VLA-4 Antagonists (i.e. Antegren)

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

Postby OddDuck » Sun Nov 07, 2004 6:07 am

John,

Progressive MS does not involve inflammation. That's the largest part of what distinguishes progressive from RRMS. Along with fewer lesion load (if any lesion load). The difference between RRMS and progressive types isn't solely based on type of symptoms at all, IF at all. (So, you are exactly correct on that point. They don't classify types of MS based on symptoms). I'm surprised you didn't locate all this about progressive MS, though. That's a fairly commonly known fact in MS.

It depends on what the treatment is targeting. If its purpose is to reduce "inflammation" (which most of the drugs, i.e. steroids, CRABS and Antegren) are geared to do, that's how they already know they won't work for progressive types. Inflammation isn't the problem in progressives. They don't know exactly what is, either, though (but they have some valid suspicions. Those suspicions were integrated in my original research findings that I was posting over the last few months. i.e. calcium influx, cAMP, etc.) But lack of inflammation is one of the key factors for how they classify types of MS (at this point.) That's why you don't see very many drugs (well, actually none really - not for "therapy") for progressive MS. They will try their best to treat progressive MS symptomatically, and with Novantrone (chemotherapy type drugs), but that's about it.

John, they DO know some things about what's happening in MS, actually many things. They know a lot about HOW the damage in MS is occurring. Just not the "why". They don't know what CAUSES these things to happen nor how to effectively treat it completely or stop it from happening in the first place. They do know "what" is happening, though. Now they need to find the appropriate drugs to stop it. The most common thing that happens (statistically) though is inflammation. And inflammation right now, is the easiest thing to try to target when developing drugs to treat it. And it hits the greatest number of MSers (which isn't fair, though, because progressive MS gets second billing, in my opinion).

And I agree with risk assessment. That's why I said for some MSers, any threat to child-bearing, etc. probably wouldn't apply at all. I targeted only a specific "group" of people where Antegren or a VLA-4 antagonist "may" pose additional risk assessment for. IF they are aware of any potential risk factors such as that. (That's the thing I'm going to be watching for. The test results that SHOW there is NO risk of Antegren diminishing or threatening women AND men's fertility, etc., not only the risk of taking it DURING pregnancy, but the risk factors BEFORE pregnancy! That's the point that is different about Antegren as compared to the CRABS.)

Dr. Claudia Lucchinetti has proven the point about inflammation and MS, which they already "knew" from statistical analysis, with her recent pathological findings. She now has PROVEN that there are totally separate disease processes (she's found four so far) going on in MS, and only two involve any type of inflammation at all (and they don't appear for the most part to be the more progressive patterns). So at the very least, she is proving the original observations about progressive MS and lack of inflammation.

Do you want to try to treat "inflammation" that you don't have? They can tell easily via tests whether you have inflammation going on or not. Why take a drug that's solely for inflammation when you don't suffer from inflammation. See what I mean? Some MSers DO try it, though. If you insist on taking a CRAB, a doctor may let you try it. But I can bet he'll try to talk you out of it. The side-effect risk wouldn't be worth trying to treat a problem you don't even have.

And IS there some thought to whether something MAY help SPMS (that is clinically evident has clearly evolved from an initial RRMS class?) Yes. They found that Betaseron may help some. But that's about the only CRAB that laboratory tests and human clinical trials have found may have a little benefit for SPMS. They've tested all these drugs on all types, John. And over trial-and-error, they can safely say what does or does not work for progressive MS based on the mechanisms of action of the drug.

Example being.........would you take a cough supressant to cure an infection? Or an antibiotic? You don't have to even know HOW you got the infection, but you know what type of drugs work on it or not. Especially the drugs that have been studied extensively, like the current MS drugs have been.

Antegren, unfortunately, is one of them. It's for RRMS. Basically, to try to hold down inflammation. BUT is doing it by targeting only ONE specific part of the complex nature of MS. And it's a very complex, fairly unknown part of it - the integrins. Frankly, that bothers me.

That's why I'm so adamant about testing something like desipramine, which my research (and also the research findings recently published regarding TZD and progressive MS) shows should be helpful for progressive MS. It's a broad spectrum type of drug, which not only helps with inflammation (if present), but more importantly has many MORE mechanisms of action that aren't related to inflammation at all! It helps prevent DNA fragmentation, increases the growth protein GAP43 (which is what regenerates axons), etc. etc.

Deb
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Postby OddDuck » Sun Nov 07, 2004 6:51 am

I'm sorry, I do want to make one more point.

An additional possible problem with Antegren in association with the fertility equation are the "indications" of what happens when/if you suddenly STOP taking Antegren.

Say you ARE a young couple. But you don't plan on having children right away, but DO want to some day. With a CRAB, it's fairly safe to wean off of it for a while or even fairly quickly completely stop taking a CRAB for a while if you want to have a family. We've seen how many people stop taking CRABS and sometimes even feel better. (Now remember, this is not an attempt at promoting CRABs, either. That's another discussion altogether on my opinion on how well the CRABs work.) Physiologically, though, there's not much of a jolt to the system (for lack of a better term), if you stop taking a CRAB.

With Antegren, there is indication that that may not be the case! I found research that indicated that if you stop Antegren, your system rebounds - to a fairly large extent. Exacerbations suddenly get much worse, etc. So...........you also may have to factor in THAT fact, also. Do you even want to START taking Antegren if you think at all that you may want to temporarily stop it in the future in order to have a family?

Stopping Antegren based on bad side-effects or something is an entirely different scenario, of course, and you may be able to switch or supplement your treatment with something that will help your system not do that 180 degree reversal. But again, how long would that take to get your system settled back down?

There is just not enough research on all this. But plenty of questions that, to date, I'm unable to find even consideration about, let alone actual research!

But I'm still looking. So far, though...........nada.........nothing.

Deb
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Postby OddDuck » Sun Nov 07, 2004 7:11 am

Well, here I go again. LOL My mind is now putting together pieces.

Plus..........if you want to strengthen the BBB, one of the best things that can be done is to increase IL10. An increase in IL10 is also beneficial in pregnancy. (There are some theories that that is probably one of the reasons women with MS have a reduction in exacerbations, etc. during pregnancy........the increase of IL10 when you get pregnant).

Targeting IL10 is much safer, more beneficial overall, etc.

The more I think about all this, the more I wonder what's up with the specificity of a VLA-4 antagonist? Especially as monotherapy for MS?

:?:

No wonder my neuros don't like talking to me. I ask some hard questions, I think, that put them right on the spot. LOL

Deb
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Postby OddDuck » Mon Nov 08, 2004 5:31 am

Well, I see from another thread that the one-year data for Antegren was published. Sounds great.

I posted this on that thread, but I thought I'd post it here, also. All I'm saying is I want to see the testing that was done that reassures the general public that blocking any of the integrins won't cause any problems, and if so, what are they?

Deb

Here's my post from the other thread:

Yea, and still no mention of contraindications (i.e. blocking VLA-4).

Deb

EDIT: The article says:
Natalizumab, a humanized monoclonal antibody, is the first alpha-4 integrin antagonist in the new selective adhesion molecule (SAM) inhibitor class.


It may be the first alpha-4 integrin, but it's not the first "integrin antagonist" or selective adhesion molecule inhibitor ever put on the market. Thalidomide was (and is now back on the market again with the following contraindications that come with it: http://www.fda.gov/cder/foi/label/1998/20785lbl.pdf )

I rest my case.
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Postby raven » Mon Nov 08, 2004 6:49 am

Which would be more important alpha-4 integrin antagonists or P-Selectin antagonists? The following appears to suggest that P-Selectin is the more important of the two.

Experimental autoimmune encephalomyelitis (EAE) is mediated by inflammatory cells recruited from the circulation to the CNS. We used intravital microscopy to investigate the mechanisms of this recruitment. No leukocyte rolling and very little adhesion was observed in healthy control mice. In contrast, both rolling and adhesion was observed in brain postcapillary venules before onset of physical symptoms of EAE. Rolling and adhesion remained elevated for 2 wk and returned to near normal levels by 5 wk postsymptom onset. Consistent with a role for P-selectin in recruitment to the CNS, P-selectin protein was detected in the brains and spinal cords of EAE mice. Expression was highest before symptom onset and decreased over the next 2 wk. The importance of alpha(4) integrin increased with time as anti-alpha(4) integrin blocked approximately 20, 50, and 60% of leukocyte rolling 2 days before disease onset, 5 days and 2 wk postonset of symptoms, respectively, and 85% of rolling 5 wk postsymptoms. Addition of anti-P-selectin to alpha(4) integrin Ab-treated mice blocked all remaining rolling at each time point. Interestingly, however, alpha(4) integrin-mediated rolling appeared to be entirely dependent on P-selectin as anti-P-selectin alone was able to completely block all leukocyte rolling. In the absence of rolling (with P-selectin Ab), a 70% reduction in adhesion was noted. A very similar reduction was seen when mice were treated with alpha(4) integrin-blocking Ab. In conclusion, we describe increased leukocyte trafficking in the brains of EAE mice with important overlapping roles for both P-selectin and alpha(4) integrin in mediating leukocyte-endothelial cell interactions.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12097407

P-Selectin expression can be effectively reduced by a humble aspirin analog, sodium salicyclate.

Deb, over to you... :wink:

Robin
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Postby OddDuck » Mon Nov 08, 2004 8:10 am

Does it matter? (Besides, that article proves my point as to how potent and complex messing with integrins is/can be.)

In the absence of rolling (with P-selectin Ab), a 70% reduction in adhesion was noted. A very similar reduction was seen when mice were treated with alpha(4) integrin-blocking Ab.


My exact point being, though, that is enough known yet about blocking any of the integrins and how it will affect reproductive functions for both men and women, not to mention birth defects, etc.?

Shouldn't more research be done first, as the implications MIGHT be important to know in order to make a fully "informed" decision regarding taking ANY integrin antagonist?

Hey.........but who am I?

Deb

EDIT: Remember, also, the chronic administration of VLA-4 antagonists and the proposed dosage as opposed to an acute administration or taking something every now and again.
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Postby Axiom » Mon Nov 08, 2004 9:36 am

OddDuck wrote:No wonder my neuros don't like talking to me. I ask some hard questions, I think, that put them right on the spot. LOL

Deb


Just want to say I'm glad you do and that you put those questions and concerns here for us to see as well.

I've been lurking for a month or so trying to educate myself and I appreciate all the info you post, even if I have to re-read some of it over and over and still shake my head. :?

I'm a mom with no medical background but at the last appt. the neuro asked if I was a nurse... when I said no, he said I get an A+ for study then. He'll be sooo thrilled when I walk in armed with my antegren questions next appt. :wink:

My daughter was Dx with MS the end of Sept. (less than a month before her 17th B-day)
I'm just trying to learn enough to make the tough decisions with her instead of saying "whatever you think Dr." That's just NOT me!

Again, thanks to all the posters here for asking the tough questions and getting info out in the open.
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Postby OddDuck » Mon Nov 08, 2004 10:02 am

Thank you, Axiom!

And I'm SO sorry to hear about your daughter. That's rough for anybody, let alone someone of her age. :cry:

I wish there was something "wise and wonderful" that I could personally say, but as you know, there probably isn't.

Hang in there, keep us posted, it's VERY nice to meet you, and all the best always!!!!

:)

Deb

P.S. Don't be a stranger! :wink:
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Postby OddDuck » Wed Nov 10, 2004 9:20 am

You know.............NOW I wonder if this thread shouldn't be moved to the sub-topic "Antegren" under the "Treatments" category?

(Hey.........it's all in the "timing"........... :wink: )

Deb
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Postby OddDuck » Wed Nov 10, 2004 11:05 am

Thanks, Arron!! :P

Deb
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Re: VLA-4 Antagonists (i.e. Antegren)

Postby HarryZ » Thu Nov 11, 2004 8:12 pm

Deb,

After reading a fair amount of info on Antegren, my response after browsing through this thread is brief and simple....I wouldn't try it for one second until after it had been out for at least 18 months and we started to see results and side-effects obtained outside the clincial trial atmosphere.

I don't have a good feeling about this drug and never have. I hope I'm wrong and that it will benefit MS patients.

Harry
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Postby OddDuck » Thu Nov 11, 2004 8:35 pm

There you are, Harry! :wink:

Yea, I hope it works out well, also. Right about now, frankly, I'm thanking the "powers that be" that I'm doing fine on what I'm currently taking (no matter WHAT they want to say it is I have or don't have), because I sure as heck wouldn't want to have to make a decision (again) about what to try. Figuring it out last year was bad enough.

If asked point blank, though, I'd have to say personally that I'd definitely wait for quite a while myself before switching to or trying Antegren.

I think we've all got our fingers crossed, huh?

Deb
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Antegren Rebound Effect - False Rumour

Postby Mman » Mon Nov 15, 2004 3:47 pm

Physiologically, though, there's not much of a jolt to the system (for lack of a better term), if you stop taking a CRAB.

With Antegren, there is indication that that may not be the case! I found research that indicated that if you stop Antegren, your system rebounds - to a fairly large extent. Exacerbations suddenly get much worse, etc. So...........you also may have to factor in THAT fact, also. Do you even want to START taking Antegren if you think at all that you may want to temporarily stop it in the future in order to have a family?



Below are the FACTS about rebound effect. In summary, in the most complete study published to data there is no rebound effect. I can find no support for the statement that 'exacerbations suddenly get much worse;' I would welcome any references for this.



From the NEJM on the P2 Antegren study:

A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
Miller D. H., Khan O. A., Sheremata W. A., Blumhardt L. D., Rice G. P.A., Libonati M. A., Willmer-Hulme A. J., Dalton C. M., Miszkiel K. A., O'Connor P. W., the International Natalizumab Multiple Sclerosis Trial Group
Abstract | Full Text | PDF
N Engl J Med 2003; 348:15-23, Jan 2, 2003.


http://content.nejm.org/cgi/content/ful ... lcode=nejm

From the Abstract:


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.


From the Text:


Safety and Tolerability

Similar numbers of patients in each group had adverse events during treatment (Table 4). Eleven serious adverse events occurred in seven patients in the placebo group, five serious events occurred in five patients who were receiving 3 mg of natalizumab per kilogram, and four such events occurred in three patients who were receiving 6 mg of natalizumab per kilogram. Four of these events were considered to be immune-mediated and related to the study drug. One patient who was receiving 3 mg of natalizumab per kilogram had an anaphylactoid reaction with urticaria and bronchospasm, which was rapidly reversed with antihistamines and corticosteroids. There were three reports of serum sickness, one in each group. Only one of these events was accompanied by a change in complement levels, and all three occurred at a single study site. These events complicated fewer than 1 in 250 infusions. Treatment was discontinued because of an adverse event in three patients in the placebo group, four in the group given 3 mg of natalizumab per kilogram, and three in the group given 6 mg of natalizumab per kilogram. One patient in the placebo group died of pleural carcinomatosis complicated by hemothorax.


Post-Treatment Follow-up

When the values obtained at month 9 and month 12 were combined, the number of new enhancing lesions and scans showing activity were similar in all three groups (Table 2). After treatment, there was no significant difference among the three groups either in the total number of relapses or in those objectively confirmed (Table 3).

___________________________________________

FWIW, there are four published Antegren studies on MS (that I am aware of):

1. A phase-1 pharmacokinetics/safety study showed that a single dose of one to three milligrams of Antegren per kilogram persisted in serum for three to eight weeks.
2. A phase-2 study showing a single infusion of Antegren did not hasten recovery from acute relapse.
3. A phase-2 study in active RRMS and SPMS of two infusions of Antegren showed reduced MRI activity and an improvement in EDSS but not relapse rate.
4. A phase-2 study in active RRMS and SPMS of six infusions of Antegren showed reduced MRI and clinical activity.


The P1 study detailed below is, I believe, the 'source' of the rebound effect comment given in the quote above, (but I cannot be sure as no citation was given in the quote).


Phase 2, Two-Dose Study in RRMS and SPMS:

N. Tubridy, P. O. Behan, R. Capildeo, A. Chaudhuri, R. Forbes, C. P. Hawkins, R. A. C. Hughes, J. Palace, B. Sharrack, R. Swingler, C. Young, I. F. Moseley, D. G. MacManus, S. Donoghue, and D. H. Miller
The effect of anti-4 integrin antibody on brain lesion activity in MS
Neurology, Aug 1999; 53: 466.

In 1999, Neurology published the results of a two-dose study of Antegren (3 mg/kg) in 72 patients with active MS; patients were followed for 24 weeks. Sixty-eight patients and 97.5% of MRI scans could be evaluated for response. Baseline MRI scans were used to determine the number of currently active lesions and an imbalance favoring placebo was noted: 1.2 active lesions/patient compared to 2.0 in the Antegren group.

The development of new lesions, following baseline correction was halved in the Antegren group during the first 12 weeks, and thus, as expected, more patients showed no new enhancing lesions in the Antegren group: 83.6%, compared to placebo at 73.1% (p=0.037). Between weeks 12 and 24, no differences between Antegren and placebo were noted, i.e. no MRI rebound occurred in the Antegren group. There was also no difference in the fate of baseline lesions, supporting data from the previously discussed study that Antegren is ineffective for ongoing inflammation. No ifferences in relapses were observed during the study, although the Antegren group suffered more relapses during the 12–24 week period than placebo, 38% versus 14%. The reason for this difference was an unexpectedly low relapse rate in the placebo group rather than an increase in the Antegren group, i.e., the relapse rate seen in the Antegren group was as
expected based on patients’ histories. It could, however, also be correlated with the leukocytosis that was observed in the Antegren group. We assume that, over extended periods of dosing, leukocytosis would resolve, and thus, if this is a causative factor for rebound—if this is indeed even an accurate description for the observation—rebound itself should be diminished. Over 24 weeks, no differences in EDSS change were
observed, although at week 12, 31% of Antegren patients had a 0.5 point improvement compared to 10% of placebo-treated patients. Further, fewer Antegren-treated patients showed a 0.5 point decline.



I hope the above facts put to rest the concerns about a rebound effect from Antegren. The larger P2 study outlined above has proved there is no rebound effect. Obviously, further studies are underway and will be done after drug approval, but the P2 data are certainly encouraging.

[Pfizer (Serono's partner in Rebif) probably referred to the Phase 1 study in their July, 2004 Earnings release and suggested a 'rebound' effect, all the while ignoring the 2003 NEJM paper and results of the P2 study on 3 times the number of patients. Talk about selective review of data! (As Serono did concerning BIIB/ELN's 8 Nov 04 Press Release). You judge for yourself whether Pfizer's release comment was ethical.]


We all await the full Antegren P3 trial results for more information. The preliminary P3 data of 66% reduction in relapses is great news for all. And note that this was a substantial improvement on P2 relapse rate reductions which were about 50%. Lets hope there is a similar improvement in P3 lesion reductions rleative to the P2 lesion reductions of 90%+.

Cheers
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Postby OddDuck » Mon Nov 15, 2004 3:50 pm

I posted the references and highlighted where Biogen itself made the finding.

And why do I get the "feeling" that you are starting to become somewhat "aggressive" or sarcastic with me again? I certainly hope I'm incorrect.

Deb

EDIT: Again, I am going to ask that you not direct your comments to any of my posts nor quote any portion of my posts, only for the attempt at discrediting me. Thank you.
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Postby Mman » Mon Nov 15, 2004 3:56 pm

And why do I get the "feeling" that you are starting to become somewhat "aggressive" or sarcastic with me again? I certainly hope I'm incorrect.


I am sticking to the facts and supporting same with references. If the post can be countered or elaborated upon with facts, then please do so. Is there anything wrong with this exchange of information?

I have not, nor will I, make any attempt to discredit or otherwise disparage anyone on this Board. I am simply reporting facts with the hope that a balanced view of Antegren is presented. Nothing more. I thought that the Board was here for information and opinion exchange - why do I feel that someone is trying to prevent that? I sincerely hope I'm wrong about this feeling.
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