Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Sasha]

I don't think (memory, memory) that I've seen this mentioned on this thread - it's something Legendrew just posted in response to a question of mine about his Rituximab article (my bolding):

"At the launch, Professor Newton will outline three new studies being carried out in Newcastle. The first involves examining whether a monoclonal antibody, Rituximab, could be used as a medicine in order to understand more about fatigue mechanisms. Rituximab is highly successful in treating rheumatoid arthritis, some cancers and the profound fatigue experienced by patients with an immune liver disease known as Primary Biliary Cirrhosis." comment taken from here: http://www.ncl.ac.uk/press.office/p...ether-to-discover-biological-causes-of-cfs-me​

It's interesting that Rituximab seems to be being used to treat the fatigue in PBC rather than to treat PBC itself, unless I'm reading too much into the wording.

Jonathan Edwards - do you find it odd that Rituximab could treat a symptom without treating the disease, given it's mechanism of action? Are there implications for ME? As I understand it, it wasn't just fatigue that improved with Rituximab in Fluge and Mella's ME work but the whole symptom complex.

 

[Snow Leopard]

Sasha It seems more along the lines of a hypothesis or speculation of the writer, rather than something that is established.

 

[Legendrew]

It's interesting that Rituximab seems to be being used to treat the fatigue in PBC rather than to treat PBC itself, unless I'm reading too much into the wording.

Jonathan Edwards - do you find it odd that Rituximab could treat a symptom without treating the disease, given it's mechanism of action? Are there implications for ME? As I understand it, it wasn't just fatigue that improved with Rituximab in Fluge and Mella's ME work but the whole symptom complex.

I found this on the wikipedia page of pbc (didn't feel like plunging the depths of pubmed this morning!) which could explain why it has a profound and somewhat direct effect upon fatigue.

"The cause of the disease is unknown at this time, but research indicates that there is an immunological basis for the disease, making it an autoimmune disorder. Most of the patients (>90%) seem to have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria."

The depletion of B-cells would obviously lower the levels of this antibody and allow for oxidative phosphorylation and hence further ATP production. I'm not sure what causes the inflammation of the small bile ducts and whether this is also antibody mediated (I'm sure they are involved somewhere) but the inflammation is likely multi-step and not as direct a mechanism - these anti-mitochondrial antibodies are likely the major factor in the profound fatigue i'd have thought.

 

[Sasha]

Sasha It seems more along the lines of a hypothesis or speculation of the writer, rather than something that is established.

Hi Snow - I'm referring to this bit: "Rituximab is highly successful in treating [...] the profound fatigue experienced by patients with [...] Primary Biliary Cirrhosis", which is presented as a statement of fact. I don't know anything about the basis for it. Do you think it's a bit more questionable? I've got no background on this at all.

 

[Sasha]

I found this on the wikipedia page of pbc (didn't feel like plunging the depths of pubmed this morning!) which could explain why it has a profound and somewhat direct effect upon fatigue.

"The cause of the disease is unknown at this time, but research indicates that there is an immunological basis for the disease, making it an autoimmune disorder. Most of the patients (>90%) seem to have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria."

The depletion of B-cells would obviously lower the levels of this antibody and allow for oxidative phosphorylation and hence further ATP production. I'm not sure what causes the inflammation of the small bile ducts and whether this is also antibody mediated (I'm sure they are involved somewhere) but the inflammation is likely multi-step and not as direct a mechanism - these anti-mitochondrial antibodies are likely the major factor in the profound fatigue i'd have thought.

That's interesting - more than one mechanism going on.

 

[Heart Face]

Is oedema classified as inflammation?

cerebral oedema - one cause is brain inflammation

 

[MeSci]

cerebral oedema - one cause is brain inflammation

The reason I ask is that you cited a piece by Malcolm Hooper (for whom I have a lot of time) that itself cites evidence of demyelination and/or oedema as evidence of inflammation, or so it seemed. Neither of these is clear evidence for inflammation as far as I know.

 

[Legendrew]

cerebral oedema - one cause is brain inflammation

As far as i'm aware oedema in itself is not inflammation but can often be caused by inflammation - i'm not sure this is relevant though as I've never seen oedema listed anywhere as a symptom of ME/CFS.

 

[cornwall13]

Professor Edwards

If the Norweigen phase 3 trial goes ahead and produces the results we want and the uk trial goes as we would like too, I know this is hypothetical, but how long would it be before there is a chance for patients to be able to use it on the NHS?

Or will the uk need a bigger study?

It would be nice to hear what sort of timescale we maybe looking at? I know this question assumes alot, but it just gives us an idea assuming the trials show significant positive results.

Regards

 

[Jonathan Edwards]

Hallo Professor Edward,

I have four questions and a simple yes or no, plus number will suffice.

Would you treat patients diagnosed ME with Rituximab who have tested positive for:

1. Increased CD4+CD25+T cells (Treg) FoxP3,
2. active co-infections such as of the herpes family HH-V6, HH-V7, CMV, EBV
3. Prevalence of children diagnosed with autoimmune condition ?
4. What are the chances (statistically) that mother and child, or several children (vertical blood line) are diagnosed with the same autoimmune disease?

Bambi

!. I s no problem.
2. I have not seen issues with these infections in my practice and I am not sure what active implies. Just have antibody titres would not worry me.
3. True autoimmunity in children is uncommon, with perhaps the major exception of type I diabetes, which seems to be autoimmune although it is an odd one. I do not know figures but my guess would be that 1 in 2-500 children have type I diabetes and that all other autoimmune conditions in children add up to no more than this and maybe less.
4. Most autoimmune conditions have a genetic bias, so children of a mother with a particular autoimmune disease have an increased risk, which may be as high as a 10% risk. There are a few very rare genetic causes of autoimmunity that are very strongly linked, like C1q deficiency. This I am fairly sure is recessive, so several children from one set of parents may be affected, although it is unlikely that the parents would be affected.

 

[Jonathan Edwards]

It's interesting that Rituximab seems to be being used to treat the fatigue in PBC rather than to treat PBC itself, unless I'm reading too much into the wording.

Jonathan Edwards - do you find it odd that Rituximab could treat a symptom without treating the disease, given it's mechanism of action? Are there implications for ME? As I understand it, it wasn't just fatigue that improved with Rituximab in Fluge and Mella's ME work but the whole symptom complex.

This is all very straightforward I think. PBC is an autoimmune response to an enzyme complex that for some reason leads specifically to damage to bile canaliculi in the liver. The tissue damage in the liver is itself symptomless and the patient may have no idea they are ill until they start itching from the effects of bile salts accumulating in the skin. They also become jaundiced from bile pigment build up. Unfortunately, once these symptoms have started the damage to bile flow is probably mostly irreversible. I would not expect rituximab to improve them much. I would hope that it might prevent further progression - but then that might be hard to measure either in off label treatments or in trials.

On the other hand, it would not surprise me that, just as we were saying for thyroid disease and diabetes, PBC patients might feel fatigued from the effects of the antibodies on the enzyme complex all over the body - I agree with Andrew. That fatigue could easily respond to rituximab because cells can make new enzyme once the antibody levels have fallen. So 'using rituximab to treat fatigue in PBC' is what I would expect people to be talking about. They may well hope that the patients also live longer or even show some recovery of bile function in the long term but that might be hard to measure and kept in the background.

I am so sad that I decided not to treat a young girl of 13 with PBC with rituximab ten years ago. I was asked to but I did not feel I could take on the responsibility because I simply had no idea what to expect and I could not expect her to understand or cope with the implications of my uncertainty.

 

[Jonathan Edwards]

Professor Edwards

If the Norweigen phase 3 trial goes ahead and produces the results we want and the uk trial goes as we would like too, I know this is hypothetical, but how long would it be before there is a chance for patients to be able to use it on the NHS?

Or will the uk need a bigger study?

It would be nice to hear what sort of timescale we maybe looking at? I know this question assumes alot, but it just gives us an idea assuming the trials show significant positive results.

Regards

I think there are too many unknowns to answer that, I am afraid. It will be an unusual situation because the drug company may be unlikely to ask for a license.

 

[Uno]

I wonder about using rituximab in someone like myself. I have a major immune problem, my CD4/CD8 cells are low, my IgA and IgG subclasses are low and I get recurrent cholangitis. I was told it was PSC by one doctor only to now be told it isn't classic PSC but my body is attacking my bile ducts and I get major infections to the point where I am on permanent antibiotics which I have been on for almost two years.

What would happen if I was to take this drug?

 

[Sasha]

I think there are too many unknowns to answer that, I am afraid. It will be an unusual situation because the drug company may be unlikely to ask for a license.

Would the situation require the drug company to ask for a license? I don't know anything about licensing. Can't anyone else ask? Assuming this relates to Rituximab being about to go out of patent, haven't there been other out-of-patent drugs licensed for new uses?

 

[MeSci]

I am so sad that I decided not to treat a young girl of 13 with PBC with rituximab ten years ago. I was asked to but I did not feel I could take on the responsibility because I simply had no idea what to expect and I could not expect her to understand or cope with the implications of my uncertainty.

It seems unfair for the whole burden of such decisions to rest on one person, and it ought to be possible instead to refer such cases to an ethics committee. I have been very impressed by the calibre of the decision-making processes in such committees as portrayed in the Radio 4 programme 'Inside the Ethics Committee'.

I'm sure we have all made decisions that we later regret, but it must be especially hard for caring, conscientious doctors when they know that their decisions can have major effects on patients, and when they have to make so many such decisions.

Maybe that's one reason that some end up apparently callous and indifferent to patients' needs, and exhibit excessive certainty and confidence that may be just a veneer. It could be easier to disengage emotionally.

 

[Jonathan Edwards]

Would the situation require the drug company to ask for a license? I don't know anything about licensing. Can't anyone else ask? Assuming this relates to Rituximab being about to go out of patent, haven't there been other out-of-patent drugs licensed for new uses?

I think sanity prevails (a bit) and drugs do get approved by NICE without drug companies pushing them, but it is an unusual situation. There may be a lot of hoo-hah, but that's not so unusual.

 

[Jonathan Edwards]

I wonder about using rituximab in someone like myself. I have a major immune problem, my CD4/CD8 cells are low, my IgA and IgG subclasses are low and I get recurrent cholangitis. I was told it was PSC by one doctor only to now be told it isn't classic PSC but my body is attacking my bile ducts and I get major infections to the point where I am on permanent antibiotics which I have been on for almost two years.

What would happen if I was to take this drug?

Dear Uno, I prefer not to comment on individual cases.

 

[user9876]

I think there are too many unknowns to answer that, I am afraid. It will be an unusual situation because the drug company may be unlikely to ask for a license.

How did licensing happen for RA, did the drug company take an interest and at what stage.

I'm surprised at the lack of interest in ME trials as I would have thought it represented a new market for them with little investment. I realise Rituximab is going out of patent soon but I believe it is also quite hard to make. Also I believe they are trying to develop an injectable form of the drug which I assume would include a patent. I can see how a drug company wouldn't want to risk the money associated with developing a new drug but I would have thought that ME offered a reasonable revenue with little investment needed hence offering a good overall return.

 

[medfeb]

Sandra Kweder of the FDA, in last year's teleconference with patients spoke briefly to the challenge of getting drug companies involved, at least in drug research in the U.S.

"One of the challenges [is] to try and get the companies interested in investing in products to treat a condition.One of the things that we've learned from experience is you've got to be able to define the condition well and they [pharma] need to - they want to know where are the rules about studying it. What am I going to have to show in order to get a drug approved?"​

​

Good definition and agreed upon rules on how to measure the effect of the drug so it can be approved.

There are a few good definitions produced by experts but there are also awful definitions that are more well known, certainly more often used, describe a very different set of patients and have resulted in studies that feed gross misperceptions of the disease

As far as how to measure drug effect, there are a number of ways that could be used. But which ones could pharma use with confidence that the FDA would accept it?

Drug research is very high risk, resulting in many dead failures after years of work. If I am pharma with a choice between this disease and some other disease that is more clearly defined and where the methods to measure effect are agreed, I expect I'd choose the other disease.

 

[user9876]

Drug research is very high risk, resulting in many dead failures after years of work. If I am pharma with a choice between this disease and some other disease that is more clearly defined and where the methods to measure effect are agreed, I expect I'd choose the other disease.

I was thinking its quite a low risk since the drug is already developed. How would the cost of say giving the drug to trials and helping with licensing compare to a marketing campaign costs to find similar numbers of potential consumers. In other industries money is often spent to open up new markets and I was seeing it in those terms.