OK this is a bit tounge in cheek, as I have known the answer foone -imod for some time, but many studies not sponsored by the manufacturer have talked about percentage effects and you have to deal with absolute numbers to grasp what is going on. This a current paper below is a company sponsored study and the results are easy to see, which is not always the case. These are reported here more than a decade after the drug was approved. Studies often focus on T cells and not enough on B cells…This is a plea to show me where I need to read so that we can understand the new -imods….They are different.
As you know I have been abit of a “clad lad” and was trying to understand how cladribine works. I had got interested in this because we were trying to develop it after a certain company “spat the dummy” and refused to do another trial that the regulators wanted, So they walked away from hundreds of millions of investment, as they were coming second in a race of two. However the company were kind enough to give us the trial data and we could see that people were being sold a pup with the it’s an “all T cells World view”. They were depleted bearly past normal levels but some B cells were being smashed.
Anyway around 2010 …the -imods won the race to become the first class of oral agents for relapsing MS There are now four of them.
How do they work?
We have been lokking at this, but you say
It is simple, they works because the drug mimics the “catnip” for white blood cells, which follow a gradient of a fat molecule (catnip called sphingosine-1-phosphate) that draws white blood cells into the blood from the lymph glands. I essentially does what natalizumab does but in a different way. Natalizumab stops the white blood cells from leaving the blood and so they are stopped from getting into the brain . The -imods take this idea one step back and if the white blood cells, can’t get out of the lymph glands, they can’t get in to the blood and they can’t get in the brain and so it stops MS…..Simples
It was a simple solution it blocked T cells entering the CNS and so you don’t get MS and at one point a case was made that it does not target a subset of cells that may be involved in controlling infection. It’s a simple concept and we have all bought into it. I teach it also
Sure you take the -imod and the white blood cells disappear from the blood, your MS goes away. Stop the -imod and white blood cells come back and if you don’t do something about it disease can come back with a vengence (rebound).
So we all bought the idea, but a short while ago, I was asked to look at this and it was obvious that it was not quite that simple, which is just as well because it would mean the T cell idea of how the drug works is probably a pile of you know what.
Because the T cells that get, and accumulate into, the CNS during MS are those that a supposed to escape the entrapment (The T memory cells expressing CD45RO butt not another receptor CCR7) to protect people from infection. Therefore it should not work…but it does work……so there was a smelly fish somewhere, as something was not quite rigtht. I did not care because whilst looking at cladribine and alemtuzumab, I decided that drugs should inhibit memory B cells if they are going to work well.
I had to scrabble around the literature to see if I could get support for this idea, but it was not easy because everyone worked on T cells and nobody cared about B cells, unless they were thinking about antibody. The CD20-depleting antibodies changed that view for some, but not some die hard T cell biologists that have concocted a story about CD20 T cells. Whilst this may be true, it made me delve into the -imods and it clearly wasn’t as simple as I thought and it is clear that some cells are being destroyed and not just trapped. Maybe this is part of the reason why in some people, cells do not come back quickly when you stop the drug.
The first -imod has been around for a decade and there have been a few studies looking at B cells and sure enough memory B cells are inhibited. Now, we have got three new -imods and the question I ask, is. ….”Is there evidence that these new -imods block memory B cell numbers”…If correct I give a sigh of relief but if not I have to change my ideas to explain what is going on.
Can I explain benefit from a T cell point of view? Yes I could if I want to
This is because although it may be evident that CD45RO memory cells escape more that the other T cell subsets, it was evident to me that there were markedly fewer of these memory cells in the blood. This is clearly seen in this paper. Less cells migrating………..less MS. It seems there is a T cell subset that is less affected and these are the “effector (CD45RA+,CCR7-) T cells and notably the CD8 T cells. This is good news because these are cells that are going to get rid of the COVID-19 virus along with the macrophages. These probably won’t be affected by migration because they are already in place in the lungs to deal with the infection. So we can explain why fingolimod does not make COVID-19 worse. But what about the COVID-19 vaccine response? I think we can.
The T cells in the blood on fingolimod are not the same as the T cells in people not on an -imod and then there is the poor vaccine response. Well we can look at this paper and see it inhibits memory B cells hence no MS, but also naive B cells, hence no new antibody response to COVID-19 vaccination.
It is simples…it is biology.
Now that is fingolimod, what about siponimod, ozanimod and ponesimod? The anwers is I don’t know fully because I don’t think these studies have been done, or reported in a way it is easy to decipher so let’s not wait a decade for this to happen with these new imods….hence my provocative title to the drug manufacturers, which is a plea to do the studies with their drugs in a way it is easy to see. I accept I may have missed them.
What do I mean? This is an example of studies which were not done my the manufacturer. I won’t say where it comes from as it is not important and I don’t want to upset anybody.
Once we have nice data, we can try and explain how they work in MS, what are the side-effect potentials and how do you exploit their properties in the COVID and post -COVID era. Fingolimod hits four of the five sphingosine-one-phosphate receptors (S1PR4), the others essentially a maximum of two. Do the two receptors not hit by the new -imods make a difference for action in MS, response to COVID-19 and COVID-19 vaccine responses?…..I’ve been making some predictions…..coming your way soon.
The prediction is that they will target memory B cells, if they don’t our ideas need to changed or maybe some are less effective than others….But what about the effects on other subsets.
So come on Pharma put me out of my misery and give me the data for the new -imods. Stop me speculating…You know speculation to a scientists is like garlic to a vampire:-)
So is the paper Fluent in explaining ideas? The study demonstrated that “within six months, fingolimod lowers lymphocyte subsets in a fingolimod-naive population to levels seen in participants treated with fingolimod for between 2 and 12 years. The greatest reductions in lymphocyte numbers in fingolimod-naive participants occurred in naive and central memory CD4+ and CD8+ T cells, and in naive and memory B cells.
They say the work “provides insights into the utility of immunological profiling to evaluate therapy response and potential infection risk”.
Are the insights easy to understand?…Have a read and let us know your thoughts.
Mao-Draayer Y, Cohen JA, Bar-Or A, Han MH, Singer B, Williams IM, Meng X, Elam C, Weiss JL, Cox GM, Ziehn M, Cree BA; FLUENT study investigators. Immune cell subset profiling in multiple sclerosis after fingolimod initiation and continued treatment: The FLUENT study. Mult Scler J Exp Transl Clin. 2022 Aug 1;8(3):20552173221115023.
Background: Fingolimod is a sphingosine 1-phosphate receptor modulator approved for relapsing MS. Long-term effects on the immunological profile are not fully understood.
Objective: Investigate fingolimod’s temporal effects on immune cell subsets, and safety outcomes.
Methods: In FLUENT, a 12-month, prospective, non-randomized, open-label, phase IV study, adult participants received fingolimod 0.5 mg/day. Changes in immune cell subsets, anti-John Cunningham virus (JCV) antibody index, and serum neurofilament levels were assessed.
Results: 165 fingolimod-naive and 217 participants treated for 2-12 years in routine clinical practice were enrolled. Levels of all monitored peripheral lymphocyte subsets were reduced from month 3 in fingolimod-naive participants. Greatest reductions occurred in naive and central memory CD4+ and CD8+ T cells, and in naive and memory B cells. Most lymphocyte subset levels remained stable in the continuous fingolimod group. Components of the innate immune system remained within reference ranges. No increase in JCV seropositivity was observed. No single cellular subset correlated with anti-JCV antibody index at any time point. Neurofilament levels remained within healthy adult reference limits throughout. No opportunistic infections were reported; no new or unexpected safety signals were observed.
Conclusion: FLUENT provides insights into the utility of immunological profiling to evaluate therapy response and potential infection risk.
Disclaimer: These are my ideas and only my ideas.