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.)
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
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:
...."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:
And Oh, yeah!!! Note THIS little tidbit hidden in THIS September 9th Forbes article: <shortened url
...."Biogen Idec also announced the departure of its head of research."....
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!"