Open Norway: Plasma cell aimed treatment with daratumumab in ME/CFS - Haukeland University Hospital

An interesting mention towards the end is that they have done a study where they followed patients without doing anything to them, in order to get a clearer picture of how their symptoms fluctuate over time.

This is a brilliant idea and the results will be useful for all drug trials in this field.

He goes quite far in saying that he believes this treatment can have a positive effect, but he also puts a lot of emphasis on how there are no guarantees and that we can’t say anything before we’ve actually got the data.

It's good he stresses that. The cyclo phase 2 makes me more hopeful for this than I would be about another phase 2 after a positive pilot trial but we still need to wait for the data.
 
Wow. So this is gonna take a lot of fundraising.

It’s absolutely ridiculous that they won’t even provide discounted drugs for the trial. Knowing full and well that the drug prices are way higher than it costs to make them due to patents.
 
This just goes to show how deep the predudice against ME runs in pharma and funding. You couldn't ask for more methodical and dedicated people to run your trials.

The pharma part makes the least sense because as Mella says, if a phase 3 showed the same results as the pilot and the cyclo studies that would be millions of potential responders...

I'm not sure if it has much to do with ME/CFS or any prejudice towards ME/CFS. I suspect it has more to do with this just being the usual way into which this abstruse system has developed into. I suspect if someone wanted to run a trial into another condition and there wasn't too much evidence to start off with (no knowledge of an ME/CFS mechanism or experiments showing the relevence of plasma cells or antibodies) they'd run into the same problems. It often seems that people run into the same problems, even if the evidence is better and there is more a priori knowledge. Of course little enthusiasm and lack of funding in ME/CFS in general probably isn't helpful.
 
I'm not sure if it has much to do with ME/CFS or any prejudice towards ME/CFS. I suspect it has more to do with this just being the usual way into which this abstruse system has developed into. I suspect if someone wanted to run a trial into another condition and there wasn't too much evidence to start off with (no knowledge of an ME/CFS mechanism or experiments showing the relevence of plasma cells or antibodies) they'd run into the same problems. It often seems that people run into the same problems, even if the evidence is better and there is more a priori knowledge. Of course little enthusiasm and lack of funding in ME/CFS in general probably isn't helpful.
I mean for them, if the trial’s going to happen either way, might as well charge full price because they make a profit. The system is designed to encourage such behaviours.
 
I think it is courageous and justified. Whether or not it will tell us something important I do not know but if anyone is going to do this, these are the right people.
Did you say something on another thread about daratumumab being not an ideal treatment choice (as opposed to a test of principle) for some reason? Because it's cumbersome or risky or something? I might have got this wrong.
 
Interview in Norwegian:
Øystein Fluge forteller om den nye studien med Daratumumab til ME-pasienter, på Haukeland sykehus - YouTube


I was hoping to get an auto-transcript from YouTube and run it through Google translate, but there seems to be no transcript. However, by mucking around with Settings (the little cogwheel thing), I'm now getting subtitles in English via some sort of live auto-translate thing.
 
I was hoping to get an auto-transcript from YouTube and run it through Google translate, but there seems to be no transcript. However, by mucking around with Settings (the little cogwheel thing), I'm now getting subtitles in English via some sort of live auto-translate thing.
I used this website to get those auto-translated subtitles, then I asked Claude Sonnet 4 to format it nicely and fix any typos without changing the content:
The idea is based on the same basic idea as our previous studies, namely that ME in a subgroup of patients is often a non-infectious disease which comes after some form of trigger in patients who are otherwise previously healthy. And what we think is that the body creates antibodies that we create against everything we have and to defend ourselves against the environment - an antibody that affects the body itself. And it has been shown in recent years that after infections, such as COVID infection or Epstein-Barr virus, mumps virus or other infections, the body creates many antibodies that affect molecules, its own molecules in the body. And some of these we believe are involved in affecting the function of so-called functional autoantibodies and may be involved in disrupting the balance in the body so that patients can get the characteristic symptoms.

Central to this is probably the regulation of blood flow in the tissue in relation to stress. It is certain that when patients are stressed, they quickly develop ME/CFS. They have problems increasing circulation enough, for example with exertion, which causes us to get these characteristic symptoms of fatigue, feeling sick, exertion intolerance, cognitive symptoms, lethargy, and things like that.

So this pilot study is based on influencing the so-called plasma cells, which are cells in the immune system that are primarily responsible for creating antibodies. And we give a medicine called Daratumumab, which is an antibody that is used in cancer treatment for patients who have so-called myelomatosis or bone marrow cancer, because it lowers the level of these plasma cells, also benign plasma cells. So when we use it, the purpose is to temporarily reduce the number of plasma cells in the system and then, as a result, the antibody levels in the blood are temporarily reduced. And then we hope that the effect can be sustained in some patients, so that when those antibodies are reduced, it leads to an improvement in the patients' symptoms.

And what we have seen in the pilot study is that 60% of those, that is, 6 out of 10 patients that we have included, have apparently had a good effect on the symptoms of the disease. And of five of the six patients have experienced a clinical improvement, then the response or improvement has been sustained for up to two years, as long as we have followed the patients. One of the patients had a relatively early relapse after 3 months, a partial relapse, while the other five patients have had a sustained effect.

We haven't had any significant side effects from this. No serious medical events. So we believe that tolerance has been good so far. We have given a little over 50 such injections. And these injections are given subcutaneously, i.e. under the skin of the abdomen. And it has actually worked well. But even though we have seen that it has had a good effect in these patients, we believe that there is reason to do a larger study. And the main reason is that we cannot draw any firm conclusions based on such a small pilot study with 10 patients. We cannot be sure that the medication alone is the cause of the observed improvements.

So that's why we have to do what we call a double-blind study where some of the patients receive active medicine and some of the patients receive inactive injections without active medicine, without either us or the patient knowing what they have received. It is certainly a double-blind and placebo-controlled study. We have planned this and are thinking of starting it, hopefully before or after the summer when the studies have been approved by the authorities.

And initially we are thinking of including 66 patients, where 44 patients will receive active medicine with this Daratumumab medicine that will reduce the number of plasma cells and 22 patients on placebo, i.e. an inactive injection that does not affect the immune system. And then these patients will be followed up for three months after inclusion in the study before they receive the first injection. And then they should be followed for 15 months after they start treatment, so 18 months in total. And when the last patient has been observed for 18 months, the study is closed. And then we will know who has received active treatment and who has received placebo and can compare the results. And then we can get a relatively certain impression of whether this medication is useful for patients, if it is important that it provides good responses that last over time in a sufficiently large proportion of patients.

So we hope that the study can get started and we hope that it can help raise the level of knowledge about the disease and perhaps be a contribution to helping develop rational treatment. But we should not draw any firm conclusions until we have seen the results from the analyzed study, that is, the double-blind study, lest we be mistaken.

We have tried to learn from all the studies we have done before in order to learn in a way to create a good protocol for the study that is now about to start. This means that we have tried to work with the inclusion criteria. We have tried to work out what impact goals we should have for the study. We have incorporated continuous step counting with activity watches throughout the entire study. We have included some tests that they can do without the patients getting too tired. And we have a number of questionnaires that the patient must fill out regularly throughout the study - validated forms that report symptom burden to try to find out whether this has a beneficial effect or not.

When it comes to the number of patients we plan to include, it is clear that we have worked in collaboration with statisticians and so on with how many patients we need to be able to show whether there is a difference between the active group and the placebo group. And it is clear that when we only really have our own data from previous studies to build on and observations from this pilot study that we have talked about, that estimate is a bit uncertain because the number of patients that is necessary to show depends on how big the difference is between the patients on average in relation to the placebo group on average, and we must be open to saying that we have tried to estimate this as best as we can.

But the number of patients that can be included is also limited by the economy because this is an expensive biomedicine. The drug company that sells this didn't want to give any discount for the research study. And it is difficult to get public funding. We've seen it here and there, so what is there is that the patients and the patient association and private individuals so far make it possible to do this study. And we are very grateful for that. And we must then try as best we can to create the best possible protocol, make the best possible assessment of how the study will be conducted so that we manage this money as well as possible.

We cannot promise that such a study will be positive, but we can try to do our best. And the underlying calculations suggest that if what we have seen in the pilot studies is fairly representative, then we should have a chance of showing a definite difference. And then we have estimated that there should be no more than 20% responses as stated in the placebo group. And compared to previous studies, we have tightened the response requirements significantly. There are much stricter requirements to meet response criteria in this study than before. And that's because of what we've learned.

We have also done a study where we have only followed patients over time without giving them treatment to try to find out what the normal variation is for different patients over time. What we want to try to avoid is to avoid what are normal symptom changes interfering with the criteria for response so that we try to separate true responses caused by drug treatment from natural variation. And then we see that we should not include patients who have the mildest degree of illness. Not because it can't be bothersome enough for the patients, but because they fluctuate too much after we include them that we are afraid that we can increase the so-called response rate in placebo.

If we don't get this study done, probably no one else will. We have been at it for a long time and we believe that we have come across a principle and a mechanism that is important to explain. And it's clear that our immune system is extremely complex and difficult and extensive. And there are many different things that influence each other. Nevertheless, when we try to say that we are reducing the plasma cells when it will reduce the antibodies that will provide improvement, there is a basic idea about how we will affect the immune system. But it is clear that we are always aware that it is much more complex than that. But it looks like that intervention is doing something beneficial for patient outcomes. As I say, it is based on two years of observation of these patients and with a backdrop of experiences from previous studies.

Edit: Better translation below.
 
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@Jonathan Edwards, I know the response rate of 60% in the pilot will be an inaccurate estimate, even if real, because of the small number of patients but I'm wondering how many PwRA don't respond to rituximab and whether they have any options if they don't?

60% would be a ton better than the 0% we've got now but would leave a lot of PwME with nothing. I'm wondering what the implications are.
 
Dr Fluge said:
It is certain that when patients are stressed, they quickly develop ME/CFS. They have problems increasing circulation enough, for example with exertion, which causes us to get these characteristic symptoms of fatigue, feeling sick, exertion intolerance, cognitive symptoms, lethargy, and things like that.

Do we know that about problems increasing circulation? I didn't think we did. Is it maybe failure of translation?
 
Do we know that about problems increasing circulation? I didn't think we did. Is it maybe failure of translation?
Central to this is probably the regulation of blood flow in the tissue in relation to stress. It is certain that when patients are stressed, they quickly develop ME/CFS. They have problems increasing circulation enough, for example with exertion, which causes us to get these characteristic symptoms of fatigue, feeling sick, exertion intolerance, cognitive symptoms, lethargy, and things like that.
For «stress» he uses the word «belastning», which translates to «load», «strain» or «burden» in this context. He later uses «anstrengelse», which translates to «exertion». So I think he means «exertion» for the first instance as well.

But he does talk about problems with increasing the circulation during exertion, and that this causes symptoms (and more lactic acid).

But the bolded sentence is wrong. He does not say anything about developing ME/CFS after stress exertion, etc. in this section, or anywhere else for that matter. He mumbles at bit here, so I assume the AI hallucinated..

Edit: the entire section reads more like a summary than verbatim quotes. I suspect that might be the case for the rest of the translation as well..
 
For «stress» he uses the word «belastning», which translates to «load», «strain» or «burden» in this context. He later uses «anstrengelse», which translates to «exertion». So I think he means «exertion» for the first instance as well.

But he does talk about problems with increasing the circulation during exertion, and that this causes symptoms (and more lactic acid).

But the bolded sentence is wrong. He does not say anything about developing ME/CFS after stress exertion, etc. in this section, or anywhere else for that matter. He mumbles at bit here, so I assume the AI hallucinated..

Edit: the entire section reads more like a summary than verbatim quotes. I suspect that might be the case for the rest of the translation as well..
Thank you, very handy to have a Norwegian person to make sense of this!
 
But the bolded sentence is wrong. He does not say anything about developing ME/CFS after stress exertion, etc. in this section, or anywhere else for that matter. He mumbles at bit here, so I assume the AI hallucinated..

Edit: the entire section reads more like a summary than verbatim quotes. I suspect that might be the case for the rest of the translation as well..
In defense of the AI, I think the issue is with the YouTube auto-translation. These are the subtitles:
Central to this is probably the regulation of blood flow in the tissue in relation to stress. It is certain that when patients are stressed, they quickly develop meltesy. They have problems increasing circulation enough in it, for example, with exertion, which causes us to get these characteristic symptoms of fatigue, feeling sick, exertion , cognitive symptoms, lethargy, and things like that .
 
In defense of the AI, I think the issue is with the YouTube auto-translation. These are the subtitles:
He says «slik at når pasientene belaster så lager de fort melkesyre…», which translates to «so that when the patients exert, they quickly create lactic acid (melkesyre)…».

edit: quickly isn’t a perfect translation. He means that they create it sooner than what you would normally.

«slik at» sounds a bit like «sikkert» (certain), which might be what threw the youtube AI for a spin.

Afaik, «meletsy» isn’t a word. But he said «melkesyre» (lactic acid). And it can kind of sound like ME/CFS, so the Youtube AI guessed based on the context.
 
Afaik, «meletsy» isn’t a word. But he said «melkesyre» (lactic acid). And it can kind of sound like ME/CFS, so the Youtube AI guessed based on the context.
Ah yeah, YouTube guessed meltsey and Claude guessed that meltsey meant ME/CFS from context. I tried another method of getting the auto-generated Norwegian subtitles and asking Claude to do the translation as well. I was adamant that it should not change content and to put anything it wasn't sure about in brackets, but it did take the liberty of adding headings. Let me know if this is better so I know for the future:
Background and Hypothesis
The concept is built on the same fundamental idea as our previous studies - namely that ME/CFS in a subgroup of patients is often a post-infectious disease that occurs after some form of trigger in patients who were previously healthy. What we believe is that the body creates antibodies that we normally produce to defend ourselves against our environment - antibodies that affect the body itself.

It has been shown in recent years that after infections, for example COVID infection or [Epstein-Barr virus], mononucleosis virus, or other infections, the body produces many antibodies that affect the body's own molecules. Some of these we believe are involved in disrupting function - so-called functional autoantibodies - and may help disturb the body's balance so that patients can develop the characteristic symptoms.

Central to this is probably the regulation of blood flow in tissues in relation to <exertion>. <So that> when patients are <strained>, they develop <lactic acid sooner than normal> and have problems increasing circulation sufficiently in tissues during exertion, for example, which causes these characteristic symptoms of fatigue, illness feeling, exertional intolerance, cognitive symptoms, [dizziness], and such things.

The Pilot Study Approach
This pilot study is based on affecting the so-called plasma cells, which are cells in the immune system that are primarily responsible for producing antibodies. We give a medication called Daratumumab, which is an antibody used in cancer treatment for patients who have multiple myeloma or bone marrow cancer, because it lowers the level of these plasma cells and [targets] plasma cells specifically.

When we use it, the intention is to reduce the number of plasma cells, particularly in the bone marrow, temporarily, and consequently reduce antibody levels in the blood temporarily. We hope that the effect can be lasting in some patients, so that when these antibodies are reduced, it leads to an improvement in the patients' symptoms.

Pilot Study Results
What we have seen in the pilot study is that 60% - that is, 6 out of 10 patients we have included - apparently have had a good effect on the symptom profile of ME/CFS disease. And in five of the six patients who have experienced clinical improvement, the response or improvement has been sustained for up to two years - as long as we have followed the patients.

One patient had a relatively early relapse after 3-4 months, a partial relapse, while the other five patients have had a sustained effect. We have not had any significant side effects from this - no serious adverse medical events. So we believe the tolerance has been good so far.

[The treatment involved] a little over 50 such injections. These injections are given subcutaneously - that is, under the skin on the abdomen. This has actually worked well.

Need for Larger Study
Even though we have seen good effects in these patients, we believe there is reason to conduct a larger study. The main reason is that we cannot draw any firm conclusions based on such a small pilot study with 10 patients. We cannot be certain that the medication alone is the cause of the observed improvements.

Therefore, we must conduct what we call a double-blind study where some patients receive active medicine and some patients receive inactive injections without active medicine, without either we or the patient knowing what they have received. These are called double-blind and placebo-controlled studies.

Planned Larger Study Design
We have planned this and are thinking of starting hopefully perhaps before or after summer, once the study is fully approved by the authorities. Initially, we plan to include 66 patients where 44 patients will receive active medicine with this Daratumumab medication that will reduce the number of plasma cells, and 22 patients on placebo - that is, an inactive injection that does not affect the immune system.

These patients will be followed up first for three months after inclusion in the study before they receive the first injection. Then they will be followed for 15 months after they have started treatment - 18 months in total. When the last patient has been observed for 18 months, the study will be closed. Then we will learn who received active treatment and who received placebo and can analyze the results.

Then we can get a relatively certain impression of whether this medicine is useful for patients and whether it provides good responses that last over time in a large enough proportion of patients.

Study Improvements and Methodology
We hope the study can get started and we hope it can contribute to raising the knowledge level about the disease and perhaps contribute to developing rational treatment. But we should not draw any firm conclusions before we have seen the results from the [randomized] study - that is, the double-blind study - so we don't make mistakes.

We have tried to learn from all the previous studies we have done to learn how to create a good protocol for the study that is now starting. This means we have tried to work on the inclusion criteria. We have tried to work on what outcome measures we should have in the study. We have incorporated continuous step counting with activity watches throughout the entire study course. We have included some tests that patients can do without becoming too exhausted. And we have several questionnaires that patients must fill out regularly throughout the study - validated forms that report symptom burden to try to find out whether this has a beneficial effect or not.

Statistical Considerations and Limitations
Regarding the number of patients we plan to include, we have clearly worked with statisticians on how many patients we need to be able to show if there is a difference between the active group and the placebo group. Since we essentially only have our own data from previous studies and observations from this pilot study to build on, the estimate is somewhat uncertain because the number of patients needed depends on how large the difference is between patients on average compared to the placebo group on average.

We must be open about saying that we have tried to estimate this as well as we can. But the number of patients that can be included is also limited by economics because this is a biological medicine. The pharmaceutical company that sells this did not want to give any discount for [supporting] the study. And it is difficult to get public funding. We have looked at this here and there.

Funding and Support
What is interesting is that patients and patient organizations and private individuals have largely made it possible to conduct this study. We are very grateful for this. We must then try as best we can to create the best possible protocol, make the best possible assessment of how the study should be conducted so that we manage this money as well as possible.

We cannot promise that such a study will be positive, but we can try to do as well as we can. The calculations underlying this suggest that if what we have seen in the pilot studies is somewhat representative, we should have a chance to show a significant difference.

Response Criteria and Patient Selection
We have estimated that there should be no more than 20% responders in the placebo group. Compared to previous studies, we have significantly tightened the requirements for response. The requirements for meeting response criteria in this study are much stricter than previously. This is because of what we have learned.

We have also conducted a study where we just followed patients over time without giving treatment to try to find out what the normal variation is for different patients over time. What we want to try to avoid is preventing normal symptom fluctuations from interfering with the response criteria, so we try to distinguish genuine responses caused by drug treatment from natural variation.

Therefore, we will not include patients who have the mildest degree of disease. Not because it may not be more than sufficiently troublesome for the patients, but because they fluctuate too much for us to be able to include them, as we are afraid this could increase the so-called response rate in the placebo [group].

Future Implications
If we don't succeed with this study, probably no one else will do it. We have [spent] a long time and we believe we are onto a principle and mechanism that is important to explain. It is clear that our immune system is extremely complex, difficult, and comprehensive. There are many different things that affect each other.

Nevertheless, when we try to say that we reduce plasma cells which should reduce antibodies which should provide improvement, this is a basic idea about how we want to affect the immune system. But we are constantly aware that it is much more complex than that. But it appears that this intervention does something beneficial for the patient course.

As I say, this is based on two years of observation of these patients and with a backdrop of experience from previous studies.

Edit: I see that it still did "likely" instead of "so that", but as you suspected, it's because that word for "certain" is in the auto-generated subtitles.

Edit: Made @Utsikt's suggested changes in <this format>.
 
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For «stress» he uses the word «belastning», which translates to «load», «strain» or «burden» in this context. He later uses «anstrengelse», which translates to «exertion». So I think he means «exertion» for the first instance as well.

Let me know if this is better so I know for the future:
The third paragraph that starts with «central» is better, even though it still uses «stress», re above. «Strained» is probably better, and it avoids the ambiguity of stress wrt mental stress etc, because he is clearly talking about physical activity here.
 
The pharmaceutical company that sells this did not want to give any discount for [supporting] the study.
I wonder if it would be worth trying to change this. For example, individuals or ME/CFS organisations could write to the drug company asking them to support the study - pointing out the severity of ME/CFS and the large numbers of people affected.

... manufactured and commercialized by Janssen Biotech, Inc, a subsidiary of Johnson & Johnson. However, the drug was developed and licensed to Janssen by Genmab. Genmab receives royalties from Janssen Biotech
There are a few organisations there that could be contacted.

Genmab A/S is a Danish biotechnology company, founded in February 1999 by Florian Schönharting, at the time managing director of BankInvest Biomedical venture fund.[7] The company is based in Copenhagen, Denmark – internationally, it operates through the subsidiaries Genmab B.V. in Utrecht, the Netherlands, Genmab U.S., Inc. in Princeton, New Jersey, US, and Genmab K.K. in Tokyo, Japan. Genmab is listed on the Copenhagen Stock Exchange in Denmark,[8] with American depositary receipts traded on the NASDAQ in the US.[9]
So, Genmab is a Danish company.

I think Janssen Biotech is headquartered in Belgium.

I'm just thinking, the small amount of funds that most of us could donate would be easily outweighed by a substantial discount on the drug cost - and a few powerful letters to the right person perhaps could achieve that. I think we'd probably need some guidance from the Norwegian ME Association on what should be done (and what has already been tried).
 
Rituximab kills cells carrying CD20, which is mostly B cells rather than their daughter plasma cells. B cells and new supply of B cells are mostly removed for about 5 months with a standard dosing. Short lived plasma cells presumably die off with the lack of supply of new ones from B cells but long lived plasma cells will not.

Daratumumab kills cells carrying CD38, which includes quite a lot of lymphoid cells but is particularly expressed on plasma cells. Daratumumab will kill a proportion of plasma cells already making antibody, including long lived cells.

If the problem in ME/CFS comes from antibody populations set up some time before, following an infection and produced by long lived plasma cells daratumumab would have logic to it.
Thanks.
 
@Jonathan Edwards, I know the response rate of 60% in the pilot will be an inaccurate estimate, even if real, because of the small number of patients but I'm wondering how many PwRA don't respond to rituximab and whether they have any options if they don't?

60% would be a ton better than the 0% we've got now but would leave a lot of PwME with nothing. I'm wondering what the implications are.

60% response rate will likely be an underestimate of the response rate since in the new trial they are excluding patients with low NK cells. All the non responders in the pilot had low NK cells.

Low NK cell patients will probably need something stronger maybe something like teclistamab. https://www.s4me.info/threads/teclistamab-for-me-cfs.44270/#post-612284
 
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