Daratumumab, isatuximab (CD38 drugs)

Just wanted to put this all in one spot:

Subcutaneous Daratumumab injection schedules from Fluge’s group.

Pilot group 1 Week 0,2,8,10
Pilot group 2 0,2,4,6,14,22,30

Amendment to pilot: 0, [10], 24, 48
(Week 10 only if no response)

Phase 2 0,2,4,24,26

Based on what Fluge et al. wrote in their dara article and comments by @Jonathan Edwards that dara likely kills cells very quickly, I’d posit that the amendment protocol would be/should be effective and the most cost effective.

In the pilot there wasn’t much/any difference between the 4 and the 7 injection treatments.

Plus dara has a long half life of about three weeks.
 
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Also Fluge note that even with the high dara dosage protocols for Multiple myeloma, NK cells are not completely depleted.

They also note in their article that for other autoimmune diseases there didn’t appear to be a relationship between effectiveness and the number of dara injections.
 
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Jaybee00 said:
Also Fluge note that even with the high dara dosage protocols for Multiple myeloma, NK cells are not completely depleted.

They also note in their article that for other autoimmune diseases there didn’t appear to be a relationship between effectiveness and the number of dara injections.
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If you look at the NK cell plots for the pilot study a few of them had NK cells go to almost 0 after the first dose.


Is this because ME patients have lower NK than MM patients?
 
V.R.T. said:
Scheibenbogen seems to be doggedly perservering nonetheless...

Glad to see this isa trial though. CD38 is all the rage it seems.
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From her latest interview:

The most promising approaches are based on monoclonal antibodies that target the cells producing autoantibodies – in other words, B cells or plasma cells. More than ten years ago, there was already a pioneering study from Norway with the drug rituximab. Many of those treated responded well to it, and some even had lasting responses; some were even completely cured. Unfortunately, the subsequent multicenter clinical trial produced a negative result.

There were many reasons for this. On the one hand, the dosage was probably not sufficient; in addition, four of the centers had less experience and may not have included the right patients. Today there are more effective B-cell antibodies with fewer side effects. Moreover, the approach has gone a step further and now directly eliminates the plasma cells, that is, the mature B cells.

www.spektrum.de

ME/CFS: »Meine Hoffnung ist groß, dass wir bald wirksame Therapien haben«

Die Expertin Carmen Scheibenbogen über Ursachen von ME/CFS, den Versorgungsmangel in Deutschland und Hoffnung auf Medikamente.
www.spektrum.de www.spektrum.de
 
Jonathan Edwards said:
This is credible, I admit. Multicenter trials tend to recruit patients with little chance of response. The motivations are wrong.
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Why should it matter? If the box has no eggs inside it doesn't matter whether the imaginary eggs are green or yellow?

The response was higher to placebo than to Rituximab across the different centers and in most of the individual centers. Fluge and Mella had a higher response to the placebo than most other centers and their placebo response was substantially higher than the response to the drug. In fact it is precisely Haukeland where the response to placebo is much higher than the response to the drug (40% response to placebo, 20% response to drug), so the argument is exactly the opposite. So if they selected patients correctly and all others didn't, the eggs are still non-existent, in fact they are even more rotten in imagination.
 
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ryanc97 said:
If you look at the NK cell plots for the pilot study a few of them had NK cells go to almost 0 after the first dose.


Is this because ME patients have lower NK than MM patients?
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Chat GPT says MM patients in active disease have low NK cells. I am guessing lots of injections are needed in MM because a lot of cells are tied up in various tumors.


  • Active multiple myeloma:
    • NK cell numbers often decrease compared to healthy people.
    • Function is impaired: the NK cells that remain are less effective at killing myeloma cells because:
      • Myeloma cells shed ligands that block NK cell activating receptors.
      • The bone marrow environment becomes immunosuppressive (lots of T-regs, myeloid-derived suppressor cells, cytokines like TGF-β).
      • Chronic stimulation leads to NK cell “exhaustion.”

  • After treatment (esp. with daratumumab):
    • Daratumumab depletes CD38+ NK cells (since NK cells also express CD38).
    • This sounds bad, but paradoxically it helps restore a healthier immune environment, because daratumumab also removes suppressive CD38+ regulatory cells and allows T cells to rebound.
    • NK cell function can partially recover during remission or after immune-boosting therapies (like lenalidomide).
 
Jaybee00 said:
Chat GPT says MM patients in active disease have low NK cells. I am guessing lots of injections are needed in MM because a lot of cells are tied up in various tumors.


  • Active multiple myeloma:
    • NK cell numbers often decrease compared to healthy people.
    • Function is impaired: the NK cells that remain are less effective at killing myeloma cells because:
      • Myeloma cells shed ligands that block NK cell activating receptors.
      • The bone marrow environment becomes immunosuppressive (lots of T-regs, myeloid-derived suppressor cells, cytokines like TGF-β).
      • Chronic stimulation leads to NK cell “exhaustion.”

  • After treatment (esp. with daratumumab):
    • Daratumumab depletes CD38+ NK cells (since NK cells also express CD38).
    • This sounds bad, but paradoxically it helps restore a healthier immune environment, because daratumumab also removes suppressive CD38+ regulatory cells and allows T cells to rebound.
    • NK cell function can partially recover during remission or after immune-boosting therapies (like lenalidomide).
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I mean here with CFS we are hoping to get away with a single shot. Meanwhile MM patients are taking like 14 shots of it?
 
OrganicChilli said:
From the Fatigatio live stream today: Carmen Scheibenbogen says they have secured funds to trial Isatuximab (she mentioned a CD38 depleting drug from Sanofi and there's only one).

She says Sanofi are interested in cooperating based on recent results.

Edit: Updated video at 23:50

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I found it notable that her slide shows the trial (AIM-ME) starting early-to-mid 2026.

Might be a bit ambitious, especially if they are waiting for the CD19/20 funding.
 
fst said:
I found it notable that her slide shows the trial (AIM-ME) starting early-to-mid 2026.

Might be a bit ambitious, especially if they are waiting for the CD19/20 funding.
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That does sound very ambitious. If it wasn't for her apparantly saying they want to start at the same time I'd say that meant they were starting AIM ME before PIONEER. Which frankly sounds like a better plan than stalling until the CD19/20 trials can go ahead.
 
V.R.T. said:
That does sound very ambitious. If it wasn't for her apparantly saying they want to start at the same time I'd say that meant they were starting AIM ME before PIONEER. Which frankly sounds like a better plan than stalling until the CD19/20 trials can go ahead.
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I agree. However, she explicitly says they want to do it in parallel. This doesn't necessarily imply exact same starting date to me, but probably funding for both arms first. So i don't think plans have changed.
 
fst said:
However, she explicitly says they want to do it in parallel. This doesn't necessarily imply exact same starting date to me, but probably funding for both arms first.
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Why don't they start with AIM-ME asap? Is there an advantage to doing everything at the same time in terms of resources or recruitment?
 
OrganicChilli said:
Why don't they start with AIM-ME asap? Is there an advantage to doing everything at the same time in terms of resources or recruitment?
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I am baffled by this. Why anchor a funded trial of a class of drug that has shown real promise in a pilot trial to a trial of a class of drug that has failed phase 3 and therefore will struggle to get funding?
 
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V.R.T. said:
I am baffled by this. Why anchor a trial of a class of drug that has shown real promise in a pilot trial to a trial of a class of drug that has failed phase 3 and therefore will struggle to get funding?
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Weirdly, AIM-ME has gained no traction on social media. German patients are normally up in arms about lack of government funding, but now that funding is available and a researcher is blocking progress, everyone's quiet. Maybe people missed the announcement?
 
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V.R.T. said:
I am baffled by this. Why anchor a funded trial of a class of drug that has shown real promise in a pilot trial to a trial of a class of drug that has failed phase 3 and therefore will struggle to get funding?
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Combination therapy, or control group maybe? I haven't really thought this through, but it could be an interesting approach. I assume the experience of being administered either drug A or B would be less distinguishable.
 

Effect of daratumumab on normal plasma cells, polyclonal immunoglobulin levels, and vaccination responses in extensively pre-treated multiple myeloma patients - PMC

pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

In conclusion, our data show that daratumumab reduces the frequency of normal PC, which is reflected in reduced levels of polyclonal IgA, IgE and IgM upon initiation of daratumumab treatment. However, our data also demonstrate that a proportion of normal PC persists during daratumumab treatment, which may be related to downregulation of CD38 on their cell surface. These resistant, normal PC are likely responsible for the stable levels of polyclonal IgG during treatment. The recovery of polyclonal IgM and IgE to baseline levels, as well as the generation of protective IgG antibodies following vaccination during daratumumab therapy, to a similar extent as observed in daratumumab-naïve patients, indicates that B cells can differentiate into PC during daratumumab treatment, which is in contrast to data obtained from vaccination studies with B-cell-depleting therapies such as rituximab.<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7271608/#b15-105e302">15</a> We therefore recommend routine vaccination, also in patients undergoing daratumumab treatment, to reduce infection-related morbidity and mortality. Furthermore, daratumumab-treated patients with low IgG levels and recurrent infections may benefit from IgG replacement therapy.
 
Jaybee00 said:

Effect of daratumumab on normal plasma cells, polyclonal immunoglobulin levels, and vaccination responses in extensively pre-treated multiple myeloma patients - PMC

pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

In conclusion, our data show that daratumumab reduces the frequency of normal PC, which is reflected in reduced levels of polyclonal IgA, IgE and IgM upon initiation of daratumumab treatment. However, our data also demonstrate that a proportion of normal PC persists during daratumumab treatment, which may be related to downregulation of CD38 on their cell surface. These resistant, normal PC are likely responsible for the stable levels of polyclonal IgG during treatment. The recovery of polyclonal IgM and IgE to baseline levels, as well as the generation of protective IgG antibodies following vaccination during daratumumab therapy, to a similar extent as observed in daratumumab-naïve patients, indicates that B cells can differentiate into PC during daratumumab treatment, which is in contrast to data obtained from vaccination studies with B-cell-depleting therapies such as rituximab.<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7271608/#b15-105e302">15</a> We therefore recommend routine vaccination, also in patients undergoing daratumumab treatment, to reduce infection-related morbidity and mortality. Furthermore, daratumumab-treated patients with low IgG levels and recurrent infections may benefit from IgG replacement therapy.
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Polyclonal IgG levels remained unchanged, which may be explained by a subset of normal PC with reduced CD38 expression that survived during daratumumab therapy.

That is a pretty striking finding. It seems to suggest that if daratumumab has any efficacy in ME/CFS it is not due to killing plasma cells!
 
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