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How does Tysabri work?
Posted: Thu Jan 03, 2008 7:02 am
by itsjustme
Hi,
Am I just too dizzy and therefor can't figure this out for myself? Or do I just have the wrong idea?
I thought Tysabri worked by being a monoclonal antibody that only attaches to MRTC's rendering them denatured so the T cells won't attack myelin. If that is how it works for MS, then why is Biogen submitting it for Crohn's disease?
I must be missing some vital information.
Re: How does Tysabri work?
Posted: Thu Jan 03, 2008 3:05 pm
by NHE
itsjustme wrote:I thought Tysabri worked by being a monoclonal antibody that only attaches to MRTC's rendering them denatured so the T cells won't attack myelin. If that is how it works for MS, then why is Biogen submitting it for Crohn's disease?
The following description is from the
Dr's Prescribing Information for Tysabri.
TYSABRI ® binds to the alpha4-subunit of alpha4beta1 and alpha4beta7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the alpha4-mediated adhesion of leukocytes to their counter-receptor( s). The receptors for the alpha4 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-alpha4-integrin antibodies also block alpha4-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. 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 alpha4beta1-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 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.
The information above that I've highlighted in bold states why Biogen is using Tysabri with Chron's. Moreover, I realize that much of the above information is written for doctors and not for patients. However, if you go to your local library or used book store, then you can find a medical dictionary to look up the terms that you aren't familiar with and then you can make an informed decision. This is the process that I went through when I was initially diagnosed and compared the three ABC drugs that were available at the time.
NHE
Posted: Thu Jan 03, 2008 5:06 pm
by msladyinca
Hi itsjustme,
I can attempt to give you my layperson's explanation of how Tysabri works for MS, and then just apply most of those principles to the inflammation cells which cause inflammation in the intestines of Crohn's patients (NHE gave you a great "medical" explanation):
These are only my experiences and layperson's opinions after having MS for 32 years, and from having 16 infusions of Tysabri since 10/16/06, and should not be construed as medical advice:
Tysabri works differently than the older generation MS medications (the ABCRs), as Tysabri is specifically designed as a Selective Adhesion Molecule (S.A.M.) that attaches itself to the T-cells (inflammation cells) that attempt to cross the Blood Brain Barrier (BBB) and enter the Central Nervous System (CNS) which is comprised of our brain, optic nerves, and spine.
This is when the T-cells see our myelin (the protective coating for our nerves) as foreign, and starts to attack it, leaving scarring (sclerosis) that shows up most of the time on a MRI as white/grey spots, which eventually leads to axonal loss (i.e., damage resulting in disability). It is also explained as a misfiring of nerve signals to the receiving nerves (which can result in such symptoms as numbness, tingling, weakness, temp. or permanent optic neuritis, fatigue, bladder problems, balance problems, and even paralysis sometimes, etc.)
Generally speaking, if lesions/spots are showing on MRI and lit up like lightbulbs, that usually means the disease process/lesion/relapse is active.
Further, even if a person still feels great while not on a Disease Modifying Drug (DMD), they can still have "silent lesions" forming with no resulting disabilities at that time...unfortunately, due to the nature of MS being a chronic and progressive disease, the resulting disabilities usually show up later, and by then, the resulting damage might be permanent. This is why most neurologists want the patient to start on one of the various DMDs, as soon as possible.
Tysabri's mechanism of action against MS: When Tysabri attaches itself to the damaging T-cells, it prevents a majority of them from crossing the BBB and entering the CNS. And even if a few do get across the BBB and enter the CNS, Tysabri is able to migrate (move) them away from our myelin, providing us with double coverage from those pesky, damaging T-cells.
This accounts for part of the fantastic studies recently reported re: Natalizumab (Tysabri) and it affect on Optic Neuritis.
Tysabri basically stops/slows the cascading effects of the continuous onslaught of damaging T-cells from attacking our myelin, which in turn, gives our body an opportunity to try and heal itself (providing the damage is not permanent).
Regarding various mis-information circulating all over the web about Tysabri, please note: Pursuant to the approved FDA labeling, Tysabri is for patients with relapsing forms of MS that generally have not responded to, or cannot tolerate, other MS treatments. What this means is that Tysabri is a first line (like the ABCRs) AND/OR a second line defense/treatment for MS.
The phrase "cannot tolerate" can be interpreted by the treating physican to include their "needle-phobic" patients...or patients with "aggressive forms of relapsing MS"... , therefore, the patient does NOT necessarily have to fail one med first in order to have Tysabri. Pursuant to Dr. Katz and Dr. Temple of the FDA, they explained to the public in a Conference Call shortly after their Advisory Committee hearings in March, 2006 that the FDA's decision/language above was purposely left open and left up to the treating physican (as it should be, in my humble opinion).
With regard to Tysabri and the use of steroids to treat a relapse: According to the TOUCH protocol, the patient CAN have SHORT courses of steroids (IVSM or Prednisone), to treat a relapse/flare-up while on Tysabri (see the NMSS website for verification and further clarification). Again, these decisions should be left up to the patient's treating physican, as the FDA intended.
Lastly, regarding PML: The experts and authors of the world renowned New England Journal of Medicine attributes PML to diminished immunosurveillance (or a very low immune system), and not to Tysabri.
Additionally, think about this for just a minute: there were 3 trial patients that developed PML: 2 of which were given Tysabri in combination with Avonex (which is another immunomodulator), and 1 Crohn's patient that had a previous severely compromised immune system due to being on Azathioprine for 6 years. Of these 3 patients - 2 died, and neither of them had MS.
This means that out of approx. 3,000 trial patients that had a confirmed dx of MS and Crohn's disease, that did not have a compromised immune system, and received Tysabri as a monotherapy (by itself), and the approx. 5,000 general population patients that also met the above criteria (me included) from 11/04 to 2/05, that's 8,000 patients total, plus the additional approx. 10,000 patients that have received Tysabri since it's relaunch in 2006 (with the same above criteria) - that's a grand total of approximately 18,000 patients - get this: not one of us developed PML and died - which is a risk factor of ZERO in 18,000 or 0:18,000.
In Crohn's disease, Tysabri is designed to inhibit the migration of immune cells into tissues (the intestines) where they may cause or maintain inflammation. Approximately one million people worldwide have Crohn's disease, which is a chronic and progressive inflammatory disease of the gastrointestinal tract, which commonly affects both men and women. The disease usually causes diarrhea, crampy abdominal pain, often fever, and at times rectal bleeding. Loss of appetite and subsequent weight loss also may occur. Complications include narrowing of the intestine, obstruction, abscesses, and fistulas (abnormal channels connecting the intestine and other organs, including the skin), malnutrition and decreased growth rate in children.
Each patient should discuss Tysabri with their treating physican, and weigh the minimal 0.1% risk of PML vs. it's enormous benefits of superior efficacy of 67%.
The above is not meant to scare anyone (because we are all different and there's no "one size fits all" explanation for a complicated disease like MS and/or Crohn's, nor a complex medication like Tysabri)- it's only meant to pass on my experiences with Tysabri and MS, and to try and help educate others in their disease...again, the above is not to be construed as medical advice by any means...it's only my (layperson's) attempt to briefly and very simply explain Tysabri's mechanism of action against MS. I hope the above information helps.
Remember dearhearts, Knowledge Is Power - MS symptoms are like snowflakes...all uniquely different for each of us - and yet - all similarly the same.
What we choose to do with the information we learn about our disease and its available therapies can make the difference between a lifetime of pain, suffering, disabilities, fear and confusion - or a lifetime filled with hope, possibilities, and a better Quality of Life.
It's our choice.
((((((((hugs to all))))))))
With much Love,
Lauren
Posted: Sat Jan 05, 2008 1:52 pm
by HarryZ
1 Crohn's patient that had a previous severely compromised immune system due to being on Azathioprine for 6 years.
This Crohn's patient had stopped all immune system altering drugs at least 8 months before going on Tysabri. He was in relatively good health with the exception of the sometimes uncomfortable Chron's symptoms. His white blood cell count was quite normal. Within the first 3 Tysabri infusions, he started to become ill and that's when the PML began its course. The docs treating him didn't know what was happening and originally the cause of death was a brain tumor. It was only afterwards with further investigation that they determined this patient died from PML.
This patient's story is one of the reasons that Tysabri is used with a lot of caution under the Touch Program. Obviously something happened that isn't fully understood in the connection between Tysabri, other immune system altering drugs and PML. The good news is that is appears to be an isolated situation...at least for the time being.
Harry
Posted: Sat Jan 05, 2008 5:41 pm
by msladyinca
Once again, incorrect information was posted:
This Crohn's patient had stopped all immune system altering drugs at least 8 months before going on Tysabri. He was in relatively good health with the exception of the sometimes uncomfortable Chron's symptoms
This patient was extremely ill with not only Crohn's disease, but Malignant Astrocytoma, receiving Remicade, Azathioprine, and then Tysabri with concomitant immunosuppressants at the same time he was receiving Tysabri. Azathrioprine can be incredibly toxic, and can decimate the immune system long after its dosing, leaving the patient susceptible to potentially fatal infection. This information can be found within this own site's research: http://www.thisisms.com/article202.html.
Furthermore, if you research the FDA AERS database, you will find that Remicade was the primary suspect for this patient's death, with Tysabri, Azathioprine and steroids being secondary suspects.
See:
4647140 ASTROCYTOMA MALIGNANT,PROGR... DE REMICADE 4647140-X 04/14/05 04/28/05 CENTOCOR, INC. Consumer
Reactions
ASTROCYTOMA MALIGNANT
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
Outcomes
Death
Drug Name Role Code Administration Route Verbatim Dose Dechallenge Code Rechallenge Code Lot # Expiration Date
REMICADE Primary Suspect INTRAVENOUS
TYSABRI Secondary Suspect
AZATHIOPRINE Secondary Suspect
IMMUNOSUPPRESSANT DRUGS Concomitant
Posted: Sat Jan 05, 2008 9:27 pm
by HarryZ
msladyinca wrote:Once again, incorrect information was posted:
This Crohn's patient had stopped all immune system altering drugs at least 8 months before going on Tysabri. He was in relatively good health with the exception of the sometimes uncomfortable Chron's symptoms
This patient was extremely ill with not only Crohn's disease, but Malignant Astrocytoma, receiving Remicade, Azathioprine, and then Tysabri with concomitant immunosuppressants at the same time he was receiving Tysabri. Azathrioprine can be incredibly toxic, and can decimate the immune system long after its dosing, leaving the patient susceptible to potentially fatal infection. This information can be found within this own site's research: http://www.thisisms.com/article202.html.
Furthermore, if you research the FDA AERS database, you will find that Remicade was the primary suspect for this patient's death, with Tysabri, Azathioprine and steroids being secondary suspects.
I beg to differ with you, Lauren. I don't know from where you are getting your information but mine is coming from the family of the patient! This patient was doing very well..... fishing and hunting and enjoying his retirement quite nicely. He WAS NOT using any of these other drugs that you have mentioned for a very long time (8 months minimum)...although some people would like us to think differently.
He was allowed to use Tysabri because of his current condition at the time and his immune system was functioning quite normally with no elevated white blood levels. It was soon after he started on the Tysabri that the PML started. Nobody seems to know just what happened between the Crohn's, Tysabri, PML and his system and I won't go into how the docs involved tried to silence the family when they started to ask a lot of questions about the misdiagnosis about his condition.
Yes, this is one isolated situation but the docs then and afterwards continued to blame his previous drug regime as the culprit. Had he not taken the Tysabri the patient would likely be alive today. The follow up theories are just that...theories and speculation. And because of what happened, Tysabri patients are watched quite closely and are not allowed to be anywhere near other immune-suppressive drugs.
Harry
Posted: Sun Jan 06, 2008 11:38 am
by msladyinca
I don't know from where you are getting your information
This Crohn's patient's cumulative medical history can be found in many places. For example, from this site's own research, see: http://www.thisisms.com/modules.php?nam ... le&sid=202
"[he had been] exposed to
years of dosing with a cocktail of potentially
lethal drugs-- that among other things, can cause delayed immunosuppression, cancer, and even PML itself [suggests Remicade], was participating in a clinical trial with another experimental immunosuppresant. Maybe his case was so bad, he had no other hope, but in such an extreme situation, the fault of his death cannot be placed squarely on Tysabri. That he died is of course tragic, but quite frankly, a serious adverse event is not entirely surprising given his
cumulative medical history."
You should probably look it up. Doesn't sound to me like he was "doing very well". You seem to forget that the medications he was on previously and concomitantly have delayed reactions of strong immunosuppression.
This patient was doing very well..... fishing and hunting and enjoying his retirement quite nicely. He WAS NOT using any of these other drugs that you have mentioned for a very long time (8 months minimum)
Anecdotal evidence provided by the family of the patient to only you is not published anywhere in the medical journals that he was "doing very well", and your arguments are with the findings of the FDA, the medical journals, and all published information regarding this patient's cumulative medical history.
You simply have your facts wrong, and anyone else reading your comments can look up the accurate facts as I have indicated them above. Others are more than welcome to make up their own minds when it comes to either your opinion or mine, and reach their own logical conclusions.
Posted: Sun Jan 06, 2008 5:41 pm
by HarryZ
This Crohn's patient's cumulative medical history can be found in many places. For example, from this site's own research, see:
I appreciate the site info but I got the first hand medical history of this patient from the family. Let's just say they have never been too happy at how and what the "experts" stated about this patient's medical situation.
"[he had been] exposed to years of dosing with a cocktail of potentially lethal drugs-- that among other things, can cause delayed immunosuppression, cancer, and even PML itself [suggests Remicade], was participating in a clinical trial with another experimental immunosuppresant. Maybe his case was so bad, he had no other hope, but in such an extreme situation, the fault of his death cannot be placed squarely on Tysabri. That he died is of course tragic, but quite frankly, a serious adverse event is not entirely surprising given his cumulative medical history."
I hear what you are saying and if one were to look at this information from a clinical point of view, it would make sense. Unfortunately, this patient WAS NOT in any kind of dire situation or even close to it!
As I had stated earlier, he had stopped taking all of those drugs months earlier and was actually feeling quite well despite the Crohn's. He was happily retired and enjoying life. He was actually in the Tysabri trial earlier but ended up being on the placebo.
But here is what REALLY bugged the family. The patient was off these other powerful drugs. The docs felt comfortable enough to put him on Tysabri, outside of the clinical trial setting. Now they obviously knew of Tysabri's immune suppressive action so why were they giving him this drug in the first place? They must have felt that there wasn't any danger but afterwards told the family and the world that the patient was severely compromised due to these other drugs and was quite ill!!! The family KNEW he wasn't feeling ill and had been well for months yet the story was being changed and the family being told not to cause a fuss!!
Anecdotal evidence provided by the family of the patient to only you is not published anywhere in the medical journals that he was "doing very well", and your arguments are with the findings of the FDA, the medical journals, and all published information regarding this patient's cumulative medical history.
I can only answer this comment but stating that the same type of "medical information" published in journals is what incensed the family when they KNEW differently. Had the situation taken place in the US, you can bet legal action would have taken place.
You simply have your facts wrong, and anyone else reading your comments can look up the accurate facts as I have indicated them above. Others are more than welcome to make up their own minds when it comes to either your opinion or mine, and reach their own logical conclusions.
Lauren, you can believe what you want to believe from the "accurate facts" and state that I'm wrong but I will place my trust in what the family, who lived with this patient, told me about the situation. The stories are on the totally opposite end of the spectrum and if you knew several of the other details (which I will not devulge on the net) you would probably change your attitude on this.
In closing, this isn't about Tysabri...it's only a drug. It's about the docs who administered this drug with this patient and how they covered their tracks afterwards when things went bad very quickly. I have always agreed with your philosophy of the patient's right choose what medication they want to try. It's that sometimes the patient isn't necessarily given the proper information.
Harry
Posted: Mon Jan 07, 2008 10:58 am
by msladyinca
Lauren, you can believe what you want to believe from the "accurate facts"
I will Harry, in fact, I feel much more comfortable believing the findings of the FDA, the medical journals, and all published information regarding this patient's cumulative medical history.
My sympathies to the family that lost their loved one. It was a tragedy indeed, but this is the risk that all patients (including myself) must decide for themselves when entering a trial for a new medication. It was his choice to enter the trial, his decision, and one that I will always respect (as should we all).
Have a nice day.
Lauren
Posted: Mon Jan 07, 2008 12:48 pm
by HarryZ
I will Harry, in fact, I feel much more comfortable believing the findings of the FDA, the medical journals, and all published information regarding this patient's cumulative medical history.
My sympathies to the family that lost their loved one. It was a tragedy indeed, but this is the risk that all patients (including myself) must decide for themselves when entering a trial for a new medication. It was his choice to enter the trial, his decision, and one that I will always respect (as should we all).
Have a nice day.
Lauren
The findings of the FDA and medical journals, in this case, are based on what information the docs gave them. And that is precisely why the family was quite upset.....what was told to them originally was different at what came out in the "published" reports afterwards. Like I said in the previous post, there was a lot more to this than what meets the eye of the "published reports".
As for deciding to use Tysabri in the end....it wasn't part of the clinical trial at that point. The patient had already participated in the clinical trial earlier and was on the placebo. The docs convinced the patient and family to use Tysabri even though they knew of his past history of immunosuppressive drugs and didn't feel there was a concern. Yet they told the FDA and medical journals that it was this same past use of these drugs that caused the problems and not the Tysabri! It's called protecting the potential "cash cow". Again, it's not the Tysabri that's at question here....it's the docs involved!
Harry
harry, harry, harry
Posted: Mon Jan 14, 2008 3:45 pm
by MeadowStream
So let me get this sraight... you are best friends now with the Belgian patient's family even though you live in Canada? After all this time it is a huge coincidence that you suddenly are close to the family, who themselves assessed Remicade as the primary suspect in their 60 year old relative's death from use of immune suppressants. Who could believe this harry? Answer: no one.
Re: harry, harry, harry
Posted: Mon Jan 14, 2008 4:46 pm
by HarryZ
MeadowStream wrote:So let me get this sraight... you are best friends now with the Belgian patient's family even though you live in Canada? After all this time it is a huge coincidence that you suddenly are close to the family, who themselves assessed Remicade as the primary suspect in their 60 year old relative's death from use of immune suppressants. Who could believe this harry? Answer: no one.
I didn't say that I was "the best of friends" with the family...you did!! I only said that I have corresponded with the family...which I have done on several occasions. If you really must know, this communication started back in September of 2005 when a family member contacted me after reading my comments on Tysabri in various MS forums. So despite your insistence, there really isn't any coincidence at all at this time. I choose to mention it now because of yet another comment on the internet about the "experts'" statements that this Crohn's patient was severely immune suppressed when he started on Tysabri. According to what I was told, that simply was not the case.
I really don't care whether you believe me or not because I know the information I have mentioned was given to me by this family member. If you really want to see the printed e-mail messages, you are welcome to visit me in London, ON Canada. Do you honestly think that I would make up this kind of story??!! If you do, then you really don't know anything about me at all.
And BTW, prior to his death, the patient had lived with Crohn's for 28 years. I suppose that you think I pulled that number out of a hat!!
Harry
Harry you are as transparent as glass
Posted: Wed Jan 16, 2008 9:49 pm
by MeadowStream
No, I am not coming to Ontario to see your "email." You have some sort of vendetta vs. Biogen and, I think, few want to see you spill your bile toward the company.
Tysabri is now being dosed in over 22,000 patients since being reintroduced in 2006 and there has not been a single case of PML. Meanwhile there have been 100s of myocardial infarctions and arrymthias that have been reported where death was the outcome and a beta interferon was the primary suspect.
How many deaths where Tysabri was the primary suspect? Answer: zero.
Guess what the family of the CD patient apparently reported as primary suspect in cause of death? Answer: not Tysabri. Weird, huh?
Guess what Harry Z doesn't like? Answer: the only efficacious and safe treatment for MS. Weird, huh?
Posted: Thu Jan 17, 2008 6:40 am
by Xenova
I always refer to this page to understand Tysabri.
http://doodah95.blogspot.com/
This page has a video of Biogen's explanation of how it works.
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shortened url>
Re: Harry you are as transparent as glass
Posted: Thu Jan 17, 2008 7:14 am
by HarryZ
MeadowStream wrote:No, I am not coming to Ontario to see your "email." You have some sort of vendetta vs. Biogen and, I think, few want to see you spill your bile toward the company.
Well, I did give you the chance to come and see for yourself that my communication with this family was not a fabrication like you stated. And it certainly isn't a secret that I don't have any respect for how Biogen has handled the entire introduction of Tysabri from the beginning.
Tysabri is now being dosed in over 22,000 patients since being reintroduced in 2006 and there has not been a single case of PML. Meanwhile there have been 100s of myocardial infarctions and arrymthias that have been reported where death was the outcome and a beta interferon was the primary suspect.
And your point is what? That the interferons are not safe? We have been told for over 15 years that the interferons are a safe and effective way of treating MS! Even James Mullen, CEO of Biogen, stated after Tysabri's initial recall, that Avonex had hundreds of thousands of patient months behind it without any evidence of PML or other serious problems. Tysabri may well turn out to be safer, the same or worse than the interferons but we won't know that for quite some time.
How many deaths where Tysabri was the primary suspect? Answer: zero.
Depends who you want to listen to, doesn't it! Dr. L. Steinman, the co-discover of Tysabri, has been quoted many times as stating that Tysabri and other drugs in the same category, are potentially dangerous from the very nature of how they work. He said that the PML issues were certainly not surprising.
My issue with Biogen isn't about Tysabri as a drug but how they rushed it into use. Before the FDA approved it the first time around, they published the outline of their marketing plan for this drug on the net, showed the huge percentage of market share they would steal away from the other MS drug makers and how many billions of dollars they would make!! They conducted simulcasts with stacked panels showing how all the docs were going to give up on these other drugs and now use Tysabri.....all in advance of FDA approval and safety data. That's what I didn't like about Biogen.
Guess what the family of the CD patient apparently reported as primary suspect in cause of death? Answer: not Tysabri. Weird, huh?
Well, if that's what you want to believe, go ahead. Just pay a lot of attention to the word "apparently" that you used!
Guess what Harry Z doesn't like? Answer: the only efficacious and safe treatment for MS. Weird, huh?
If that's the conclusion that you come up with then you really have missed the boat!!
Harry