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

[Hutan]

@JamBob, have you seen the thread?
Autoantibodies research in POTS: promising or not? (sorry, don't know how to link)

eg

http://www.dysautonomiainternational.org/page.php?ID=200

Dysautonomia International Announces $200,000 Research Grant
to Study Often Misdiagnosed Neurological Condition

EAST MORICHES, NEW YORK (February 12, 2015) - Dysautonomia International, a not-for-profit patient advocacy organization focused on disorders of the autonomic nervous system, has awarded a three-year $200,000 grant to Dr. David C. Kem at the University of Oklahoma to support innovative new research on postural orthostatic tachycardia syndrome (POTS). The $200,000 grant is the largest private grant ever awarded for POTS research.

POTS is a debilitating neurological condition that impacts an estimated 1-3 million Americans; 85% are young women between the ages of 12 and 40. POTS is often misdiagnosed, resulting in an average six-year diagnostic delay. There is currently no cure for POTS, and few effective treatments, but Dysautonomia International is seeking to change that.

Dr. Kem is a George Lynn Cross Research Professor of Medicine at the University of Oklahoma Health Sciences Center and Oklahoma VA Medical Center. Last year Dr. Kem's research team, working with researchers at Vanderbilt University, identified adrenergic receptor antibodies that they believe may be contributing to symptoms in some POTS patients, providing evidence that POTS may be an autoimmune disease (when your immune system attacks your own body). This grant will allow Dr. Kem's team to continue their pursuit to develop a blood test for these antibodies that could potentially be used to help diagnose POTS, and to develop new treatment options targeting these antibodies. "We're researching potential drug therapies that may be used to block and inhibit production of these autoantibodies, and thereby lesson their burden on the patient," says Dr. Kem.

The grant was made possible by a donor family that wishes to remain anonymous, whose daughter has POTS and an inherited connective tissue disorder known as Ehlers-Danlos syndrome, which is found in approximately 30% of POTS patients. She has also tested positive for some of the antibodies involved in this research. The three-year post-doctoral fellowship position created with the funding will be named the "Meghan's Hope POTS Research Fellowship" in honor of their daughter.
​

In my experience, POTS and NMH blur into one another - my heart rate and blood pressure are just generally not working right.

 

[Sidereal]

Can NMH be autoimmune? Are there any studies into this? Thanks

I haven't seen any studies on this topic.

 

[greeneagledown]

Someone might have already commented on this, but for what it's worth, it appears that 6 of the patients in this study had mono (glandular fever) upfront when they first got ME/CFS, and of those 6, 3 of them responded very well and went into long-term remission. The 3 patients who went into long-term remission all came down with ME/CFS as teenagers, while the 3 mono patients who didn't go into long-term remission came down with ME/CFS much later in life. Obviously a tiny sample size, but I'll be interested to see what happens in the big phase 3 trial. Maybe patients whose ME/CFS was precipitated by a mono infection during adolescence or early adulthood are especially likely to benefit from Rituximab.

 

[Kati]

Someone might have already commented on this, but for what it's worth, it appears that 6 of the patients in this study had mono (glandular fever) upfront when they first got ME/CFS, and of those 6, 3 of them responded very well and went into long-term remission. The 3 patients who went into long-term remission all came down with ME/CFS as teenagers, while the 3 mono patients who didn't go into long-term remission came down with ME/CFS much later in life. Obviously a tiny sample size, but I'll be interested to see what happens in the big phase 3 trial. Maybe patients whose ME/CFS was precipitated by a mono infection during adolescence or early adulthood are especially likely to benefit from Rituximab.

Thank you so much for this @greeneagledown
I got mono at age 39. I am a non-responder.

 

[EtherSpin]

Kati do you mean that you are a non responder in theory or that you have trialled Ritux?
I got bad nerve damage from glandular at age 13 but my full ME symptoms with an unknown virus at age 27 and had shingles 3X since then, CMV once properly, a couple of reactivations. this is intriguing

 

[EtherSpin]

I have had M.E for 17 years but my OI symptoms only became apparent and very rapidly a few years ago when my M.E became more severe. Perhaps I had OI before but not enough to notice....

any passing out in your teens ? that was my first signal. 2 or 3 times, particularly if constrained to a standing position where I couldn't move my legs much and was under bright light, singing in groups on stage did it twice though once I made it off with out actually blacking out.

 

[charles shepherd]

A few more thoughts on Rituximab and the situation in the UK….

I think we do also need to be looking at the 'UK roadmap' for Rituximab.

And if it really is a safe and effective form of treatment for at least a subgroup of people with ME/CFS, when could it be made available here in the UK to those would benefit from it - something that we all want to see.

If the large scale clinical trials are just left to the Norwegians, and let's assume that their phase 3 clinical trial produces some positive results in the summer 2017 when it finishes (which probably won't get published till 2018) this may help to get the drug made available in Norway.

But it won't mean that Rituximab will then get a product license here in the UK and NICE will recommend its use in ME/CFS

For this to happen, the UK regulatory authorities will require sound evidence of both safety and efficacy of Rituximab in ME/CFS from a number of high quality, preferably multicentre, phase 3 cinical trials

Phase 3 clinical trials are randomised controlled trials, like the one the Norwegians are currently setting up, and they are, not surprisingly, extremely costly to carry out.

If we don't start looking at how this could be done here in the UK - and it's interesting to note that the comments from Professor Simon Wessely in the New Scientist which suggest that he would also support this type of large clinical trial - then we are probably creating a situation whereby there is no real possibility of this drug becoming available for use in the UK for at least another five years.

I base this assumption on a scenario whereby we wait for the (hopefully positive) results of the phase 3 Norwegian trial in 2017/2018, then set about organising a phase 3 clinical trial here, and hope that others may follow suit.

This will take another 2 to 3 years to plan, set up, carry out, and analyse the results.

Which takes us up to 2021 or 2022...…

A long time to wait!

Having said that, the work on B cell status being carried out at UCL is very important and could help us to identify people with ME/CFS who are more likely/less likely to respond to Rituximab.

So well done to Invest in ME for funding this work

A further small clinical trial, as is proposed, that makes use of this information may well add to our knowledge of Rituximab.

And as repeatedly stated, the MEA Ramsay Research Fund would be very happy to consider a research grant application from the research group involved to help fund this small trial once the protocol, location, start date etc have been agreed confirmed

But I do believe that we also need to making moves right now to try and get a large multicentre phase 3 clinical trial taking place here in the UK, just as is happening in Norway.

Which is why I will be raising this when the Board of the UK Research Collaborative meets at the MRC next week.

Because if we don't, it could well be a very long time before people with ME/CFS here in the UK, who could benefit from Rituximab, will have access to it.

Dr Charles Shepherd
Hon Medical Adviser, MEA

 

[user9876]

A few more thoughts on Rituximab and the situation in the UK….

I think we do also need to be looking at the 'UK roadmap' for Rituximab.

And if it really is a safe and effective form of treatment for at least a subgroup of people with ME/CFS, when could it be made available here in the UK to those would benefit from it - something that we all want to see.

If the large scale clinical trials are just left to the Norwegians, and let's assume that their phase 3 clinical trial produces some positive results in the summer 2017 when it finishes (which probably won't get published till 2018) this may help to get the drug made available in Norway.

But it won't mean that Rituximab will then get a product license here in the UK and NICE will recommend its use in ME/CFS

For this to happen, the UK regulatory authorities will require sound evidence of both safety and efficacy of Rituximab in ME/CFS from a number of high quality, preferably multicentre, phase 3 cinical trials

Phase 3 clinical trials are randomised controlled trials, like the one the Norwegians are currently setting up, and they are, not surprisingly, extremely costly to carry out.

If we don't start looking at how this could be done here in the UK - and it's interesting to note that the comments from Professor Simon Wessely in the New Scientist which suggest that he would also support this type of large clinical trial - then we are probably creating a situation whereby there is no real possibility of this drug becoming available for use in the UK for at least another five years.

I base this assumption on a scenario whereby we wait for the (hopefully positive) results of the phase 3 Norwegian trial in 2017/2018, then set about organising a phase 3 clinical trial here, and hope that others may follow suit.

This will take another 2 to 3 years to plan, set up, carry out, and analyse the results.

Which takes us up to 2021 or 2022...…

A long time to wait!

Having said that, the work on B cell status being carried out at UCL is very important and could help us to identify people with ME/CFS who are more likely/less likely to respond to Rituximab.

So well done to Invest in ME for funding this work

A further small clinical trial, as is proposed, that makes use of this information may well add to our knowledge of Rituximab.

And as repeatedly stated, the MEA Ramsay Research Fund would be very happy to consider a research grant application from the research group involved to help fund this small trial once the protocol, location, start date etc have been agreed confirmed

But I do believe that we also need to making moves right now to try and get a large multicentre phase 3 clinical trial taking place here in the UK, just as is happening in Norway.

Which is why I will be raising this when the Board of the UK Research Collaborative meets at the MRC next week.

Because if we don't, it could well be a very long time before people with ME/CFS here in the UK, who could benefit from Rituximab, will have access to it.

Dr Charles Shepherd
Hon Medical Adviser, MEA

How about raising it with NICE early to keep them up to date and informed early.

 

[Scarecrow]

If the large scale clinical trials are just left to the Norwegians, and let's assume that their phase 3 clinical trial produces some positive results in the summer 2017 when it finishes (which probably won't get published till 2018) this may help to get the drug made available in Norway.

But it won't mean that Rituximab will then get a product license here in the UK and NICE will recommend its use in ME/CFS

For this to happen, the UK regulatory authorities will require sound evidence of both safety and efficacy of Rituximab in ME/CFS from a number of high quality, preferably multicentre, phase 3 cinical trials

Phase 3 clinical trials are randomised controlled trials, like the one the Norwegians are currently setting up, and they are, not surprisingly, extremely costly to carry out.

If we don't start looking at how this could be done here in the UK - and it's interesting to note that the comments from Professor Simon Wessely in the New Scientist which suggest that he would also support this type of large clinical trial - then we are probably creating a situation whereby there is no real possibility of this drug becoming available for use in the UK for at least another five years.

I base this assumption on a scenario whereby we wait for the (hopefully positive) results of the phase 3 Norwegian trial in 2017/2018, then set about organising a phase 3 clinical trial here, and hope that others may follow suit.

This will take another 2 to 3 years to plan, set up, carry out, and analyse the results.

Which takes us up to 2021 or 2022...…

A long time to wait!

Charles, I don't know if you noticed my question to you yesterday but this is why I was asking if there is anything that we can do as groups or individuals to make this happen. I don't fancy waiting until 2022 plus however long it then takes to agree that rituximab will be provided on the NHS plus however long it takes to wait my turn in line.

 

[charles shepherd]

Charles, I don't know if you noticed my question to you yesterday but this is why I was asking if there is anything that we can do as groups or individuals to make this happen. I don't fancy waiting until 2022 plus however long it then takes to agree that rituximab will be provided on the NHS plus however long it takes to wait my turn in line.

Sorry - I didn't see your question yesterday

I'm afraid I don't have a satisfactory answer as to what individuals can do right now

As far as the charities are concerned at this point, I think the most important thing to do is some chasing around to get some idea as to whether bodies such as the MRC and NIHR, which have the financial capacity to fund large clinical trials, feel that this is something which should now be regarded as a high priority item.

The MRC, for example, can issue what are called highlight notices when they want to highlight and encourage research grant applications for specific items of research

We can also pursue this through our parliamentary contacts etc

As far as individuals are concerned I don't think there is anything in the way of campaigning, writing to MPs etc that should be done at the moment

 

[valentinelynx]

The medicine cost of a maintenance dose is not $5800 to $6800. It is more like half of that.




https://www.rheumatology.org/publications/hotline/0506newdrugs.asp


Maintenance dose = 500 mg.


Even though it would have been $6000 it would have been relatively cheap compared to other medicines. People get it for R.A, and other diseases that is less disabling than ME. It costs proabably $100,000++ to have people on benefits yearly.

I take a pain medication that costs the insurance over $20,000 per month.

 

[charles shepherd]

How about raising it with NICE early to keep them up to date and informed early.

The process of getting the NICE guideline on ME/CFS revised is now quite complicated

We had a meeting with Professor Mark Baker from NICE, which was quite encouraging:

http://www.meassociation.org.uk/201...statement-by-the-me-association-10-july-2014/

But the decision to revise an existing NICE guideline now rests with NHS England

We will be having a meeting with NHS England next month to discuss this

With regard to Ritiuximab and NICE, they aren't going to make any decisions on recommendations until the drug is given a product license to treat people with ME/CFS by the UK drug regulatory authorities

Which takes us back to my key point - in order to do this we will need (certainly here in the UK) sound evidence on both safety and efficacy from a number of independent large scale high quality RCTs/phase 3 clinic trials

Positive results from further small scale trials will support the case for Rituximab - but it's unlikely that they will result in a product license for use in ME/CFS being granted

If we don't have these results from large clinical trials, it will be many years before Rituximab becomes available (if it as safe and effective as it appears from the Norwegian work) here in the UK…...

 

[user9876]

The process of getting the NICE guideline on ME/CFS revised is now quite complicated

We had a meeting with Professor Mark Baker from NICE, which was quite encouraging:

http://www.meassociation.org.uk/201...statement-by-the-me-association-10-july-2014/

But the decision to revise an existing NICE guideline now rests with NHS England

We will be having a meeting with NHS England next month to discuss this

With regard to Ritiuximab and NICE, they aren't going to make any decisions on recommendations until the drug is given a product license to treat people with ME/CFS by the UK drug regulatory authorities

Which takes us back to my key point - in order to do this we will need (certainly here in the UK) sound evidence on both safety and efficacy from a number of independent large scale high quality RCTs/phase 3 clinic trials

Positive results from further small scale trials will support the case for Rituximab - but it's unlikely that they will result in a product license for use in ME/CFS being granted

If we don't have these results from large clinical trials, it will be many years before Rituximab becomes available (if it as safe and effective as it appears from the Norwegian work) here in the UK…...

Basically what I was wondering is it worth talking with both the UK drug regulatory authority and NICE (and NHS England) to understand what they are likely to require in terms of evidence so that a trial can be set up to meet their needs. I do like your suggestion that it would be good to have a large multisite trial within the UK.

 

[Snow Leopard]

Which takes us back to my key point - in order to do this we will need (certainly here in the UK) sound evidence on both safety and efficacy from a number of independent large scale high quality RCTs/phase 3 clinic trials

One of the reasons why there are very large sample sizes mentioned on https://en.wikipedia.org/wiki/Phases_of_clinical_research is because trials have to be fairly large for enough statistical power to understand the rates of adverse effects. In our case, however, the drug has already been approved for humans (for other conditions) and a large amount of data on the safety of this drug in humans has already been generated.

Surely, beyond the clinical trials that are currently being done, the extensive safety data for Rituximab for RA is likely to be sufficient? It would be strange to argue that the safety of the drug in ME patients could be much worse.

Beyond that, all that is really necessary is data of efficacy which does not require such large sample sizes for statistical significance when the effect size is strong.

 

[Sasha]

Surely, beyond the clinical trials that are currently being done, the extensive safety data for Rituximab for RA is likely to be sufficient? It would be strange to argue that the safety of the drug in ME patients could be much worse.

What's your view on that, @Jonathan Edwards?

 

[user9876]

One of the reasons why there are very large sample sizes mentioned on https://en.wikipedia.org/wiki/Phases_of_clinical_research is because trials have to be fairly large for enough statistical power to understand the rates of adverse effects. In our case, however, the drug has already been approved for humans (for other conditions) and a large amount of data on the safety of this drug in humans has already been generated.

Surely, beyond the clinical trials that are currently being done, the extensive safety data for Rituximab for RA is likely to be sufficient? It would be strange to argue that the safety of the drug in ME patients could be much worse.

Beyond that, all that is really necessary is data of efficacy which does not require such large sample sizes for statistical significance when the effect size is strong.

I would have thought they should look at a risk reward ratio so even if they have the general risk data they should compare this against the benefits where maybe they would like a couple of large trials.

 

[Vitalic]

I wonder how this postulated autoimmune variant could lead to PEM? If it is affecting blood flow then you can see how it would cause earlier short-term physical exhaustion, but not necessarily this hallmark delayed effect sometimes up to 24-48 hours after exertion, and including not only muscular fatigue but symptoms consistent with immune activation.

Although it is interesting that I have observed in my own case the gap between exertion/PEM has gradually decreased over time, to the extent I can now do some exercise and start feeling the effects within an hour, this gradual degradation is quite alarming and I can't help but feel it is an integral part of, or perhaps a byproduct of, the overall pathological process.

 

[bertiedog]

My own opinion is that it's seems likely there's a strong probability that a subset of fibro patients will respond to rituximab. The fibro population may be very heterogeneous, but perhaps no more than the CFS population.

I run the local Fibro support group and have met over a hundred members over the years and I agree with your statement. For some exercise helps them but for others its a disaster. Some are extremely thin but the majority have a big issue with maintaining normal weight.

A minority are able to carry on with work but most have to give it up. I especially feel for the younger ones because they can be so disabled and all they are offered are toxic drugs which don't seem to help much.

Pam

 

[Marco]

An interesting excerpt from the discussion :

Interestingly, recent studies have indicated a possible autoimmune basis for Postural Tachycardia Syndrome (POTS) with autoantibodies to autonomic receptors [27]. Studies have also suggested that in subsets of Chronic Regional Pain Syndrome (CRPS) patients, associations to partly agonistic autoantibodies to β2-adrenergic receptors and to muscarinic-2 receptors were reported [28]. CRPS has been shown to improve after intravenous immunoglobulin therapy, and has been proposed as a prototype of a novel kind of autoimmunity with a possible two-hit process involving pre-existing autoantibodies that may become pathogenic after a triggering event such as trauma or infection [29]. It is worth noting that POTS is detected in approximately 15% of ME/CFS patients [30], and both POTS and CRPS are seen primarily in young women and have features that partly overlap with ME/CFS such as fatigue, brain fog, and central sensitization.

It may all be irrelevant but at least I now have some company out on a limb :

An autoimmune contribution to CRPS now appears likely given recent findings that 90% of an adult CRPS cohort had autoantibodies (agonistic, therefore upregulating) to either the beta(2)-adrenergic receptor (β2AR) or the muscarinic acetylcholine receptor (M2R). Fifty percent of the cohort had autoantibodies to both. 10

The actions and distribution of these receptors closely match CRPS symptoms: β2AR or M2R receptors are found in the cerebellum, reticular formation, motor cortex, and thalamus in the brain, in the sympathetic and parasympathetic nervous system, the heart, the pyramidal motor pathway to skeletal muscles, in peripheral nerves, and in astrocytes and microglia.

Interestingly Alan Light’s team 11 recently found a threefold upregulation of gene expression for the adrenergic alpha2a receptor in ME/CFS patients following exercise. In addition, several studies have found autoantibodies to muscarinic acetylcholine receptors in ME/CFS 12, 13 and Sjogren’s Syndrome 14. Evidence for autoimmunity in FMS is scant but fibromyalgia does appear to occur co-morbidly in autoimmune diseases such as lupus, rheumatoid arthritis and autoimmune thyroid disease 15.

Read more: From Chronic Regional Pain Syndrome to Fibromyalgia to ME/CFS? The ‘Spreading Neuroinflammation’ Model http://www.cortjohnson.org/blog/201...lgia-mecfs-spreading-neuroinflammation-model/

 

[Bob]

I wonder how this postulated autoimmune variant could lead to PEM? If it is affecting blood flow then you can see how it would cause earlier short-term physical exhaustion, but not necessarily this hallmark delayed effect sometimes up to 24-48 hours after exertion, and including not only muscular fatigue but symptoms consistent with immune activation.

I agree with your thoughts - My own bias is that the answer to ME/CFS is not autoimmunity to epithelial cells. But I'm happy that they're looking. It might lead to unexpected answers.