Project description of ME/CFS treatment with TNF-alpha inhibitor Etanercept (Enbrel®)

[Ninan]

And btw: The guy I know who tried Enbrel got an eye infection or something like it. It made him almost blind on one eye. If they have a lot of adverse reactions like that then maybe quitting makes sense. Anyway, he got his sight back when treated and stopping Enbrel and has had no major adverse reactions from Remicade. Instead he's slowly getting better and is now able to spend some time out of bed. He has RA too, that's why he gets to be treated, but the drugs are obviously doing something for his ME symptoms too.

 

[deleder2k]

Interesting! I'd love to a chat with Mella or Fluge, but I guess they are more than busy at the moment.

 

[LaPerla]

According to this site (The Norwegian ME-Association), it looks like the Enbrel-study has been stopped. http://me-foreningen.com/meforeningen/innhold/div/2014/01/Forskningsrådet-Sykdommer-vi-ikke-forstår-CFS-ME-og-klinisk-forskning-26-november-2013.pdf (page 9, link in norwegian).

On a presentation on the 26th of November 2013, Drs. Fluge and Mella informed that Enbrel-treatment was tried on four patients. Two of the patients did not respond to the treatment, while the other two got worse. Fluge and Mella therefore decided not to continue this study.

 

[Ninan]

According to this site (The Norwegian ME-Association), it looks like the Enbrel-study has been stopped. http://me-foreningen.com/meforeningen/innhold/div/2014/01/Forskningsrådet-Sykdommer-vi-ikke-forstår-CFS-ME-og-klinisk-forskning-26-november-2013.pdf (page 9, link in norwegian).

On a presentation on the 26th of November 2013, Drs. Fluge and Mella informed that Enbrel-treatment was tried on four patients. Two of the patients did not respond to the treatment, while the other two got worse. Fluge and Mella therefore decided not to continue this study.

Thanks!

 

[deleder2k]

Ah, thanks. I haven't read that. Looks like Enbrel is out of the picture then. I wonder if they think they can treat the 1/3 that didn't respond to rituximab.

 

[ukxmrv]

I did pretty well on Humira but I only had injections off on and for a few months. It's so long ago now I can't remember exactly how many or how long,

What I gained from the Humira was less sore throats, glands and pain. Especially less pain right in my bones.

My high TNF-a went down.

It's a pity to hear that other patients have done badly on a similar drug and also the reports here. We are all so different.

 

[deleder2k]

Yes. They thought it could be something to easy symptoms. Too bad!

 

[Jonathan Edwards]

I hope that someone could explain why TNF-alfa inhibitors, like Rituximab will work. Maybe @Jonathan Edwards knows?

As has been said by others, TNF inhibitors might be expected to reduce symptoms because one of the symptoms associated with TNF production is fatigue and malaise. So TNF might be involved in some types of ME. What makes this seem relatively unlikely, although the Norwegian team were right to investigate, is that TNF production usually shows itself in other ways. The CRP level is usually high, although different people have different CRP calibration so 40 for one person might equate to 8 for another. That means that a 'normal CRP' of 3 may be normal for the first person but high for the second, whose real normal level is 0.8. My understanding is that some people with ME do have modest rises in CRP so maybe TNF is relevant there, but for most it seems not to show up.

Another feature of TNF production is that it brings in white cells to the tissue where the TNF is produced and that usually shows up as swelling. In RA there is lots of TNF and joints swell up. In Lupus complement may be more important in the inflammatory process and there is often no swelling of the RA type. On the other hand it is quite possible that TNF production in certain tissues could produce symptoms without visible swelling. The obvious example would be TNF production by microglia in the brain at a level low enough not to affect blood brain barrier but enough to upset internal receptors that could signal fatigue/malaise. I am not yet convinced that this is likely to be a reality but I know that it is an idea under investigation. The only downside of low level TNF production in brain is that the TNF inhibitor biological drugs like enbrel and remicade may not get into brain much.

If I had been asked to predict whether TNF inhibitors would help in ME I think I would have guessed that they might help a small subset, maybe people with modest CRP rises, but not most people. My impression from talking to the Norwegians and what has been said here is that so far results have not been very encouraging - so maybe as expected. My suspicion is that if symptoms can be blocked with a cytokine inhibitor we may need to look at rather different cytokines. Interferons, IL-17a and IL-8 are on the radar maybe. What might be even better is if we can identify a 'relay switch' that turns on a whole bunch of malaise-making mediators and block it with a small molecule. The obvious analogy for that would be traditional steroids, which switch off dozens of proteins. However, steroids themselves are not good news in the long term and are probably not hitting quite the right range of molecules.

Years ago, while studying RA I had this little fantasy that I would become famous by discovering that parsnip juice contained just the right molecule to completely cure the disease. (No kidding.) I had no real expectation that I would ever find anything useful. Then suddenly I found myself with the prospect of discovering that something really did cure RA. In the event it didn't cure but it could produce complete remission for years and that wasn't bad. But I still hanker after that parsnip juice molecule, and so I think does Dr Fluge. It does not have to cure, but if you could abolish symptoms with a daily drink of something tasty, who cares. We really want small drinkable molecules. In realistic terms that might mean kinase inhibitors, which exist, but are tricky to get specific and free of side effects. So rituximab is the lead at the moment but just as it popped up in 1996 from nowhere maybe something else will pop up sometime soon.

 

[deleder2k]

Thank you so much for contributing! That was very interesting. I really hope that something would pop up. Hopefully it will. As said earlier here, the Norwegian Rituximab discovery could be much important than Rituximab treatment itself. Hopefully researchers can now base their projects on the the hypothesis that ME/CFS is an autoimmune disease - at least for a major subgroup.

One week ago I heard from a woman who faced a allergic reaction after being stung by a bees. She received Betamethasone, and experienced a relapse for 1-2 weeks before her ME/CFS symptoms came back. She e-mailed Dr. Olav Mella at Haukeland University Hospital. She received an answer back from him that he wasnt surprised at all. He told her that he many experienced the same effect with "those" kind of medicines. Due to side effects, long term use is ruled out.

Wikipedia: Betamethasone is a potent glucocorticoidsteroid with anti-inflammatory and immunosuppressive properties.

Could this be something that one could take once in a while? I guess we're talking about intra muscular injections.

 

[Jonathan Edwards]

Wikipedia: Betamethasone is a potent glucocorticoidsteroid with anti-inflammatory and immunosuppressive properties.

Could this be something that one could take once in a while? I guess we're talking about intra muscular injections.

There are conditions for which occasional jabs of steroid are very helpful - RA is one - or used to be before we had better medicines. But even one off doses can produce mood swings that can be unpleasant. I suspect it has been tried many times for people with ME and presumably clinicians have not been impressed by results.

 

[liquid sky]

Years ago, while studying RA I had this little fantasy that I would become famous by discovering that parsnip juice contained just the right molecule to completely cure the disease. (No kidding.) I had no real expectation that I would ever find anything useful. Then suddenly I found myself with the prospect of discovering that something really did cure RA. In the event it didn't cure but it could produce complete remission for years and that wasn't bad. But I still hanker after that parsnip juice molecule, and so I think does Dr Fluge. It does not have to cure, but if you could abolish symptoms with a daily drink of something tasty, who cares. We really want small drinkable molecules. In realistic terms that might mean kinase inhibitors, which exist, but are tricky to get specific and free of side effects. So rituximab is the lead at the moment but just as it popped up in 1996 from nowhere maybe something else will pop up sometime soon.

What exactly does this mean? Are you talking about something that really helps RA or just a dream that you had?

If ME is an autoimmune disease, the drugs that help PwME will be very individualized. It is that way with all autoimmune diseases. One TNF Alpha inhibiter will help one person and do nothing (or make worse) another person. That is the nature of the autoimmune beast. There is no one answer for all and no answers for some.

I really do hope that ME is not just an autoimmune disease, but rather an infectious disease with autoimmune aspects.

 

[rosie26]

I was wondering if Prof was giving us a secret something to us about parsnips maybe I will definitely continue putting parsnip in my beef and vegetable soup from now on. Enjoy your posts @Jonathan Edwards - thanks for being here with us and a part of our ME community - it's encouraging having you here.

 

[Jonathan Edwards]

My apologies, liquid sky, I had assumed that everyone would realise I was talking about rituximab, since that's why I ended up this list - because Dr Fluge suggested I was invited to an IiME meeting. Rituximab helps the large majority of people with RA and also with a wide variety of other autoimmune diseases. TNF blockade also helps a majority of people with RA. Individualisation tends to have a lot more to do with the occurrence of side effects or drug resistance due to anti-drug antibodies, or contraindications because of other problems. There isn't much difference between TNF inhibitors in terms of initial response for a given patient. I do agree, however, that things are likely to be much more individualised for ME since I suspect it is at least six diseases, some of which may be autoimmune but others of which will not.

I am a bit surprised to hear someone wish that ME was an infectious disease since our attempts to cure persistent infections, particularly viruses, are often ineffective, and for fairly obvious reasons. Rituximab does regularly cure certain types of autoimmune disease. Perhaps the best example is immune thrombocytopenia, which last time I heard was producing long term remission without continued therapy in about a third of patients. And even in RA there are now drugs to maintain patients symptom free for a very good proportion. I personally doubt that there are any infectious diseases with autoimmune aspects - its either one or the other in most cases. The old idea of molecular mimicry never held up except in Guillain Barre syndrome.

 

[Jonathan Edwards]

Parsnips are tasty but I suspect that's about it. Maybe rhubarb juice... Or one of those fruit they have in South America we never hear of like Guanabana - now that's tasty.

 

[deleder2k]

It looks delicious! I remember hearing about a juice with a lot of electrolytes which supposedly would be beneficial. Lets drink a lot of Parsnip juice, @rosie26!

Rituximab is very expensive. The patent expired in 2013 (in Europe), but could we really see prices plummet with biosimilars? I guess that making a biosimilar drug like Rituximab is not the same as copying Aspirin. Are they exactly the same? Biocad received approval in Russia for their "AcellBia" biosimilar of Rituximab in May. If approved in Western Europe, could this be used against whatever Mabthera Rituximab is used against now? Or do we need new trials?

 

[rosie26]

Parsnips are tasty but I suspect that's about it. Maybe rhubarb juice... Or one of those fruit they have in South America we never hear of like Guanabana - now that's tasty.

Prof. There has to be the right molecule in something somewhere.... I often use to wonder about bark... on trees.

South America sounds an interesting continent to visit. I notice people coming back from holidaying there - they have loads of stories to tell.

 

[rosie26]

@deleder2k parsnip juice would be a very strong tonic Thanks for all the Norway Rituximab updates. It's great.

 

[Ninan]

I had rhubarb pie yesterday and while it tasted wonderfully I didn't get better. Isn't the general theory something like "the less tasty (more disgusting), the better for you"? In that case I would suggest trying cow tounge or snails for ME.

But seriously, "at least six different diseases"? That's interesting, @Jonathan Edwards Seems like you've done some thinking there? I wish someone would start some real categorization here. The ones I've heard of don't seem to take into account all of the most common differences between PWME:s, only some of them. And there are, as we all know, quite a few (English is not my first language so please excuse any strange formulations):

Onset: Infectious / non infectious
Infections: Impaired immune system (catches every cold there is) / Over active immune system (never gets a virus)
Course of illness: Relapsing form / non-relapsing form / gets worse over time / constant over time
Symptoms: Gut, sensory sensitivity, pain, orthostatic problems -- Don't have it / smaller issue / huge issue

Etc etc.

Another perspective I miss is the "crash course" perspective. I think most of us who have had ME for a number of years know that the symptoms don't just pop up independently from one another. They follow a certain track and one thing seems to lead to another. For example, when I'm about to crash, I can feel the blood disappearing from my head. I get dizzy and parts of my head feels kind of cold. (I guess you could think this is something I imagine, I've asked myself that many times. But I'm pretty sure I don't.)

If I can stop that from happening (My little arsenal consists of support stockings, water and salt, licorice root, vein contracting medications, lying down with my feet up etc.) I can usually stop the crash altogether or at least shorten it a lot. Before I started doing this the crasches were bad and lasted for weeks or more (I don't have the relapsing kind; how I feel depends on what I do). Now I'm usually able to stop them simply by raising my blood pressure (which I guess is what I do with the methods mentioned). It helps so much more than just resting. The sensory sensitivity, the worsened fatigue etc all come after that first thing. And if I fix it they don't show up at all. Does that mean that, at least in me, the lower blood flow to the brain caused by overexertion is the intermediate variable (or whatever is the correct term in English) causing the other symptoms?

I believe there are many of us who have discovered these patterns and use them to treat ourselves. And I think they may hold some clues as to what is happening.

 

[DanME]

@deleder2k my brother works for a big pharm. company and explained to me, why the prices will drop for biosimilars, but the drop in prices won't be as huge as in other generics.

Usually, if a patent for a drug falls, ten to twenty other companies will flood the market with a generic version on the exact expiring date and the price will drop immediately. This happened e.g. with Viagra (in Europe) in 2013 and the price went down from 500€ per package to 50€ in only one day. The companies get approval for their generic drug, if they validate the use of the same chemicals and a similar composition of the pill (or infusion).

Biosimilars are a different story. First, it is not easy to "synthesise" antibodies.
You need to inject a mouse with an antigen, harvest certain b-cells, which reacted to it, fusion them with other cells and modify the antibody to look more human. It is a complex and expensive process and a biosimilar is never exactly like the original drug (nature is a bit random). This is why, a company, which copies an antibody, has to do a new trial in order to show, if the copied antibody works. If they show, it works e.g. in RA, they get approval for all the other diseases and uses as well.

Only a handful of companies (usually the big ones) are capable of copying Retuximab. The difficult production process, less competition and the costs of new trials to get approval are the reason, why the price won't fall like in other generics.

We can maybe expect a 25-50% reduction in prices.

(Interestingly, I ve just read, that Roche got approval for a new antibody, called Obinutuzumab, which works pretty much like Rituximab, but has a much longer half life (up to 12 month) and is more effective in killing B-cells. Maybe good news for us

 

[MeSci]

There are supplements that reduce TNF-alpha (activity) and other pro-inflammatory cytokines, as discussed in the abstracts and other snippets I have posted here. I just look at two, but there are others.