New multiple sclerosis drug can 'cut relapses by nearly 50%'

[BurnA]

Yes the review paper came from my department - and the optimism was based on the lupus patients I entered into the first lupus study carried out by my PhD student Maria Leandro (they were under the overall care of David Isenberg) and continued usage in the department. Venkat Reddy is still doing a PhD with us on new anti-CD20s. I don't put my name on papers these days.

I have a suspicion that ocrelizumab is going to be irrelevant to ME anyway since the data so far are with rituximab and if companies want to move on from that it will probably be something further down the development line or from a different company.

Ocrelizumab is very similar to rituximab and was developed as a way of getting around the patent lifespan problem, showing some rather marginal advantage in B cell killing if I remember rightly. There are now what look like significantly better antibodies coming along but ocrelizumab is what Roche has been taking forward in development. It is essentially the same as rituximab but probably slightly more potent.

Can i ask what do you see as a future treatment for ME ? Would it be better B cell depleting agents (new anti CD-20s) or more specific treatment ? At a guess how far off commercial production would these be and are you aware of any in initial trials at the moment ?

Can you see a day when autoantibodies are targeted specifically (where relevant )?

Thanks

 

[Jonathan Edwards]

Can i ask what do you see as a future treatment for ME ? Would it be better B cell depleting agents (new anti CD-20s) or more specific treatment ? At a guess how far off commercial production would these be and are you aware of any in initial trials at the moment ?

Can you see a day when autoantibodies are targeted specifically (where relevant )?

Thanks

I suspect there will be lots of different treatments for different pathways to ME and for treatment of the manifestations directly. I don't think there is any way to predict what they will be, or even whether ones currently under study will be amongst them.

 

[BurnA]

I suspect there will be lots of different treatments for different pathways to ME and for treatment of the manifestations directly. I don't think there is any way to predict what they will be, or even whether ones currently under study will be amongst them.

OK thanks, its just when you said there looks like significantly better antibodies coming along, i inferred you had something specific in mind.Do you ?

 

[Jonathan Edwards]

OK thanks, its just when you said there looks like significantly better antibodies coming along, i inferred you had something specific in mind.Do you ?

Just that there are more powerful relatives of rituximab now.

 

[nandixon]

If more complete B-cell depletion seems a desirable thing, and the newer generation anti-CD20 mAbs are "too expensive" relative to a generically priced, off-patent rituximab, then I still think the potential might exist to augment rituximab's effectiveness with respect to B-cell depletion by combining it with Ampligen, as I noted in these two posts:

http://forums.phoenixrising.me/inde...m-by-which-rituximab-works.38844/#post-622063

and

http://forums.phoenixrising.me/inde...m-by-which-rituximab-works.38844/#post-622093

It's interesting, too, that Ampligen by itself may already have been found to be a useful treatment for some ME/CFS. So not only might there be a synergistic effect between rituximab and Ampligen (for B-cell depletion proposes) but there might be some sort of beneficial additive effect as well.

Of course, using generic rituximab plus Ampligen might be as expensive or more expensive than a newer anti-CD20 mAb. Not sure how the economics might work out.

 

[BurnA]

If more complete B-cell depletion seems a desirable thing, and the newer generation anti-CD20 mAbs are "too expensive" relative to a generically priced, off-patent rituximab, then I still think the potential might exist to augment rituximab's effectiveness with respect to B-cell depletion by combining it with Ampligen, as I noted in these two posts:

http://forums.phoenixrising.me/inde...m-by-which-rituximab-works.38844/#post-622063

and

http://forums.phoenixrising.me/inde...m-by-which-rituximab-works.38844/#post-622093

It's interesting, too, that Ampligen by itself may already have been found to be a useful treatment for some ME/CFS. So not only might there be a synergistic effect between rituximab and Ampligen (for B-cell depletion proposes) but there might be some sort of beneficial additive effect as well.

Of course, using generic rituximab plus Ampligen might be as expensive or more expensive than a newer anti-CD20 mAb. Not sure how the economics might work out.

Sorry, I dont see the connection between economics and combining ampligen with RTX.
As i understand, they are two completely different drugs that do two completely different things. Either there is a scientific reason to combine them or there isnt. Cost of either drug would not be a factor imo.

 

[nandixon]

Sorry, I dont see the connection between economics and combining ampligen with RTX.
As i understand, they are two completely different drugs that do two completely different things. Either there is a scientific reason to combine them or there isnt. Cost of either drug would not be a factor imo.

For simplicity, say that generic rituximab (RTX) costs $1500 per treatment (infusion), and that Ampligen costs $1500 per treatment (for this purpose), i.e., a total of $3000. Say that a newer, more effective relative of RTX costs $6000 per treatment. If RTX plus Ampligen depletes the B cells as effectively as that newer relative (which the study I linked to shows the potential for), it might cost half as much to achieve the same effect.

 

[BurnA]

For simplicity, say that generic rituximab (RTX) costs $1500 per treatment (infusion), and that Ampligen costs $1500 per treatment (for this purpose), i.e., a total of $3000. Say that a newer, more effective relative of RTX costs $6000 per treatment. If RTX plus Ampligen depletes the B cells as effectively as that newer relative (which the study I linked to shows the potential for), it might cost half as much to achieve the same effect.

OK. I think my issue is your line "(which the study I linked to shows the potential for)"... also this was described as a fairy story by @Jonathan Edwards. I dont have the technical abilty to discuss it in any depth, sorry.

 

[Jonathan Edwards]

The evidence that ampligen would enhance B cell depletion if added to rituximab in humans with normal CD20 expression looks to me to be hanging by a hair. In contrast we already have other drugs that are known to synergise with rituximab in humans through a mechanism that is understood. Various compounds that interfere with the BAFF/APRIL system of signals are being combined with rituximab or other CD20 antibodies at present. One trial in lupus was stopped because Ig levels want lower than the researchers liked - apparently indicating that combinations we already have may be able to wipe out all B and plasma cells - if the researchers have the guts to use them.

I am intrigued that Tom Tedder got involved in using Ampligen - presumably Hemispherx hand it out to scientists to try to get them to prove it is a wonder drug - since they need somebody to prove it is a wonder drug sooner or later if they are to remain solvent.

 

[BurnA]

One trial in lupus was stopped because Ig levels want lower than the researchers liked - apparently indicating that combinations we already have may be able to wipe out all B and plasma cells - if the researchers have the guts to use them.

For the ignorant, if we could wipe out all B and plasma cells, is this the holy grail in terms of B cell depletion theory ?
What would this mean in terms of autoimmune disease progression / treatment for a patient ?

 

[A.B.]

For the ignorant, if we could wipe out all B and plasma cells, is this the holy grail in terms of B cell depletion theory ?
What would this mean in terms of autoimmune disease progression / treatment for a patient ?

The holy grail would be wiping out only the defective B cells.

 

[BurnA]

The holy grail would be wiping out only the defective B cells.

OK but in terms of where we are now, would it be a leap forward to wipe out all B and plasma cells or just a baby step ?

 

[A.B.]

OK but in terms of where we are now, would it be a leap forward to wipe out all B and plasma cells or just a baby step ?

I'm going to preface this by saying that I'm not an expert. I have just followed the discussion, the many answers by Edwards, and the research papers. It is also not yet proven that ME/CFS is autoimmune.

The idea is that pathogenic B cells are stuck in a vicious cycle where they perpetuate themselves and produce auto-antibodies. The more complete the B cell depletion, the more effective the therapy is in relieving symptoms. If the pathogenic B cells are completely wiped out, the cycle is broken and the patient (assuming no permanent damage or other problems) is cured. This is what at appears to have happend with some lucky ME/CFS patients that were given Rituximab. Other patients responded but eventually relapsed. This would be consistent with an incomplete B cell depletion (but there could also be other reasons).

 

[Jonathan Edwards]

I'm going to preface this by saying that I'm not an expert. I have just followed the discussion, the many answers by Edwards, and the research papers. It is also not yet proven that ME/CFS is autoimmune.

The idea is that pathogenic B cells are stuck in a vicious cycle where they perpetuate themselves and produce auto-antibodies. The more complete the B cell depletion, the more effective the therapy is in relieving symptoms. If the pathogenic B cells are completely wiped out, the cycle is broken and the patient (assuming no permanent damage or other problems) is cured. This is what at appears to have with some lucky ME/CFS patients that were given Rituximab. Other patients responded but eventually relapsed. This would be consistent with an incomplete B cell depletion (but there could also be other reasons).

Yes I agree with both posts. We would like just to kill bad cells but until we know how finding a way to kill all B lineage cells seems to be important. If that does produces good remission but with relapse then we would have to consider T cell memory being involved as well and think about how to deal with that.

 

[BurnA]

If that does produces good remission but with relapse then we would have to consider T cell memory being involved as well and think about how to deal with that.

Apologies if these are dumb questions but has T cell memory been shown to exist and is it understood or just speculated ? And how would it be dealt with ?

 

[Jonathan Edwards]

Apologies if these are dumb questions but has T cell memory been shown to exist and is it understood or just speculated ? And how would it be dealt with ?

Memory is what T and B cells are for. They form the adaptive immune system - the part that learns and remembers specific antigens. In a normal immune response both have to remember the antigen and agree it is foreign. But in autoimmunity that doesn't work properly. Most immunologists assume that the T cells remember wrong but nobody has ever shown that. We know the B cells remember wrong because they make antibodies to self. But it is still possible that the T cells do remember if not wrong at least disadvantageously. Maybe they remember food antigens (like gliadin in coeliac disease) or commensal bacterial antigens that they would do better to forget.

 

[BurnA]

One trial in lupus was stopped because Ig levels want lower than the researchers liked - apparently indicating that combinations we already have may be able to wipe out all B and plasma cells - if the researchers have the guts to use them.

If wiping out all b and plasma cells is what we want, can we accept low Ig levels? Can you weigh up the risk reward on that ?

Do you think cyclophosphamide could be a likely combination therapy with RTX ? Could this help with possible t cell memory ?

 

[BurnA]

Just that there are more powerful relatives of rituximab now.

If a portion of the non responders aren't responding due to inadequate b cell depletion ...is it posssible they would respond with the more powerful relatives ?

Also, if we speculate that 50% respond to RTX, and if there are some who don't achieve adequate b cell depletion, does that mean in theory there a more than 50% potential responders? Could this mean that the majority of patients fall under the one umbrella of autoimmune / immune dysregulation but they respond differently to RTX not because of a difference in underlying disease but because of how they individually respond to RTX?

 

[Gemini]

This seems like quite a major development for MS. Results of phase iii trial for MS using Ocrelizumab (a humanized anti-CD20 monoclonal antibody.)

MS breakthough announcement regarding Ocrelizumab from Univ Calif SF April 2016:

Excerpt: "Compared to interferon [treatment], ocrelizumab reduced clinical MS attacks, blocked the development of new myelin inflammation by over 95%, and delayed disability progression by 40 percent."

http://universityofcalifornia.edu/news/wrapping-multiple-sclerosis

How B-cells were implicated in MS & Dr. Hauser's rituximab trial might interest @Jonathan Edwards.

Their 4-stage "treatment-driven" MS research strategy is quite interesting:
1. Ocrelizumab to shut down disease progression
2. A remyelinating agent to repair damaged neurons
3. Microbiome modification (probiotics, antibiotics or diet) to create an environment that prevents initiation or perpetuation of disease
4. Early detection/treatment to stave off disease progression altogether

 

[Rrrr]

Has this article already been posted?

http://www.businessinsider.com/first-drug-for-aggressive-multiple-sclerosis-wins-fda-approval-2017-3

It is also fascinating to read about how the med got approved. It took 40 years. Jeeesh.