-treated patients felt significantly better compared to placebo (p=0.03).{tc \l 2 ""}



There has been a lot of speculation on whether Tysabri (Antegren) would be beneficial for high EDSS score individuals, and/or whether it would be useful with those with SPMS. Based on these data, anyway, it appears the jury is out on these issues. I do NOT know whether there are further data in this regard.
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Postby better2gether » Mon Dec 20, 2004 5:30 am

HarryZ

HarryZ wrote:Observer,

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


This is message 311883 by an anonymous messenger:

"You are all wrong- I used to work for Elan and Antegran's problem is resistance build up by patients- In other words looses impact at 18 months and continues downward spiral past that. 1st 18 months have good data. "

Strange that someone that used to work for Elan can't write 'Antegren' correct.
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Postby HarryZ » Mon Dec 20, 2004 6:53 am

Strange that someone that used to work for Elan can't write 'Antegren' correct.[/b]


I'm not sure that I would place too much emphasis on spelling when it comes to internet communication. Prior to using a "spellchecker", I made several spelling and/or typing errors in my messages and most posts today include a number of mistakes.

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Postby finn » Mon Dec 20, 2004 7:32 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:08 pm, edited 1 time in total.
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Postby Observer » Mon Dec 20, 2004 5:36 pm

Finn

The posting times are weird, but I'm in not in the U.S. or Europe so my posts will appear to be at stange times relative to these areas.

My guess is the interpretation of the data rests on its statistical significance. Freedman noticed a trend to higher relapse rates of the high natalizumab group after the dosage had been stopped. Miller et al. found no statistical significance to this trend, I think. Pure speculation, but I think again this is why no one else has picked-up on Freedman's hypothesis.

I agree with you: one never knows how vested interests impacts interpretations of data and events. Human nature, I suppose.
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Postby HarryZ » Sun Jan 02, 2005 8:57 am

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.


The authenticity of the Cafepharma website has been questioned in the past. I just came across this posting on the Brain Talk MS Forum.

"If any of you are interested in how these salesmen, act, and think about their own jobs, check out this website: www.cafepharma.com It can be very very interesting... I asked this district manager if the website was "true"to form and he said most definitely...many of the forum posts are accurate. He used to be in the field, but now only manages so has a dual perspective."

The thread is about Michael Moore doing a new documentary film on the medical industry in the US. Of course, pharmaceutical companies will be heavily targeted. Some people like Moore's films, others can't stand them! But rest assured the drug companies are a little twitchy!

Harry

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