Teriflunomide as a neuroprotective

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I do not normally post on the lower efficacy (on relapses) treatments, but teriflunomide seemed to outperform its effect on relapse rate when it comes to saving nerves.

This week we had the Mr-CD20 (Prof Piehl) from Sweden come and give us a lab talk about yep you guessed it, anti-CD20. It is always a breathe of fresh air to hear the Swedish Neuros. They are very collaborative and just get on and do it.

This week for fun, I have been a bit combative (Challenging I would call it) towards the neuros to say that I think you do not have to give anti-CD20 every six months and perhaps for some people you can stop dosing just like you do with cladribine and alemtuzumab. I have made an argument that this would not be surprising as they are all essentially working the same way. Yes I am deluding myself as it is clear many people do not accept this. The only way to know this is to do a trial. Can this be done?

ProfG countered the argument that actualy people are being underdosed

Data from Hauser et al. AAN 2019 Presentation 001. People were stratefied according to Body mass Index in people treated with ocrelizumab This was done in Quartiles = Quarter (25%) blocks. This did not affect the relapse rate (graph) however it did effect B cell repletion (line graph. 1 is minimal depletion) and smaller people repleted slower(light blue dotted line) and progressed less (bright green dotted line) in RRMS and PPMS compaired to the biggest people (Solid line dark blue or green) . Q1 is the lowest 25%, Q2 is 25-50%, Q3 is 50-75% and Q4 is 75-100%

I have no problem with this view. In the examples above we have people getting the same dose who were between 38-170kg and there are differences in B cell depletion/repopulation and progression. However, do we have to dose every 6 months in every body.

Some people want to do a trial, but it is simply to delay treatment until CD19 return and then you give another shot of anti-CD20. In the COVID-19 era, people have had their ocrelizumab/rituximab delayed because of COVID-19 and this has been safe. Therefore, do we need a trial with such low ambition? However, Mr-CD20 (actually Prof-CD20) told us that this study/trial has been done (n=~160) and the paper is on the way. Can you guess what happened?

Will the UK neuros believe it and change practice?. I think not as they will say they used rituximab and we use ocrelizumab, so we need the evidence. However, what about a delay based on return of memory B cells, as has been done with rituximab. This is one part of the ADIOS design.

However, I still do not think this will change practise as I suspect many neuros are risk averse. This view was re-inforced by Prof-CD20, who was not sure neuros would buy into treatment with ocrelizumab for a year (3-4 cycles) and monitor and reteat on activity. It is clear that some people will reactivate. I agree it has happened with alemtuzumab and cladribine but pharma did these trials and neuros went along with the label. However for ocrelizumab or other anti-CD20, I have a sinking feeling on this one and suspect this is not going to happen in my working lifetime:-(.

Perhaps at best you could have an induction followed by a lesser active treamtnet. ProfG proposed the iTeri study….I think originally it would have been alemtuzumab followed by teriflunomide, but with alemtuzumab falling out of favour, you may get cladribine followed by interferon or perhaps a BTK inhibitor. Maybe you could get ofatumumab followed by an S1P1 modulator. I doubt you will get teriflunomide used by another company. However maybe we should. ProfG has made the case that maybe teriflunomide has some neuroprotective potential .

Here is an experimental study where they induced nerve damage by starving the nerves of oxygen (energy) and took brain slice cultures and showed that teriflunomide could protect against nerve damage.

Wolters A, Reuther J, Gude P, Weber T, Theiss C, Vogelsang H, Matschke V. Teriflunomide provides protective properties after oxygen-glucose-deprivation in hippocampal and cerebellar slice cultures. Neural Regen Res. 2021 Nov;16(11):2243-2249. One of the major challenges in emergency medicine is out-of-hospital cardiac arrest (OHCA). Every year, about 53-62/100 000 people worldwide suffer an out-of-hospital cardiac arrest with serious consequences, whereas persistent brain injury is a major cause of morbidity and mortality of those surviving a cardiac arrest. Today, only few and insufficient strategies are known to limit neurological damage of ischemia and reperfusion injury. The aim of the present study was to investigate whether teriflunomide, an approved drug for treatment of relapsing-remitting-multiple-sclerosis, exerts a protective effect on brain cells in an in vitro model of ischemia. Therefore, organotypic slice cultures from rat hippocampus and cerebellum were exposed to oxygen-glucose-deprivation and subsequently treated with teriflunomide. The administration of teriflunomide in the reperfusion time on both hippocampal and cerebellar slice cultures significantly decreased the amount of detectable propidium iodide signal compared with an untreated culture, indicating that more cells survive after oxygen-glucose-deprivation. However, hippocampal slice cultures showed a higher vulnerability to ischemic conditions and a more sensitive response to teriflunomide compared with cerebellar slice cultures. Our study suggests that teriflunomide, applied as a post-treatment after an oxygen-glucose-deprivation, has a protective effect on hippocampal and cerebellar cells in organotypic slice cultures of rats.

Although you can do human brain slice cultures, In this study rat half maximal protection occurred at 3.53 ± 0.14 µM. According to the internet, Teriflunomide can cross the bloodbrain barrier (BBB) with 1–2% of serum concentrations (in the range of 2.5–4.1 μM) reaching the CNS (Kaplan J, Cavalier S, Turpault S. Biodistribution of teriflunomide in naive rats vs rats with experimental autoimmune encephalomyelitis. ECTRIMS Online Library, 2015). The blood levels in humans are 45microgramme/ml, so 1% of this would be about 2 micromolar, so it is possible it is relevant.

COI: Multiple but none relevant

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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11 comments

  • I sometimes wonder if there is any other disease area that has such a good blog devoted to it.

    I doubt it…

  • “ However, I still do not think this will change practise as I suspect many neuros are risk averse”

    I wonder what their patients would say if they put the concept, and the scientific thought that underpinned the suggestion, to them?

    Our risk tolerance as patients is often far different from that of people without MS who stroke their chins and umm and ahh about the ins and outs.

    It ought to tell them something if that woman was willing to starve herself to death (see Mirror article) about our commitment.

    We only have one life and there is no pause button. If something seems a good idea – scientifically – many of us are willing to have a go.

    What have we got to lose? Are the risks grater than the guaranteed transition to disability?

    Again: extremely frustrating to find that our docs aren’t asking patients if they’d be willing to take these risks.

    It is hardly coercive to lay out the typical progress of the disease for a patient, warts and all, so any decision is not a ‘now’ choice but a more holistic assessment.

    Keep being combative.

    • Again: extremely frustrating to find that our docs aren’t asking patients if they’d be willing to take these risks.

      I seem to remember Prof G asking would you be willing to do 3-4 lumbar puncture for a trial and the answer was a resounding yes, but rather than taking 6 months to recruit, it was 2-3 years as people were not so willing…so I guess it depends on who you ask

      • You are comparing apples and oranges with your example.

        I Agree with your general point. I also think that many people, seeing what is involved – I presume you have taken a few for the team over the years – may suddenly baulk.

        Unless they can make a direct connection to a potentially positive effect on their MS I imagine the altruism may be stronger in intent than action. Blood donation is a good example of the disparity between stated intent and opening a vein for a stranger.

        WIIFM – always the big decider in this.

        • As a no neuro I am relatively powerless too…..actually less powerful as you can mobilise the MS Societies to make people listen…

          However, would they expose the risk averse?…I bet they have the prescription details of the differnt hosptials

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