Dr Bieger and Dr Mikovits discuss treating ME patients with Rituximab

[Daisymay]

One of the major reasons why US physicians do not like rituximab for RA is that they do not get many infusion fees (they actually told me this at an advisory board). If it was only one infusion every nine months they would be even less keen. Maybe that is why the company tried 2 x 500mg rather than the much more sensible 1 x 1000mg (higher peak level).

Shocking.

 

[Jonathan Edwards]

Just for interest, there's no oral form of rituximab, but there is a new (probably much more expensive) subcutaneous version of rituximab (licensed in Europe in 2014) that can be administered in just 5 minutes (by injection under the skin):
http://www.roche.com/media/store/releases/med-cor-2014-01-24.htm
http://www.roche.com/media/store/releases/med-cor-2014-03-28.htm

Yes, I think this was the basis of the mistake on the video. What puzzles me is why anyone would want to give rituximab subcutaneously in five minutes when the IV dose is given incredibly slowly to avoid allergic reactions. If you give the drug subcutaneously in five minutes and the person is allergic to it there is pretty little you can do about it - especially if they are on the bus home, or as has happened with another sister drug, in bed that night. IV is much less likely to produce a local inflammatory reaction than subcut so I really do not see the advantage, but I guess that it has been tested and shown to be safe. I personally would not want to receive rituximab from anyone who was not able to put up an IV - and that is the sort of thing that worries me quite a lot.

 

[Sherlock]

As far as I know there is no logic in any other variation. Nobody is attempting to kill one lot of B cells and not another. Autoimmune B cells are exactly like normal B cells except in that they recognise self rather than non-self. There is nothing to suggest you can kill one rather than the other as far as I know. The reason why rituximab seems to hit the autoimmune clones harder than the others probably has to do with plasma cell half life.

Speculating along with Mikovits' viral angle, it seems at least possible that virus infected autoimmune B cells (as opposed to normal autoimmune B cells, so to speak) are more prone to RTX-induced apoptosis.

Apoptosis came to mind because she mentioned lipid rafts, in which CD20s can associate to enhance pro-apoptotic signalling.
CD20-mediated apoptosis: signalling through lipid rafts
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782791/

Even so, apoptosis has always been mentioned as the least important MOA. So maybe she was instead referring to rafts as an entry point for a virus.

 

[deleder2k]

Yes, I think this was the basis of the mistake on the video. What puzzles me is why anyone would want to give rituximab subcutaneously in five minutes when the IV dose is given incredibly slowly to avoid allergic reactions. If you give the drug subcutaneously in five minutes and the person is allergic to it there is pretty little you can do about it - especially if they are on the bus home, or as has happened with another sister drug, in bed that night. IV is much less likely to produce a local inflammatory reaction than subcut so I really do not see the advantage, but I guess that it has been tested and shown to be safe. I personally would not want to receive rituximab from anyone who was not able to put up an IV - and that is the sort of thing that worries me quite a lot.

Roche states that one need to successfully complete one full infusion without side effects before the subcut version. They also say that one need to stay there for 15 minutes or so after all sub-cut injections.

The reason Øystein Fluge did not include it in the latest study is because they couldn't find a matching placebo solution.

 

[Sherlock]

What puzzles me is why anyone would want to give rituximab subcutaneously in five minutes when the IV dose is given incredibly slowly...

Because the patients love the idea. I'd imagine the very 1st dose should for ideal safety be given by IV.

Btw, that's the same concept as is being promoted against pancreatic cancer, though in reverse: instead of using an enzyme to let the drug break out of its connective-tissue pocket and get into circulation, an enzyme is added to break down connective tissue (made by the tumor) that gets in the way of the cytotoxic chemo getting to the tumor.

 

[deleder2k]

Shocking.

This is a proof of a broken system. When patients are hindered the best available treatment when it is cheaper AND better... I can't believe it.

 

[Sherlock]

Why is an oral liposomal mab not feasible? Are the mabs too big to fit inside?

Btw, speaking of a relatively quick injection, Zevalin (an anti-tumor, anti-CD20 MAHA with an attached beta-radiation emitting isotope) is given by a nurse/tech in a nuclear medicine dept. A plexiglass shield is employed on the syringe. The tech watches the clock to give the injection evenly over a ten minute period. It has to be made up in a nuclear pharmacy that morning, and costs ~$20,000 for the one time dose - so plain old RTX is give beforehand as a cheap(er) means to clear the way before the Zevalin.

 

[Jonathan Edwards]

Why is an oral liposomal mab not feasible? Are the mabs too big to fit inside?

Any large protein given by mouth will be broken down by gut enzymes. Liposomes might sneak though a tiny bit but in general I think they would be broken down as well. I cannot see any real need to give rituximab any way other than IV since it tends to be given only once every six to twelve months and patients need supervision for allergic reactions - which are much easier to predict and control with IV use.

 

[Sherlock]

ny large protein given by mouth will be broken down by gut enzymes

The proteases get into the liposome, right through the lipid bilayer?

[edit] Or are you saying that the liposomes would be broken down, exposing the mabs to proteases?

 

[deleder2k]

Any large protein given by mouth will be broken down by gut enzymes. Liposomes might sneak though a tiny bit but in general I think they would be broken down as well. I cannot see any real need to give rituximab any way other than IV since it tends to be given only once every six to twelve months and patients need supervision for allergic reactions - which are much easier to predict and control with IV use.

If the trial by Øystein Fluge and Olav Mella succeeds wouldn't that mean that their dosing regime would be preferred? I.e every 3. months. If sub-cut is safe after one IV infusion (without side effects) then one can save a lot of time. One frees up space at the hospital, a nurse is only needed for 15-20 minutes max, instead for up to 7 hours. It will also be benefit patients - especially those who are most affected. If this become standard treatment for a majority of PWME we're talking about thousands that needs to be treated in a short period of time. The fact that it takes only a few minutes to complete a sub-cut injection means that resources can be allocated into treating more patients.

 

[Jonathan Edwards]

The proteases get into the liposome, right through the lipid bilayer?

[edit] Or are you saying that the liposomes would be broken down, exposing the mabs to proteases?

The latter most likely.

 

[Jonathan Edwards]

If the trial by Øystein Fluge and Olav Mella succeeds wouldn't that mean that their dosing regime would be preferred? I.e every 3. months. If sub-cut is safe after one IV infusion (without side effects) then one can save a lot of time. One frees up space at the hospital, a nurse is only needed for 15-20 minutes max, instead for up to 7 hours. It will also be benefit patients - especially those who are most affected. If this become standard treatment for a majority of PWME we're talking about thousands that needs to be treated in a short period of time. The fact that it takes only a few minutes to complete a sub-cut injection means that resources can be allocated into treating more patients.

I am sceptical. What about people who become allergic to the drug on their third cycle (like my friend Mrs A). These are no more than a percent or so but that is in some ways what worries me. Does the company have enough safety data? 15-20 minutes is no use if the person is going to get an allergic reaction six hours later - as happens with another anti-CD20 that was given subcut. I would personally not want to cut corners. It may be OK but when rituximab was first used IV and care was not taken to follow guidelines there were a lot of unnecessary adverse reactions.

 

[deleder2k]

Patients should be observed for at least 15 minutes following MabThera subcutaneous administration. A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions.

Patients should be instructed to contact their treating physician immediately if symptoms that are suggestive of severe hypersensitivity or cytokine release syndrome occur at any time after medicinal product administration.


Adverse reactions reported in MabThera subcutaneous formulation usage

The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in two open-label trials involving patients with follicular lymphoma during induction and maintenance (SABRINA BO22334) and during maintenance only (SparkThera BP22333). In SABRINA, severe administration-related reactions (grade≥3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation. These events were Grade 3 injection site rash and dry mouth.

In SparkThera, no severe administration-related reactions were reported.

More here: https://www.medicines.org.uk/emc/me...+1400+mg+Solution+for+Subcutaneous+Injection/

I did not know that many experienced adverse events after 2nd infusion. Sounds scary. If you're 30 minutes from the hospital I would guess you're in trouble if you experience bronchospasm.

 

[NK17]

This is a proof of a broken system. When patients are hindered the best available treatment when it is cheaper AND better... I can't believe it.

This is a disturbing fact, one of too many ...

 

[SOC]

I so wish you Jonathan Edwards were directly involved in these studies and trials.

Yeah, because he knows so much more about it than Mella & Fluge. Who volunteers to call M&F and tell them we think they need help with their research and JE is just the guy?

 

[Aurator]

I so wish you Jonathan Edwards were directly involved in these studies and trials.

Who volunteers to call M&F and tell them we think they need help with their research and JE is just the guy?

They've already rung me about this in fact.
I felt it my duty to tell them he's absolutely up to his eyeballs at present answering queries on PR - to the point where he hasn't even got time to have his dinner most days.

M&F told me to pass on their concerns for his welfare in that case, and that we were lucky to have JE as a member of PR in the first place, let alone have him running himself ragged keeping up with all our questions and solicitations. I reassured them that I'd pass on their valuable counsel.

 

[rosamary]

They've already rung me about this in fact.
I felt it my duty to tell them he's absolutely up to his eyeballs at present answering queries on PR - to the point where he hasn't even got time to have his dinner most days.

M&F told me to pass on their concerns for his welfare in that case, and that we were lucky to have JE as a member of PR in the first place, let alone have him running himself ragged keeping up with all our questions and solicitations. I reassured them that I'd pass on their valuable counsel.

YehYeh

They've already rung me about this in fact.
I felt it my duty to tell them he's absolutely up to his eyeballs at present answering queries on PR - to the point where he hasn't even got time to have his dinner most days.

M&F told me to pass on their concerns for his welfare in that case, and that we were lucky to have JE as a member of PR in the first place, let alone have him running himself ragged keeping up with all our questions and solicitations. I reassured them that I'd pass on their valuable counsel.

Yes. Tell him to go and chill out for a bit. Give him two days off.

 

[Marky90]

Just wanted to say that i am so very grateful you are on these boards @Jonathan Edwards , its so cool to understand, albeit superficially, whats going on. Ive been reading up on immunology, and its so exiting. I think autoimmunity must be the cause for most cfs-cases in some way. It makes a lot of sense, its the perfect unknown virus.. It was there all the time..

 

[alex3619]

This is a disturbing fact, one of too many ...

The use of antibiotics to treat H. pylori was held up for years because doctors were required not to discuss it at pharma sponsored conferences. After the fact this issue was made public.

 

[beaker]

Just wanted to say that i am so very grateful you are on these boards @Jonathan Edwards , its so cool to understand, albeit superficially, whats going on. Ive been reading up on immunology, and its so exiting. I think autoimmunity must be the cause for most cfs-cases in some way. It makes a lot of sense, its the perfect unknown virus.. It was there all the time..

But the real trick is ( if you are right) what causes the auto-immunity ?