New pilot study in the loop from the researchers at Haukeland

[Kati]

Thank you, @Jonathan Edwards and @deleder2k !
So MTX was only effective in combination with other drugs, not stand allone.

With the paucity of clinical trials, at the moment, things are N=1 experiments. Not enough data.

 

[deleder2k]

Thank you, @Jonathan Edwards and @deleder2k !
So MTX was only effective in combination with other drugs, not stand allone.

Yes. That is correct, but they nailed it down to MTX. According to Fluge and Mella the effect, the timeframe and the properties of MTX made it the only plausible drug that could lead to remission for that patient. That's the reason they tried RTX. And as we now know; RTX works fine stand allone!

I really hope the open study will be released soon. I look forward to reading it! I hope PLOS ONE, or the journal they'll publish the article in this time, quickly accepts and publishes it. We need it now! With the OMI report, cytokine study and with the upcoming spinal fluid study things are really looking good.

 

[Freddy]

Maybe Kati is right, not enough data...
The only question coming to my mind is: if the nailed it down to MTX (@deleder2k), why did they study RTX and not MTX? But perhaps @Jonathan Edwards gave the answer (MTX produces only minor changes immonologically, as I understood him).

 

[Joolz]

@Freddy :
Here's what Fluge/Mella wrote in the first RTX-paper from 2009:

The MIME chemotherapy regimen contains methotrexate (Mtx) in moderate doses (30 mg/m2 intravenously every third week). Based on the observed clinical benefit on CFS symptoms in this patient from MIME, the lack of improvement from the three other chemotherapy regimens, and the known (but poorly understood) immunomodulatory effects of low-dose weekly Mtx treatment in e.g. rheumatoid arthritis, we speculated that the observed clinical improvement was related to Mtx. One of the effects of weekly oral Mtx is a moderate B-cell depletion [12]. (...)
This case series of B-cell depletion was initiated after an original clinical observation of unexpected and markedly improved CFS symptoms in a patient treated for Hodgkin's disease with the MIME chemotherapy regimen. We speculated that the initial observed effect was related to Mtx, which is given in moderate doses in the MIME regimen (30 mg/m2/3 weeks, comparable to weekly doses used in the treatment of connective tissue diseases (5–15 mg/m2/week). We postulated that a main mechanism inducing the symptoms in CFS is a deregulation of the immune system involving B-lymphocytes directly or indirectly. B-cell depletion was induced with an anti-CD20 monoclonal antibody, as is standard practice with few side effects in patients with B-cell lymphomas, rheumatoid arthritis and related connective tissue diseases [15,16].

(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711959/) They also write how MTX worked for the first pilot patient (slower than RTX).

BTW, "patient no. one" also received cyclophosphamide but apparently didn't respond to it.

I think Prof Scheibenbogen might have some experience with using MTX off-label on CFS patients, but I'm not sure.

 

[Joolz]

Also know a patient had a major improvement after IVIG, but I don't think they aren't going that road.

Are you referring to IVIG or immunoglobulins in general? There's not only one, there's more of them who had significant improvement (they used Gammanorm i.m.), but only one story (now two including the RTX/Valcyte/immunoglobulin patient) made it to the press. I got the impression that about 50% had experienced improvement, although it took some time (half a year) to see symptoms improve. In contrast to RTX, not all symptoms improve. And remission seems to be rare. :-(

Unfortunately, AFAIK there will not be any IVIG/SCIG study on CFS patients in Norway during the next years.

 

[deleder2k]

Are you referring to IVIG or immunoglobulins in general? There's not only one, there's more of them who had significant improvement (they used Gammanorm i.m.), but only one story (now two including the RTX/Valcyte/immunoglobulin patient) made it to the press. I got the impression that about 50% had experienced improvement, although it took some time (half a year) to see symptoms improve. In contrast to RTX, not all symptoms improve. And remission seems to be rare. :-(

Unfortunately, AFAIK there will not be any IVIG/SCIG study on CFS patients in Norway during the next years.

I know one patient got better after one Kiovig infusion(s) http://www.baxterhealthcare.com.au/downloads/healthcare_professionals/cmi_pi/kiovig_pi.pdf

 

[DanME]

@Freddy :
Here's what Fluge/Mella wrote in the first RTX-paper from 2009:
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711959/) They also write how MTX worked for the first pilot patient (slower than RTX).

BTW, "patient no. one" also received cyclophosphamide but apparently didn't respond to it.

I think Prof Scheibenbogen might have some experience with using MTX off-label on CFS patients, but I'm not sure.

Do you know, in what way the other pilot patients responded to cyclophosphamide?

I thought Prof Scheibenbogen had only used RTX and not MTX. But it may be possible.

 

[alex3619]

I'm not aware that there have been any trials using steroids. Does anyone else know of any studies?

Steroids were a standard therapy several decades ago. They were largely abandoned due to long term side effects. However this is very much a dosage thing. Heavy immunosuppression might not be necessary, or perhaps pulsed doses could be used. However there will be considerable resistance to this therapy in the medical community.

 

[alex3619]

I really don't understand how one can patent a drug that is from 1954!

Simple. You don't just patent drugs. You patent formulations. Its a technicality. Many drugs are being repackaged and relabeled under new names, with new patents, because they changed the dosage, or applied it at a different dosage to another disease, or added something extra, etc. So the formulation is different. If its different enough you get a new patent. So old drugs are given a new lease of life, which is very cheap for drug companies.

Or to put it another way, you patent inventions, and a slightly different invention can be enough for a new patent.

 

[alex3619]

Here is what I am trying to understand. What is the basis for using methotrexate in the mix, even occasionally? This is an anti-folate, and it seems to me that a very high percentage of us have low folate metabolism normally. Why make it lower? Is this implying that lower folate activity is a good adaptive response to ME? If so then why do so many respond positively to methyl folate etc? Questions, questions, and the answers are not very clear.

 

[deleder2k]

Simple. You don't just patent drugs. You patent formulations. Its a technicality. Many drugs are being repackaged and relabeled under new names, with new patents, because they changed the dosage, or applied it at a different dosage to another disease, or added something extra, etc. So the formulation is different. If its different enough you get a new patent. So old drugs are given a new lease of life, which is very cheap for drug companies.

Or to put it another way, you patent inventions, and a slightly different invention can be enough for a new patent.

Thank you, Alex.

If the Phase 3 of Rituximab is positive and becomes standard treatment of ME would every hospital in the civilized world pay a small fee for treating patients? Or how does this work?

 

[alex3619]

Thank you, Alex.

If the Phase 3 of Rituximab is positive and becomes standard treatment of ME would every hospital in the civilized world pay a small fee for treating patients? Or how does this work?

How it works it a commercial matter, and I am not legally or otherwise trained in this area. I do think though that if RTX in combination with something else, at a standardized dose, is found to be optimal, a new patent might be applied for. Then they will market that. However this will increase cost which might not be a good thing for patients.

RTX is a biological so its not clear there will be issues with generics. I am not sure where that will lead. MTX can be a generic, and so very cheap.

I would really like to know if low folate metabolism patients are a subgroup, and if so are a responder or non responder subgroup. If they are a responder subgroup, then a disturbing question needs to be asked: is taking methyl folate for this subgroup driving their ME while temporarily reducing symptoms?

If they are a non responder group, then we have a marker for deciding who not to use MTX on.

I do realize though that it is probably far too early in the research to answer these questions.

In any case, no matter the theory, if a drug is making people better, reliably, and especially in dbpcRCTs, then its great evidence, and theory be damned. Time for a new theory.

 

[alex3619]

If the Phase 3 of Rituximab is positive and becomes standard treatment of ME would every hospital in the civilized world pay a small fee for treating patients? Or how does this work?

I am going to take a different aspect of this question in this reply. How it works is very dependent on the systems available country by country. At current cost I am guessing RTX is a restricted drug. I am encouraged if they are finding that repeated doses give high response rates, not only because I was hoping this would happen, but because if this is the case then the evidence is strong that even at high cost its worth doing in any health system. It saves money in the long run.

Countries with strong private health insurance will find the insured should have it available easily. Rich countries with national health systems could make it available. Poorer countries with national health systems may find very few get it. Those in countries with no national health system and inadequate insurance are likely to either not be treated or have to wait a long time. Which sucks.

There are additional hoops to jump through in Australia over this issue. We will have the Therapeutic Goods Administration to consider (think Aussie FDA) and the PBS scheme, which is about government subsidy for expensive and needed drugs.

 

[deleder2k]

But will RTX be more expensive for all diseases or just if it used to treat ME?

I'd like to add that several bio similars are approaching the market. In Russia they have a version that is being used today, and in India and other countries they use the Reditux. Big pharma is joining the party in 2016 if I am correctly. That will lower prices.

On the other hand, if cyclophosphamide works out money won't be an issue. It is literally free!

 

[alex3619]

Rituximab is in the process of coming out of patent. That means it should, in theory, come down in price. On the other hand if a new patent is lodged this will prop up the price, for everyone (depending on the basis of the patent). From my understanding of how this works in the case of antidepressents, they start releasing the new formulation under patent, then restrict the old formulation.

Now what I do not know is if the new patent can stop generics of the old formulation. I would think not, but this is not my area.

 

[Snow Leopard]

I doubt the price for RTX will come down until the generics are actually shown to have similar efficacy, safety and more importantly, approval in key regulated markets.

So any generic versions of RTX used for ME would require a whole new set of trials to prove efficacy, along with underlying trials in humans in general to demonstrate safety (requires somewhat large trials).

 

[alex3619]

So any generics used for ME would require a whole new set of trials to prove efficacy

In the case of bio-equivalents I think this is very likely. In the case of generic versions of the identical drug I am not sure it would ever be necessary.

 

[deleder2k]

I doubt the price for RTX will come down until the generics are actually shown to have similar efficacy, safety and more importantly, approval in key regulated markets.

So any generic versions of RTX used for ME would require a whole new set of trials to prove efficacy, along with underlying trials in humans in general to demonstrate safety (requires somewhat large trials).

These trials have been underway for many years. Looks like 2016 is the year when they'll launch in Europe.

 

[Snow Leopard]

These trials have been underway for many years. Looks like 2016 is the year when they'll launch in Europe.

Studies to find out the efficacy for which diseases? Non-Hodgkin Lymphoma? RA?

 

[Joolz]

Do you know, in what way the other pilot patients responded to cyclophosphamide?

The other pilot patients in the first RTX study? They didn't receive cyclophosphamide. The first patient received it as part of the BEACOPP cancer protocol (the C stands for cyclo). I don't know the dosage though.