V.R.T.
Senior Member (Voting Rights)
Was this all from the anktiva? How many injections were there for that?
Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al
ryanc97
Senior Member (Voting Rights)
Like 4. Yes all from anktiva. Fever and chills are common if you look at the literature.
DiBelloBr
Established Member
Although it is a pilot study without a control group, it seems clear that Daratumumab works for some patients (and works very well).
And what also seems clear is that it may be a matter of time before symptoms return in these patients (there is already one responder being retreated in the study extension, and we have 6-year data from Cyclophosphamide and Rituximab where a significant proportion of responders eventually experienced a return of symptoms).
It does not seem feasible for Daratumumab to be used again at every relapse — both due to safety concerns (high risk of hypogammaglobulinemia, reduction of NK cells, and infections), and due to a potential reduction in efficacy with each new cycle (because of decreased NK cells and therefore reduced ADCC, but also due to the induction of resistance in plasma cells through lower expression of CD38).
I know that F/M are testing hypotheses, trying to identify the lowest effective dose of Daratumumab in order to maximize safety, and I deeply commend them for dedicating their lives and resources to this work even before the pandemic led to an explosion of cases, and at a time when governments and the vast majority of the medical community did not believe that CFS was an organic disease (many unfortunately still do not).
My impression is that an important next step, after demonstrating the benefit of Daratumumab in a subgroup in a phase 2 study, would be to determine how to maintain remission (or perhaps continue testing hypotheses with the participants who completed the pilot study?). My impression is that it may be useful to intervene before the disease evolves to AAB production by plasma cells, whether with Rituximab (which also has important safety concerns, but much more long-term experience and does not induce reduced expression of CD20 in B cells), or Belimumab (which is only approved for SLE, and unfortunately was not effective in Myasthenia Gravis, probably because it involves LLPCs).
With COVID-19, the eyes of the scientific community have begun to turn toward CFS, but at the same time that F/M struggle to secure research funding, they also hold the patent for the use of B-cell and plasma cell–targeted therapies in CFS (no judgment, since they were pioneers in this area when no one believed in it).
And what also seems clear is that it may be a matter of time before symptoms return in these patients (there is already one responder being retreated in the study extension, and we have 6-year data from Cyclophosphamide and Rituximab where a significant proportion of responders eventually experienced a return of symptoms).
It does not seem feasible for Daratumumab to be used again at every relapse — both due to safety concerns (high risk of hypogammaglobulinemia, reduction of NK cells, and infections), and due to a potential reduction in efficacy with each new cycle (because of decreased NK cells and therefore reduced ADCC, but also due to the induction of resistance in plasma cells through lower expression of CD38).
I know that F/M are testing hypotheses, trying to identify the lowest effective dose of Daratumumab in order to maximize safety, and I deeply commend them for dedicating their lives and resources to this work even before the pandemic led to an explosion of cases, and at a time when governments and the vast majority of the medical community did not believe that CFS was an organic disease (many unfortunately still do not).
My impression is that an important next step, after demonstrating the benefit of Daratumumab in a subgroup in a phase 2 study, would be to determine how to maintain remission (or perhaps continue testing hypotheses with the participants who completed the pilot study?). My impression is that it may be useful to intervene before the disease evolves to AAB production by plasma cells, whether with Rituximab (which also has important safety concerns, but much more long-term experience and does not induce reduced expression of CD20 in B cells), or Belimumab (which is only approved for SLE, and unfortunately was not effective in Myasthenia Gravis, probably because it involves LLPCs).
With COVID-19, the eyes of the scientific community have begun to turn toward CFS, but at the same time that F/M struggle to secure research funding, they also hold the patent for the use of B-cell and plasma cell–targeted therapies in CFS (no judgment, since they were pioneers in this area when no one believed in it).
OrganicChilli
Senior Member (Voting Rights)
Wouldn't they recover after a year or so?
Utsikt
Senior Member (Voting Rights)
Hi and welcome!
That was also said about Ritux which turner out to be a complete bust in the blinded trial. It’s too early to tell.
Depending on what the disease mechanisms are, that might not be possible with b-cell depletion. We don’t know if it targets the lynch pins or if something else is maintaining the cycles.
There is no evidence of auto-antibodies in ME/CFS as far as I’m aware.
Jonathan Edwards
Senior Member (Voting Rights)
I don't know of evidence of reduction in CD38 expression in plasma cell clones follwoing treatment. It would surprise me a bit. There might be selection by survival for lower expressing clones but presumably relapse would be due to new clones not yet exposed to selection?
jnmaciuch
Senior Member (Voting Rights)
I think the idea comes from cancer where that selection-by-survival dynamic is quite important because of the rapid proliferation and competition between cancerous cells harboring different mutations. I agree that the same dynamic probably doesn’t apply to a (suspected) antibody-mediated disease
Jonathan Edwards
Senior Member (Voting Rights)
Yup, that was my thought.
ryanc97
Senior Member (Voting Rights)
Why is this clear? One responder being retreated = 1/6 relapse. Cyclo and ritux are not the same drug. It is not comparable.
Jonathan Edwards
Senior Member (Voting Rights)
And these are not 'responders', merely people who improved subsequent to treatment!
DiBelloBr
Established Member
Yes, you are right. What applies to MM wouldn’t apply here. Thanks
DiBelloBr
Established Member
That’s a good point. Just using the same term that the authors of the paper we are discussing used to refer to the group of six volunteers who showed improvement.
They might be responders to the drug, but it’s inaccurate to call them that.
DiBelloBr
Established Member
Actually, 2/6 relapsed (one of them had a partial relapse during the study).
My point is that not everyone sustained the response over time (even after cyclophosphamide, rituximab, or daratumumab), so either retreatment should be considered (and it was) for those who relapse, or a strategy to maintain remission (e.g., after a second cycle of daratumumab). Since the authors suggest in the title of the paper that plasma cell depletion is being investigated, I was speculating about ways to avoid intermittent use of daratumumab over the years, as I’m not aware of this type of long-term application for this drug.
I mentioned rituximab (which might have a different effect following Daratumumabe) and cyclophosphamide together because both were included in the same 6-year follow-up article for the same disease.
I know it’s too soon, as we know little (or nothing) about the pathophysiology and we don’t have any drug approved in a phase 3 trial. I’m speaking from the perspective of a patient who hadn’t seen this degree of improvement following a drug tested in CFS before. Since everything is being tested based on hypotheses, I was simply putting forward another hypothesis: that a drug used after remission is achieved might have a different effect than if it were used during the symptomatic phase, for those who relapse and need it.
DiBelloBr
Established Member
Hi,
You’re right. I was speaking from the optimistic, not the scientific, perspective of a patient with CFS who had never seen this degree of improvement in daily step counts and scores following a drug treatment in a CFS publication.
It just seemed like too much of a coincidence not to mean something, even for a pilot study (scores can be easier to bias, but not having PEM despite such a large increase in steps, plus the correlation with NK cells and the sustained drop in IgG among those who remained well). I know there are many other possible biases that could be used to argue against the idea that the drug truly works (misdiagnosis, evaluator selection bias, and correlations based on such a small sample size, etc). In any case, anything is still possible, and this is simply my personal impression that some people with CFS might benefit from daratumumab—perhaps also a form of hope.
I suggested some maintenance treatment ideas based on the hypothesis of plasma cell, B-cell, and autoantibody involvement, which seems broadly aligned with what the authors may be considering, but it’s really a shot in the dark (even more so than the already speculative step of testing rituximab or daratumumab in the first place).
From my perspective, as a patient and also a physician, everything is still in the dark, and their line of thinking seems the most promising. I hope they find something conclusive soon.
Thanks for your thoughtful and polite comments.
Utsikt
Senior Member (Voting Rights)
Yes, Dara is used for b-cell depletion, but it has many other effects, some known and some unknown. Cell depletion per se might be irrelevant for ME/CFS.
I think the «responders» had a similar step count with Ritux, when you correct for the different types of sensors. See e.g. this comment.
There are also some anecdotes about long-lasting but eventually unsustainable increases in activity following Lightning Process courses.
And of course the spontaneous recoveries in the NIH study (the effort preference one).
Yes, it might be a bit too soon for those discussions because there are still so many unknowns.
They tested ritux because as oncologists they observed that some pwME/CFS that got cancer and was treated for their cancers also had their ME/CFS get a lot better.
Venicequeenf
Established Member
What do you mean by that? As germany now starts a trial with the same class of medication?
DiBelloBr
Established Member
F/M declare at the end of the paper their conflict of interest based on their involvement in a patent owned by Haukeland University Hospital, with F/M listed as inventors (we just don’t know in which jurisdictions the patent is valid).
Others can investigate it (the use of these mechanisms in CFS) as well, particularly when financed by governments, which would make more sense because they would not be waiting to profit from the patent itself, but rather from controlling a disease that is reducing their workforce and GDP. However, profits related to the patent/royalties would go to F/M / University in both scenarios (if the patent is valid in Europe). In the case of Germany, Sanofi is also involved and would have an even greater interest in the sale of Isatuximab, potentially moving faster than the Norwegian study with Daratumumab if they succeed.
This is how I interpreted the situation… F/M really want this research to move forward, while other researchers wouldn’t have the same financial incentive in case of success (except for pharmaceutical companies, which is the most common situation).
V.R.T.
Senior Member (Voting Rights)
I haven't seen any kind of a timeframe for the ixatuximab study, afaik there isnt a protocol or anything anywhere yet.
It would be good if it finished before or at the same time as dara, esp if both were positive. It would provide an added degree of confidence for off label prescription and phase 3.
Jonathan Edwards
Senior Member (Voting Rights)
I don't see patents as being a significant incentive for Fluge and Mella. They have a personal commitment to try to solve a biomedical problem that at least for one of them is very close to home. They don't cut corners. They actually want to get a useful answer. They will have good salaries and live in a nice place.
The chances of Haukeland getting much out of a discovery are probably quite small. I am personally familiar with this situation and pharma lawyers are way ahead of university lawyers. The best you can do is get another pharma company to hire even better lawyers to quash unjustified patents.