New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

[alex3619]

There are indeed other biosimilar drugs. They call them biosimilar due to the same action, but its really a different drug in chemical terms, though with similar manufacture and development processes. Manufactured antibodies are typically grown, bioengineered and so on. They can however modify them in simple ways, including chemical tags and so on. However my knowledge of this is way way out of date, and it would not surprise me if this story changes at some point ... advances happen faster and faster in many ways.

 

[catly]

Just because a specific medicine works for one patient but not the other doesn't mean that they suffer from different diseases.
Take for example Rituxumab for RA only works for 70% of RA patients. As a matter of fact it is not unusual for an RA patient to try 4 or 5 RA meds until they find one that works.

Exactly, RA is a great example but so are treatments for cancer, hypertension, diabetes etc. It's the general rule, I think , for most diseases- hence the new buzz word sweeping the medical field is "personalized medicine".

 

[Bob]

I know this is slightly if topic, but I've just been wondering... Does anyone happen to know if rituximab has been used to treat IBS/IBD or OI or fibro or autoimmune thyroid disease? (These are all fairly common potential autoimmune complications or comorbidities of ME, so it would be interesting to know if they responded to rituximab in their own right.)

 

[Sasha]

I know this is slightly if topic, but I've just been wondering... Does anyone happen to know if rituximab has been used to treat IBS/IBD or OI or fibro or autoimmune thyroid disease? (These are all fairly common potential autoimmune complications or comorbidities of ME, so it would be interesting to know if they responded to rituximab in their own right.)

Dunno but I read (New Scientist?) something somewhere from one of F&M's patients about how they could now 'be upright' after rtx, and wondered if that was a reference to OI symptoms. I think I read somewhere that all the ME symptoms clear up, not just fatigue.

 

[leokitten]

Hi @leokitten Rituximab knocks out all b-cells, actually, but perhaps it could be that another group of cells need to be knocked out as well, so I partially agree with you.

If we have a pathogen, it maybe that on top of affecting the B-cells, the pathogen also lives somewhere else, say, bone marrow, or brain.

It certainly sucks to be a non-responder

I think when they investigate more closely the make up of B-cell subsets in non-responders they are going to find something, that these patients do have the same disease but their B-cell differences causes Rituximab to not work as well.

In the present study, B-lymphocyte counts in peripheral blood were recovered in all patients after end of follow-up, and possible mechanisms for sustained clinical responses are not obvious. Pilot immunophenotyping analyses of B-cell subsets (naïve versus memory versus transitional versus plasmablasts) after B-cell regeneration (i.e. at 36-40-44 months follow-up) are in progress, aiming to investigate possible differences between sustained responders, patients with partial or complete relapse, and non-responders.

The relationships between rituximab treatment, B-cell depletion, B-cell subsets and clinical responses have been studied in rheumatoid arthritis (RA) [16]. An increased fraction of memory cells was detected in those with early relapses [17]. In B-cell depletion naïve RA-patients, low levels of CD27+ memory B-cells may predict later response to rituximab treatment [18]. Rituximab targets short-lived autoreactive plasma cells more consistently than the more long-lived protective plasma cells [19,20]. In systemic lupus (SLE), B-cell clones producing autoantibodies had a more rapid turnover than B-cells producing protective antibodies [21], making autoreactive B-cells more vulnerable to rituximab treatment.

 

[msf]

Dr Shepherd, do you mean that for a drug to be approved for use on the NHS additional testing is required? So for instance, if Eravacycline passes its phase 3 trial and is approved by the FDA, will the NHS require additional trials to be done before it allows patients to be treated with this antibiotic on the NHS? Or is this only for very expensive drugs?

 

[snowathlete]

I know this is slightly if topic, but I've just been wondering... Does anyone happen to know if rituximab has been used to treat IBS/IBD or OI or fibro or autoimmune thyroid disease? (These are all fairly common potential autoimmune complications or comorbidities of ME, so it would be interesting to know if they responded to rituximab in their own right.)

There have been trials of rituximab in IBD, certainly I am aware of some studies in ulcerative colitis that have been reported and I think there is an ongoing study in the UK on it too. However, I think I read one paper that said it had no significant impact. I don't expect it to work for most with UC. Though, just as with ME/CFS and many other diseases, there are different patient groups with UC and it could conceivably help some while not helping others.

 

[Sidereal]

I think it would be interesting if a smaller trial involving broader CFS definitions was done after the larger trials with stricter definitions.

It would be a shame to take the claim that these people have "mental disorders" for granted rather than actually checking if it's a disease that responds to B cell depletion.

I don't know what a mental disorder is. Until someone produces extraordinary evidence to the contrary I think we can safely assume that all psychiatric phenomena have their basis in the physical world i.e. the body.

I totally agree with you that it would be interesting to see how many broadly defined CFS patients respond to this treatment but first I think we need to study cohorts of strictly defined ME patients so that we can first show whether this drug reliably works in, say, cohorts of CCC/ICC ME patients in different countries, which would put this disease on the map, give it some credibility/legitimacy and provide some of us with a viable treatment.

For political reasons I think it would be a huge mistake to first study a more broadly defined tiredness cohort since this could very well produce a null result which would then be reported worldwide as "Immune modulator rituximab does not work for chronic fatigue: it's psychosomatic after all".

 

[alex3619]

Several issues to think about with respect to responders and nonresponders:

FIrst, differences may be found in patients if they have different antibodies to related parts of the same affected tissues. This should not make any difference with Rituximab though.

Second, while some might have antibody attacks on these same parts (receptors, ion channels, mediating hormones etc.) the fault might be different in different groups. Some might have genetic or other biochemical factors involved (toxins, intolerances, defective genes) while others have antibody assaults. Only the antibody subgroup will be effectively treated by Rituximab. Those with just an antibody assault should respond completely. Those with a genetic problem will not respond. Those with both will have delayed or limited response.

In this scenario it is important to realize the TARGETS are the same, it is what is DAMAGING them that differs.

There may also be genuinely different diseases with similar symptoms.

So far we do not have good data to differentiate these options, with the caveat that Rituximab knocks out all (most?) antibodies over time, especially with repeat doses, due to removing cells that lead to antibody production. So its also possible that different subgroups have different targets, with different antibodies, but there is still likely to be a non-antibody mediated subgroup.

Secondary interactions between B cells and the rest of the immune system in ME and CFS also need investigating.

In short, until the science is completed and gives us some answers we are still in the dark. Its just that instead of being on the moors at night in a thunderstorm and heavy cloud and no torch, we are finally in our house and searching for that spare flashlight in one of the rooms, although we cannot recall which room it is in, or what part of the room. We are getting closer.

 

[JamBob]

I know this is slightly if topic, but I've just been wondering... Does anyone happen to know if rituximab has been used to treat IBS/IBD or OI or fibro or autoimmune thyroid disease? (These are all fairly common potential autoimmune complications or comorbidities of ME, so it would be interesting to know if they responded to rituximab in their own right.)

I know that there was a very small trial of Rituximab in newly diagnosed Addison's disease (autoimmune adrenal insufficiency) patients and they managed to reverse the disease in one of the patients.

http://www.ncbi.nlm.nih.gov/pubmed/22767640

 

[alex3619]

I don't know what a mental disorder is. Until someone produces extraordinary evidence to the contrary I think we can safely assume that all psychiatric phenomena have their basis in the physical world i.e. the body.

Actually, playing Devils Advocate, I argue that is not entirely the case, just mostly the case, with the caveat that I think thought is an outcome, function or process of brain.

The exception is false belief systems, such as found in extreme cult brainwashing as an example. Yet I hesitate to medicalize this as it has no clear boundaries, and risks everyone being described as having a mental disorder, if for no other reason than if you re not omniscient you will have beliefs about things that are false. Such belief systems would not be a problem with brain function, but with the information encoded in the brain. The brain is fine, the info is fubar.

We also cannot entirely separate the effect of thought or perception about events on brain function. Yet I would argue that this either results in A/ false belief systems or B/ brain changes, and that false belief systems are unlikely to affect brain function to any significant extent. The problem with psychogenic theories is they are A/hypothetical, B/ unproven and C/ argue the equivalent that if an explanation explains the first inch it must explain the whole mile. Its this quasi-philosophical and hypothetical view of thought and function where psychobabble dwells.

Its not that psychobabble (specifically psychogenic disease) has zero hypothetical value, its that its still fully hypothetical and lacks any substantive evidence, with hypotheses that are borderline magic ... and not on the rational side of that border either.

 

[mango]

someone just asked me how fluge & mella define "in remission". i can't find it in the paper, i'm not sure what i should be looking for... can someone please point me in the right direction?

@Jonathan Edwards, could you help please?

 

[charles shepherd]

Dr Shepherd, do you mean that for a drug to be approved for use on the NHS additional testing is required? So for instance, if Eravacycline passes its phase 3 trial and is approved by the FDA, will the NHS require additional trials to be done before it allows patients to be treated with this antibiotic on the NHS? Or is this only for very expensive drugs?

For a drug such as this to be made generally available on the NHS for use in a specific condition like ME/CFS there would have to be sound consistent evidence from what are called phase 3 clinical trials that it is likely to be a safe and effective form of treatment for at least an identifiable subset of people with ME/CFS.

A drug such as this would not be automatically granted a product license simply because it had been approved by an overseas regulatory body - but this would certainly help in the case of a body such as the FDA.

 

[charles shepherd]

There have been trials of rituximab in IBD, certainly I am aware of some studies in ulcerative colitis that have been reported and I think there is an ongoing study in the UK on it too. However, I think I read one paper that said it had no significant impact. I don't expect it to work for most with UC. Though, just as with ME/CFS and many other diseases, there are different patient groups with UC and it could conceivably help some while not helping others.

What is probably more interesting is the UK trial which is looking at the use of Rituximab in primary biliary cirrhosis - a condition which has an interesting overlap with ME/CFS, in particular the debilitating fatigue that occurs in PBC. This trial is being carried out by the same group in Newcastle that are involved in research into autonomic nervous system dysfunction and mitochondrial dysfunction in ME/CFS.

Newcastle trial:

http://www.nhs.uk/Conditions/Primar...ion=Primary biliary cirrhosis&pn=1&Rec=0&CT=0

 

[Snow Leopard]

For a drug such as this to be made generally available on the NHS for use in a specific condition like ME/CFS there would have to be sound consistent evidence from what are called phase 3 clinical trials that it is likely to be a safe and effective form of treatment for at least an identifiable subset of people with ME/CFS.

What do you mean by "identifiable subset"?

 

[charles shepherd]

What do you mean by "identifiable subset"?

People with ME/CFS who have a clinical and/or immunological signature who are more likely to respond to a particular form of treatment.

As we learn more about the use of this drug, it may turn out that there are clinical characteristics - such as length of illness, type of onset - viral/non viral, degree of severity etc - that are linked to response rates

At there same time there may be immunological markers involving various parts of the immune system orchestra - cytokines, B cells etc - that help to predict response, or a non response

 

[anniekim]

Glad to see the MEA thinking strategically, Charles - I'd like to see all our charities and ME rituximab experts getting together and coming up with a strategy and some advocacy goals to get this happening, whether it's a move towards rituximab or cyclophosphamide.

I'd love to know what patients should be doing in terms of advocacy around this, in the UK.

It's a huge opportunity both for advocacy off the back of the findings (of the 'look, it's a real disease!' and 'donate, a cure is achievable!' variety), and for advocacy towards getting us rituximab or similar-acting treatments faster.

Itching to DO something!

Meanwhile, I hope people are exploiting the opportunity by hijacking the media.

"Large scale phase 3 trials are very costly to set up and in the case of Rituximab, where evidence on longer term maintainance treatment would also be required, this means that from start to finish and publication of results you may well be looking at three years.

So I think we need to be persuading someone who could afford to fund a decent phase 3 clinical trial to do so here in the UK....sooner rather than later and certainly before late 2017/early 2018 when we will hopefully have the results of the phase 3 Norwegian trial that is now in progress."

@charles shepherd and @Sasha I think I must be misunderstanding but does the proposed rituxamb study by invest in M.E at UCL not fit the bill of a phase 3 trial here in in the UK?

 

[Snow Leopard]

People with ME/CFS who have a clinical and/or immunological signature who are more likely to respond to a particular form of treatment.

As we learn more about the use of this drug, it may turn out that there are clinical characteristics - such as length of illness, type of onset - viral/non viral, degree of severity etc - that are linked to response rates

At there same time there may be immunological markers involving various parts of the immune system orchestra - cytokines, B cells etc - that help to predict response, or a non response

What do you think will happen if the Haukeland and UCL trials are successful in terms of efficacy, but no specific clinical characteristics/patterns are discovered that lets us identify who are most likely to respond? Lets say that by 2020 still nothing is discovered. Does this mean patients in most countries (who require what you mention) will be left in treatment limbo?

 

[Daisymay]

For a drug such as this to be made generally available on the NHS for use in a specific condition like ME/CFS there would have to be sound consistent evidence from what are called phase 3 clinical trials that it is likely to be a safe and effective form of treatment for at least an identifiable subset of people with ME/CFS.

A drug such as this would not be automatically granted a product license simply because it had been approved by an overseas regulatory body - but this would certainly help in the case of a body such as the FDA.

So roughly how many phase three trials are we talking of here and do you mean they would have to be done in the UK ? If so we'll be waiting for decades......

 

[Kati]

Psychogenic proponents simply move on to a new disease when proven wrong. Where are all those promoting psychotherapy for stomach ulcers? Arthritis? Lupus? MS? They moved on. Unfortunately it was CFS, ME, fibro and MCS they mostly moved on to. I have commented on this many times now. We have speculated that they started positioning for rebranding some time ago.

It took a great many years for antibiotics to be widely used for gastric ulcers. More than a decade. It was patients who made it happen.

If we can find one country, such as Norway, that is curing patients and publishing numbers, we can have slogans like:

"Thousands cured in Norway. Here? ZERO."

or "Why is [Insert your own country] a Zero?"

in my area, the psych lobby is hitting fibro hard.
-They are trying to lump with other chronic pain condition.
- recommending no specialist referral
- minimal contact with GP
- no opioids
- CBT
- Avoid disability at all cost.