"but this effect was not carried forward in the six months after treatment" I'm not sure if this means after the drug was stopped or 6 months into the trial. Perhaps other readers may know more about this earlier trial.
A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
David H. Miller, M.D., Omar A. Khan, M.D., William A. Sheremata, M.D., Lance D. Blumhardt, M.D., George P.A. Rice, M.D., Michele A. Libonati, M.S., Allison J. Willmer-Hulme, Ph.D., Catherine M. Dalton, M.B., Katherine A. Miszkiel, M.B., Paul W. O'Connor, M.D., for the International Natalizumab Multiple Sclerosis Trial Group
Background In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein 4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an 4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.
Methods In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing–remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.
Results There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).
Conclusions In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
Why not put ALL the information out there to let the reader decide, rather than simply a part which supports one view or the other?
The trial itself was 6 months, so clearly this means the 6 months AFTER the trial, and AFTER Tysabri administration was stopped. What the authors of that correspondence are saying is that, after Tysabri was stopped, its beneficial effects also stopped.
And the competition saying that Tysabri patients have increased infections? Uh huh. Relative to placebo, yes, I think it was 2% of Tysabri versus 1% of placebo. Uh, that's 2% of the trial, which means 98% had no such effect. Looks to me like Teva, Serono and Pfizer are trying to misuse basic statistics. Why am I not surprised?
Harryz, it is odd that you would reference the results of a 6-month study, as all along you have been saying that the 1 YEAR RESULTS from Tysabri Phase 3 trials are not long enough. Seems to be a contradiction. 6 months is OK, 1 year is NOT OK, and we now need more data? What gives?
And this information just came out? Oh, really? The original P2 results were published in the Jan 2003 NEJM, almost 2 YEARS AGO. I hardly think that is 'just coming out.'
Any idea then, why the comment was made that long term use of the drug was not of any benefit to the progression of MS?
This is a short abstract of an earlier Natalizumab trial that shows totally different results than the Tysabri trials. How such a difference exists I simply don't know but is another reason as to why I am so cautious about Tysabri. When the abstract refers to "but this effect was not carried forward in the six months after treatment" I'm not sure if this means after the drug was stopped or 6 months into the trial. Perhaps other readers may know more about this earlier trial.
Notwithstanding that neither the P3 tysabri trial nor the drug's label has made any claim regarding 'benefit to the progression of MS', has Tysabri been advertised as a cure?
Furthermore, you can read that long-term disability progression
was NOT an endpoint of the P2 study (check the NEJM Abstract) nor even of the 1yr P3 Tysabri trial. The P2 trial was only 6 months long, and all know that is insufficient time to generate reliable changes to EDSS. (If I have to obtain citations to this effect, please advise and I can do the homework.)
I am very surprised that you'd only now be aware of this important part of the history of Tysabri. But then again, I know very little about the CRABs, so I probably should not be surprised. Mea culpa.
But I wonder - WHY do you never find ANYTHING positive about Tysabri? All of your information is only negative? Is this truly happenstance, or is there some other agenda? Please let me know. TIA.
And in spite of the suggestion in your reply to me, I did READ your post but was thoroughly disappointed. How about the courtesy of reading my post, and responding thoroughly and with fact-supported assertions (and please no unamed sources or knowledgeable, unreferenced MS researcher contacts)?
In your post (quoted above), you are first flatly stating that the P2 and P3 results are totally different and only THEN asking whether any other readers know more about this trial. Well, much of the trial information is freely available and your statement is proven to be false by the original January 2003 P2 abstract (which I posted) and the P3 trial results.
I'm sorry, but I have to wonder why you wouldn't post the P2 abstract. Why would you make a statement that can easily be verified to be untrue (that the P2 and P3 results are 'totally different')? If, on the other hand, you believe your original statement, perhaps you could indulge me by explaining your reasoning on how they are 'totally different'?
But I go on too long, and I'm tired. I'll just say that there is a reason why it is illegal to cry 'fire' in a crowded movie theater if the alarm is false. And if one continues to cry 'fire' when there is not any, the call rightfully goes ignored. I guess what I'm saying is that it would be refreshing to see the pluses/minuses, not only the minuses or half the story. Thats IMHO, by the way.
I'll give you the last word, and I hope that my concerns are allayed by your or other's response to my comments. Perhaps I have this all wrong, and if so I apologize. But if I do have it wrong, please lead me thru my error. Thanks in advance.
Mittelbrunn, M., Molina, A., Escribese, M. M., Yanez-Mo, M., Escudero, E., Ursa, A., Tejedor, R., Mampaso, F., Sanchez-Madrid, F. (2004). VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses. Proc. Natl. Acad. Sci. U. S. A. 101: 11058-11063 [Abstract] [Full Text]
Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11058-63. Epub 2004 Jul 19. Related Articles, Links
VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses.
Mittelbrunn M, Molina A, Escribese MM, Yanez-Mo M, Escudero E, Ursa A, Tejedor R, Mampaso F, Sanchez-Madrid F.
Servicio de Inmunologia, Hospital de la Princesa, Universidad Autonoma de Madrid, Madrid 28006, Spain.
The integrin alpha 4 beta 1 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of alpha 4 beta 1 during the formation of the immune synapse is currently unknown. Here, we show that alpha 4 beta 1 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-alpha 4 antibodies, VLA-4 colocalizes with the CD3-zeta chain at the center of the synapse. In addition, antibody engagement of alpha 4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4(+) T cell differentiation and naive T cell priming by dendritic cells. The in vivo administration of anti-alpha 4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of alpha 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.
PMID: 15263094 [PubMed - indexed for MEDLINE]
J Clin Invest, April 2001, Volume 107, Number 8, 995-1006
Copyright ©2001 by the American Society for Clinical Investigation
Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis
Bradley E. Theien1, Carol L. Vanderlugt1, Todd N. Eagar1, Cheryl Nickerson-Nutter2, Remederios Nazareno3, Vijay K. Kuchroo3 and Stephen D. Miller1
1 Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois, USA
2 Biogen Inc., Cambridge, Massachusetts, USA
3 Center for Neurologic Diseases, Harvard University, Boston, Massachusetts, USA
Address correspondence to: Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611, USA. Phone: (312) 503-7674; Fax: (312) 503-1154; E-mail: email@example.com.
Received for publication November 6, 2000, and accepted in revised form March 13, 2001.
Initial migration of encephalitogenic T cells to the central nervous system (CNS) in relapsing experimental autoimmune encephalomyelitis (R-EAE), an animal model of multiple sclerosis (MS), depends on the interaction of the 4 integrin (VLA-4) expressed on activated T cells with VCAM-1 expressed on activated cerebrovascular endothelial cells. Alternate homing mechanisms may be employed by infiltrating inflammatory cells after disease onset. We thus compared the ability of anti–VLA-4 to regulate proteolipid protein (PLP) 139-151–induced R-EAE when administered either before or after disease onset. Preclinical administration of anti–VLA-4 either to naive recipients of primed encephalitogenic T cells or to mice 1 week after peptide priming, i.e., before clinical disease onset, inhibited the onset and severity of clinical disease. In contrast, Ab treatment either at the peak of acute disease or during remission exacerbated disease relapses and increased the accumulation of CD4+ T cells in the CNS. Most significantly, anti–VLA-4 treatment either before or during ongoing R-EAE enhanced Th1 responses to both the priming peptide and endogenous myelin epitopes released secondary to acute tissue damage. Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. "
Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-03-0974.
Submitted April 8, 2003
Accepted August 18, 2003
Differential effects of treatment with a small molecule anti-VLA-4 antagonist before and after onset of relapsing EAE
Bradley E Theien, Carol L Vanderlugt, Cheryl Nickerson-Nutter, Mark Cornebise, Daniel M Scott, Stuart J Perper, Eric T Whalley, and Stephen D Miller*
Microbiology-Immunology/Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL, USA
Biogen Inc., Boston, MA, USA
* Corresponding author; email: firstname.lastname@example.org.
Interaction of VLA-4 with its ligand VCAM-1 is required for CNS migration of encephalitogenic T cells in relapsing experimental autoimmune encephalomyelitis (R-EAE). Anti-VLA-4 mAb treatment prior to EAE onset inhibits disease induction, however, treatment initiated after the appearance of clinical symptoms increases relapse rates, augments Th1 responses, and enhances epitope spreading perhaps due to the activation of costimulatory signals. To negate the potential costimulatory activity of intact anti-VLA-4, we examined the ability of BIO 5192, a small molecule VLA-4 antagonist, to regulate active PLP139-151-induced R-EAE. BIO 5192 administered one week after peptide priming, i.e. before clinical disease onset, delayed the clinical disease onset, but led to severe disease exacerbation upon treatment removal. BIO 5192 treatment initiated during disease remission moderately enhanced clinical disease while mice were on treatment and also resulted in post-treatment exacerbation. Interestingly, BIO 5192 treatment begun at the peak of acute disease accelerated entrance into disease remission and inhibited relapses, but treatment removal again exacerbated disease. Enhanced disease was caused by the release of encephalitogenic cells from the periphery and the rapid accumulation of T cells in the CNS. Collectively, these results further demonstrate the complexity of VLA-4/VCAM interactions, particularly in a relapsing-remitting autoimmune disease.
Mult Scler. 2004 Oct;10(5):540-8. Related Articles, Links
Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment.
Deloire MS, Touil T, Brochet B, Dousset V, Caille JM, Petry KG.
EA 2966 Neurobiology of Myelin Diseases Laboratory, University Victor Segalen Bordeaux 2, Bordeaux, France.
Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients. In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised. Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observed in vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.
PMID: 15471371 [PubMed - in process]
Yea, that's the thing. And that statement is just a general one. Actually, it's a good thing for the rats for THAT disease, but could be a bad thing for MS in many ways.
The thing is, a VLA-4 antagonist stops T-cell migration, but does NOT stop macrophage migration into the brain and/or CNS. For some conditions, that can be a good thing, but in MS, that is NOT always a good thing.
So.....basically, a VLA-4 antagonist can stop the immune system T-cells from entering the brain, but will not stop APCs from entering the brain. So, the probability is that IF any types of MS pathogenesis is from antigens sneaking in and isn't solely an immune system dysfunction, then in the long run, that is a bad thing. (Hence, that may be where and why we are hearing the rumors about Antegren not working for long. Even the findings from Biogen that I posted above indicate the same thing.)
The thing with a VLA-4 antagonist, though, is that when it is used in connection with stem cell research, the very fact that it is so potent and does manipulate what crosses the blood-brain barrier and blocks "certain" other things from crossing COULD be helpful. If you want stem cells to cross over the BBB without interruption from other bodily processes trying to stop them, then it could be great. (Again, though, all this research is in its infancy and a VLA-4 antagonist is nothing to just play around with.)
The other possible problem, though, is the fact that it doesn't allow ANY T-cells to cross. Hence why it says that over time, the body switches to a mainly TH1 immune response. In MS, you want to keep your immune system predominantly TH2. Plus, this allows a HUGE margin for infection, etc. to run rampant should you ever pick something up.
My question also then is...........you DO want the "good" interleukines to do its work in MS (i.e. such as IL10, and other anti-inflammatory cytokines), so if you take Antegren as a monotherapy, how long WILL it take before it stops working? And especially since Antegren only works via ONE mechanism of action, where are the balancing mechanisms that you need to balance out what it's doing?
I think the advice that person got (that I posted above - no wait, maybe it was in another thread - but I won't name names) from her neuro was a good one. Antegren MAY need to be used in combination with something else.
Biogen's OWN research points out many possible difficulties, doesn't it? That's what I found a little disturbing, shall we say. What changed in under a year with their research? Or is getting Antegren on the market more for the goal of supplementing stem cell research in the future?
It's going to get interesting, I'd say.
Oh.....actually........here's the bottom line of it all, that Biogen ITSELF found:
"...Collectively, these results suggest that treatment with anti–VLA-4 Ab has multiple effects on the immune system and may be problematic in treating established autoimmune diseases such as MS. "
I just couldn't find ANYWHERE, from any researchers, that VLA-4 antagonists had yet been "manipulated" or combined with anything to any extent where the above statement may now prove to be false.
That's why I say it'll be interesting to see what research Biogen has been holding back. Actually, I don't think it's research at all. I personally think that the only thing Biogen has been holding back is clinical trial results on humans. Which "might" mean nothing much as far as whether all of the above laboratory findings by them (and many others) has changed at all!
I would just use extreme caution and be VERY prudent before proceeding with Antegren. That's all. Just exercise extreme caution. (Of course, that's just MY personal advice. Take it or leave it.) Maybe I'd suggest that a person pose these very same probing questions to their neuro first, before proceeding with Antegren, also. It never hurts.
Ok...here's a bit of an explanation regarding myelin degradation in MS. I forgot to mention that a VLA-4 antagonist does not stop B cells from crossing, either. It only stops T cells. So....if some types of MS ARE exacerbated due to B cells, that could pose a problem, also. The following is just an excerpt that helps describe some of the complex problems that happen in MS:
"....This chaos of chemicals causes the inflammation of the blood-brain barrier, thinning it so that T-cells, B-cells and macrophages may enter. Macrophages complete the process by stripping the myelin sheath directly off the nerves. In turn, they release necrosis factor alpha, which is believed to damage oligodendracytes - the cells that produce myelin - making the damage irreparable. (2) The replication of T-cells, the secretion of more and more cytokines, and the eventual destruction caused by the macrophages is cyclic. The myelin can be come inflamed, swollen, or even detached from the nerve fibers. Eventually, it is destroyed and hardened patches of scar tissue form over the fibers (5)."
In any event, another bottom line that I state is that it is important to maintain a "balance" of physiological processes when treating MS.
Oh, and did you know that interferon-1b (Betaseron) has some effect on VLA-4 also, but isn't as potent and does have some other mechanisms of action that balance things out. (And as another plug for my pet project, desipramine also helps strengthen the BBB by minor action on VLA-4.) So..........IFN1b does much of the same thing. Well, there's a positive for a CRAB, huh? I believe you DO want to strengthen the BBB in MS, but just how much? Ya know? I don't think that's the sole answer, is all.
I hope this helps.
The Tysabri Phase 2 trials were 'sliced and diced' and came out very positively reviewed (more on that in my next post). The only reason that the Phase 3 trials were not fully released is that the FDA made the decision to release the drug to the public BEFORE these were completed.
Now, why would they do that? I can tell you why in a very broad
context: their view of the data (and they have ALL the data) was that the drug is so good to withhold it from the public is not ethical.
It is disappointing that the totality of the drug trials on Natalizumab that are available are not referred to - only this or that one, depending on who is making the point (me, being postive on Tysabri referencing any postives in the trials, others, being more skeptical, referencing any negatives in the trials). May I suggest that anyone interested read all of the trial data that are published
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