Some time ago we reported this paper, we have deposited in MedRXiv. This is important to read.
The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis David Baker, Gareth Pryce, Louisa K James, Monica Marta, Klaus Schmierer doi: https://doi.org/10.1101/2020.01.09.20016774
Given the turn of events with COVID-19, I now repost this and suggest that you have a read if you are taking ocrelizumab, rituximab and even ofatumumab and are in the worrying place of determining if you should have another course of treatment or not. Your neuro may not have found this paper, as it is not on some of the search engines. Make sure people in your ocrelizumab, rituximab goups have read this.
Some of you may decide not to carry on treatment, especially as medical advice may go that way as it has been suggested that you delay infusions, so you may be doing the study that we want to do. However the data may get lost, unless it gets collected.
If you are taking anti-CD20 treatment, in fact if you are taking any medication please, please, please make sure you sign up to the MS Register (Click here) if you live in the UK. This way, where-ever you are in the UK, your story can get captured and the results of these COVID-Virus induced trials will get captured
For example is there an effect of drug holiday on disease activity
If you live elsewhere MSBase (Australia) and NARCOMS (North America). Therefore, once this pandemic is over, we can apply to Rod and the other Giys and Gals at the MS Register to see if people stopped taking therapy for an extra few months to determine if people were still protected from MS. If so it says that you don’t need to dose as frequently.
Will stopping anti-CD20 treatment protect you from COVID-19? I guess it depends how quickly your B cells return. However, this does not occur quickly and takes months and the epidemic may have come and gone by then. Whilst there is antibody circulating it can deplete any new B cells that you make.
I suspect the makers of ofatumumab, which is injected under the skin every month, will be saying if people were using their drug, which is going through the regulatory approval process at the moment, that the B cells will return very quickly after you stop. So the effects may be reversible and with COVID-19 around. It becomes very attractive.
So why did we put the paper above online. We want this work (paper) in the citable public domain, as it helps to support the idea we may not need to have a dose of ocrelizumab every 6 months, forever. This is because we wonder if the risk of infection increases with time as your B cells are persistently depleted. Importantly, it provides the the background info for we or others to apply for grants to do the ADIOS study. This is about safety and the study will get done. It is been done as people run out of money and have to stop treatment in the US
I would think it is time for the manufacturer to do this, as they can shut me up and even get me on the advisory panel…., they can do it quicker and than any academic can do it and they can control how the information is present, just like they could have done so with the phase II study above.
Importatly we ask can we get away with fewer doses. The question is whether ocrelizumab is an immune-reconstitution therapy (IRT) based on the idea that there is a comonality of CD20 depletion with cladribine, which is an IRT and also to some extent with alemtuzumab, that also induces long-term depletion of memory B cells.
Even if it is not an IRT, do we have to deplete so often? As in comparison to the CD19 B cells, which are depleted for 6 months with rituximab (top graph), if we look at the bottom graph we can see that memory CD19 B cells are still depleted at 12 months. So maybe we can have immature and mature B cells return, which are the cells that would respond to a new viral infection and this still protects us from new infection. This is part of the logic of extended dosing interval treatment of natalizumab to control MS but protecting against PML. This seems to let in CD4 and macrophages and keep out CD8T and B cells (which contain the memory B cells)
Now if you read the ocrelizumab paper (above) you can see that ocrelizumab is much more potent than rituximab and depletes CD19 for some time. So it is takes on average 12-15 months for the CD19 cells to replete..in some people it takes up to 3 and a quarter years. Based on the rituximab data we would expect it takes longer for the memory B cells to recover. We don’t have the data on this…Why is it being hidden? If this population is important then you may get treatment benefit for longer than 6 months.
This concept is supported by rituximab in MS where efficacy seemed to hold MS at bay for a year based on work in the initial clinical trials reported in 2008.
Studies continue to support this concept…but it could be wrong.
I am not a neuro and am not recommending anything but this may be of relevance in this worrying time. As is speaks to the information about if you stop ocrelizumab for a while will your MS come back….Again based on rituximab stoppers there is no apparent rebound effect.
In the study presented in the paper, people got three or four courses of ocrelizumab and then got nothing for 18 months and the drug may have still been work, so if you have to postpone treatment it is possible that you are still protected from MS. Now I have to hold my hands up and say the 18 month data is weak because either people dropped out of the study or the data had not yet been collected, but at 12 months drug free the data may be more believable
Now the worry I have, and I am thinking out loud here, is if people stop taking drug, it is possible that with time as your immatutre B cells come back, then there may be antibody around and anti-drug antibodies could form.
The fact that antibody is humanised does not mean you can’t make an antibody response. Give people 600mg and your anti-drug response is 0.4% give people 20mg and your antidrug response is nearly 20%. If you stop taking drug at some point the levels equivalant to taking 20mg will occur…what happens then?
If anti-drug antibodies do occur, it could be possible that it stops the drug working in a few people if you start the same treatment again. So if you do stop maybe ask you neuro to save some blood serum if they can do it legally as some places have Biobanks. We have the capacity to measure anti-drug responses to any CD20 reagent and could probably check this before people start up again. Probably I am worrying for no reason and if it did occur no worries, as you could swap to a different variant…..maybe some company would sponsor us to look at this and help getting bandwidth for the paper work and hands to do the study. But you may be doing an important experiment. We missed an opportunity to find out what causes relapse/rebound when you stop fingolimod.