Open 2022 Pilot study in Norway - Daratumumab in ME/CFS

Kalliope

Kalliope

Senior Member (Voting Rights)
Fluge et al are recruiting six moderate to severe ME patients for a pilot trial on Daratumumab.

Participants need to be able to travel to Haukeland University Hospital in Bergen and been diagnosed according to the Canadian criteria from 2003.

They need to be between 18 and 65 years old and have been sick for at least 2 years.

They will be asked to regularly fill out questionnaires and to use a FitBit watch to register level of activity. This registration will begin with a period of minimum 12 weeks without any treatment, in order to register symptoms and activity.

Daratumumab will be given as a subcutaneous injection in the stomach 4 times with 2 weeks interval. Blood tests will be taken every time. Then there will be a follow up period for nine months after first treatment.

As they have extra focus on safety, they will do the study in two steps. An independent group will be making an evaluation after the first two patients have 4 treatments. If there are no unexpected and severe side effects, the last four patients can start the treatment.

The study is to last for 1 or 1 1/2 years.

Information in Norwegian here:
https://helse-bergen.no/kliniske-studier/daratumumab-ved-mecfs
 
Wikipedia on Daratumumab:

Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38,[2] which is overexpressed in multiple myeloma cells.[3] Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.[4]

Daratumumab was granted breakthrough therapy drug status in 2013, for multiple myeloma. It was granted orphan drug status for multiple myeloma, diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma.[5]

Side effects
Treatment of multiple myeloma with daratumumab potentially increases the patient's susceptibility to bacterial and viral infections, due to the killing of natural killer cells (which are the main innate immune system defense against virus).[14] Daratumumab frequently causes human cytomegalovirus (CMV) reactivation by an unknown mechanism.[15] Injection related reactions (inflammation-like) are also common.[16]

https://en.wikipedia.org/wiki/Daratumumab
 
Interesting... so they still think there might be something more to explore here, with using monoclonal antibodies for immunosuppression. This time targeting a slightly different array of immune cells than they did with rituximab (which binds to CD20).

"Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38..."

CD38
Tissue distribution
"CD38 is most frequently found on plasma B cells, followed by natural killer cells, followed by B cells and T cells, and then followed by a variety of cell types.[12]"

Plasma cell
"Plasma cells, also called plasma B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes[1][2] and secrete large quantities of proteins called antibodies in response to being presented specific substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen (foreign substance), where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell.[3]"​
 
Jonathan Edwards said:
I would be very cautious about using drugs of this sort in the presence of the pandemic. Patients may have unfortunately died because rituximab has blocked their ability to respond to vaccination. Covid has completely changed the rules about using immunosuppression in the developed world.
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Good point. I hope they have thought about it and are able to take precautions at the hospital. It's a cancer ward, so they must be? As far as I understand the injection only takes a few minutes, so participants don't have to stay for hours in a room with other people for treatment.

Otherwise moderate/severe participants will mean housebound, so hopefully exposure can be kept at minimum if the participant's families also are willing and able to be careful.

But what a dilemma this must be for clinicians and patients in a pandemic.. And in this country we now pretend the pandemic is over so it's even more difficult for those who are clinically vulnerable to be safe.
 
Kalliope said:
Good point. I hope they have thought about it and are able to take precautions at the hospital. It's a cancer ward, so they must be? As far as I understand the injection only takes a few minutes, so participants don't have to stay for hours in a room with other people for treatment.

Otherwise moderate/severe participants will mean housebound, so hopefully exposure can be kept at minimum if the participant's families also are willing and able to be careful.

But what a dilemma this must be for clinicians and patients in a pandemic.. And in this country we now pretend the pandemic is over so it's even more difficult for those who are clinically vulnerable to be safe.
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I think I've seen two other health care personell with a (surgical) mask on the last three weeks at the hospital. Not easy for CVs at all :(
 
More information at Current Research Information System In Norway (CRISTIN) where there's a description of the research project with a summary of the hypothesis behind trying this drug.

Google translated:

We have recently summarized our hypothesis (Fluge, Tronstad and Mella, Journal of Clinical Investigation, 2021).

We think that ME/CFS occurs as an abnormal immune response after infection, where B lymphocytes/plasma cells and autoantibody are important.

Antibody response after infection persists and causes vascular dysregulation, with inadequate self-regulation of blood flow in relation to the needs of the tissue, which causes hypoxia in the tissue under load.

Such exercise-related tissue hypoxia will result in compensatory autonomic adaptations, most often with activation of the sympathetic nervous system to maintain circulatory homeostasis, as well as metabolic adaptations to maintain energy balance.

We believe that in some patients the production of antibodies from "early" plasma cells is affected by rituximab.

In the majority, however, antibody production takes place from "mature" plasma cells where the effect of rituximab cannot be expected.

The observed effects of cyclophosphamide and other interventions, such as immune adsorption from plasma, or treatment with proteasome inhibitors affecting plasma cells, are consistent with this.

Since 2016, we have considered the possibilities of conducting a pilot study with plasma cell-targeted treatment with the anti-CD38 antibody daratumumab.

The treatment is used for bone marrow cancer (multiple myeloma).

In the last couple of years, there are several small studies that have shown good results with daratumumab for various autoimmune diseases that have been refractory to other drugs.

A study is underway in Norway for patients with immune-mediated thrombocytopenia.

The use of daratumumab in these small studies has had a favorable side effect profile.

https://app.cristin.no/projects/show.jsf?id=2538921
 
Jaybee00 said:
OK other than your caveats above, do you think that there is a theoretical basis for Dara being effective for MECFS?
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The original idea of targeting B cells in ME was because some patients seemed to get better after having B cells depleted (for cancer). Then a large trial showed no effect from B cell depletion. So I think it is hard to put any weight on a theory related to B cells - the original reason did not hold up.
 
Kalliope said:
The observed effects of cyclophosphamide and other interventions, such as immune adsorption from plasma, or treatment with proteasome inhibitors affecting plasma cells, are consistent with this.
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Can anyone recall, have we seen much in the way of good evidence that immune adsorption from plasma helps?
Or anything about proteasome inhibitors?

I think this is the paper referred to in the CRISTIN description
Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),2021,Fluge,Mella,Tronstad
 
Jonathan Edwards said:
I would be very cautious about using drugs of this sort in the presence of the pandemic. Patients may have unfortunately died because rituximab has blocked their ability to respond to vaccination. Covid has completely changed the rules about using immunosuppression in the developed world.
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How months-long COVID infections could seed dangerous new variants
Tracking SARS-CoV-2 evolution during persistent cases provides insight into the origins of Omicron and other global variants. What can scientists do with this knowledge?
Virologist Sissy Sonnleitner tracks nearly every COVID-19 case in Austria’s rugged eastern Tyrol region. So, when one woman there kept testing positive for months on end, Sonnleitner was determined to work out what was going on.
Before becoming infected with SARS-CoV-2 in late 2020, the woman, who was in her 60s, had been taking immune-suppressing drugs to treat a lymphoma relapse. The COVID-19 infection lingered for more than seven months, causing relatively mild symptoms, including fatigue and a cough.
My bolding

https://www.nature.com/articles/d41586-022-01613-2
 
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Jonathan Edwards said:
The original idea of targeting B cells in ME was because some patients seemed to get better after having B cells depleted (for cancer). Then a large trial showed no effect from B cell depletion. So I think it is hard to put any weight on a theory related to B cells - the original reason did not hold up.
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The idea is that long lived plasma cells are involved (I dont know how effective Daratumumab is against them specifically)
 
Jonathan Edwards said:
The original idea of targeting B cells in ME was because some patients seemed to get better after having B cells depleted (for cancer). Then a large trial showed no effect from B cell depletion. So I think it is hard to put any weight on a theory related to B cells - the original reason did not hold up.
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I had to log into this forum only to comment this, because I am worried about anyone, especially a person regarded as expert, spreading such information on forums where patients are taking advice srsly, that they lack in RL so the opinions like this have even more weight.

Rituximab failed in SLE, MS, and a handful of others autoimmune disease. Especially interesting in Sjogrens, too. Nobody is having much doubts about SLE/SS being B-cells/autoantibody disease. Meanwhile, SLE has never been more tied to B-cells "only" autoimmune where recent CAR-T trials that vipe also plasmacells CD19 are extremely successful in the most sick SLE patients who failed - Rituximab.
Some case reports show the same w daratumumab

I don't see why MECFS would be different and who uses argument that because Rituximab (that does not deplete many autoantibodies!) failed - it must not be linked to Bcells.

And on a PERSONAL EXPERIENCE: I had all the MECFS symptoms with PEM and all and had positive GPCR via BerlinCures -Bioassay - 3.5x increased ie 5.5 was the value), super fatigued, (also CellTrend ELISA), i responded very well to single IVIG and my BerlinCures went to 0 this corresponded to having AMAZING ENERGY, first time in 15 yrs. This was 2019, since then I dont feel like i have MECFS symptoms.
I still have SFN/pOTS, that improved only partially etc, but nontheless, despite n=1 even my personal experience convinced me antibodies cause this


Hope daratumumab trial is successful!
 
Pibee said:
Rituximab failed in SLE, MS, and a handful of others autoimmune disease. Especially interesting in Sjogrens, too. Nobody
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Actually the situation is more complicated, @Pibee.
The first trial in SLE was done by Maria Leandro and myself and it was clear that major benefit occurred in a good proportion of cases. The companies involved set up very poorly designed trials initially so it has taken 20 years to show formally that B cell depleting antibodies do work in SLE (recently by Reddy in our department and others). There has never actually been any doubt in physicians' minds that rituximab worked - as indicated by it being used regularly in SLE since 2004. Rituximab worked in the first trial in MS (I was at the report meeting in Palo Alto around 2008) but the companies involved decided to shelve development because it was running out of patent. Subsequently B cell depleting antibodies have been shown to be effective.

Sjogren's belongs to the group of ANA-related disorders where the antigen is a nuclear protein. Leandro and I established very early on that autoantibodies of this sort show little fall after B cell depletion. So it was no surprise when little benefit was seen.

We have been needing a method to deplete plasma cells as well as B cells in these conditions since 1998. Anti-CD38 was considered very early on but again the companies dragged their feet. But to make sense it would need to be used alongside a B cell depleting agent because simply blocking plasma cells should do nothing to stop new clones arising and making autoantibody.

I have a lot of respect for Drs Fluge and Mella but it is important to remember that B cell depletion was only used in ME because of some chance findings with limited B cell depletion in lymphoma cases. If ME is an autoimmune disease with long lived plasma cells involved then these cases would not have benefited from simple B cell depletion - so there is no longer any motivation to pursue this unless we have evidence of autoantibodies. The studies of autoantibodies show almost no difference from controls.

I have never said that ME cannot be linked to B cells. However, since the evidence is very weak it is hard to justify trying treatments on ME patients that have not even been proven to be safe and effective in well recognised autoimmune disorders.
 
Jonathan Edwards said:
Subsequently B cell depleting antibodies have been shown to be effective.

Sjogren's belongs to the group of ANA-related disorders where the antigen is a nuclear protein. Leandro and I established very early on that autoantibodies of this sort show little fall after B cell depletion.
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apologies if this is a basic question, but I had thought that SLE was like Sjogren’s disease, in that both belong to the group of ANA disorders where the antigen is a nuclear protein? With SLE classic signature being anti-dsDNA? But B-cell depleting drugs only work for SLE despite this, but not Sjogren’s?

can I also ask what is the reason a B-cell depleting therapy like Rituximab works for MS when there are no known serum antibodies?
 
Hi @Debwaldy,

Sorry this is complicated, as you point out.
Nuclear autoantigens showing an 'ANA' include DNA (not a protein) and nucleoproteins.
Lupus is the one autoimmune disease that has a whole range of autoantibodies, probably because it involves an indiscriminate failure of complement-mediated deletion of unwanted B cells. So in lupus you have anti-DNA antibodies and also anti nucleoprotein antibodies such as anti-Sm or anti-RNP and also anti-Ro.

If you treat lupus with rituximab the anti-DNA goes down but not the anti-Sm or anti-RNP much.

Alongside lupus are a range of diseases which tend to have just autoantibodies to one nuclear antigen and it is a protein. Those include scleroderma (anti-Topo-1 or anti-centromere) and Sjogren's which has the anti-Ro and anti-La pair. Anti-RNP on its own goes with 'mixed connective tissue disease. Most of these diseases don't seem to respond much as one would expect from the antibodies to nuclear proteins not going down much. It is a bit more complicated for scleroderma because the pathology is often already irreversible.

Nobody quite knows why rituximab works for MS but note that MS has abnormal antibody populations in the brain ('oligoclonal bands'). Those must come from plasma cells derived from B cells that have nipped in to the central nervous system. I predicted that rituximab would work for MS on the basis that I thought that relapses occurred when some more B cells got into the CNS. It doesn't really matter whether these are making autoantibodies or any old antibodies, antibody is toxic to CNS tissue at high level anyway.

I am not sure that my model was right but rituximab does work. Presumably one way or another replacing disease is dependent on continued existence of B cells and rituximab can remove those
 


Some good news on the dara trial is released.

They show 3 patients. They also show steps, which I like a lot more than the SPF PF score.

The two responders had lower initial IGG levels, just like the cyclo trial.

@Jonathan Edwards How come the dara didn’t lower IGG much in patient 2?
 

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