Open Pilot study in Norway - Daratumumab in ME/CFS

Subcutaneous dara is dara plus hyaluronidase-FIHJ. Does anyone what FIHJ stands for? Thanks.

 

I cannot find a specific explanation but I suspect it means that the hyaluronidase is specifically a human recombinant preparation. FIHJ might mean something like 'for infection, human recombinant- type J'.

Why you would want to use hyaluronidase for treatment of autoimmunity is hard to follow. The use of hyaluronidase is said to relate to tumour penetration, which would not be relevant. In this case it might be intended to improve absorption from subcutaneous tissue but that seems a bit dubious.

 

It's not "FIHJ", it's "fihj". When you see a hyphen followed by four lowercase characters after the name of a biologic, that's what is called a "distinguishing suffix":

https://www.fda.gov/files/drugs/pub...Biological-Products-Guidance-for-Industry.pdf

ETA: found the specific one!

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/761145Orig1s000NameR.pdf

 

From the page for the study at Haukeland University Hospital (Google translate) :

«In order for daratumumab to be absorbed by the body, it is combined with another substance called hyaluronidase. Hyaluronidase is an enzyme (protein) that regulates how quickly daratumumab is absorbed by the body.»

 

Yes, it's odd because other monoclonals have been given subcutaneously without hyaluronidase.
Moreover, there doesn't seem to be any hurry about getting a monoclonal absorbed if it is intended to act over a period of days or weeks.

The technology may have changed since I was involved. It may be that without hyaluronidase a significant amount antibody is lost to local tissue degradation.

Most of the sites mentioning hyalronidase- fihj in the context of daratumumab say the hyaluronidase is to penetrate tumour, which maybe is wrong.

 

Intuitively makes sense. Can’t find anything conclusive myself. A quicker release could maybe saturate CD 38 receptors faster, and thus allow for lower dosing? (https://pmc.ncbi.nlm.nih.gov/articles/PMC5511594/)

 

@Jonathan Edwards

Do these data potentially change your mind about Daratumumab being a viable treatment for MECFS?

Also why is it that people with lower initial IGG respond better to both dara and cyclo?

I thought that high IGG potentially indicated autoimmune diseases involvement. So therefore wouldn’t you expect high IGG patients to respond better to these treatments?

 

I wouldn't expect total IgG levels to be terribly relevant to any response.
And we are expecting a fall over that time frame so not sure it needs to link to symptoms.
The improvement in symptoms is substantial but then we don't have any controls and we saw things like that with rituximab.

Initial levels of IgG are unlikely to mean anything. I don't see enough data to generalise ?

 

I thought high IGG meant a more severe disease state, therefore harder to treat?

 

Total IgG is not usually raised in autoimmunity. It can be, in some very specific conditions like Felty's Syndrome and Sjögren's syndrome but these are anomalous. Low IgG is a more typical feature of lupus - it can be seriously low. Autoimmunity is also more common in people with various Ig deficiencies. High IgG levels are much more a mark of benign or malignant B cell neoplasia.

 

Just want to add my comments to these slides as I am impressed (and hopeful)

1. slide RCT 2025?
- results Pilot study in Norway n= 10 after 1 year : promising and well tolerated
- A larger placebo controlled RCT trial is going to be planned (in 2025?)




***
2. With regards to the second slide (attached) : 2 responders + 1 non-responder

- The 3 patients seem to be Moderate ME CFS - according to steps (2000/day)
- 2 responders increase daily steps from around 2000 to around 10,000 in 1 year ( + big increase SPF PF + DSQ score)

I am impressed by these results - basically going from Moderate to Mild
- Maybe even severe/moderate to very mild - as average 10,000 might allow to work
- making the assumption that the no-nonsense Norwegians Fluge & Mella know by now how to select the ‘hard-core’ ME CFS patients (long-term pre-Covid, severely disabled, Mostly housebound etc.)
I guess all Moderates would sign for that - if chances of worsening are minimal

So the only possible concerning is the 1 non-responder (with little IgG Change) dipped in steps / functionality for 4 months - and recovered to the same baseline (roughly).

Purely based on my exposure to 100s of long-term ME CFS patients anecdotes and reading research trials:
- the chances of having a crash from anything (e.g. visiting a hospital for a trial when severe-moderate) are much bigger than having a huge remission in 1 year

Still, we need to wait for the actual results and hopefully they can start the placebo RCT trial very soon.

***
3. Hope they will give more data and clarity on their theory on the relation between (a) lowering IgG and (b) A positive treatment response.
- from their presentation it seems a defining marker for them

 

Average 10’000 steps is higher than the population average. That almost sounds like remission going from step count alone.

 

Interesting to know is dr. Habets from Germany is also currently doing his mini Long Covid trial n=6
(a bit of a maverick doc, but at least he’s trying)

n=6https://twitter.com/user/status/1862512893238841591

 

I thought measuring IgG in this study was to have a proxy measure of plasma cell depletion and therefore aberrant IgG autoantibodies potentially driving ME?

 

But if you know that there will be some plasma cell loss and that will lead to lower IgG the occurrence of a fall across the board tells you nothing much. Plasma cell populations are very heterogeneous and autoantibody producing plasma cells fall into different compartments in different diseases and different individuals with those diseases so individual IgG falls do not tell us anything useful about relative autoantibody falls in those individuals.

My main point was that high or low IgG levels at the start do not tell us anything about presence of autoimmunity. In autoimmunity people have a different spectrum of antibody affinities, not more antibodies.

 

Am I the only one who’se quite excited by this. 2 near remissions out of 3 sounds quite promising. Do the researchers who did this have a good reputation?

Edit, the 3 patients is an example group while the pilot has 10 ppl total. my bad.

 

Something else he mentioned in the video that might be interesting: "We just got a paper accepted in Molecular Psychiatry, where a few patients with OCD were treated with Rituximab, and actually, it worked."

Thread: Three cases with chronic obsessive compulsive disorder report gains in wellbeing and function following rituximab treatment, 2024, Gallwitz et al

 

Yes. Ingrid is not in the same group as Jonas. Ingrid did her Ph.D. in Bergen with Fluge’s group. The only knock on Ingrid is that she doesn’t respond to emails even from Norwegians.

 

@Jonathan Edwards or anyone else.

Do we know why 4 injections are needed? And why the 2 week interval?

Since Dara is really expensive, if patients could get away with 3 injections (and get enough cd38 depletion), it would really be a cost saver.