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

[Waverunner]

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?

DanielBR already gave a good answer. I don't know about a biosimilar for Rituximab but I do know about biosimilars for trastuzumab and infliximab. The latter may be of more interest to us. An infliximab biosimilar just got approved. The name is Remsima (by Celltrion). In 2012 I read an article about it being 70% cheaper than the original but according to latest news, it only is 30% cheaper. But we might see higher price drops during the next years.

 

[Jonathan Edwards]

I don't know that much about the realities of biosimilar production and pricing but it sounds from what I have heard that the main issue is just quality control to avoid but reactions. The sequence of the DNA needed for the rituximab molecule is known and the cell culture system is standard so I doubt that there is much that needs to be done other than follow a recipe. What may be more difficult is following a recipe under the stringent conditions needed for this sort of process. My understanding is that because of quality control concerns rituximab biosimilars would have to go through toxicity trials at least. I am sure that they will come through and I suspect they will be 30-50% cheaper. What is harder to predict is the policy of healthcare systems. There will be a fight over the new Roche antibody in terms of whether its advantages over rituximab will justify usage if the price is higher. I am not sure how much advantage one can expect in RA but in conditions that can go in to long term remission, which might include some ME if the data from Norway hold up, the new drug might increase long term benefit rate considerably. The catch 22 is that the drug company will not want to advertise that since they want drugs to go on being used, not stopped.

 

[deleder2k]

Thank you again, @Jonathan Edwards. According to Fluge, the cost of Rituximab won't be an issue for CFS/ME use, at least not in Norway. I guess he is correct. The cost of having sick people on benefit programs are enormous. If we also include all the pain and suffering, I can't see why Rituximab would be too expensive given the results stay the approximately the same.

@DanielBR, I have also read about that. Obinutuzumab has performed better than Rituximab in trials for Chronic Lymphocytic Leukemia. Median Progression-Free Survival was 26.7 months with Obinutuzumab and 16.3 with Rituximab (+Chlorambucil) presented in New England Journal of Medicine, January 8, 2014.

Pre-clinical studies suggest that obinutuzumab is a more potent anti-CD20 mAb than Rituximab at inducing antibody-dependent cellular cytotoxicity (ADCC) and direct cell death (DCD). I don't know if that matters for ME/CFS sufferers or not. I don't know if does matter if one uses 2 or 4 weeks to kill the B-cells or not.

Dah.. I understand nothing of this. Maybe I should sign up for med. school. Hopefully the Parsnip juice will get me through 6 years of studies.

 

[DanME]

I haven't read into the topic of Obinutuzumab (who invents these names??), but I certainly will. I ve just read that the potency was improved by glycolisation (adding some sugar molecules). But I don't know, why this works.

ADCC = Rituximab doesn't kill B Cells directly. The artificial Antibody tags them as "To be killed by the immune system". Then other immune cells (mostly our old friends the NK cells) come and destroy them. We use a natural process in our advantage.

My best guess is, the added sugars make the antibody a better and more visible tag. So B Cells are killed faster, for a longer time and cells, which hide away (eg inside the Bones) can be killed as well. But I only speculate.

To the topic of prices. Huge prices for special drugs are very common. Most drugs for autoimmune diseases, all kinds of cancer, HIV and a lot of others cost a fortune and our socialised health insurances (at least in richer countries) have no problem to compensate the costs. A total of 15.000€ for a good ME treatment won't be a problem at all. Especially if you get the people back to work and off the benefits. Some cancer treatments with only limited success cost more than 200.000€.

 

[lansbergen]

ADCC = Rituximab doesn't kill B Cells directly. The artificial Antibody tags them as "To be killed by the immune system". Then other immune cells (mostly our old friends the NK cells) come and destroy them. We use a natural process in our advantage.

When the other immune cells don't work well you have a problem.

 

[DanME]

When the other immune cells don't work well you have a problem.

Not necessarily. Once tagged, the immune system as dozens of ways to kill the cell. Not only NK cells.

 

[lansbergen]

Not necessarily. Once tagged, the immune system as dozens of ways to kill the cell. Not only NK cells.

I did not mean only NK cells.

 

[liquid sky]

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.

I agree that Rituximab can be an amazing drug for some diseases. I have taken it and it did help my ME, but it also damaged my lungs. As far as TNF inhibitors are concerned, I have seen some patients do very well with one and not respond to another(not related to side effects or antibodies, just no response). Just my experience. I see autoimmune diseases as a deep, dark well where some get better, but others are maimed for life with little help from the expensive drugs. Once again based on personal experience.

Correct me if I am wrong, but does not HIV and HTLV both have autoimmune aspects to their disease processes? I think because my disease started with a viral process, I feel this cannot be ignored. There are viruses that we know take up residence in the human body for life in some/most people. Borrelia Burgdorferi, various herpes viruses, polio viruses, etc. Most likely, a lot of others do the same, but we are unable to detect them or unaware of them.

Modern medicine is amazing when it comes to surgical interventions, curing some acute bacterial infections, etc. There needs to be a paradigm shift, as anciendaze says, when it comes to long term infectious processes; the long, slow, burning infection that is able to hide from our standard tests today. That is where I see hope for ME and many other now incurable diseases. I never knew that people could feel like they were deathly ill for decades, but I do now.

 

[Waverunner]

To the topic of prices. Huge prices for special drugs are very common. Most drugs for autoimmune diseases, all kinds of cancer, HIV and a lot of others cost a fortune and our socialised health insurances (at least in richer countries) have no problem to compensate the costs. A total of 15.000€ for a good ME treatment won't be a problem at all. Especially if you get the people back to work and off the benefits. Some cancer treatments with only limited success cost more than 200.000€.

The problem I see is that many PWCs are focusing on the point of time, where CFS will be recognized as a severe chronic disease. This point of time has not been reached, yet. I'm always optimistic but what makes you think, that this will change anytime soon? There is no socialized healthcare system in the world, which pays for CFS and Rituximab. On the contrary, some private insurances do. To sum things up, Rituximab and many other monoclonal antibodies are readily available but no socialized healthcare covers and allows using them for CFS.

Looking at the price of these drugs is a very reasonable thing to do (at least as PWC) because I highly doubt, that government will pay for them anytime soon. Even if Norway delivers the wanted results, how will the German or UK healthcare system pay for Rituximab, when they don't even recognize CFS as a real disease, which requires treatment besides behavioral therapy? I hope, that the possible results of Norway produce enough evidence and lay the ground for the first, well accepted, immune system based treatment approach towards CFS. Otherwise I don't see any change for PWCs in the near future.

 

[DanME]

The problem I see is that many PWCs are focusing on the point of time, where CFS will be recognized as a severe chronic disease. This point of time has not been reached, yet. I'm always optimistic but what makes you think, that this will change anytime soon? There is no socialized healthcare system in the world, which pays for CFS and Rituximab. On the contrary, some private insurances do. To sum things up, Rituximab and many other monoclonal antibodies are readily available but no socialized healthcare covers and allows using them for CFS.

Looking at the price of these drugs is a very reasonable thing to do (at least as PWC) because I highly doubt, that government will pay for them anytime soon. Even if Norway delivers the wanted results, how will the German or UK healthcare system pay for Rituximab, when they don't even recognize CFS as a real disease, which requires treatment besides behavioral therapy? I hope, that the possible results of Norway produce enough evidence and lay the ground for the first, well accepted, immune system based treatment approach towards CFS. Otherwise I don't see any change for PWCs in the near future.

This is a very good point and I agree with you. First of all, CFS must be recognised as a serious disease. Otherwise we won't get the necessary treatment at all. But I see a great momentum in research the last couple of years. A long time the work was done by ambitious doctors, who tried to help the patients, but hadn't the resources to do proper research and big studies. But now a lot of university hospitals around the world got involved (Bergen, Berlin, Stanford, Miami, Sydney, Newcastle, Columbia, London etc.). That is why I am optimistic and hopeful. The moment somebody finds an underlying pathology, which holds up, the research will skyrocket and no health insurance can't deny treatment anymore. We are now on the radar of some very good scientist.

The way I see it, CFS or ME are no mystery diseases. With enough research and effort the scientist will eventually find out, what's wrong with us. Don't get me wrong, what happened to all of us is a catastrophe. We are decades behind on research and treatment possibilities and the neglect of our disease is one of the big failures of modern medicine. But once the science really gains momentum, we won't need another 30 years. Things will develop very fast. The scientific capabilities made a quantum-leap. Just ten years ago, we needed millions of dollars and a couple of years to analyse a full human genome. Now we need just one day and a thousand dollar.

 

[Waverunner]

The way I see it, CFS or ME are no mystery diseases. With enough research and effort the scientist will eventually find out, what's wrong with us. Don't get me wrong, what happened to all of us is a catastrophe. We are decades behind on research and treatment possibilities and the neglect of our disease is one of the big failures of modern medicine. But once the science really gains momentum, we won't need another 30 years. Things will develop very fast. The scientific capabilities made a quantum-leap. Just ten years ago, we needed millions of dollars and a couple of years to analyse a full human genome. Now we need just one day and a thousand dollar.

I fully agree with you. Technology is improving tremendously, it's time we put it to use. Just yesterday I saw a webinar about the CRISPR/Cas9 gene editing system. That's just unbelievable. We might or in fact we are able to edit genes accurately and at low cost. Finding the mutated genes might let us cure diseases on the genetic level. Add the other -omes and we could reach a whole new level in medicine. I'm still scared however, because time is running out for some PWCs and the medical field has not been very eager to adapt new technologies in the past. For example, the microbiome seems to play a very important role for many diseases, especially IBD but also diabetes and heart disease. Still you won't find any mainstream doctor, who will use cheap 16S rRNA sequencing to test his patients. The technology is great, but doctors don't use it. In addition to this we lack new probiotics. I have no idea, why this is the case but I hope CFS can access available drugs soon.

 

[Bob]

In addition to this we lack new probiotics.

There are a number of interesting research projects, developing what they call "synthetic stools", whereby they have isolated quite a number of bacteria from healthy people's guts, and have grown the bacteria in a lab, and are now testing the product on C-Difficile patients, in the form of an oral capsule. (This is intended to replace the need for fecal transplants.)
(The synthetic stools are in white powder form, rather than brown-goo form, so that's an improvement on presentation!)
They have had some success treating C-difficile patients.

From what I've read, I expect some of these synthetic stools to be approved by the FDA sometime soon (months, or perhaps a bit longer?)
I can't remember all the details, and I haven't saved all the links where I've read about it.
But I can find the name of one of the products, if anyone is interested.

If these synthetic stools are approved for treating C-difficile, then I reckon they'll soon be tested on IBS patients and various other autoimmune patients, including ME patients with gut problems.

 

[Waverunner]

From what I've read, I expect some of these synthetic stools to be approved by the FDA sometime soon (months, or perhaps a bit longer?)
I can't remember all the details, and I haven't saved all the links where I've read about it.
But I can find the name of one of the products, if anyone is interested.

That's excellent news. Thanks, Bob. I'm sorry for putting us completely OT. I'll open another thread (http://forums.phoenixrising.me/inde...ion-of-clostridium-difficile-infection.31851/). I would be very interested to know the name, please feel free to answer.

 

[ukxmrv]

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.

I belonged to Infertility groups who were also looking at supplements to reduce TNF-a. These were groups looking at the immunological aspects to miscarriage etc. Some of these patients had access to repeat TNF-a tests and the supplements weren't having much of an effect on their TNF-a blood tests sadly.

 

[MeSci]

I belonged to Infertility groups who were also looking at supplements to reduce TNF-a. These were groups looking at the immunological aspects to miscarriage etc. Some of these patients had access to repeat TNF-a tests and the supplements weren't having much of an effect on their TNF-a blood tests sadly.

Do you know which supplements they used?

 

[ukxmrv]

Do you know which supplements they used?

Everything that was mentioned on the internet, from alternative practitioners or their private doctors. It was like the ME groups in that people hunted for clues everywhere and then shared the information like you did and then they tried them and compared notes. All the stuff that you mentioned on that link of yours.

It was a huge ongoing topic for years and is still ongoing. I only dip in every now and then. Hundreds of members on those groups. Imagine the ME groups but with more money, health and time. Those who could afford it stopped trying the supplements and went for the Humira/Enbrel. There was a black-market and a drugs exchange, even in the UK. Patients sold drugs that they could not tolerate or exchanged them for others.

 

[MeSci]

Just did an internet search for 'tnf supplements' and found this paper about natural TNF inhibitors, which looks interesting.

Figure 1 lists a number of supplements that are claimed to be effective.

I've been careful to cite scientific studies rather than 'health sites' which are of variable reliability.

I don't know why results were negative in the groups cited by @ukxmrv. Not disputing it of course.

 

[Sherlock]

http://clinicaltrials.gov/ct2/show/NCT01730495?term=Etanercept cfs&rank=1
This study has been terminated.
(After inclusion of four patients, two experienced moderate worsening of symptoms)

 

[Sherlock]

I don't know why results were negative in the groups cited by @ukxmrv.

Maybe TNF production in that patient group is so ramped up that the relatively weak effect of plant compounds has no effect.

 

[Thomas]

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.

Just a random layman question from the above post: My illness most likely started as a result of a flu vaccine I received. Of course GBS is an accepted possible complication of this vaccine (and the flu itself I believe). One of my doctors, Dr. Byron Hyde has long casually hypothesized that acute onset ME, perhaps especially those as a result of flu vaccine reactions, could be either a very low grade GBS. Or some other type of autoimmune reaction that affects the CNS rather than mostly the peripheral nervous system.

If any of this sounds at all possible, do you think that this type of ME would be more amenable to treatment or more resistant to it? How would molecular mimicry add to this? By treatments, I am referring to Rituximab, Enbrel, maybe even Ampligen.

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.

I have a second question if you don't mind: My local GP who knows nothing of ME but is very sympathetic mentioned he could me Enbrel under my very mild psoriasis issues (in order for insurance to cover it). I was hesitant because I'm afraid of getting any worse from this med. But when I first got sick 4 years ago and up until 2 years ago my CRP was so low it was almost undetectable. But since then, I had once instance where it was above normal but then fell back to normal but still slightly higher than before. Also, my ESR began at 1 at the beginning of my illness and as of March 2014 at my last physical, it was at 14 (reference range 0-15). Do you think this information merits a trial of Enbrel?