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Status of Rituximab-ME/CFS Studies

sensing progress

Senior Member
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296
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Tucson, AZ
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MS Trust were reporting on trials involving Rituximab, but have said last year that they have been terminated in favour of a new drug similar to Rituximab but in development, named: ocrelizumab.

I am obviously interested in this development, not least to learn if this new drug will overcome the side effects present in Rituximab; and whether it will affect the Norwegian trial in any way. If anyone can find out, would they post it here or let me know?

I'll have a dig around too of course and might even drop the Norwegian's a line at some point.

MS Trust information: November 2011: http://www.mstrust.org.uk/research/drugsindevelopment/rituximab.jsp

Ocrelizumab: http://www.mstrust.org.uk/research/drugsindevelopment/ocrelizumab.jsp

Just to clarify. I am not saying the ME trial will go the way of the MS one i.e. be terminated. I am just interested to learn a bit more about a possible new drug that will do the same at Rituximab but potentially might have less dangerous side effects.

Original postings: http://www.mecfsforums.com/index.php/topic,11477.msg132387.html#msg132387

One word directly from Roche is that as the drug comes off patent in 2013 (Australia) they are not interested in trials for ME.
 
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51
One word directly from Roche is that as the drug comes off patent in 2013 (Australia) they are not interested in trials for ME. Maybe one of the generic companies will be more helpful!!!!
Am i cynical but do I really think that ocrelizumab has less side effects..than rituximab or is it just different enough for a new patent????
 
Messages
764
Location
Israel
More on the Open Medicne Instute and Rituximab

I'm a patient of Dr Kogelnik at the Open Medicine Institute. He gave me a brief summary of the hypothesis they are working on with Rituximab and did mention its one of the trials his collaborative group is pursuing. Here is how I understood it. One, some or all of the implicated herpes viruses, EBV, CMV and HHV-6 can enter and damage and cause B cells to become dis-regulated. B cells are key to creating antibodies specific to a particular antigen. When your B cells have been damaged by one of the viruses, they do not function correctly and may even produce harmful antibodies. Rituximab is used in cancer treatment to destroy B cells which have become cancerous. In CFS/ME, B cells that are damaged must be removed so the body can regenerate new fresh B cells. By combining antivirals and Rituximab, your current B cells are destroyed and the antivirals prevent the virus from reinfecting the new fresh B cells. The hypothesis is that by first killing off all your B cells with Rituximab and allowing your body to generate news ones while preventing re-infection of the new ones with anti-virals, one of the CFS mechanisms is halted.

The subset of patients where this would make sense would be those where your B cells are involved. I'm not yet sure how that is determined or if its based on which of the 3 virus is involved. My understanding is that each of the 3 Herpes viruses infect immune cells but I do not know if one is specific to B cells and therefore defines the subset. I have high HHV-6 titers but none for EBV or CMV. He mentioned after testing that I probably wasn't a Rituximab trial candidate. The next time we speak, I was planning on asking about the specifics. ...

Thanks for telling us. I am a member of the National CFIDS Foundation and I remember someone in it telling me that they think this illness might be starting in the bone marrow. B cells are made in the bone marrow aren't they?
 
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445
Location
Georgia
Rituximab is now an officially approved treatment for rheumatoid arthritis, vaculitis, Wegner's syndrome as well as lymphoma. It has much anecdotal evidence for being effective in treating Myasthenia Gravis, Lupus, MS and several other serious autoimmune illnesses. It is called "B cell ablation therapy" because it mostly wipes out the B cells in the human body. B cells produce inflammatory cytokines, such as IL-6 or TNF-a which seem to be highly implicated in the genesis of these illnesses. Under rituximab therapy, doctors have noted a commensurate decline in these inflammatory hormones as the B cells are gradually killed off. Usually the B cells have to be wiped out for a couple of years to achieve complete remission (as is the case with RA). The therapeutic pathway of rituximab is completely transparent and logical. The dynamic is indisputable.

Rituximab has now been prescribed to well over 100,000 recorded patients. There is a solid baseline for negative outcomes and side effects. The most lethal side effect is PML, a reactivation of a virus in the lining of the brain. The incidence in the use of Rituximab is approximately 1 death per 42,000 treatments. Biogen, creators of rituximab back in the late 90s, is now is pushing another monoclonal antibody Ocrelizumab for MS. Ocrelizumab has a PML incidence of 1:10,000, and it is less effective in controlling MS symptoms. The logical thing would be to continue testing rituximab in a host of autoimmune diseases, but Biogen has nothing to gain because it is off patent. The drug can be prescribed off label. It is cheapest when infused at a rheumatologist or oncologist's office, for somewhere between $6000 and $10000 per dose. The effectiveness of a dose seems to be between 6 and 8 months. Hospitals, as usual, charge astronomical amounts, usually between $15000 on up per dose.

The histories of long-term rituximab users have been tracked for a number of years. The drug was first marketed in the late 90s. Researchers have been surprised to find that none of the suspected consequences of wiping out B cells, for years at a time, have come to pass. No notable increased cancers, few new infections. Rituximab is safe and effective when taken long term. The body is not left defenseless when this component is removed. This has lead some researchers to conclude that the immune system is redundant and adaptive enough to make up for the loss of the B cells. Even after annihilation of B cells by rituximab, the body's defenses some how regroup and continue on successfully defending the body against cancer and infection.The total number of cases studied, in one article, was 124,000 patients. So the evidence supporting its relative safety is well established.
 

Snow Leopard

Hibernating
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10 years is nice, but not enough to conclude it is safe and effective long term...

What is the status of the Phase III trial in Norway - do they have full funding yet?
 

snowathlete

Senior Member
Messages
5,374
Location
UK
I'd rather a drug used for ten years than a brand new drug. Beggars can't be choosers and my ME makes me feel like a beggar.
my own research into EBV lead me to conclude that if it is the cause of ME then it is in the bone marrow.
I even posted asking if anyone with ME had ever had a bone marrow transplant, but didn't get much response. There have been claims that BMT has cured people of some pretty nastybdiseases including HIV. Haven't looked into how true that is mind you.
 

user9876

Senior Member
Messages
4,556
I'd rather a drug used for ten years than a brand new drug. Beggars can't be choosers and my ME makes me feel like a beggar.
my own research into EBV lead me to conclude that if it is the cause of ME then it is in the bone marrow.
I even posted asking if anyone with ME had ever had a bone marrow transplant, but didn't get much response. There have been claims that BMT has cured people of some pretty nastybdiseases including HIV. Haven't looked into how true that is mind you.
I know someone who was diagnosed with fibromyalga (but also ME type symptoms) who has recently had a bone marrow transplant and the pain has gone. Its too early to tell if fatigue has gone due to the immune suppressent drugs and graft vs host disease (where the new immune system attacks the host).

It is however a very dangerous process. The chemo to kill the old bone marrow can kill you but the worst thing is infections which can again kill you.

BMT cure auto immunne diseases (which is what Fluge and Mella speculate ME is) and hence it wouldn't conclude it is an infection in the bone marrow. I read one paper on RA which suggested a BMT was far too dangerous an option.
 

Kati

Patient in training
Messages
5,497
I'd rather a drug used for ten years than a brand new drug. Beggars can't be choosers and my ME makes me feel like a beggar.
my own research into EBV lead me to conclude that if it is the cause of ME then it is in the bone marrow.
I even posted asking if anyone with ME had ever had a bone marrow transplant, but didn't get much response. There have been claims that BMT has cured people of some pretty nastybdiseases including HIV. Haven't looked into how true that is mind you.

There is a paper out there for rheumatoid arthritis patients. They were subjected to bone marrow biopsy before Rituximab.tthose who had EBV in their bone marrow were more likely to be responders of Rituximab and the amt of EBV in their bone marrow decreased. I showed this paper to Dr K.

http://www.ncbi.nlm.nih.gov/pubmed/20547657


ETA Bone marrow translplant is a pretty nasty procedure, for an unrelated donor the mortality is pretty high, I would advance 1in 3. Infection and graft versus host (rejection) are involved. Then the morbidity post transplant can be quite bad as well.
 
Messages
445
Location
Georgia
Rituximab is one of the most exhaustively studied drugs out there. There are tens of thousands of patients showing it is safe and effective. Our bodies, as always, continue to amaze us; when the B cells are removed, the rest of the immune system picks up the slack. That is rock solid in the published data.

I can't understand why Klimas, Kognelnik are dinking around with the herpes-virus-in-the-B-cells line of research. There is absolutely no research showing herpes viruses in the B cells cause CFS. It is a wild guess by speculative researchers. As shown by RA, rituximab is safe and effective, even after years of infusions. Why not copy the Norwegians and put your money in two years of infusions, and see if long-term CFS sufferers actually improve. The first study only provided one infusion. With that, 1/3 of patients went into *complete remission*. How about a study giving PWCs infusions twice a year, which might actually return many PWCs to a normal life. The speculative thinking of some researchers continues to baffle me. Being the authors of paradigms must more important than actually helping people. As usual, the competent but humble Norwegians have it right. Just give the damn rituximab. Don't worry about being a scientific rock star.
 
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445
Location
Georgia
My father underwent a bone marrow transplant. I'll take whatever miniscule danger presented by long-term rituximab use over the agony of bone marrow transplant. Be aware, if CFS is truly an autoimmune, it means there is no "one-time cure". Because the human body is paradoxically reacting to stimuli which is probably tolerated by most healthy folks. The PWC will probably have to take the treatment for a life time, since there is no pathogen to be killed, as it is autoimmune. The B cells are simply over reacting for some unknown reason. There needs to be a study which infuses patients at the normal RA remission dosage; two years, four infusions. I'll bet the remission rate moves from 1/3 to a figure quite a bit higher. BTW this is not all rocket science. All one has to do is search in PubMed carefully to see the definitive results.
 

user9876

Senior Member
Messages
4,556
My father underwent a bone marrow transplant. I'll take whatever miniscule danger presented by long-term rituximab use over the agony of bone marrow transplant. Be aware, if CFS is truly an autoimmune, it means there is no "one-time cure". Because the human body is paradoxically reacting to stimuli which is probably tolerated by most healthy folks. The PWC will probably have to take the treatment for a life time, since there is no pathogen to be killed, as it is autoimmune. The B cells are simply over reacting for some unknown reason. There needs to be a study which infuses patients at the normal RA remission dosage; two years, four infusions. I'll bet the remission rate moves from 1/3 to a figure quite a bit higher. BTW this is not all rocket science. All one has to do is search in PubMed carefully to see the definitive results.

Reading one paper by Jonathan Edwards who started using Rituximab for RA it is not the B-cells that are necessarily over reacting but there could be a complex immune cycle between the B and T cells.

http://rheumatology.oxfordjournals.org/content/40/2/205.full


In the original hypothesis [12], disease perpetuation was ascribed to IgG RF‐committed B‐cell clones. It was argued that clones of this type should not return in the short term, following adequate depletion, unless continued IgG RF production provides sufficient stimulus to low‐affinity RF clones to affinity‐mature and/or class‐switch to replace the original clones. The relapse of the two subjects with persistently high IgM RF levels would fit with this, but the evidence is so far circumstantial. Moreover, IgM RF may be a poor surrogate for IgG RF. Existing IgG RF assays were considered to be unreliable for use on unfractionated serum.

The results are also consistent with the alternative possibility that RA is driven by autoreactive T lymphocytes, which depend on antigen presentation by B lymphocytes for maintaining their activation. This would imply a failure of T‐cell tolerance, which ceases to generate disease, either temporarily or in the long term, following interruption of T–B lymphocyte interaction. It would accommodate interactions with RF‐specific B lymphocytes, as presenters of complexed antigen, but with RF secretion being epiphenomenal.


I agree bone marrow transplants are horrible although I think they are becomming safer. Even then you could end up having Rituximab which they use if EBV starts to reoccur as it can cause post transplant lymphomas.
 
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445
Location
Georgia
Yes, that's correct, the B cells signal the T cells to over-react at particular sites. Technically, it is the T cells that are doing the damage at the site. For example, T cells over-react at the joint cartilage, after being stimulated by the B cells to do so.
 

sensing progress

Senior Member
Messages
296
Location
Tucson, AZ
Yes, that's correct, the B cells signal the T cells to over-react at particular sites. Technically, it is the T cells that are doing the damage at the site. For example, T cells over-react at the joint cartilage, after being stimulated by the B cells to do so.

Where did you learn so much about immunology MishMash? You seem pretty knowledgeable.
 

Hip

Senior Member
Messages
17,910
The interesting thing about bone marrow is that it is a major source of the microglia immune cells in the brain. Around half the microglia in the brain are made originally in the bone marrow (from hematopoietic stem cells), and then from the bone marrow they migrate to the brain via the bloodstream. If there were an intracellular infection in the bone marrow, then these bone marrow-derived microglia could act as Trojan horses, bringing infection into the brain.

Conditions such as ME/CFS and autism appear to have chronically activated microglia, perhaps indicating some infection is present. Bone marrow transplants have cured Rett syndrome (an autism-like syndrome) in mice.

Makes you wonder if anyone has examined the bone marrow of autistic kids, or ME/CFS patients, to see if their bone marrow cells might contain an intracellular infection (such as a non-cytopathic enterovirus infection, or say a Chlamydia pneumoniae infection). In which case, just wiping out this bone marrow infection may be as good as replacing the marrow, with less agony to go through compared to a bone marrow transplant.
 

alex3619

Senior Member
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13,810
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Logan, Queensland, Australia
If Rituximab works, and it appears it does, then it means the symptoms are B cell mediated. That does not mean B cells are the cause. It means they are a component in a pathway. Its not just about intereacting with T cells either - the entire immune system has complex talk between pieces, and also talks to the nervous system. Its a clue as to the pathology, but doesn't say for sure the cause is B cells.

My current best guess is a combination of Rituximab, antivirals (or antibiotics depending on patient copathogens), anti-inflammatories and anti-oxidants will be more successful, though the protocol for these has yet to be determined. Its also possible that repeated dosing will result in an increasing rate of full remission. Its also being used much more often than twice a year, up to six times from what I gather: this prevents relapse, iirc.

Bye, Alex
 

lansbergen

Senior Member
Messages
2,512
If Rituximab works, and it appears it does, then it means the symptoms are B cell mediated. That does not mean B cells are the cause. It means they are a component in a pathway. Its not just about intereacting with T cells either - the entire immune system has complex talk between pieces, and also talks to the nervous system. Its a clue as to the pathology, but doesn't say for sure the cause is B cells.

Did you see this. http://stke.sciencemag.org/cgi/content/abstract/genesdev;23/16/1971
Anciendaze found it
 

user9876

Senior Member
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4,556
In which case, just wiping out this bone marrow infection may be as good as replacing the marrow, with less agony to go through compared to a bone marrow transplant.

For leukemia patients the bone marrow is wiped out with the hope that the leukemia cells will be killed and a healthy bone marrow will grow back. It doesn't always work - sometimes the leukemia cells are too strong. It still has many of the dangers associated with a BMT. THe chemo can kill as well as the lack of an immune system.Where they think the leukemia has a good chance of comming back they do a bone marrow transplant after this first chemo.

A bone marrow transplant basically involves a further lot of chemo and maybe radiotherapy followed by an infusion of stem cells.
 

heapsreal

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I wonder how other immune stimulants/modulators like ampligen and immunovir etc but mainly ampligen, im thinking as many people improve on this and this increase nk cell and t cell function, but doesnt affect/kill b-cells, maybe it does something to stop new b-cells being infected, if its b cells being infected is the theory, or depleting b-cells somehow turns on the lazy t cells and nk cells to work properly??
The immune system is a complicated web?? Its really speculation how ritux works in cfs/me.
I think they need to really look at treatments like ritux and ampligen that have dramatically improved some people and work backwards, trying to figure out how they help cfs/me.