Daratumumab, isatuximab (CD38 drugs)

Seems like isatuximab is a “stronger” CD 38 drug than Daratumumab.
Anyone have any guesses why Fluge’s group went with Dara over isatuximab?

https://en.wikipedia.org/wiki/Isatuximab


“Chemically, isatuximab is similar to the structure and reactivity of daratumumab, hence both drugs show the same CD38 targeting. However, isatuximab shows a more potent inhibition of its ectozyme function. The latter gives potential for some non-cross reactivity. Isatuximab shows action of an allosteric antagonist with the inhibition of the CD38 enzymatic activity. Additionally, isatuximab shows potential where it can induce apoptosis without cross linking.[22]Lastly, Isatuximab reveals direct killing activity when a larger increase in apoptosis is detected in CD38 expressing cancer cells. Furthermore, isatuximab demonstrated a dose dependent inhibition of CD38 enzymatic activity. However, daratumumab with the same experimental conditions shows a more limited inhibition without a dose response.[23]”
 
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Jaybee00 said:
Anyone have any guesses why Fluge’s group went with Dara over isatuximab?
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Daratumumab is a high risk drug, so maybe isatuximab is even riskier?

I don't know, of course, but I find the idea of using immune-suppressing cancer drugs really scary. Even if effectiveness for ME/CFS was established, I wouldn't automatically accept treatment if the only option was a drug like this. I might be persuaded, but it wouldn't be an easy call.
 
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I am not sure that the information given above tells us much about efficacy. I would not expect inhibitory effects on CD38 to be relevant. What is relevant is cell killing, which is unrelated. It says something about differences in killing but what matters is simply the effect on Ig levels in humans. Differences in pharmacology exist for rituximab and ocrelizumab etc but may not make a lot of difference to usage. There may well be patent reasons for making claims like this.
 
Jaybee00 said:
Who said that Daratumumab is a high risk drug?
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The fact that the common or very common side effects include sepsis, pulmonary oedema, pancreatitis, increased risk of infection, and others.

These aren't trivial.

Statements about drugs being well tolerated need questioning too. They could mean "well tolerated in a small and atypical group", or "well tolerated, considering the patients have relapsed blood cancer".
 
Just an observation.

With the first cyclo study (Rekeland et al.) it looked like the critical factor for response was whether you had either of the two HLA risk alleles.

Then in Rekeland’s dissertation, she didn’t delve into the HLA alleles again, but noted that the baseline (low) IGG levels were the critical factor for a response to cyclophosphamide.

Then in the talk that Rekeland gave in Sweden last year she brought up low IGG as being the important factor with respect to response to Daratumumab.

Now in the recent talk in Berlin, Fluge mentioned that high baseline NK cells is the key factor to responding to Daratumumab, and doesn’t mention low IGG or the risk alleles as critical factors for responding to Daratumumab.

Was thinking about this because we were all freaking out about our IGG levels, and we now maybe we should freak out about our NK cell quantity.

ETA—maybe you would be a super-responder if you had the 2 risk alleles, low IGG and high NK cells?
 
I like the idea that daratumumab might work but yes, there is no real evidence yet.

It just struck me that the confusion might be because cyclo works and Dara doesn't - for ME/CFS.
And the ones with ME/CFS in the Dara study are the ones with low NK numbers as Klimas and co would have it. The 'responders' have some other problem that may get better after Dara treatment for whatever reason. But I don't think we have good evidence for that either.

Let's wait and see.
 
Jonathan Edwards said:
It just struck me that the confusion might be because cyclo works and Dara doesn't - for ME/CFS.
And the ones with ME/CFS in the Dara study are the ones with low NK numbers as Klimas and co would have it. The 'responders' have some other problem that may get better after Dara treatment for whatever reason.
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You mean you think it’s possible that patients with ME/CFS symptom but with high NK cells might have a different disease from patients with ME/CFS symptoms but with low NK cells?
 
EndME said:
there is also no evidence yet that there is any "response"
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I’m pretty convinced by the limited data presented. But maybe I also send money to Nigerian Princes to claim my 20 million in gold bullion.

But here’s the thing—you could have a Phase III trial with huge numbers of patients and “significant” responses and there will be people claiming the trial wasn’t valid or good enough because it didn’t include enough red haired, left handed hemophiliacs, and they didn’t use significance levels of p<.00000001. Different people require different levels of evidence.
 
Jaybee00 said:
I’m pretty convinced by the limited data presented. But maybe I also send money to Nigerian Princes to claim my 20 million in gold bullion.

But here’s the thing—you could have a Phase III trial with huge numbers of patients and “significant” responses and there will be people claiming the trial wasn’t valid or good enough because it didn’t include enough red haired, left handed hemophiliacs, and they didn’t use significance levels of p<.00000001. Different people require different levels of evidence.
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It is not a question of left handed haemophiliacs or red haired people, it is not about semantics, convincing or different levels of evidence and one doesn't need massive sample sizes either.

We know from the Rituximab trials that a significant amount of "responses" are not responses at all, but simply placebo-like effects (including natural recovery, regression to the mean, Hawthorne effect etc), because those effects are witnessed in people that did not receive any drug to begin with! So it's very possible that, that is all that is being witnessed. That is knowledge one cannot neglect.

So it's not about having a different level of statistical significance or larger sample sizes but it's about having a control group that actually offers control over these hidden variables (which is something a well chosen placebo in a triple blinded study hopes to accomplish).
 
Jonathan Edwards said:
And the ones with ME/CFS in the Dara study are the ones with low NK numbers as Klimas and co would have it. The 'responders' have some other problem that may get better after Dara treatment for whatever reason. But I don't think we have good evidence for that either.
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Just trying to understand what you could imply here.

You mean the responder ME-patients (with starting high NK cells) might :
- have different disease mechanism vs non-responder ME-patients with low NK cells?
- or maybe a different phase / phenotype ME ?
- Or some immune comorbidity - others patients don’t have


(hypothetically, assuming it’s not placebo, random, etc etc)
 
Arfmeister said:
Just trying to understand what you could imply here.
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My worry was that the 'responders' are people with another illness that easily gets better who are having a placebo response to Dara whereas these with low NK have ME/CFS. The conclusion being that Dara doesn't do anything specific but the higher NK cell levels pick out people who can get better spontaneously.
 
There was a member on here who I believe is no longer active that suggested that some patients with an ME/CFS diagnosis may have a type of Neuro-Sjogrens.

FWIW, on Twitter I see people who say that they have both (neuro) Sjogrens and ME/CFS
 
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