Revimmune

A board to discuss future MS therapies in early stage (Phase I or II) trials.

Revimmune

Postby bromley » Tue Jul 31, 2007 6:00 am

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Postby Lyon » Tue Jul 31, 2007 6:34 am

Thanks for the link Ian.
Now that I'm ahead of you in posts and can rest on my laurels a little (what DOES THAT mean?). I'm trying to spend less time on the internet and I otherwise wouldn't have seen this one.
Unlike Revimmune, no other approved therapy for MS has shown a recovery of neurologic function and all others have been approved on the more limited basis of reducing the risk of disease exacerbation or progression. Accentia’s proposal to use the restoration of neurologic function as the endpoint will be the first filed with the FDA.
Not to badmouth CTX because, as you've mentioned, I own controlling stock in the company and I'd like everyone to be on it, not just people with MS :wink:

Seriously, in a lot of ways this particular point in time seems a little like the "lawless west" of MS therapies. Since no one knows a tinker's damn about the MS disease mechanism, if you have a treatment which seems to have a profound effect it seems that you can make about any claim you want. Who's to prove you wrong?

It's very, very, very unlikely that Cyclophosphamide has any neuroregenerative effect in itself but the high percentage of fast progressing, young people who have and are indicated for this treatment evidently has shown a tidy 42% improvement in function, when in reality stopping the disease process and a person's ability to heal is most likely the only thing responsible for the noticed improvement.

At any rate, it seemed to me that if I badmouthed HDC it might make me seem more open minded about the whole thing. I'm off to let my stockbroker know that I want more Accentia shares.

Bob
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Postby bromley » Tue Jul 31, 2007 7:13 am

Bob,

I thought you'd like that one.

In an ideal world a treatment would knock out relapses, inflammation and nerve degeneration and promote remyelination / repair of nerves.

We can only work with what we have. Some of the powerful immunotherapies may only affect relapses / inflammation and in the long run have little affect on disease progression, but if a person is having disabling relapses then some of these more risky treatments can do the business. Individuals will need to make a decision based on their own circumstances and a full understanding of the risks.

Like you I am trying to limit my time on MS websites now that I have made my treatment choice. Unfortunately, even news webistes such as the BBC have included MS stories in the last couple of weeks.

I am soon off on holiday for two weeks without internet access. But the autumn looks interesting with a couple of key conferences - ECTRIMS in October and The Charcot Foundation in November. The programme for the latter is set out in the link.

http://www.charcot-ms.org/main.php?pag= ... 8&sid2=128

Good luck with the shares.

Ian
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Postby Lyon » Tue Jul 31, 2007 8:36 am

Hi Ian,
Have an enjoyable vacation....I've heard Fiji is nice at this time of year.

Some of the powerful immunotherapies may only affect relapses / inflammation and in the long run have little affect on disease progression,
We all are in for some interesting lessons over the next few years but I think we'll find that there is a big difference between stopping the faulty immune process at a point prior to relapses/inflammation (as I think these "powerful immunotherapies" are doing) and (ineffectively) trying to control relapses and inflammation after they are well underway (as we've done with "suppression" in the past/currently are doing).

I only wish that most people would take the time to seriously consider what a vast difference there is between "injuring/weakening/dampening/suppressing" the immune system long term and temporarily alleviating the faulty immune system so that a healthy one can replace it.

Which is really more dangerous? It seems almost obvious that, in the long run, lifelong suppression is more dangerous than temporarily alleviating the immune system and enduring a short period of heightened risk.

I've avoided the recent "pitiful" MS gene discovery conversations. Obviously a helminth lover like myself is fully aware that, rather than genetic predisposition+environmental trigger, the real situation involves everyone in the developed world having an environmental predisposition and MS requires additional genetic and or environmental factors.

Look all they want, find and add up the effects of all the damned genes they want, it's not going to add up to genetic predisposition. GENETIC RESEARCHERS: save yourself the effort and send me your research dollars...you're wasting your time!

Bob
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Postby robbie » Tue Jul 31, 2007 9:21 am

temporarily alleviating the faulty immune system so that a healthy one can replace it.

So what you saying Lyon is that Campath or one of these type drugs will cure ms or can it come back after time even with a new immune system? I know we just have wait for that answer i guess. Is this a reasonable assumption. I really hope it works 100% so there is no question about it' s ability to rid this. To me if i was on this therepy because it's so invasive one failure of anyone in the trial would be crushing..I commend those who are brave enough to try it.
Had ms for over 19 years now.
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Postby Lyon » Tue Jul 31, 2007 12:36 pm

robbie wrote:So what you saying Lyon is that Campath or one of these type drugs will cure ms or can it come back after time even with a new immune system?
Hi robbie,
What I'm saying is that "IF" Campath or HDC eliminates every speck of the old immune system....or at least the parts specific to MS and "IF" the new immune system comes in healthy, you are rid of this particular bout of MS.

The problem is that everyone who now has MS has shown to have, or at least has shown to have encountered the necessary predispositions and/or triggers to start the disease process the first time.

Our not being able to identify the predispositions/triggers keeps us from making a valid estimate as to the chances of again meeting those conditions or estimating how long it might take.

I think I mentioned 20 or 30 years in that earlier post but I was only basing that on how old someone usually is upon diagnosis and the time needed to reacquire MS could be less than that...if those conditions were again met, but even then would ONLY be if someone never took further treatment.

With Campath I think yearly re-treatments are part of the plan. From what I can tell, with HDC they give you the initial treatment regimen and supposedly (time will tell) you never are treated again.

The "good?" thing about HDC is that even though is it pretty invasive, if it eliminates the immune system as effectively as researchers think (and it seems to) it should be a Godsend for the people who have several autoimmune diseases because it would simultaneously end them all.

Bob
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Postby robbie » Tue Jul 31, 2007 1:56 pm

Sounds really good Lyon, when i said that these drugs are invasive i was thinking that a severe relapse must be pretty invasive itself so if it stops these attacks then it's worth it and then some. I really hope that it works for all that try it so there is something that people know for sure and can count on working. I have never had any severe attacks,ON was about the worst so i don't know how they must feel, i took the long road to the party :) .Thanks for you answer Lyon .
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Postby Lyon » Tue Jul 31, 2007 2:20 pm

I hope the same things robbie. I'm not terribly familiar with Campath but Cyclophosphamide has been around a while and has long been used in high dose with cancer and has a known history. If nothing else, someone being treated with it will have a pretty good idea what they are getting into.

This, from the Johns Hopkins website http://autoimmune.pathology.jhmi.edu/aiday3.cfm
Robert Brodsky [ Bio ]
In the late 60s bone marrow transplant began to make its appearance in the medical practice, but a major block to its success was the need to suppress the patient's own immune system to the point where it would accept the bone marrow from other patients (allogeneic transplant). To achieve this goal, George Santos, the founder of the Johns Hopkins bone marrow transplant program, introduced the use of high-dose cyclophosphamide (Cytoxan), a well-known drug used long term in low doses as immunosuppressant. Lyle Sensenbrenner, another Hopkins oncologist, noted that several of the patients Santos treated with high-dose cyclophosphamide were recovering their own bone marrow, instead of the donor's. He then theorized that cyclophosphamide could be used to rebuild the bone marrow in patients with severe aplastic anemia (SAA) for whom all other therapeutic options had run out.

SAA is a lethal disease (about 80% mortality one year after the diagnosis) characterized by a >75% reduction in the cellularity of at least two of the three marrow blood cell lineages (erythroid, myeloid, and lymphoid), and mediated by an autoimmune attack of T lymphocytes against hematopoietic stem cells. Dr. Sensenbrenner treated 10 young patients with SAA using the high-dose cyclophosphamide regimen, but then left Hopkins in 1987 and no one ever kept track of how his cyclophosphamide-treated patients fared long term --- until 1994 when Dr. Robert Brodsky came along. To his amazement, Dr. Brodsky found that 7 of the 10 original SAA patients were not only alive but completely disease-free, with no relapse and no secondary disease. He published these findings in Blood (87: 491-494, 1996), concluding the paper with a note of caution : "Although encouraging, these results remain preliminary. The study was small and the patients were relatively young. Hence, further studies with high-dose cyclophosphamide need to be performed".

Dr. Brodsky then expanded the treatment to 20 additional patients with SAA using the following high dose cyclophosphamide protocol: 50 mg/Kg/day of cyclophosphamide for four days, followed by G-CSF to begin 6 days after the last cyclophosphamide dose. The treatment was successful in 85% of the patients, thus confirming and expanding the original findings. It is now known how cyclophosphamide works, and why the bone marrow responds to this drug by bouncing back and recreating its own three blood cell lineages. Cyclophosphamide is activated in the liver to phosphoramide mustard, which kills most of the actively replicating cells, such as the bone marrow cells. Phosphoramide mustard is inactivated by the enzyme aldehyde dehydrogenase; thus, the cells that express this enzyme are resistant to phosphoramide attack. T and B lymphocytes, the cells that mediate the damage in autoimmune diseases, contain very little aldehyde dehydrogenase, and so are easily destroyed by cyclophosphamide. Hematopoietic stem cells represent less than 1% of the bone marrow cells, and have the capacity to generate cells of all the three blood lineages. Stem cells can be distinguished into two pools. The low quality pool is made by large, lin+ and DR+ stem cells which do not express the enzyme aldehyde dehydrogenase; the high quality pool is made by small, lin-, DR- cells which express aldehyde dehydrogenase. Thus, stem cells of the high quality pool are resistant to cyclophosphamide. This means that patients receiving cyclophosphamide will have destroyed the existing mature blood cells, but will retain the ability to create new blood cells, avoid therefore the need for bone marrow transplant. Simply put, cyclophosphamide ablates the bone marrow, but reboots its ability to form new hematopoietic cells, including new, nonautoimmune lymphocytes.

The high-dose cyclophosphamide treatment is effective, safe, represents 1/3 of the cost of a classical bone marrow transplant and avoid the reinfusion of the autoreactive lymphocytes that may contaminate the graft. The treatment has a mild toxicity: complete alopecia (that begins about 2 weeks after the first dose), nausea and vomiting for the first 4-5 days, and lowering of the blood cell counts. During this period, patients require transfusion of blood products (usually 1-2 units of red blood cells and 2-3 units of platelets), develop febrile neutropenia in about 70% of the cases, and may develop infections that require hospitalization .

With this background, the high-dose cyclophosphamide treatment is being tried in patients with other severe autoimmune diseases. For example, it has been tried in 6 patients with pemphigus and in 13 patients with severe and unresponsive lupus erythematosus systemic. All 6 patients with pemphigus have a good response, specifically 4 are in complete remission and 2 are in partial remission after the treatment. Of the lupus patients, 6 are in complete remission, 3 in partial remission and 4 have no response. In summary, high-dose cytoxan a) effectively ablates all the bone marrow cells, except the high quality stem cells, which are protected through the enzyme aldehyde dehydrogenase and can thus repopulate the marrow and "reboot" the immune system; b) cures severe aplastic anemia; c) can also cure other severe autoimmune diseases.

Report prepared by Patrizio Caturegli
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Postby Jean » Wed Aug 01, 2007 12:16 am

I am also interested in the "reset button" method provided by HDC, and especially in bone marrow / hematopoietic stem cells transplants, and I've read a couple of articles about it. I'm not sure HDC completely resets your immune system : it just cuts down production of lymphocytes or white cells in general. (inclunding faulty ones) In order to have a complete reset, some researchers have tried to destroy completely patients' immune system (lymphoid irradiation) then re-implant "clean" stem cells. It seemed to work in several cases, but not for everyone, in spite of a full reset. This is worrying for "reset researchers" because it would mean that a full immune reset cannot necessarily stop the disease. Another hypothesis : people who show disease progression could have caught MS a second time (be put in contact again with the hypothetic environmental trigger). Hard to say, but it seems MS is more complicated than just a faulty immune system, and there's maybe something behind this. Check "ASTIMS" on google for for info (Autologous Stem Cell Transplantation In MS).
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Postby Lyon » Wed Aug 01, 2007 6:31 am

Hi Jean,
In reality what is considered the total "immune system" consists of a lot more than what we, who are concerned with MS consider it, but in the field of MS the lymphocytes ARE the immune system and the bone marrow is the parent....the creator of the immune system.

What you're talking about, a total reboot (or the attempt) has been used on luekemia since the 1960's and was based on the assumption that the MS process is also reciprocated in the bone marrow, which would also have to be eliminated and re-created. The total reboot was the first thing that came to the minds of researchers and it's what they were familiar with. In truth, the lead researcher in the Stony Brook cyclophosphamide study is an oncologist and not the expected neurologist.

The most interesting recent findings of the Campath and HDC researchers is that only eliminating the lymphocytes and sparing the bone marrow is less unpleasant for the patient, involves less recuperation time, less danger to the patient, higher success rates and reduces the risks of long term side effects than what you refer to as a total reboot.

As I mentioned earlier, cyclophosphamide and campath have been used in different ways with different levels of success/failure over the years and there are all kinds of abstracts/studies reflecting that.

Because the preponderance of abstracts/studies DO NOT reflect the results of simple lymphocyte elimination, almost the easiest thing to do is to read the wrong information and come to an incorrect conclusion.

Bob
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Postby bromley » Wed Aug 01, 2007 9:59 am

Bob,

Didn't want you twiddling your thumbs while I'm enjoying sunny Florida. Here is an interview with Dr Weiner which mentions rebooting and Revimmune.

Ian

http://www.accentia.net/media/revimmune_ms2.html


PS If you were near Naples in the next couple of weeks, I'd invite you for a drink at the bar of the luxury hotel I am staying at. Unfortuntely, there is a strict dress code and shiny shirts are barred. Perhaps when you've smartened yourself up we can meet up some time in the future.
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Postby viper498 » Wed Aug 01, 2007 12:24 pm

Ian,

Loriyas lives in Naples... If you are really there then that would be cool to meet her in real life.

Brock
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Postby bromley » Wed Aug 01, 2007 1:25 pm

Brock,

If you are really there then


Why doesn't anyone believe me?

I fly to Miami this Friday. Will spend a week in Port Charlotte and then a week at the Registry (now called the Naples Grand).

It's not my fault that the US postal service took the chocolate out of the package I sent you. Dom, Finn and Shayk have all been recipients of chocolates from London. I have met Muu for lunch twice and Jaded once - I even went to Raven's wedding in June. I do exist - I don't lie (sometimes slightly exaggerate).

I'll send you something else in the autumn (the fall).

Ian
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Postby Loriyas » Wed Aug 01, 2007 1:41 pm

I will be in town the week you will be in Naples, Ian. It would be great to get together for coffee. Email me if you want to do that. I'll be out of town starting tomorrow for the weekend then I'll be back on Monday. We're going to the Keys. If we can get together I can the report back to everyone that you were actually in Florida!

Lori
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Postby bromley » Wed Aug 01, 2007 2:02 pm

Lori,

I have PM'd you (don't want everyone knowing our business!).

Unlike the UK, North America is massive, so thankfully no chance of Lyon (or indeed Harry Z) driving down and gate crashing the party.

See you soon

Ian
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