Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al

ryanc97 said:
Does the very binary response tell us anything at all? There were no middle responders for example - all reached normal levels or remained at baseline
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May also be a consequence of choice of outcome measures.

For example for the placebo-controlled trial the outcome measures seems to be:
Primary: DSQ-SF total score
Secondary: 2 modified DSQ-SF scores, SF-36 Physical Function, steps, Function level, AEs
and then a whole host of exploratory outcome measures (FUNCAP, heart rate and HRV, handgrip strength, NASA lean, workload, PVP,....).
 
What is the link between the measure used and this binary response in this case? It’s either line went up by a big amount or line stayed flat.

No line went up in the midele
 
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ryanc97 said:
What is the link between the measure used and this binary response in this case? It’s either line went up by a big amount or line stayed flat.

No line went up in the midele
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Insofar that not all of the data of the study might look like that, but then I realised that expect for a few exceptions (like NIRS which might have failed for other reasons and as a consequence is also not part of the larger trial and HRV which is probably anyways not particularly interesting) they are reporting all data.

But I would suggest that at least one or 2 people are looking a bit variable, which should be expected.
 
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He is an autoantibody specialist.
 
He agrees with me it’s an LLPC problem. Or he believes AABs are responsible for a lot of unsolved chronic illnesses. So suggested he reach out to FM and they are working on a project using blood samples from the pilot study with the end goal of finding out if it is an AAB problem or not
 
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Nice work introducing them @ryanc97 will be interesting to see what they turn up.

Do you know if he/they are also looking at NK cells themselves? We’ve talked before about the idea of memory in the innate immune system as well as the adaptive, there seems to be increasing discussion of memory here and in NK cells.

I think you do get situations in Daratumumab with NK cells killing other NK cells. Now if there is a problem for us with these memory NK cells and you want nice new fresh ones to kill them then boosting numbers of fresh ones makes sense. I can definitely see that being a possibility. And maybe there’s something like differential CD38 expression on different NK cell subtypes to boot. Just speculation but some thoughts that have been floating around my head recently. And an alternative to traditional auto-antibody or ‘exhausted’ NK cell mechanisms.
 
Jonathan Edwards said:
There are a whole range of possible ramifications f a positive result. But in very simple terms it might mean B cells and antibodies are involved (maybe in some way we are not familiar with yet) and it might alternatively mean that activation of a whole range of immune cells, inluding NK cells, t cells and macrophages is involved, through a particular signal pathway.

But if the drug is effective it should not take too long to find out which.
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If daratumumab were found to be effective, is it possible or even likely that there could be a similar but different mechanisms in different responders? For example, could it be that ME/CFS is caused by different antibodies with different targets in different patients but that by depleting the long lived plasma B cells producing these different antibodies, the treatment works for all?

Do we know if F&M are collecting the samples before and after treatment that would be necessary to work out the mechanism if daratumumab was found to be effective? Or would that only be done as a separate study after trials are completed?
 
hotblack said:
Do you know if he/they are also looking at NK cells themselves? We’ve talked before about the idea of memory in the innate immune system as well as the adaptive, there seems to be increasing discussion of memory here and in NK cells.

I think you do get situations in Daratumumab with NK cells killing other NK cells. Now if there is a problem for us with these memory NK cells and you want nice new fresh ones to kill them then boosting numbers of fresh ones makes sense. I can definitely see that being a possibility. And maybe there’s something like differential CD38 expression on different NK cell subtypes to boot. Just speculation but some thoughts that have been floating around my head recently. And an alternative to traditional auto-antibody or ‘exhausted’ NK cell mechanisms.
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You can get NK cell therapy or infusions, but they are expensive.

In MM researchers engineer cd38 KO NK cells via gene editing then they infuse them. Unfortunately those are only in trials and there is no way we can get them
 
I know this is purely speculative, but, if Daratumumab actually worked, wouldn`t we expect to see patients reporting improvement trying the treatment off-label by now? Improvement should happen within 10 weeks, which is a massive advantage here compared to when patients were trying rituximab offlabel.

Seems like a couple of patients have tried it already, yet personally I have not been able to find a single case of what looks like off label improvement. Looking at the different FM studies you would expect at least some placebo improvement if enough patients try it.

Maybe Fluge and Mella really do produce super placebo, or maybe they did get lottery numbers lucky (or unlucky) in the P1 depending on how you see it.

The only change I have heard of has been a worsening of symptoms. Which again shows the massive risks doing these offlabel treatments when we don`t even know if they work. I can only reiterate that ppl should not try these treatments at the current moment.
 
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Rick Sanchez said:
I know this is purely speculative, but, if Daratumumab actually worked, wouldn`t we expect to see patients reporting improvement trying the treatment off-label by now?
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Just to speculate about things that might make an effective treatment appear to be ineffective when used randomly:

Incorrect diagnosis
Additional diagnoses
Different doses
Different schedules
Drug and supplement interactions
Turbulent period with excess activity

Essentially all of the things you try to control in a trial, or in medicine in general.
 
Rick Sanchez said:
I know this is purely speculative, but, if Daratumumab actually worked, wouldn`t we expect to see patients reporting improvement trying the treatment off-label by now?
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High cost of and difficult logistics of obtaining Dara is limiting the number of experimenters.

Also no evidence that it works in males in the pilot. And females tend to be more risk adverse.
 
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Rick Sanchez said:
I know this is purely speculative, but, if Daratumumab actually worked, wouldn`t we expect to see patients reporting improvement trying the treatment off-label by now? Improvement should happen within 10 weeks, which is a massive advantage here compared to when patients were trying rituximab offlabel.

Seems like a couple of patients have tried it already, yet personally I have not been able to find a single case of what looks like off label improvement. Looking at the different FM studies you would expect at least some placebo improvement if enough patients try it.

Maybe Fluge and Mella really do produce super placebo, or maybe they did get lottery numbers lucky (or unlucky) in the P1 depending on how you see it.

The only change I have heard of has been a worsening of symptoms. Which again shows the massive risks doing these offlabel treatments when we don`t even know if they work. I can only reiterate that ppl should not try these treatments at the current moment.
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This is what has been concerning me in the last few weeks.

Some of these patients will have had a small dose like Habets was giving but i assume not all...

I would really like this drug to work for at least some of us but I do find the lack of positive off label stories concerning. You would think there would be at least a couple. Just think how many can be found for other drugs that probably don't work, like long covid antivirals or whatever.

There's the one bloke who seems to have responded after 6 months and thats about it for dara. Obviously these stories without good trial data aren't proof of efficacy but their absence is disqueting.

Perhaps dara is less accessible than other drugs so less people who are potential responders for whatever reason try it and have a chance to respond positively. Or perhaps it simply doesn't work.

I think if these severe patients respond that will be a pretty good indication there may well be some merit to this drug for MECFS.

Perhaps we'll here more at Charite
 
I'll just say this - can't give too much info away yet - I collect and record most people (except 1) who tries Dara and Tecli off label. With things like NK and IGG if available. I would say there are maybe 10 people who did either Dara or Tecli off label.

There are a few male improvers (partial) from Dara, some in fatigue, some in PEM. But the response is much later than 8 weeks, maybe 12-16 weeks. In the study to reach full health, they took at least half a year.

There are no improvements from Teclistamab, in fact, worsenings. Which makes me think BCMA is not really expressed on the bad LLPC.
 
When the rituximab study P3 results came out, one thing that particularly surprised me was how many patients come out and said they expected the trial to fail, because they or someone they knew had tried the drug. Including well known community advocates.

From my experience of being in the MECFS community for a long time now, I would say that a lot more people are trying it without telling anyone about it, or trying it without really being part of an online community like reddit or Twitter. As in a lot more people than anyone who wasn`t around for rituximab expects. This really isn`t to gatekeep. I think it`s just hard to wrap your head around things you weren't around to experience.

I am not trying to spread doom and disappointment. I was very bullish on this study and donated to it. I just want to warn that the current situation is eerily like the rituximab study. I know a lot of lurkers keep an eye on this thread. So if you are considering trying this before the Ptwo study results are out, don`t. Just wait. Two years seems like an eternity early on in MECFS, I know, but time teaches you otherwise.

I agree completely Vrt. I wouldnt see any success stories as proof of anything. But the complete absence of any story that at least claims a doubling in step count or something similarly tangible is worrying at this point.
 
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