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

[Snow Leopard]

I have, incidentally, just written to Andy C at the New Scientist to ask him to remove the link to Mental Health Topics in his coverage of Rituximab and ME/CFS:


Morning Andy

You will not be surprised to learn that there is quite a lot of comment appearing on the social media following your item on Rituximab.

Please get Andy to remove the crap about 'Yuppies', the comparison to Morgellons etc. These associations create known harm, due to priming of readers, who then learn to associate these concepts (eg CFS and Morgellons) together.

 

[charles shepherd]

I don't really get why there needs to be a phase 3 study done in the UK, unless of course it's because of the general fear of foreigners that seems quite prevalent in the medical community in the UK. The only argument I can see for it is that they want to make sure that the Norwegian patients in the study are representative of ME patients in the UK, but then surely ever country with ME patients should then do such a study?

This has nothing to do with conspiracy theories and 'fear of foreigners'. Most of the UK medics (including psychiatrists) I have discussed the trials with so far have been impressed by what is being done in Norway

I suspect that Jonathan may also comment on this point when he has time…….

The simple answer is that here in the UK the authorities that license a drug for general use have to be satisfied that it is as safe as it can be in context (accepting that all drugs have side-effects, some serious) and effective in at least a well defined group of patients

Here in the UK, NICE will also want to know if an expensive drug like this is going to be cost effective for approval on the NHS

So I'm afraid that one positive phase 3 trial result from Norway in 2017/2018 isn't going to be strong enough in the case of something like Rituximab here in the UK

Which is why we (and everyone else) need to have the safety and efficacy of Rituximab confirmed in a number of other independent RCTs

And that is why I am saying that in parallel with the other very useful work that is going on here in the UK at UCL, we also need to be talking to MRC etc about a phase 3 trial

 

[duncan]

I would be a little concerned if the CDC got to pick the patient sample if such a trial were to take place in the United States.

I would think there are safety nets in place in the UK to ensure real ME/CFS patients are used in trials such as those suggested by Charles Shephard? It would be a shame if individuals from the BSP school got to determine who was permitted in as part of the trial sample.

 

[alex3619]

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?"

 

[Sidereal]

I would be a little concerned if the CDC got to pick the patient sample if such a trial were to take place in the United States.

I would think there are safety nets in place in the UK to ensure real ME/CFS patients are used in trials such as those suggested by Charles Shephard? It would be a shame if individuals from the BSP school got to determine who was permitted in as part of the trial sample.

Good point Duncan. Imagine a phase III trial stuffed with Oxford criteria CFS clients referred from UK fatigue clinics. It's the stuff of nightmares.

 

[Sasha]

I would be a little concerned if the CDC got to pick the patient sample if such a trial were to take place in the United States.

I would think there are safety nets in place in the UK to ensure real ME/CFS patients are used in trials such as those suggested by Charles Shephard? It would be a shame if individuals from the BSP school got to determine who was permitted in as part of the trial sample.

The researchers who run the individual studies are responsible for choosing the sample of patients. It's not controlled by government bodies or by external parties.

 

[duncan]

@Sasha , selection is controlled by government bodies when that body or agency is managing the study - at least, that is the case in the US. There, the NIH can and does run studies unilaterally quite often. In those cases, the NIH principal investigator is in charge of selecting patients.

And even if there is an independent effort, that would not necessarily shield the process from selection bias. I would guess there are BSP proponents represented throughout the medical landscape.

Unless you are suggesting Fluge and Mella would govern selection in the UK? I'm not sure how that works. But even then I suspect that others would direct candidates from within the UK to them.

 

[Sasha]

I'm surprised that anyone other than the PI would be responsible for details of study design but maybe it's different in the States. I'm not suggesting F&M would manage anything in the UK - that would be for any UK PI.

 

[A.B.]

Good point Duncan. Imagine a phase III trial stuffed with Oxford criteria CFS clients referred from UK fatigue clinics. It's the stuff of nightmares.

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.

 

[Bob]

The researchers who run the individual studies are responsible for choosing the sample of patients. It's not controlled by government bodies or by external parties.

Unfortunately, funding bodies are the final arbiters, because they get to say yes or no to specific study designs.

 

[Yogi]

Why do the New Scientist need to go to Prof Weasel, who is he? This made me so angry.

There is now a strong case to be made for a larger trial," says Simon Wessely of King's College London, who has treated people using cognitive behavioural therapy. "The belief that [CFS] is all in the mind has been around since the beginning," he says. "It's tragic that it might take a study like this to take sufferers seriously."

He is trying to rewrite history. He and his psychiatrist partners in crime have been responsible for the creation of thebelief that CFS is in the mind. He must not be allowed to rewrite history and move on to abuse and exploit other patients with other diseases.

The 4th quote is noteworthy.

http://www.meactionuk.org.uk/wessely.html

• 
  Beard and Mitchell have returned to obscurity, but their disease is back with a vengeance. My local bookshop has just given ME the final seal of approval - its own shelf ............... A little more psychology, a little less T-cells would be welcome"

 

[Snow Leopard]

The only argument I can see for it is that they want to make sure that the Norwegian patients in the study are representative of ME patients in the UK, but then surely ever country with ME patients should then do such a study?

There is no need for every nation to do a study. Each nation will decide (in terms of drug approval, subsdies) based on meta-analysis of all existing trials.

 

[Simon]

New! Improved!
updated blog (just my bit) - more positive and less boring. Hey, it's hard to blog well with little time and a fading brain..

Fluge & Mella's pre-trial study highlights life-changing potential of rituximab
Sasha's bit remains the same - it was already perfect

I'd also love to know what people make of this bit from the blog:

Mega-responders?
However, for me, the big story of this study is the substantial group who did exceptionally well, though I should stress this is my interpretation of the data in the paper rather than anything the authors have claimed. There is a wealth of data in the paper, down to the level of individual patients. Seven patients – a quarter of those who had maintenance rituximab doses – showed a response that looks close to recovery at the end of the trial, that is, at 32 to 36 months, which is the final data point on the graph of outcomes. Fatigue, SF-36 Physical Function and self-rated daily functioning scores all look very impressive:

• Seven patients reported the maximum possible fatigue improvement from baseline, that is, major improvement in all four fatigue symptoms. One patient was actually just shy of the maximum, scoring approximately 5.9 out of 6.0 (Fig 2A).
• Seven had an SF-36 Physical Function score of 85 or more, which is equal to or better than the population average (Fig 5A).
• Seven had function levels of 80% or higher (someone at 80%-90% is defined as having “slight restrictions in physical or social functioning, who may perform all activities almost as a completely healthy person, but at a reduced pace or duration”), with two scoring 100% (Fig 6B).

All of the patients in the study started with low scores in each of these three areas, so those highs represent huge progress. There is no guarantee that the same seven patients have top scores in each of those three areas, but it seems very plausible.

While the placebo effect and response-bias may occur, they are relatively modest effects. And with ME/CFS, natural recovery rates are low. So these ‘mega-responder’ results strike me as very impressive, and important. Such life-changing improvements are not a common feature of ME/CFS clinical trials.

 

[charles shepherd]

Please get Andy to remove the crap about 'Yuppies', the comparison to Morgellons etc. These associations create known harm, due to priming of readers, who then learn to associate these concepts (eg CFS and Morgellons) together.

New Scientist website classification of ME/CFS is now being removed following our request this morning:

Hi Charles….we’re delinking it from the mental health site as we speak!! Sorry, it was an oversight that didn’t occur to us, but you’re absolutely right.

And sorry I didn’t manage to get your comments in….the story was already through by the time we received them, unfortunately.

I’m really grateful for the comments, however, and do keep in touch on this topic!! I think it could be an exciting and hopeful time for at least some of the patients with the condition

Andy

 

[Bob]

I heard that because of the patent expiration, it would not pay for them to invest money in trials. Is it possible to extend a patent?

It's common for a manufacturer to give a compound a slight tweak, so that it has very similar properties but can be patented as a brand new drug. But I suppose it might only be worth doing this for drugs that are high revenue earners. I don't know if rituximab would fit into that category.

...my more generic question is to what extent does the Rituxan success make it easier to start attracting any drug development company.

I think you're right... Once there is a demonstrably successful treatment, with a good success rate, it gives other manufacturers something to hook on to... They can start testing bio-similars that are still under patent, and it can give them an idea about what other drugs in their armoury might be worth testing for ME/CFS. (i.e. various b-cell modulators.) There are various drugs that have similar or alternative mechanisms that they might consider worth testing. Fluge and Mella are already testing a variety of drugs. Drug manufacturers are desperate to extend their range to new patients, but they've got to have a degree of certainty before they pump their dollars into it.

It certainly sucks to be a non-responder

Don't forget that Fluge and Mella are testing other drugs on patients who haven't responded to Rituximab.

I don't really get why there needs to be a phase 3 study done in the UK, unless of course it's because of the general fear of foreigners that seems quite prevalent in the medical community in the UK. The only argument I can see for it is that they want to make sure that the Norwegian patients in the study are representative of ME patients in the UK, but then surely ever country with ME patients should then do such a study?

I guess it's like proverbially knocking the authorities on the head with a successful research trial. With one study, they can uhm and ah, with two studies they might start to take it seriously, and with three studies they might finally take some action. Not that it should be like that, of course.

 

[charles shepherd]

I guess it's like proverbially knocking the authorities on the head with a successful research trial. With one study, they can uhm and ah, with two studies they might start to take it seriously, and with three studies they might finally take some action. Not that it should be like that, of course.

Bob - That's a very good way of summing up how things work here in the UK!

But I think we may need more than 3 good studies given the cost of this drug…...

 

[Sasha]

New! Improved!
updated blog (just my bit) - more positive and less boring. Hey, it's hard to blog well with little time and a fading brain..

Well, it was hardly that!

Sasha's bit remains the same - it was already perfect

And I wouldn't go that far but I had loads more time than you to write a much shorter thing and I didn't have to make sense of a 54-page paper while I was at it! Still don't know how you managed that.

 

[alex3619]

It's common for a manufacturer to give a compound a slight tweak, so that it has very similar properties but can be patented as a brand new drug.

This drug is a biological agent. Its grown, not tweaked at the chemical level. They can substitute with another drug, a biosimilar drug, what they cannot do is tweak it ... unless the science of protein and gene manipulation has advanced much more than I am aware. The can however adjust a formulation. More of something, less of something, that's a new product. Patents are for inventions, marketable products.

 

[alex3619]

They can start testing bio-similars that are still under patent, and it can give them an idea about what other drugs in their infantry might be worth testing for ME/CFS. i.e. various b-cell modulators.

This, I think, is a valid hope.

 

[Bob]

This drug is a biological agent. Its grown, not tweaked at the chemical level. They can substitute with another drug, a biosimilar drug, what they cannot do is tweak it ... unless the science of protein and gene manipulation has advanced much more than I am aware. The can however adjust a formulation. More of something, less of something, that's a new product. Patents are for inventions, marketable products.

Thanks Alex. I haven't got any insight into the design and manufacture of these biologicals, so I'm unaware of how easy or difficult it is to create a biosimilar. But I think someone recently said that there are a number of rituximab biosimilars in the pipeline from various manufacturers. I don't have any details though, so I might be wrong.