Antegren/Tysabri approved!

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

Postby finn » Sun Nov 28, 2004 4:09 am

Sorry, time to leave the board.

-finn
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Postby Ptwo » Sun Nov 28, 2004 5:17 am

Harry, My niece is still considered RR by her team of doctors (group that runs the local ms center) but 8+ years after diagnosis her ms is definitely picking up steam.

Until 9 months ago she was following CAM methods for treating her ms with continual progression in her attacks. What started as once a year event has become 4 times a year. She has since started Betaseron ( I think it was the exacerbation that closed off her wind pipe for 30 seconds at a shot for a couple days that scared her into trying it)and showed no results for the first 6 months.

She has MRI's every 3 months and this last one showed no new lesions for the first time. Unfortunately the side effects are wearing her down and I don't think she'll be staying on the drug. She thinks the once a month infusion will fit her life a lot better than having the flu symptoms 24/7 and if it works like advertised it'll be just what the doctor ordered.
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Postby OddDuck » Sun Nov 28, 2004 5:56 am

I wasn't going to jump in here at all, and this is all I'm going to say.

From my observation from reading the foregoing posts, over and over again, it has been remarked (in trying to make a stance opposite from Harry's) how much "data" or information is "NOT" known.

Doesn't that..........uh..........sort of back up Harry? Not necessarily prove him incorrect nor provide an opposite viewpoint at all? :?

Since so much data (clinical or otherwise), and/or information (stock, etc.) IS still unknown apparently (EVERYONE agrees on that point), how can any definite opinions be formed yet at all?

Just wondering...................

Deb
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Postby HarryZ » Sun Nov 28, 2004 7:35 am

Also, the two year trials are or nearly are fully complete. Again, the FDA would have asked the companies for a review of all available 2yr data on efficacy, safety, etc before approving the drug. Why wouldn't they?


Remember the FDA approved Vioxx as well and we saw what happened there. Perhaps they were not given the damning data by Merck and it was only when one of the FDA's own employees testified( he obviously discovered something) before a Senate Committee that Merck decided to pull the drug off the shelves. And the FDA tried to put a muzzle on that employee who eventually went public!

The FDA as made a condition of approval for Tysabri...Biogen must supply them with the Phase III 2 year data when it becomes available. So it sounds like they have little if any of this information.

With the Vioxx scandal looming large, wouldn't the FDA be much more diligent in performing their tasks? I would guess they would. They must have went thru the data with a mircoscope, IMHO.


You would like to think so but the data is only as good as the people who provide it. The FDA was very aware of the Vioxx problems but tried to keep it hushed for a long time until one of their own blew the whistle. Makes you wonder how diligent they are and what they do when they find something wrong with a drug.

Harryz stated "The one year data that they have taken that 66% rate from is already suspect!" I don't know what is suspect, but this statment suggests the FDA has been duped or ignored something. Is this what is being said or implied? IMO that's probably way off the mark. But who knows? Certainly not me.


It's not me saying this...it's others who have written me. When the trials get properly peer reviewed I guess we'll find out one way or the other.


People are concerned that the data have not been released in a peer-reviewed journal. First, the trials are not yet complete (at least data analysis is not complete), and then the results must be written-up and submitted for peer review. This entire process could take 6-12 months. Take a look at Antegren's P2 results - published in NEJM in Jan, 2003 yet the trials were complete 1+ years before then.


This is why some MS docs are not happy with Biogen's process with Tysabri. Their initial schedule was to follow the standard time plan for drug trials and they changed it. This made the normal peer review impossible and is again why the term "suspect" is being used by these docs.

I can find no substantiation of an 18 month reduction in efficacy, or anything about the basis (theoretical or experimental) for such statements. It is odd, however, that this is the same as the Vioxx time that heart problems appear with Vioxx.


I believe this concern originated from comments taken from a drug rep communication site where a former Biogen rep made the statement. How reliable is that...who knows....was it fact or sour grapes...who knows? But the 18 month efficacy has surfaced from MS docs who also have made mention of it. Again, peer review has to take place.

Bottom line: Would the FDA have ignored any data existing which suggested an 18-month efficacy drop or a rebound effect? I think not. IMHO it is fair to conclude, in the absence of any proof, that there is NO 18-month efficacy drop or a rebound effect. If the 2 yr data show otherwise, I would be very, very surprised.


I used to fully trust the FDA but not any more....not after the Vioxx affair.

Again, we need the peer review.


I have seen no one, except CRAB makers, criticizing the data in print. I am not a statistician, but the data look very good to me.


But others have criticized it.....we'll have to wait until these "critiics" have the opportunity to review all the data.

BTW, I'm positive on Tysabri, though am not an MS sufferer. Just call me an interested observer.


A lot of the "doubt" on Tysabri started to surface as bits and pieces of the trials were released to the public. That's when the competitiors (expected) and other independent docs started to ask a lot of unanswered questions.


A lot of interesting comments and perspectives on Tysabri.....far more than any other MS drug what got approval.

Harry
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Postby HarryZ » Sun Nov 28, 2004 7:47 am

Hi Finn,

Nice to see you "lurking" :-))

Harry likes to create conspiracy theories, but at least one of his comments is a fact: Tysabri's ability to halt the long term progression of RRMS is not proven yet.


I wish it was me "creating" these theories! But the info comes from other sources who are far more knowledgeable than me when it comes to trials and how research is carried out.

There was another trial done on Tysabri at St. Mike's MS Clinic in Toronto. They gave Tysabri to MS patients who were suffering serious exacerbations to see if the drug had any effect on dampening the attacks. The results.....no difference from those on placebo.

I don't know how many other trials for SPMS/PPMS were done during the past few years but so far all indications show that there isn't any effect on these two type of MS.

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Postby Observer » Sun Nov 28, 2004 8:33 am

I was going to continue lurking, but I feel compelled to comment.

First, good disussion and thanks for the replies. Agree that more data re needed - they always are. Hey, if no one would take a chance on drug therapies, we would never advance.

A couple of comments on the efficacy of Tysabri in SPMS or PPMS:

1. The drug has not yet been tested against these forms of MS.

2. As for possible efficacy, tell the parents of the 5yr old previously mentioned that they should not try Tysabri. Good heavens, I bet they are ecstatic that Tysabri was tried. As a parent with young children, its absolutely a wonderful story. Period.

3. It will be interesting to see what happens as Tysabri is available, and those on SPMS or PPMS try it, given they have few other options. I and I'm sure the whole MS community anxiously await those results. I hope and am sure that all of us are hopeful that it will work.

4. The study at St. Mikes MS Clinic in Toronto - were these folks PPMS or SPMS, or just the patients who had an exacerbation? Did these patients have any other therapeutic options? I don't think that because this patient group did not show any therapeutic effect of a single Tysabri dose on an MS exacerbation, one can conclude that it is not effective in PPMS or SPMS. We need some real data, and with the drug's approval this should be forthcoming over the next year or so.


5. We all await the EDSS results in early 05. I note that nothing has apparently been proven to help EDSS (maybe I'm wrong - did Avonex help EDSS?). At any rate, I am hopeful that Tysabri will be the first.


As for suggestions that Biogen Idec and Elan might have withheld data from the FDA based on Avonex results of 5-10 years ago, all I can say is ..... anything is possible. Maybe.

But I note that Finn failed to mention this passage from his link about the reason that patients withdrew:

"Fourth, Filippini and colleagues state that interferons' ". . . effect beyond one year is uncertain . . .". This conclusion is based on a sensitivity analysis for the 2-year relapse data. Although in the main analysis for the second year the effect on relapses is highly significant and homogeneous for all three studies, interpretation of the alternative scenarios is flawed by significant heterogeneity. The authors note that the study that causes this heterogeneity (interferon beta-1a once a week intramuscularly pivotal trial) had a high rate of patients not completing the second year on study. But they do not take into account that non-completion was nearly exclusively due to early termination of the trial that was decided after an interim analysis, which yielded positive results with respect to the main outcome. Since the decision to stop the trial was based on a recommendation of the external patient safety monitoring board, Filippini and colleagues' calculation based on the worst-case scenario (that all patients who did not complete were treatment failures) does not make sense. The same critique also applies for the 2-year data on progression presented in figure 3 of their report. "


It appears that the FDA made the decision to approve because early withdrawers WERE ALREADY exhibiting positive results. There appears to be no hidden non-responder population, as suggested.

Even though Biogen's data was definitely 'interpreted' the FDA approved Avonex. We just have to hope that the approval process has improved since.



Even though Biogen's data was interpreted, it appears that the interpretation was worst case and would have only gotten better had the withdrawers been included! My goodness, where is the need to improve the FDA process here? Have I missed something?

As always, looking for good disourse. When the EDSS data are out in 2005, I hope we all have reasons to rejoice.
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Postby finn » Sun Nov 28, 2004 9:48 am

Sorry, time to leave the board.

-finn
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Postby Ptwo » Sun Nov 28, 2004 10:16 am

Harry, the phase II trial included SPMS patients, I haven't seen a breakdown between RR and SP groups but the over all results were positive.


I don't know how many other trials for SPMS/PPMS were done during the past few years but so far all indications show that there isn't any effect on these two type of MS.



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Postby Observer » Sun Nov 28, 2004 5:39 pm

Finn

Thanks for the reply. Agree that it is a bit off-topic but it is relevant to the extent that it highlights clinical trial data and how they can/might be manipulated.

I cannot find in the text where it indicates that a Cochrane Review made the statement you quote.


"We found no definitive evidence to corroborate therapeutic claims for Avonex. We had to extract key data, known to the investigators but not present in their publications, in order to arrive at this conclusion; which we find an unwelcome development.

With respect to lost to follow-up, an authoritative definition is that these are patients who "become unavailable for examinations at some stage during the study" for any reason, including "clinical decisions . . . to stop the assigned interventions".1 Thus, the patients were lost to follow-up. "

Can you clarify? TIA

Note that the only reference I can find to a Cochrane Review is as follows

The original Cochrane Report3 of treatment of multiple sclerosis with interferon concluded that the "the efficacy of interferon . . . was 'modest' after one and two years of treatment". Filippini and co-workers' conclude that "the clinical effect beyond one year is uncertain".


which is from Paty, Amason, Li and Traboulsee's comments.

The link you provided is very interesting, and I note that no distinction is typically made in it between any of the beta-interferons. I wonder, if Avonex is not effective, whether Betaseron and Rebif are also ineffective. Mechanism of action is the sam, just dosage differs. (If I understand it correctly.)

It appears that investigators have now made changes to protocols, as Fillipini, Munari, Ebers, D'Amico and Rice's comment suggests all data must be made available to publish:

Both Ludwig Kappos and Jörg Kesselring, and Goodin stressed the need to consider relapse rate. We could not undertake a quantitative analysis of relapse rate because it was assessed differently among the trials, and the PRIMS and OWIMS studies did not report relapse rate. We always contacted sponsor companies and trialists for additional details, but the companies did not give sufficient information and the principal investigators did not have access to the primary data. This problem could be addressed by making the primary data available, as is now required for a study to be published


By the way, my understanding is that the Tysabri AFFIRM trial data may be available in detail at the AAN meeting in April, 2005. SENTINEL was somewhat behind AFFIRM time-wise, so not sure if that will also be presented. Lets hope ALL the data are indeed presented so the MS Community can make fully-informed decisions about treatment options.
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Postby OddDuck » Sun Nov 28, 2004 6:01 pm

What I am curious about here during these discussions is why all of you are not referring to what Biogen Idec THEMSELVES have stated in their own product insert that comes with Tysabri?

In addition to being able to read the link at http://www.tysabri.com/downloads/produc ... mation.pdf, I have copied it below. (The "charts" contained in the product information didn't line up correctly, so you'll need to go to the link to see it in a correct table format.)

Anyway, I have highlighted some interesting statements (written by Biogen Idec themselves, remember), and I'm only going to simply add in "red" highlight, some of my comments and/or the questions I personally would like to see answered from future data from Biogen Idec in connection with those statements.

I believe that some of you "may" find Biogen Idec's own words will answer some of your musings. But, that's just my opinion.

Do I wish to start a discussion about this? No. I'm just going to wait for more data and/or information to come out before I form any conclusive opinions myself. Again, I am STILL in the "questioning" stage, and personally (and I repeat, strictly PERSONALLY) am not entirely pleased with Tysabri..............yet.

Thanks.

Deb

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

TYSABRI® (natalizumab)

DESCRIPTION

TYSABRI® (natalizumab) is a recombinant humanized IgG4k monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to a4-integrin. The molecular weight of natalizumab is 149 kilodaltons. TYSABRI® is supplied as a sterile, colorless, and clear to slightly opalescent concentrate for intravenous (IV) infusion.

Each 15 mL dose contains 300 mg natalizumab; 123 mg sodium chloride, USP; 17.0 mg sodium phosphate, monobasic, monohydrate, USP; 7.24 mg sodium phosphate, dibasic, heptahydrate, USP; 3.0 mg polysorbate 80, USP/NF, in water for injection, USP at pH 6.1.

CLINICAL PHARMACOLOGY

General
TYSABRI® binds to the a4-subunit of a4b1 and a4b7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the a4-mediated adhesion of leukocytes to their counterreceptor(s). The receptors for the a4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MadCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-a4-integrin antibodies also block a4-mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, TYSABRI® may further act to inhibit the interaction of a4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.

The specific mechanism(s) by which TYSABRI® exerts its effects in multiple sclerosis have not been fully defined. Uh, isn't that what Biogen Idec's tests and clinical trials so far are supposed to tell us? In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells, and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of a4b1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain.

Data from an experimental autoimmune encephalitis animal model of multiple sclerosis Isn't EAE suspect itself as to whether or not it is even a good model for human MS? That's what I've heard anyway. demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of
natalizumab. The clinical significance of these animal data is unknown. Ok, I truly don't mean to sound sarcastic, but........excuse me? So what did the foregoing just tell ME? Perhaps not much?

Pharmacokinetics

Following the repeat intravenous administration of a 300 mg dose of natalizumab to multiple sclerosis patients, the mean maximum observed serum concentration was 98 ± 34 mcg/mL. Mean average steady-state natalizumab concentrations over the dosing period were approximately 30 mcg/mL.

The mean half-life of 11 ± 4 days was observed with a clearance of 16 ± 5 mL/hour. The distribution volume of 5.7 ± 1.9 L was consistent with plasma volume.

Pharmacokinetics of TYSABRI® in pediatric multiple sclerosis patients or patients with renal or hepatic insufficiency have not been studied.

Pharmacodynamics

TYSABRI® administration increases the number of circulating leukocytes, (including lymphocytes, monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space.

TYSABRI® does not affect the number of circulating neutrophils (see PRECAUTIONS, Laboratory Tests).

CLINICAL STUDIES

TYSABRI® was evaluated in two ongoing randomized, double-blind, placebo-controlled trials in patients with multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0.

In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Hold the phone! "Suspected relapse"? While on Tysabri? I thought the efficacy was so good it reduced relapses tremendously, so why or how could there have been that many relapses while on Tysabri that could even BE measured? Ok....call me confused. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

Study 1 enrolled patients who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Ok.....this to me sounds like people with very mild MS.....perhaps extremely mild? Or people who haven't had hardly any relapses to speak of? I'm confused again.

Median age was 37, with a median disease duration of 5 years. Oh, ok....this might clarify it. People with MS for five years who have never been treated. Why never treated? Ok......wait........ it doesn't clarify it for me at all. Patients were randomized in a 2:1 ratio to receive TYSABRI® 300 mg IV infusion (n=627) or placebo (n=315) every 4 weeks for up to 28 months.

Study 2 enrolled patients who had experienced one or more relapses while on treatment with AVONEX® (Interferon beta-1a) 30 mcg intramuscularly (IM) once weekly during the year prior to study entry. Median age was 39, with a median disease duration of 7 years. Patients were evenly randomized to receive TYSABRI® 300 mg (n=589) or placebo (n=582) every 4 weeks for up to 28 months. All patients continued to receive AVONEX® 30 mcg IM once weekly. Results for each study were analyzed at a pre-specified time and are shown in Tables 1 and 2. Median patient time on study was 13 months in both studies. Safety and efficacy of treatment with TYSABRI® beyond one year are not known. Well, to me anyway, this statement from Biogen Idec itself sort of answers the 18 month argument, doesn't it? Or am I missing something? If Biogen Idec doesn't know yet, how can anybody else?

The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies has not been evaluated. Ok, we all know this one. I just highlighted this to show that Biogen Idec knows it, also.

(THE FOLLOWING TABLES DID NOT COPY INTO THIS POST CORRECTLY. PLEASE GO TO THE WEBSITE TO VIEW IN CORRECT FORMAT)

Table 1. 13-Month Clinical and 1-Year MRI Endpoints in Study 1 (Monotherapy Study)
TYSABRI® Placebo
n=627 n=315
Clinical Endpoints
Annualized relapse rate
Relative reduction (percentage)
Percentage of patients remaining relapse-free
0.25 0.74
66%
76% 53%
MRI Endpoints
New or newly enlarging T2-hyperintense lesions
Median
Percentage of patients with:
0 lesions
1 lesion
2 lesions
3 or more lesions
0.0 3.0
60% 22%
18% 13%
6% 7%
16% 58%
Gd-enhancing lesions
Median
Percentage of patients with:
0 lesions
1 lesion
2 or more lesions
0.0 0.0
96% 68%
3% 13%
1% 19%
All analyses were intent-to-treat. For each endpoint, p<0.001. Determination of p-values: relapse rate by Poisson regression
adjusting for baseline relapse rate, EDSS, presence of Gd-enhancing lesions, age; percentage relapse-free by logistic regression
adjusting for baseline relapse rate; and MRI endpoints by ordinal logistic regression adjusting for baseline lesion number.
Table 2. 13-Month Clinical and 1-Year MRI Endpoints in Study 2 (Add-On Study)
TYSABRI® Placebo
plus AVONEX® plus AVONEX®
n=589 n=582
Clinical Endpoints
Annualized relapse rate
Relative reduction (percentage)
Percentage of patients remaining relapse-free
0.36 0.78
54%
67% 46%
4 of 11
TYSABRI® Placebo
plus AVONEX® plus AVONEX®
n=589 n=582
MRI Endpoints
New or newly enlarging T2-hyperintense lesions
Median
Percentage of patients with:
0 lesions
1 lesion
2 lesions
3 or more lesions
0.0 1.0
67% 40%
26% 29%
4% 10%
3% 21%
Gd-enhancing lesions
Median
Percentage of patients with:
0 lesions
1 lesion
2 or more lesions
0.0 0.0
96% 76%
3% 12%
1% 12%
All analyses were intent-to-treat. For each endpoint, p<0.001. Determination of p-values: relapse rate by Poisson regression
adjusting for baseline relapse rate, EDSS, presence of Gd-enhancing lesions, age; percentage relapse-free by logistic regression
adjusting for baseline relapse rate; and MRI endpoints by ordinal logistic regression adjusting for baseline lesion number.

INDICATIONS AND USAGE

TYSABRI® is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. This indication is based on results achieved after
approximately one year of treatment in ongoing controlled trials of two years in duration. The safety and efficacy of TYSABRI® beyond one year are unknown. Again, I found this statement sort of an answer to others' previous speculations regarding same - right from the horse's mouth, as they say.

Safety and efficacy in patients with chronic progressive multiple sclerosis have not been established.
I would consider this another answer from Biogen Idec to whether or not this works for progressive MS types. I'd say if Biogen Idec can't say, then can anybody else?

CONTRAINDICATIONS

TYSABRI® should not be administered to patients with known hypersensitivity to TYSABRI® or any of its components.

WARNINGS

Hypersensitivity
TYSABRI® has been associated with hypersensitivity reactions, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%. These reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can
include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies to TYSABRI®.

If a hypersensitivity reaction occurs, discontinue administration of TYSABRI® and initiate appropriate therapy (see ADVERSE REACTIONS, Infusion-related Reactions). Patients who have experienced a hypersensitivity reaction should not be re-treated with TYSABRI®. The
possibility of antibodies to TYSABRI® should be considered in patients who have hypersensitivity reactions (see ADVERSE REACTIONS, Immunogenicity).

PRECAUTIONS

Immunosuppression

In Studies 1 and 2, concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection. The safety and efficacy of TYSABRI® in combination with other immunosuppressive agents have not been evaluated. Patients receiving
these agents should not receive concurrent therapy with TYSABRI® because of the possibility of increased risk of infections.
I just found this to be "of note" is all.

Information to Patients

If patients experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with or without associated symptoms) during or following an infusion of TYSABRI®, they should report these symptoms to their physician immediately (see WARNINGS, Hypersensitivity).

Laboratory Tests

TYSABRI® induces increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed increases persist during TYSABRI® exposure, but are reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of
neutrophils are not observed.

Drug Interactions

After multiple dosing, interferon beta-1a (AVONEXÒ 30 mcg IM once weekly) reduced TYSABRI® clearance by approximately 30%. The similarity of the TYSABRI®-associated adverse event profile between Study 1 (without co-administered AVONEX®) and Study 2 (with
co-administered AVONEX®) indicates that this alteration in clearance does not necessitate reduction of the TYSABRI® dose to maintain safety (see ADVERSE REACTIONS, General).

Results of studies in multiple sclerosis patients taking TYSABRI® and concomitant interferon beta-1a (AVONEXÒ 30 mcg IM once weekly) or glatiramer acetate were inconclusive with regard to the need for dose adjustment of the beta-interferon or glatiramer acetate.
I apologize, but upon reaching this point, I'm beginning to notice the frequency of the use of the words "unknown" and "inconclusive", etc.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human chromosomal aberration assays. Natalizumab showed no effects on in vitro assays of a4-integrin positive tumor line proliferation/cytotoxicity. Xenograft transplantation models in SCID and nude mice with two a4-integrin positive tumor lines (leukemia, melanoma) demonstrated no increase in tumor growth rates or metastasis resulting from natalizumab treatment.

Reductions in female guinea pig fertility were observed in one study at dose levels of 30 mg/kg, but not at the 10 mg/kg dose level (2.3-fold the clinical dose). A 47% reduction in pregnancy rate was observed in guinea pigs receiving 30 mg/kg relative to control. Implantations were seen in only 36% of animals having corpora lutea in the 30 mg/kg group versus 66-72% in the other groups.

Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose. Based on what data performed on whom, when, etc. etc.? Just curious.

Pregnancy (Category C)

In reproductive studies in monkeys and guinea pigs, there was no evidence of teratogenic effects at doses up to 30 mg/kg (7 times the human clinical dose based on a body weight comparison). In one study where female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at post-natal day 14 with respect to control (3 pups/litter for the group treated with 30 mg/kg natalizumab and 4.3 pups/litter for the control group). In one of five studies that exposed monkeys or guinea pigs during pregnancy, the number of abortions in treated (30 mg/kg) monkeys was 33% versus 17% in controls. No effects
on abortion rates were noted in any other study. TYSABRI® underwent trans-placental transfer and produced in utero exposure in developing guinea pigs and cynomolgus monkeys. When pregnant dams were exposed to natalizumab at approximately 7-fold the clinical dose, serum
levels in fetal animals at delivery were approximately 35% of maternal serum natalizumab levels. A study in pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetus. These changes included mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. In offspring born to mothers treated with natalizumab at 7-fold the clinical dose, platelet counts were also reduced. This effect was reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring.
There are no adequate and well-controlled studies of TYSABRI® therapy in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. If a woman becomes pregnant while taking TYSABRI®, discontinuation of TYSABRI® should be considered.

All of the above highlighted statements, I will not comment on, as I have expressed my concern about same previously. I will only say that I "may" have been correct when I said that if I knew the "possible" risks, that Biogen Idec must have known also. They did SOME testing, didn't they? I wonder why they felt the need? This was a little "more" testing than is usual for most drugs (from what little I know anyway). But still not enough in my opinion. And I have MANY questions. But, again, I say no more about that. Only time will tell now.

Nursing Mothers

It is not known whether TYSABRI® is excreted in human milk. Because many drugs and immunoglobulins are excreted in human milk, and because the potential for serious adverse reactions is unknown, a decision should be made whether to discontinue nursing or TYSABRI® taking into account the importance of therapy to the mother.

Geriatric Use

Clinical studies of TYSABRI® did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients.


Pediatric Use

Safety and effectiveness of TYSABRI® in pediatric multiple sclerosis patients below the age of 18 have not been studied. TYSABRI® is not indicated for use in pediatric patients.
Well, it "appears" from this statement that Biogen Idec itself says safety in patients below the age of 18 have not been studied, so that takes care of that argument in my mind anyway.

Immunizations

No data are available on the effects of vaccination in patients receiving TYSABRI®. No data are available on the secondary transmission of infection by live vaccines in patients receivingTYSABRI®.

ADVERSE REACTIONS

General

The most frequently reported serious adverse reactions with TYSABRI® were infections (2.1% versus 1.3% in placebo, including pneumonia [0.6%]), hypersensitivity reactions (1.3%, including anaphylaxis/anaphylactoid reaction [0.8%]), depression (0.8%, including suicidal ideation [0.5%]), and cholelithiasis (0.8%) (see WARNINGS, Hypersensitivity and ADVERSE REACTIONS, Infections).
The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of TYSABRI®), were urticaria (1%) and other hypersensitivity reactions (1%) (see WARNINGS, Hypersensitivity).
Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of TYSABRI® cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse
reaction information does, however, provide a basis for identifying the adverse events that appear to be related to drug use and a basis for approximating rates.

A total of 1,617 multiple sclerosis patients, in both controlled and uncontrolled studies, have been exposed to TYSABRI® with a median duration of exposure of 20 months.

Table 3 enumerates adverse events and selected laboratory abnormalities that occurred in Study 1 at an incidence of at least 1 percentage point higher in TYSABRI®-treated patients than was observed in the placebo group. The adverse event profile in Study 2 was similar.

Table 3. Adverse Reactions in Study 1
Adverse Events
(Preferred Term)
TYSABRI®
n=627
Percentage
Control
n=312
Percentage
General
Headache
35%
30%
8 of 11
Adverse Events
(Preferred Term)
TYSABRI®
n=627
Percentage
Control
n=312
Percentage
Fatigue
Arthralgia
Allergic reaction
Urinary urgency/frequency
Chest discomfort
Local bleeding
Rigors
Syncope
Infection
Urinary tract infection
Lower respiratory tract infection
Gastroenteritis
Vaginitis*
Tonsillitis
Psychiatric
Depression
Gastrointestinal
Abdominal discomfort
Abnormal liver function test
Skin
Rash
Dermatitis
Pruritus
Menstrual disorders*
Irregular menstruation/dysmenorrhea
Amenorrhea
Neurologic
Tremor
*percentage based on female n
24%
15%
7%
7%
4%
3%
3%
2%
18%
15%
9%
8%
5%
17%
10%
5%
9%
5%
4%
7%
2%
3%
18%
11%
3%
5%
2%
1%
1%
1%
15%
14%
5%
5%
3%
14%
9%
3%
7%
4%
2%
2%
0%
2%

Infections

In Studies 1 and 2, the rate of infection was approximately 1 per patient-year in both TYSABRI®-treated patients and placebo-treated patients. The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections. Most patients did not interrupt treatment with TYSABRI® during the infection. In Study 1, the incidence of serious infection was 2.1% in TYSABRI®-treated patients versus 1.3% in placebo-treated patients. No difference was seen between treatment groups in Study 2.

Infusion-related Reactions (see WARNINGS, Hypersensitivity)

An infusion-related reaction was defined in clinical trials as any adverse event occurring within 2 hours of the start of an infusion. Approximately 22% of TYSABRI®-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 17% of placebo-treated patients.
Events more common in the TYSABRI®-treated patients included headache, dizziness, fatigue, hypersensitivity reactions, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients
receiving TYSABRI®. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion.

Patients who became persistently positive for antibodies to TYSABRI® were more likely to have an infusion-related reaction than those who were antibody-negative (see ADVERSE REACTIONS, Immunogenicity).

Immunogenicity

Patients in Study 1 and Study 2 were tested for antibodies to natalizumab every 12 weeks. The assays used in these studies were unable to detect low to moderate levels of antibodies to natalizumab.Antibodies were detected in approximately 10% of multiple sclerosis patients receiving TYSABRI® at least once during treatment with persistent antibody-positivity in 6% of patients. Approximately 90% of patients who became persistently antibody-positive by this assay had developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralizing in vitro.

The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels. Across studies, the week 12 pre-infusion mean natalizumab serum concentrations in antibody-negative patients were approximately 17 mcg/mL compared to <1mcg/mL in antibody-positive patients. Persistent antibody-positivity to natalizumab was associated with a substantial decrease in the effectiveness of TYSABRI®. In Study 1, the annualized relapse rate of persistently antibody-positive TYSABRI®-treated patients (0.75) was similar to the annualized relapse rate in subjects who received placebo (0.74). A similar phenomenon was also observed in Study 2.

Infusion-related reactions most often associated with persistent antibody-positivity included hypersensitivity reactions, urticaria, rigors, nausea, vomiting, and flushing. Additional adverse events more common in persistently antibody-positive patients included myalgia, hypertension,
dyspnea, anxiety, and tachycardia.

The long-term immunogenicity of TYSABRI® and the effects of low to moderate levels of antibody to natalizumab are unknown (see ADVERSE REACTIONS, Infusion-related Reactions). Darn, there's that word again! "unknown" Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody-positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TYSABRI® with the incidence of antibodies to other products may be misleading.

OVERDOSAGE

Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of TYSABRI® that can be safely administered has not been determined.

DOSAGE AND ADMINISTRATION

The recommended dose of TYSABRI® is 300 mg IV infusion every four weeks. Dilute TYSABRI® concentrate 300 mg/15 mL in 100 mL 0.9% Sodium Chloride Injection, USP, and infuse over approximately one hour. Do not administer TYSABRI® as an IV push or bolus injection
(see Preparation Instructions).
Observe patients during the infusion and for 1 hour after the infusion is complete. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction (see WARNINGS, Hypersensitivity).

Preparation Instructions

Use aseptic technique when preparing TYSABRI® solution for IV infusion. Each vial is intended for single use only.

TYSABRI® is a colorless, clear to slightly opalescent concentrate. Inspect the TYSABRI® vial for particulate material prior to dilution and administration. If visible particulates are observed and/or the liquid in the vial is discolored, the vial must not be used. Do not use TYSABRI® beyond the expiration date stamped on the carton or vial.
To prepare the solution, withdraw 15 mL of TYSABRI® concentrate from the vial using a sterile needle and syringe. Inject the concentrate into 100 mL 0.9% Sodium Chloride Injection, USP. No other IV diluents may be used to prepare the TYSABRI® solution.
Gently invert the TYSABRI® solution to mix completely. Do not shake. Inspect the solution visually for particulate material prior to administration.
Following dilution, infuse TYSABRI® solution immediately, or refrigerate solution at 2-8°C, and use within 8 hours. If stored at 2-8°C, allow the solution to warm to room temperature prior to infusion.
DO NOT FREEZE.

Administration Instructions
Infuse TYSABRI® 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP over approximately one hour. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP.

Use of filtration devices during administration has not been evaluated. Other medications should not be injected into infusion set side ports or mixed with TYSABRI®.

HOW SUPPLIED
TYSABRI® concentrate is supplied as 300 mg natalizumab in a sterile, single-use vial free of preservatives. Each package contains a single-use vial. NDC 59075-730-15

Storage
TYSABRI® single-use vials must be refrigerated between 2-8°C (36°-46°F). Do not use beyond the expiration date stamped on the carton and vial label. DO NOT SHAKE OR FREEZE. Protect from light.

If not used immediately, store the TYSABRI® solution for infusion at 2-8°C (36°-46°F). TYSABRI® solution for infusion must be administered within 8 hours of preparation.

I61061-1 Issue date [November/2004]
TYSABRI® (natalizumab)
Manufactured by:
Biogen Idec Inc.
14 Cambridge Center
Cambridge, MA 02142 USA
1-888-489-7227
Distributed by:
Elan Pharmaceuticals, Inc.
San Diego, CA 92121
© 2004 Biogen Idec Inc. All rights reserved.
TYSABRI® is a trademark of Elan
AVONEX® is a trademark of Biogen Idec
U.S. Patent Numbers: 5,840,299, 6,033,665, 6,602,503, 5,168,062, 5,385,839, 5,730,978
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Postby Observer » Sun Nov 28, 2004 8:36 pm

Finn

Ahh, now I understand. Re-reading what you've said suggests a subtle distinction which I missed: the authors of the statement

We are pleased to have the opportunity to highlight the MSCRG study, since we found it the most unclear of those reviewed. We found no definitive evidence to corroborate therapeutic claims for Avonex. We had to extract key data, known to the investigators but not present in their publications, in order to arrive at this conclusion; which we find an unwelcome development.



are indeed the individuals involved with MS Cochrane Reviews. Does this mean that the statement is the official position of the Cochrane Review?

I note the following abstract from the Cochrane Library, which claims modest efficacy with beta interferons. Is the official line of the Cochrane Library that Rebif and Betaseron work, and that Avonex does not, or is the above statement simply the opinion of these particular Cochrane reviewers? The abstract does not make such a claim about Rebif/Betaseron vs Avonex; perhaps it does in the full text:

http://www.update-software.com/Abstracts/AB002002.htm

An excerpt is as follows:

Main results: Although seven trials involving 1215 participants were included in this review, only 919 (76%) contributed to the results concerning exacerbations and progression of the disease at two years. Specifically interferon significantly reduced the occurrence of exacerbations (Relative risk [RR] 0.80, 95% confidence interval [CI] 0.73 to 0.88, p < 0.001) and progression of the disease (RR 0.69, 95% CI 0.55 to 0.87, p = 0.002) two years after randomisation. However, the correct assignment of dropouts was essential to the demonstration of efficacy, most conspicuously concerning the effect of the drug on disease progression. If interferon-treated participants who dropped out were deemed to have progressed (worst case scenario) the significance of these effects was lost (RR 1.31, 95% CI 0.60 to 2.89, p = 0.5). The evolution in magnetic resonance imaging (MRI) technology in the decade in which these trials were performed and different reporting of data among trials made it impossible to perform a quantitative analysis of the MRI results. Both clinical and laboratory side effects reported in the trials were more frequent in treated participants than in controls; there was no information after two years of follow-up. The impact of interferon treatment (and its side effects) on the quality of life of patients was not reported in any trial included in this review.

Reviewers' conclusions: The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment. Longer follow-up and more uniform reporting of clinical and MRI outcomes among these trials might have allowed for a more convincing conclusion.



One has to wonder whether this points-out one of the limitations of the Cochrane Reviews - access to all of the data. I would hope that this limitation could and has been remedied.

At any rate, I am getting far off-topic. In the end, thanks Finn for pointing-out a clear concern - all the data should be made available to the FDA and other interested parties. On the other hand, as Samuel Clemens said, there are 3 types of mendacity - lies, damn lies, and statistics. How might all the data be presented and evaluated - could it be used to mislead (either positively or negatively)? Most likely.

With regard to Tysabri, I would think/hope the FDA has obtained all the data and analysed it quite thoroughly. Heres to seeing the 1yr and 2yr data in early 2005.
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Another take on the label

Postby rndlph » Sun Nov 28, 2004 9:48 pm

I also read the new Tysabri label with great interest, but was far less frustrated by it than OddDuck appears to have been.

OddDuck:
Data from an experimental autoimmune encephalitis animal model of multiple sclerosis Isn't EAE suspect itself as to whether or not it is even a good model for human MS? That's what I've heard anyway. demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of
natalizumab. The clinical significance of these animal data is unknown. Ok, I truly don't mean to sound sarcastic, but........excuse me? So what did the foregoing just tell ME? Perhaps not much?

ME:
EAE is an imperfect model because people are not mice. However, the action of Antegren in mice with EAE is here described. The pretty clear implication is that if it works this way in mice with EAE and it is shown to be effective in people with MS, then a similar mechanism is likely at work in people. It is refreshing to see that the mechanism of action for Antegren is not a a complete mystery, no?


OddDuck:
In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Hold the phone! "Suspected relapse"? While on Tysabri? I thought the efficacy was so good it reduced relapses tremendously, so why or how could there have been that many relapses while on Tysabri that could even BE measured? Ok....call me confused. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

ME:
Uh, there is no claim that the treatment is perfect. Moreover, this refers to ALL ARMS OF THE TWO STUDIES. This includes people who received placebo. A placebo is an inert substance with no treatment value. You do indeed seem to be confused. Or are you just being obtuse for snide effect?

OddDuck:
Study 1 enrolled patients who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Ok.....this to me sounds like people with very mild MS.....perhaps extremely mild? Or people who haven't had hardly any relapses to speak of? I'm confused again.

Median age was 37, with a median disease duration of 5 years. Oh, ok....this might clarify it. People with MS for five years who have never been treated. Why never treated? Ok......wait........ it doesn't clarify it for me at all. Patients were randomized in a 2:1 ratio to receive TYSABRI® 300 mg IV infusion (n=627) or placebo (n=315) every 4 weeks for up to 28 months.

ME:
Some people spend a lot of time spinning conspiracy theories and arguing with the FDA, the pharmaceutical industry, and the medical profession ad nauseum, and do not start treatment. I know this is hard to believe, but it is true. Also, some people are not able to tolerate the existing therapies. Many doctors do not think the currently available therapies are worth the side effects. Not everyone is on treatment. Thankfully, there were enough people to populate the control group. The study participants had active disease. I don't see what the problem is here. It is clearly not in the interests of the study to have patients with extremely mild, inactive disease. They are trying to demonstrate efficacy, not conceal it.

OddDuck:
The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies has not been evaluated. Ok, we all know this one. I just highlighted this to show that Biogen Idec knows it, also.

ME:
The correlations between MRI and disability progression are weak, yes, but I will be stunned when all of the dust settles that white matter lesions turn out to be a good thing. I am very interested in how treatments affect plaques as witnessed by MRI. Who isn't?

OddDuck:
Patients receiving
these agents should not receive concurrent therapy with TYSABRI® because of the possibility of increased risk of infections.[/b] I just found this to be "of note" is all.

ME:
Yes, we are messing with the immune system here. We are affecting where white blood cells go. If you start messing with that with another therapy, you better watch out.

OddDuck:
Results of studies in multiple sclerosis patients taking TYSABRI® and concomitant interferon beta-1a (AVONEXÒ 30 mcg IM once weekly) or glatiramer acetate were inconclusive with regard to the need for dose adjustment of the beta-interferon or glatiramer acetate.[/b] I apologize, but upon reaching this point, I'm beginning to notice the frequency of the use of the words "unknown" and "inconclusive", etc.

ME:
So what? This is a complicated problem we are dealing with here.


OddDuck:
Reductions in female guinea pig fertility were observed in one study at dose levels of 30 mg/kg, but not at the 10 mg/kg dose level (2.3-fold the clinical dose). A 47% reduction in pregnancy rate was observed in guinea pigs receiving 30 mg/kg relative to control. Implantations were seen in only 36% of animals having corpora lutea in the 30 mg/kg group versus 66-72% in the other groups.

Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose. Based on what data performed on whom, when, etc. etc.? Just curious.

ME:
From the context, I would say we are talking about male guinea pigs here.

OddDuck:
Immunogenicity

Patients in Study 1 and Study 2 were tested for antibodies to natalizumab every 12 weeks. The assays used in these studies were unable to detect low to moderate levels of antibodies to natalizumab.Antibodies were detected in approximately 10% of multiple sclerosis patients receiving TYSABRI® at least once during treatment with persistent antibody-positivity in 6% of patients. Approximately 90% of patients who became persistently antibody-positive by this assay had developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralizing in vitro.

The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels. Across studies, the week 12 pre-infusion mean natalizumab serum concentrations in antibody-negative patients were approximately 17 mcg/mL compared to <1mcg/mL in antibody-positive patients. Persistent antibody-positivity to natalizumab was associated with a substantial decrease in the effectiveness of TYSABRI®. In Study 1, the annualized relapse rate of persistently antibody-positive TYSABRI®-treated patients (0.75) was similar to the annualized relapse rate in subjects who received placebo (0.74). A similar phenomenon was also observed in Study 2.

Infusion-related reactions most often associated with persistent antibody-positivity included hypersensitivity reactions, urticaria, rigors, nausea, vomiting, and flushing. Additional adverse events more common in persistently antibody-positive patients included myalgia, hypertension,
dyspnea, anxiety, and tachycardia.

The long-term immunogenicity of TYSABRI® and the effects of low to moderate levels of antibody to natalizumab are unknown (see ADVERSE REACTIONS, Infusion-related Reactions). Darn, there's that word again! "unknown" Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

ME:
Are you actually reading this? Right before they say something unknowable (at this point) is unknown, they say some astounding things about antibodies. Unless I am reading this incorrectly, they identify a direct releationship between high levels of antibodies and lack of efficacy. (They are owning up to the neutralizing effects on the label!) This sounds to me as though doctors should be able to do a test for neutralizing antibody levels and to discontinue treatment if they are too high. How refreshing when compared to the dueling marketing bullshit of "neutralizing antibodies" with the CRABs, where the "clinical significance" is unknown. There is an annoying "unknown" for you.

The label is really something to be excited about. Read it carefully and go over any questions you have with your neurologist.

Does anyone have any information about availability?

Cheers,
Dave
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Postby Observer » Mon Nov 29, 2004 2:52 am

Sort of OT to this thread, but since we are talking about data, there was an interesting article in the NY Times today about what data are released from clinical trails.

Contracts Keep Drug Research Out of Reach
By BARRY MEIER

http://www.nytimes.com/2004/11/29/busin ... earch.html

You might have to register, but its free.

The article uses the antidepressant issues with adolescents as an example, but the broader applicability is clear.
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Postby OddDuck » Mon Nov 29, 2004 4:48 am

Or are you just being obtuse for snide effect?


Here we go again. You can stop with the tone and hateful words toward me. That was totally uncalled for and is not acceptable on this Board. If your opinion is different than mine, fine. But trying to speak to or with me in such a disrespectful manner as you have all throughout your post will not be tolerated. You can't simply explain your position without a feeble attempt to discredit and demean me personally in the process? Now THAT'S really impressive, huh?

Being a paralegal, I'll have you know that I do this for a living. You better believe I know exactly how to read things. My interpretations stand up in court. Do yours?

Now....again....no further discussion with me, especially if you are unable to remain respectful!

Deb

P.S. Oh, yea, I did research FOR a neurologist, so when you speak to YOURS "maybe" you are receiving some of MY input along with his. You never know.

EDIT: I would also like to add that if you or anyone else don't "like" my questions or comments, simply ignore them. Please do not go on the personal "attack". ESPECIALLY if what I'm saying is thought of so harshly and is thought I don't know what I'm talking about.......then why worry so much about what I say? Simply ignore it.
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Re: Another take on the label

Postby HarryZ » Mon Nov 29, 2004 7:54 am

Dave,

EAE is an imperfect model because people are not mice. However, the action of Antegren in mice with EAE is here described. The pretty clear implication is that if it works this way in mice with EAE and it is shown to be effective in people with MS, then a similar mechanism is likely at work in people. It is refreshing to see that the mechanism of action for Antegren is not a a complete mystery, no?


If you read Dr. Behan's Pathogenesis of MS, he states that MS in that poor mouse isn't ANYTHING like MS in humans. I doubt one can conclude anything from the mechanism in the mouse to what may be happening in a human with MS. Behan goes on to say that there has never been a treatment in the MS mouse that has worked in humans.


Or are you just being obtuse for snide effect?


For the life of me, I just don't understand why people find it necessary to write personal sarcastic comments like this. They serve no purpose, create tension and certainly detract from the thread. And they are not permitted on this forum!

If you want to disagree with anyone's comments, but all means do so. Different points of view can make a topic very interesting. But please, leave the sarcastic, personal barbs at home.....they have no place here!!

Harry
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