Patent: Method for the treatment of CFS using an inhibitory or cytotoxic agent against plasma cells, 2021, Fluge, Mella

I've just come across a patent from Fluge and Mella which looks like it was updated/published in March 2021 entitled 'Method for the treatment of chronic fatigue syndrome using an inhibitory or cytotoxic agent against plasma cells'.

The description of the patent is a long read:
https://worldwide.espacenet.com/pub...T=D&ND=3&date=20210304&DB=EPODOC&locale=en_EP

I've selected a few random key paragraphs from the patent below which may not make total sense without reading the whole patent:

'In a first aspect, the present invention relates to a method for the treatment of chronic fatigue syndrome (CFS) comprising administering to a patient in need thereof a therapeutically effective amount inhibitory or cytotoxic agent against plasma cells'

'In particular, the present inventors recognized that an immediate or a rapid relief, e.g. within a week or weeks, from start of administration of said inhibitory or cytotoxic agent against plasma cells, e.g. by carefully increasing the dose, can be observed. In contrast to medication such as Rituximab for a treatment of CFS, which is characterized by a remarkable lag time before clinical responses, as described, e.g. WO 2009/083602'.

'Patients responding to Rituximab may have autoantibody production from immature plasma cells (plasmablasts). For most ME/CFS patients with autoantibody- production from the mature plasma cells, not responding to Rituximab, a possible way to treat ME/CFS could thus be by using a regimen that targets mature plasma cells, either because of plasma cell vulnerability to a drug with a general mode of action, or to a molecular targeted therapy directed against specific epitopes on mature plasma cells'.

'Consequently, ME/CFS can be treated with drugs that induce apoptosis and reduce autoantibody production in plasma cells. Specifically, this may be achieved by a proteasome inhibitor like Bortezomib'.

'An alternative approach for plasma cell depletion is to target the mature plasma cells directly, including memory cells, with antibodies directed toward epitopes on their surface. Such epitopes are not necessarily specific for plasma cells and must be used with care. A commercially available drug directed at CD38 (Daratumumab) is used for treatment of myeloma, because the myeloma cells typically have high densities of CD38 antigen'.

'An embodiment of the present invention, a combination of at least two inhibitory or cytotoxic agent against plasma cells may be provided'.

'In a preferred embodiment, a combination of an anti CD20 antibody and representing a biological entity of a B-cell depleting agent and Methotrexate, representing a chemical entity of a B-cell depleting agent, can be used for treating chronic fatigue syndrome of myalgic encephalomyelitis. Administration of these entities may be effected simultaneously, separately or sequentially'.

'For example, in a first regimen either the antibody or Methotrexate is administered to the subject while in a second regimen the other agent is administered'.

'In an embodiment, first the proteasome inhibitor is administered for 2-3 cycles, and thereafter, preferably with a period of time of at least two weeks, like four weeks or two months, the B-cell depleting agent is administered in four courses (1 , 2, 3 or 4 courses'.

'The administration may be systemically or locally via the enteral or parenteral way. For example, topical administration may be affected, e.g. by a patch or pavement for sustained release alternatively, an inhibitory or cytotoxic agent against plasma cells may be administered by way of inhalation or by other mucosal ways'.


They also have a couple of patient examples to illustrate the invention, I assume they are real cases.

Patient 2:

'Patient 2 was a woman aged 46 years, who had ME/CFS of moderate-to-severe disease severity, i.e. she was housebound and in periods more or less bedridden. She had previously participated in the open-label trial assessing cyclophosphamide intravenous infusions in ME/CFS mentioned herein, and experienced a clinical response lasting for almost a year before gradual relapse. She received the first course of Bortezomib subcutaneously at 1.0 mg/m<2>days 1 , 4, 8 and 11, with a minimal skin reaction at the injection site and no other side effects. She received the second and third courses at 1.3 mg/m<2>approximately 4 weeks apart.

From 7 weeks after start of Bortezomib intervention, she experienced a gradual and consistent improvement of all her ME/CS symptoms, with increasing energy, less pain, less PEM, less dizziness and improved cognitive function. Her Fitbit armband verified her description of improvement, with increasing steps per 24 hours from mean 1500-2000 before intervention to approximately 4000, up to 7000 on single days, after response. She received in total 6 courses of Bortezomib, but after the last course she noted discomfort in her lower extremities at the legs and feet, and some constipation. She had a lasting response until 6 weeks after the last Bortezomib infusion, in total 16 weeks, before gradual relapse. Therefore, she then received Rituximab infusions 4 months apart, and has now again an increasing degree of clinical response approximately 4 months after start of Rituximab infusions'.

 

Interesting, but intimidating drug combo. Both case reports were responders to previous interventions, suggesting some degree of known auto-immunity. Both relapsed after 6-7 weeks.

 

For completeness this is the Patient 1 case summary:

Patient 1 :

Patient 1 was a woman aged 37 years, who had ME/CFS for 22 years. She participated in the first double-blind randomized trial using Rituximab versus placebo (two infusions two weeks apart, followed by observation), as described herein. She had no improvement during that study, and after unblinding of the trial she was shown to be allocated to the placebo group. She then later participated in the open-label phase II trial using Rituximab maintenance, as described herein, and the experienced a long-standing and impressive clinical response lasting for more than 3 years before gradual relapse. The patient was then retreated with Rituximab, again with the same pattern and a long-lasting clinical response for more than 3 years before again gradual relapse.

In September 2019 she had a mild-to-moderate ME/CFS severity but with increasing symptoms, and it was decided to offer her the proteasome-inhibitor bortezomib according to the present invention. She received Bortezomib subcutaneously says 1 , 4, 11 and 15. In the first course she had 1 ,0 mg/m<2>(i.e. 70% of the dose used in malignant plasma cell disease, multiple myeloma), with no bortezomib-associated side effects except an exanthema around the injection site, with some erythema and itching at the skin on the abdominal wall. She received the second course at approximately four weeks, with Bortezomib 1 ,3 mg/m<2>subcutaneously (100% dose) at days 1, 4, 8 and 11 , with increasing local reaction at the injection site and with some transient fatigue and pain in the muscles as possible side effects. She therefore received the third course of Bortezomib as an intravenous infusion with the same dose 1.3 mg/m<2>, given at days 1 , 4, 8 and 11. After the third intravenous course she had a transient exanthema along the vein on the arm in which she had received the infusion, interpreted as an allergic reaction and we decided to stop further Bortezomib treatment.

However, at week 10 from start of bortezomib treatment, she experienced gradual improvement of all her ME/CFS symptoms, such as post-exertional malaise (PEM), pain especially in muscles and joints, cognitive disturbances and sleep problems. She had increasing energy, increased exertion and was able to perform many new tasks. Knowing the disease from many years of experience, she was certain that the intervention had a positive effect on the ME/CFS symptoms. The self-reported symptom improvement was supported by measured steps per 24 hours (Fitbit armband) and in the response period we registered more than 10.000 steps per day.

The effect lasted for approximately 7 weeks before she started experiencing gradual relapse of the ME/CFS symptoms. Therefore, she has received Rituximab infusions 4 months apart, and is in stable and impressive clinical response now.

 

Holy cow, that is interesting. Looked at the price of Bortezomib, and it ain't cheap. What is your thoughts on the proposed treatment/patent, and the safety of Bortezomib, dr. @Jonathan Edwards?

 

Bortezomib has had a reputation for having side effects but does reduce plasma cells, at least in some situations. I don't know if the patent is still central to the ideas of F & M. I suspect the right thing to do would be to find a more intensive B/plasma cell protocol that works better than rituximab for RA or lupus and then maybe try that. At least we know that in those diseases it would be relevant. Trying out new B cell targeting protocols in ME/CFS seems to me marginal.

 

I thought you said it doesn't really reduce non-malignant plasma cells......

 

I think this point might be important....the responders might have been patients with the 2 HLA risk alleles--what about the rest of us??

 

I’m pretty sure you are on to something here. Hasn’t Fluge hinted towards narrowing the inclusion criteria several times lately?

 

Yes, what I said: it does not kill a high percentage of non-malignant plasma cells.

And so I also said:

Which was simply to agree that it is a plasma cell targeting agent and therefore likely to fall under F & M's patent.

I have been hoping for years for a combination protocol that kills enough non-malignant plasma cells to reverse autoimmune diseases long term. That might include Bortezomib as a component. My understanding is that F & M are also looking towards a deep depletion strategy including the option of combination.

So bortezomib is likely to be useless as a single agent but could be included in the sort of strategy F & M have patented.

 

The key thing to remember I that the weight of evidence is that none of these people are responders to anything here. They got better during studies but looking at all the evidence together much the most likely explanation is that these were coincidental or placebo responses.

When I originally looked at the rw data from the Rituximab studies I was struck but the fact that in the blinded study there was no consistent kinetics to anything. It did not look like there was any bona fide effect. I encouraged F & M to do the further blinded study because it looked from the 6 month time point that there might be some real effect. That was not confirmed.

We also have the observation that in the open label study patients showed very stereotyped kinetics of a sort that were consistent with what they would at that time have been led to believe was expected. That I am afraid is a strong pointer to a placebo response or some other bias to the reporting of outcome of the sort we are used to from PACE.

The bottom line is that for known autoimmune diseases rituximab (or obinutuzumab) is a far better treatment than any of these other things like cyclo or bortezomib. Iff rituxmb has no effect I cannot see the justification for trying cyclo or bortezomib until we know that there is specific protocol that includes them that has significant advantages for known autoimmune states.

 

Sorry, I should probably know this, but what are the 2HLA risk alleles?

 

https://www.s4me.info/threads/human...syndrome-me-cfs-fluge-mella-et-al-2020.14329/

 

But the argument might be that hypothetically a proportion of ME-patients have long lived plasma cell pathology which Rituximab dont affect? Its obv. somewhat a shot in the dark, but if cyclo proved to work in phase 3 you could argue for trying it in lack of other options.

 

If patients have long lived plasma cells contributing to pathology then they pretty much have to be non-neoplastic, since Ig levels are normal. So they are part of an immune response. Everything we know from theory and practice in autoimmunity suggests that trying to deal with the problem just at the plasma cell stage will not be safe and effective. You would have to make people permanently immunodeficient. And the plasma cells are likely to be immediately replaced from memory B cells.

As I said, the validity of such an approach should be established in a known autoimmune disease before applying it to something that just might be autoimmune.

 

I’d happily be a guinea pig for F & M and submit to clinical trials. Compared to being offered brain retraining/ brainwashing therapy, this is an easy choice for me.

 

Unfortunately you then have to move to Bergen or close (Ive considered it haha)

 

Thanks.. So we are talking e.g. bortezomib with obinutuzumab, or obinutuzumab with bortezomib and cyclo? Or is this too dangerous