DACLIZUMAB

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DACLIZUMAB

Postby OddDuck » Sat Oct 08, 2005 9:11 am

Ok..........here we go (and I better start dodging the rotten eggs that will be about to be thrown at me. But then again, I was on the mark with Tysabri last time, so maybe I'll come out of this one a little more unscathed.)

Daclizumab:

Ok, let's see how much about daclizumab (e.g. Zenapax) I can quickly fill you in on. I'll come from the basics (so forgive me if I'm telling you some things you already know).

Ok.......in a nutshell, daclizumab (Zenapax) is a very strong immunosuppressant that appears to have originally been developed to assist with heart and renal transplant rejections. What it basically does is inhibit the production or activation of the cytokine IL-2. (Hey, in organ transplants, with VERY close and careful monitoring, AND short term use; it is possibly a lifesaver.) BUT.........

Here is a bunch of FDA info http://www.fda.gov/cder/biologics/produ ... 121097.htm

Notice all the cross-outs and blank pages? Especially in this report:
http://www.fda.gov/cder/biologics/revie ... 1097r2.pdf

There is red flag number one.

Also, although I haven't provided you a link here, I don't believe, note the package insert that comes with Zenapax. Again, I say, it's a bit "lacking".

Now.............note THIS study:

http://www.ohsu.edu/ohsuedu/newspub/rel ... splant.cfm

(After review, carefully compare what the FDA says against what this article says. You might find some things a little contradictory.) Also, look carefully at the number of deaths in clinical trials. And also note "why". The increase in "bacterial" infection. BAD news!! I researched further. The particular "bacterial" infections that are connected with inhibited IL-2 are from "superantigens". In other words, things like TB, borrelia, systemic infection, toxic shock, sepsis, things like that. MANY bacterial infections in the world, as you know, are already becoming resistent to antibiotics, and death often happens pretty quickly. And many of these everyday bacteria that we all are exposed to are held in check in everybody's body by our immune system. Bottom line, held in check by IL-2. And this concern doesn't even take into consideration what we already know is the risk that is being run, when being treated with immunosuppressants, from the possible increase or activation of viral infections.

Combine something like daclizumab with another cytolytic or anything that modulates or helps to control inflammation (such as steroids........the VERY thing that is given to MSers, mainly RRMSers constantly) and you've possibly got real trouble.

Messing with IL-2 can be nasty. Real nasty. Again, in organ rejection, it can be and is needed under very close monitoring (it is even suggested via hospitalization) and most often for short-term use. But in or for a basically non-fatal disease like MS? Pardon my scoff, but...........yeah, right!!! Here's why:

First, it is not really even known for certain that MS is truly an autoimmune disease. There is a lot of argument regarding all that. They are still totally "experimenting" with that theory. It appears that among other cytokines, etc., an MS lesion contains a lot of IL-2 (but, they aren't sure if it's the IL-2 that is the cause of the lesion, or if it's the IL-2 that is coming to the RESCUE of the cells that are being attacked by whatever it is that exacerbates MS in the first place). Ok, so they want to "see" what will happen in MS by inhibiting IL-2. Maybe you can find more animal studies regarding inhibiting IL-2 and MS mice than I have so far. Anyway, the body needs IL-2, as I've quickly mentioned above. Plus, how often and how much research can you really find that indicates that in general neurology practice an MSer's blood is ever checked via ELISA or better yet, via ELISPOT on any kind of regular basis to see what, if anything, ANY of the cytokines are doing, and if they are too high or too low anyway. I can tell you. They never do it. (When I pressed about that matter, the neuros I "talked" to got really defensive and angry.)

EXCEPT............in progressive MS. (Now remember, RRMS patients are the least sick of them all. Some can have RRMS for 30 years and barely be aware they have it at all.)

In progressive MS, which does not involve inflammation, it has been fairly well concluded that IL-2 in those patients is ALREADY too low, hence why they "may" get so bad so rapidly as opposed to RRMS. Another problem with MS is trying to classify (as you have already seen) which "type" (as is currently defined) that a patient has. And there is no way of knowing at what point RRMS may "switch" to progressive MS (but many eventually do.) Red flag number two......what happens if someone with PPMS accidentally receives this drug?

Ok...........we've already seen deaths in clinical trials which were done under fairly stringent monitoring conditions. We know in a nutshell what inhibiting IL-2 can/will do, especially if taken under long-term use. And we know that neuros are very haphazard with prescribing many medications for symptomatic relief in MS, ALONG with actual MS disease therapy via immunomodulating and immunosuppressing agents and drugs. What's your best guess, about what may come of this one?

If all these risks are FULLY DISCLOSED in layman's terms to patients, and physicians are PROPERLY advised, etc., then fine.

NOW.............combine BIOGEN with clinical trials and marketing of daclizumab. HAH! Pardon me for being skeptical.

Well, this all still lacks detail and substantive material, but I hope it's enough for now for you to see why I'm "concerned". My gut feeling again is "Caution, Will Robinson" and "I hope I'm wrong."

Here are a few minor interesting items with regard to daclizumab:

In 2003:

...."Daclizumab labeling revised
The FDA and Roche recently revised the Warnings, Precautions, Adverse Reactions, and Clinical Studies sections of the daclizumab (Zenapax) labeling to include new safety information describing the increased mortality noted in a cardiac transplant study. Also added was other information regarding hypersensitivity reactions." ....

Hmmmmmm.......well, I certainly didn't see a black box, but maybe I missed it. I'm going to fetch the PDR when I get a second. ;-)

Also [emphasis added]:

Biotech Loses Ground in May
…as the economy stalls and the IPO market softens

San Francisco, CA - June 02, 2004

….”In May, shares of Protein Design Labs (PDLI) dropped 10% in a single day after the company reported a first quarter net loss of 13 cents per share, compared with a net profit of 5 cents per share for the year ago quarter as increased research and development spending cut into higher revenue. Share price fell another 10% during the month, ending May down 20%, after the company reported that its drug Zenapax failed to meet the primary endpoint in a Phase II clinical trial in patients with moderate or severe ulcerative colitis. Corixa Corporation (CRXA) shares also slid in May, dropping 13%, after the company reported a net loss of 38 cents per share compared to a net loss of 37 cents per share one year previous.” ….

That reminds me, ..........I saw the above a while ago, too, although not in a press article.........I mean, I read the fact that Zenapax REALLY aggravates and/or even may "cause" colitis and Crohn's. More research is needed to confirm the percentage of that risk.

And Protein Design Labs is the very entity that Biogen is in the process of obtaining SEC (? - my mind escapes me for the moment) approval to purchase. http://www.pdl.com/index.cfm?navId=607

Read this one real quick, also:

http://biz.yahoo.com/bizj/050802/1144098.html?.v=1

And Oh, yeah!!! Note THIS little tidbit hidden in THIS September 9th Forbes article: <shortened url>, to-wit:

...."Biogen Idec also announced the departure of its head of research."....

Oh, really????? ;-)

Ok.........I looked it up in the 2005 PDR. There is a box warning allright, but it says:

"Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ZENAPAX (daclizumab). The physician responsible for ZENAPAX administration should have complete information requisite for the follow-up of the patient. ZENAPAX should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources."

Read the above carefully. "Laboratory" medical resources? Yeah, right........ONLY if the clinical trial is done in an educational/teaching hospital. Not in a neuro's office or clinic (where most pharma clinical trials are held.)

Plus..........who knows........maybe I'm totally off-base. But........why test a drug as strong as this for a more minor disease like RRMS? And on RRMS, which gee.........don't we already know the percentage of probable "misdiagnosed" cases of THAT! So, let's shoot up a lot of people who have simple fibromyalgia or stress related neuropathies with this stuff.

Oh, yeah..........I can just picture the full disclosure people who may have RRMS (and associated cognitive and emotional problems) will receive and understand so they can weigh the risk/benefit ratio. Uh huh..........

BUT........maybe I'm wrong.

*****************************

Back to drugs like daclizumab (the "mABs"). Harry posted in a different thread another article that he found: http://www.thisisms.com/modules.php?nam ... pic&t=1489 (Why does this stuff never end?)

Let me just point out a couple of items from that article (I can't resist commenting on them - my comments are in all caps below) [emphasis added, too]:

...."Monoclonal antibodies (mAbs) are not good drugs, at least they are not good drugs in any conventional sense. Many of the fundamental qualities of mAbs are just the sort of characteristics that used to make pharmaceutical manufacturers run a mile." ....

AND THEY STILL SHOULD MAKE A PHARMA RUN A MILE.

...." That doesn't sound like much—especially given all their undrug-like qualities, but these days, any element of certainty looks like a haven in a storm of risk. And it is their predictability that really endears mAbs to the pharmaceutical industry.

From the outset, their binding characteristics are known. Antibodies can be readily labeled to demonstrate in animal or early human studies precisely where they localize. The path to humanized or human antibodies is technically complex and littered with potential royalty leaks, but it is well trodden and the costs are standard items. The passage of mAbs through clinical trials is reliable: according to Tufts, attrition rates are significantly lower than for small molecules (p. 1073)."...

REMEMBER THAT STATEMENT IN BOLD ABOVE IF/WHEN FULL DISCLOSURE ISN'T GIVEN IN CLINICAL TRIALS FOR MS BECAUSE THE MEDICAL EXPERTS DIDN'T "KNOW" AND SOMETHING TOTALLY ADVERSE AND "UNKNOWN" HAPPENS (unknown, yeah right). WE KNOW, DON'T WE?? I GAVE YOU A SYNOPSIS OF THE PROBABILITIES.

...."Where mAbs have produced unpleasant surprises in the clinic, it is usually because of insufficient grasp of the biology of the target antigen, especially in murky, relatively unexplored areas."...

GEE, NO KIDDING? LET'S SEE..........IS MULTIPLE SCLEROSIS A MURKY, RELATIVELY UNEXPLORED AREA? WHAT DO YOU THINK? AND WHAT DO THEY HAVE A SUFFICIENT GRASP ON IN THE FIRST PLACE? I REST MY CASE ALREADY.

...."The molecular explanation for Tysabri's toxicity is not yet known but bookmakers versed in the molecular arts are laying shorts odds that by blocking 41 integrin so well, Tysabri restricts immune cell migration, thereby allowing the previously dormant polyomavirus JC license to wreak havoc in the brain. Even the most specific mAb will be doomed if its antigen target moonlights in processes unrelated to the target indication that are crucial for normal function. ..."

FIRST, CAN I AGAIN JUST ASK, "IT TAKES A 'BOOKMAKER VERSED IN THE MOLECULAR ARTS' TO ASCERTAIN WHAT TYSABRI WOULD DO? I DON'T THINK SO. I FIGURED IT OUT, DIDN'T I? TRY SAYING INSTEAD, "IT ONLY TAKES COMMON SENSE"!!

AND LAST, BUT NOT LEAST, LET'S REMEMBER THE LAST SENTENCE IN BOLD ABOVE..........'IF' IT MOONLIGHTS IN PROCESSES UNRELATED TO THE TARGET INDICATION THAT ARE CRUCIAL FOR NORMAL FUNCTION' ??????? BETTER TO SAY "WHEN IT MOONLIGHTS....."

WELL, NOBODY CAN SAY I HAVEN'T AGAIN SAID "CAUTION WILL ROBINSON!"
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Postby raven » Sat Oct 08, 2005 10:46 am

Hiya Deb,

I've got to disagree with a few bits and pieces. I think we can all agree that the immune system is a massively complex and interrelated beastie. You're quite correct to highlight that knocking out one particular aspect can have very unwelcome consequences elsewhere. Given that fact what do you suggest researchers do, give up? Some small molecule compounds have been identified that appear to give some benefit but nothing has come close to arresting the disease. And even then they aren't a guarantee of safety, look at vioxx! Genetic manipulation? That's just as dangerous

In an ideal world some bright spark researcher would come up with a completely safe treatment that knocks MS out completely. This isn't an ideal world and there's no reason to suppose that such a treatment will ever be discovered.

why test a drug as strong as this for a more minor disease like RRMS?


Im my book RRMS is not a minor disease and it may well be that a radical intervention is the only way of getting rid of it.

In my own case I was going downhill rapidly, I made a judgement call based upon the best information I could get hold of. At the moment that call appears to be paying off. If at some point in the future it turns around and bites me in the bum then so be it. At least I will have tried.

This isn't rotten eggs ;) I just feel the expectation that a perfectly safe treatment will become available is unreasonable.

Robin
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Postby SarahLonglands » Sat Oct 08, 2005 10:48 am

Hi Deb,

I'm going to have to be quick because David has been on leave all week and I have hardly seen him because I have been so busy, but I just couldn't resist this perfect example of chickens coming home to roost!

Surely it doesn't take any brain cells to realise that if you use a very strong immunosupressant on someone, infections, whether bacterial or viral can just run riot: background infections which someone might have carried around for years without causing much trouble. You were shown to be correct in your assertions about tysabri, now daclizumab seems to be following the same lines even before it has really got off the ground. Well, really, six transplant patients dieing from a bacterial infection in the first year compared to none in the placebo arm! Just wait until they try it on people with assumed RRMS: they will be dropping like flies.

:oops: I deleted this section because Robin and I were posting at the same time and he must have thought I was talking about campath, which I wasn't, only naclizumab. :oops:

I probably don't need to avoid the eggs because people will just think I am a stupid artist.

I hope you continue to do well, though: I'm sure you will! :wink:

Sarah
Last edited by SarahLonglands on Sun Oct 09, 2005 1:32 am, edited 1 time in total.
An Itinerary in Light and Shadow Completed Dr Charles Stratton / Dr David Wheldon abx regime for aggressive secondary progressive MS in June 2007, after four years. Still improving with no relapses since starting. Can't run but can paint all day.
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Postby raven » Sat Oct 08, 2005 11:08 am

It is also just as easy and no more incorrect to speculate that these people, by having their immune systems 'rebooted' may avoid the conversion to the progressive forms of the disease altogether.

As there is no long term data to back up either position it's a moot point.

The only thing that I know to be fact is that I have regained 1.5 EDSS points and am now able to continue my life. If that changes for the worse then at least I have bought myself some very precious time.

Robin
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Postby OddDuck » Sat Oct 08, 2005 12:04 pm

Robin!!! Hiya!!

I was hoping this would bring you out of the shadows! No, I'm not advocating a perfectly safe treatment, I'm only advocating that patients be fully informed of the risks, and that's all.

The bottom line of my opinions are what I stated within above, and that is:

If all these risks are FULLY DISCLOSED in layman's terms to patients, and physicians are PROPERLY advised, etc., then fine.

All else is nothing in comparison.

How are you doing, anyway?? (Oh, you just said you were still doing much better! That's great!)

And Sarah!! Hi to you, too! I'm still doing great, by the way!! I hope the same holds true for you, too!

Deb
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Postby OddDuck » Sat Oct 08, 2005 12:07 pm

Oh, and Robin? I guess it depends on a person's definition of RRMS. Rapidly declining health or increasing disability in MS as you describe wouldn't still be considered RRMS in my book. That's progressive MS.

It all depends on degree, I suppose.

How's your grey matter doing these days? :wink:

Deb
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Postby raven » Sat Oct 08, 2005 12:24 pm

Tee Hee, me in the shadows? Never gonna happen ;)

I'm doing great thanks Deb. I'm not hiding, it's just that MS is no longer the demon it was for me. Rather than testing myself each day, looking for signs of an impending relapse I'm just getting on with life, trying to pay the bills etc.

Even in RRMS disability accrues. In fact if you take parenchymal fraction as a marker of disease it decreases at a fairly steady rate in RRMS patients regardless of relapses.

I would really love to get a peek at the full Campath trial data to see whether that decrease is halted. To me that would settle a lot of arguments.

As for my grey matter, I believe that I'm still capable of the odd thought or two but who knows ;)

I do know I can stand on one leg! wheeeeeee.... :D
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Postby OddDuck » Sat Oct 08, 2005 12:41 pm

Yeah...........same here. Work has gotten real busy lately, and I've been getting my sticky little fingers into all kinds of pies! HAH!

Paying bills..........yepper, that's one of 'em! :D

You know I never had a doubt one that either one of us was still not capable of an "odd" thought or two! (Wait, is that a double negative?) hehehe............ (Sorry, it's been ages since I've had the opportunity to tease you.)

I'd say something about the one leg remark, but I better not! :wink:

Naw.........all teasing aside, you know I think that's terrific!

By the way, speaking of grey matter, without being able to divulge too much, I believe our previous "grey matter" discussion here on thisisms is getting a perusal again by a researcher or two. Not sure what good will come of it, but it sure is flattering, huh?

And speaking of Wesley, where and how has HE been lately? WESLEY?! Wesley!! Where for art thou, Wesley?!

Deb
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Postby bromley » Sat Oct 08, 2005 12:52 pm

OddDuck,

I completely agree with you about fully disclosing the possible risks of any medication, particularly the heavy duty immuno-suppressants such as Campath and Dacluzimab. But as I've noted before, for those with this grim disease you are caught between a rock and a hard place. On the one hand there is a strong likelihood of becoming very disabled (particularly in the progressive stage) if you do nothing, on the other hand there is a risk of death if you go for the heavy duty drugs (happened with Antegren and Campath). Very difficult decisions and come down to individual's views about what they want from life etc. On Dacluzimab, the results from the small trial with one of the interferons did look impressive and as reported this drug looks tempting. If one decides to go for the heavy duty stuff then the key thing is for regular check ups / blood tests etc.

I'm really glad that Robin has seen good results. I saw Dr Coles at Cambridge to discuss getting onto the Campath trial. To his credit he assessed me as too mild and ran through the many possible risks with the treatment.

Bromley
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Postby OddDuck » Sat Oct 08, 2005 1:05 pm

Believe me, bromley, I know that only too well. And I totally understand the frustration (and that's putting it mildly, I know.)

EDIT: I mean.........I may have ended up finding out I don't have MS after all, but I spent two years being diagnosed with it and thinking I did have it, so went through it myself. And now, I'm left with the anger and fear of many others being mis-diagnosed as having MS who don't. It happens more often than previously thought. That is the other possible problem with being diagnosed with RRMS...........the question is, are you SURE? 8O :?
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Postby HarryZ » Sat Oct 08, 2005 5:54 pm

Raven,

Given that fact what do you suggest researchers do, give up?


Not wanting to speak for Deb, but I don't think that she is saying this at all. Deb, like me, just wants these pharma companies to come clean with these potential trial patients and the docs BEFORE they start in the trials....and to be totally honest with what happens during the trials.

We've already seen how Biogen/Elan operated in their handling of Tysabri. Now they are going to be involved with Daclizumad. Why am I not very comfortable and trusting with these companies?!!

When I first started to read up on Daclizumad a couple of months ago, I certainly didn't feel comfortable with this drug. Now, after reading Deb's posting, I don't like it....period!!

Harry
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Postby raven » Sun Oct 09, 2005 1:56 am

Hi Harry,

I completely agree that all known risks should be divulged a priori. There is no justification whatsoever for witholding such information. I haven't really looked at Daclizumab so cant comment one way or the other on it.

I do know however that as a participant in a trial for one of the 'heavy duty' drugs, I have accepted that all kinds of nasties could occur. In my case the choice was straightforward. I have no dependants to consider and my quality of life was deteriorating as rapidly as my health. 'Wait and see' was simply not an option for me; I opted to become an MS mouse :D

Everyone has a right to say 'this drug is not for me' when they begin to say 'this drug is not for you' they presume too much.

Hey Deb, I find it rather amusing that people are looking at our little grey matter discussion. It was fun to participate in though.

Robin
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Postby OddDuck » Sun Oct 09, 2005 5:13 am

Believe it or not, (but Robin does know, I believe), I truly am pro-choice. It's when people aren't given all the information (because it's withheld by some entity or another in order to just inflate their bank accounts), is when it concerns me. And everybody should know me by now, I'm simply very opinionated is all.

And hey, you gotta admit, our little grey matter discussion (among others, I believe) is/was actually on the leading edge of MS research! (I think, anyway.) Grey matter was presented at the ECTRIMS Conference in Greece, too.

:wink:
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Postby HarryZ » Sun Oct 09, 2005 5:52 am

Hi Robin,

I completely agree that all known risks should be divulged a priority. There is no justification whatsoever for withholding such information.


A basic assumption that most of us feel is being offered but the family of Anita Smith (Tysabri trial patient that died from PML) I guess feels differently. They are suing Biogen/Elan over this very issue.

Take care.

Harry
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Postby raven » Sun Oct 09, 2005 6:36 am

Harry

We appear to be violently agreeing with each other :)

I deliberately used a priori in my post. The term 'a priori' is considered to mean propositional knowledge that can be had without, or 'prior to', experience. The questions in the Tysabri case must be did Biogen know ahead of time that there was a conclusive and substantial risk of PML, and did they fail to inform the patients of that risk.

I don't want to get into the Tysabri debate. I don't have the facts and it is now a matter for the courts.

Deb, I know very well that you're pro-choice. I have always respected your opinions and also your research. I also enjoy the 'sparring' that goes on from time to time ;)

I may not be very bright but I can lift 'eavy fings... ;)
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