Teriflunomide’s secrets

T

Barts-MS rose-tinted-odometer: ★★★★★

What should be our therapeutic target in MS?  Reducing relapses and MRI activity, NEDA (no evident disease activity) or saving the end-organ (brain volume loss)? 

I have been pushing the for the latter, i.e. the most important treatment target must be protecting the end-organ and saving or protecting as many neurons, axons and synapses as possible in people with MS (pwMS) so that can age normally and live as near normal life as possible. To achieve this we need to diagnose and treat MS as effectively as possible (Time is Brain) and to promote a brain-healthy lifestyle and to treat MS holistically (minimal gains hypothesis).

This principle of protecting the end-organ is not new and was probably first promulgated by the kidney doctors in relation to loss of kidney function in chronic kidney disease; every nephron (the kidney’s equivalent of a neuron) is sacred. Every neuron is sacred! The difference between kidney doctors and neurologists is that they can always put their patients on dialysis and offer them kidney transplants. We, neurologists, don’t have that luxury and what awaits our patients with progressive loss of end-organ (brain atrophy) is unemployment, worsening cognitive impairment and physical disabilities and the consequences (bladder, bowel, falls, walking aids, wheelchairs, dementia, etc). 

What is interesting is that not all DMTs are made equal when it comes to protecting the end-organ. At the top of the rankings are HSCT and alemtuzumab followed by natalizumab and then there are the also-rans. What is interesting is the impact on brain volume loss is not necessarily linked to the DMTs ability to switch of focal lesions (relapses and MRI activity). A good example of this is teriflunomide, which has only a modest effect on relapses (~35% reduction in relapse rate) compared to say anti-CD20 therapies, which after 6 months of treatment almost completely stop relapses and MRI activity, but these two classes of therapy have a similar impact on slowing down brain volume loss. 

Teriflunomide is clearly doing something at the level of the end-organ that anti-CD20 therapies are not. This study below in subjects with CIS shows that teriflunomide works very well, on the end-organ, even early on in the disease, but not all subjects are responders. This begs the question; what is it about teriflunomide’s mode of action that explains its remarkable effects on brain atrophy? I have hypothesised in the past about teriflunomide’s broad-spectrum anti-viral effects and have proposed doing the iTeri study, i.e. using an anti-CD20 or other depleting DMT as true induction therapy and then using teriflunomide (or another DHODH inhibitor) as the maintenance therapy. The hypothesis is to allow peripheral B-cell reconstitution or recovery to occur in the presence of anti-EBV agents, which will prevent EBV-infected autoreactive (MS causing) B-cells returning. The problem we are having with the iTeri study is trial design; i.e. how do you design a trial that will convince the regulators of its efficacy and get the drug licensed as a maintenance therapy? Would the regulators accept non-inferiority or safety design? Another reason for this study design is to derisk anti-CD20 therapies. The doubting Thomas in me is saying there is no way someone with MS can stay on an anti-CD20 therapy indefinitely. 

Maybe I am wrong, but let’s not stick our heads in the sand. Relapses and focal MRI activity are not MS. The real MS is smouldering MS and all the processes that cause accelerated brain volume loss. Let’s focus on smouldering MS and ask questions about what needs to be done to tackle these processes. What is ot about HSCT, alemtuzumab, natalizumab and possible teriflunomide that differentiates the DMTs into two classes. For example, could it be the T-cell? 

Zivadinov et al. Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS. Ther Adv Neurol Disord. 2020 Nov 11;13:1756286420970754. 

Background: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS).

Methods: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2.

Results: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy versus placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; p = 0.0359) and 28.6% (WB; p = 0.0286); month 24, 40.2% (CGM; p = 0.0416) and 43.0% (WB; p < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (p = 0.0004) and 47.3% (p < 0.0001) during years 1-2, respectively, and 6.6% (p = 0.0570) and 35.9% (p = 0.0250) during years 1-5. In patients with the least (bottom quartile) versus most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; p = 0.0024) and 58% (WB; p = 0.0028) during years 1-2, and 42% (CGM; p = 0.0138) and 29% (WB; p = 0.1912) during years 1-5.

Conclusion: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.

If you enjoy reading this blog you may want to support Prof G’s challenge

After his recent accident in which he sustained a broken pelvis and cervical spine, he has set himself a rehab challenge to walk 5 km unsupported by the end of the year (‘Prof G’s bed to 5km Challenge’). He is raising money for Queen Mary University of London to support Dr Ruth Dobson and Dr Angray Kang’s COVID-19 MS Antibody Study. So please donate if you can, every little helps and will get this study completed on time.

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About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

27 comments

  • So in the iteri theory, the replenished b-cells are protected from ebv infection. However, what is it about hsct and lemtrada that prevents this reactivation. Is ebv not still lurking somewhere following these treatments?

    • EBV may be lurking and explain why some people fail these treatments. Nobody has looked closely enough post-alemtuzumab or post-HSCT.

  • If you need volunteers for iTeri I’d be happy to take part, I’m sure lots of other MS patients are in the same boat – having been promised the world with the new “wonder drug” being less than impressed when “look no lesions / relapses” becomes “yes but I’m still deteriorating, WTF??”

    Also – could it be that long-term CD20 depletion actually does the opposite of what’s wanted and makes MS deterioration worse than it would otherwise have been? (that would require some pretty hardcore statistical analysis, also not sure there’d be much interest in funding it – everyone seems to have bought into the wonder of CD20).

    Or could it be that not all MSes are the same?

    Not so much PP / SP / RR / CIS – that’s already discredited and entirely arbitrary. More that some peoples’ MS is B-cell mediated, some are T-cell mediated, some are both, some are neither and something else? That might explain why different people have such wildly different responses to treatments – for some CD20 treatment doesn’t just stop the MS in its tracks but they start to recover / redevelop functionality they’d previously lost. Whereas others undergo slow decline. Probably the same on other therapies. Anecdotally, I experienced cognitive recovery on Tecfidera though sadly developed severe acute T-cell lymphopenia so had to stop – from what I’ve read I’m not the only one… I’ve only experienced deterioration on ocrelizumab. But that’s just me.

    It seems the more we find out about what MS actually is and how it works, the less we know. And this might actually be a good thing – you’ll get there eventually.

    Also – wishing you a continued speedy recovery 🙂

  • The thing I love most about being English is the phrases used in the English language. I’ve followed this blog from the start and have read all Prof G’s posts about ideas for tackling the real MS. My elderly father used a phrase the other day which I hadn’t heard for some time “he’s all mouth and no trousers”. I had to look the meaning up:

    “The colloquial British-English phrase to be all mouth and (no) trousers means to tend to talk boastfully without any intention of acting on one’s words.”

    When I used to go to football matches with my father he would also use the phrase “He talks a good game” which means “To speak very convincingly about one’s plans, abilities, or intentions, especially when one’s actions don’t live up to one’s words.”

    When you have recovered, 2021 should be the year for action. Some of these ideas for addressing the real MS should be acted on – no more excuses (dog ate my homework, I was hit by a motorbike, Covid 19 etc.). I don’t want to get to the end of 2021 and none of your ideas have been taken forward. Or is Prof G “all mouth and no trousers”? As a runner Prof G might prefer the Nike slogan “Just do it”.

    Yes, I know this all sounds rude and poor Prof G is recovering (does anyone care how the motorcyclist is?), but we need to start moving these ideas forward as time is brain (as we keep being told).

    • Sid what I am not telling you is that a variant of the iTeri study is quite a way down the line in terms of planning and trying to get done (funded).

      Many studies on this blog see the light of day so it is not necessarily more ‘ mouth than trousers’. For example, PROXIMUS, ZEUS (now STAR-MS), NEDA (now DELIVER-MS), O’HAND, SIZOMUS, CLAD-B, CLADRI-PLUS, PROXIMUS, CHARIOT-MS, DODO, UNDER&OVER and FAM-V are all had their debut on this blog and are either finished or started.

      Yes, there are some trials that don’t get done, for example, the PAPA study (rituximab or teriflunomide post-alemtuzumab to prevent secondary autoimmunity), but when the funding was offered to us for the PAPA study it was too late in the day and ocrelizumab as on the market and the EMA then made alemtuzumab 2nd-line, which is why we turned the funding down; we would not have bn able to recruit for the study. If the PAPA study had been done when we came up with the design alemtuzumab may still be used at the moment is one of the least prescribed DMTs despite it being the most effective. Yes, we failed to convince Sanofi-Genzyme of the importance of this study and the rest is history.

      And yes we are working on getting a few of our other studies funded as we speak, for example, ATTACK-MS, ADIOS, iTERI and its variants, HAART, OXO and DAPZONE-P/S. We are really not as idle as you think we are; maybe we do enough work to consider us being more ‘trousers than mouth’? 😉

      • I was jesting (a bit). What I’m not seeing as yet are the results of these studies (so many studies). And more importantly, whether any positive results will result in new approaches being approved and available to patients. There is so much promise in the avenues being pursued, but it won’t mean a jot unless I can pop into Boots the chemist and buy a cheese and onion sandwich, a packet of razor blades and a box of super strength Black Swan terifizz tablets to treat my smouldering MS.

    • You mean, “s*** or get off the pot” or go into politics and then preach from the bully pulpit. Yeah the English language is colorful.

  • What’ do you have have in mind for the timeline of teriflunomide initiation in the iTeri study? Is there an overlap beteeen the induction drug and teriflunomide? Is there immunosuppressant worries?

  • Very interesting. We know brain atrophy is a hard to measure marker and it takes a long time and large population to detect meaningful differences. I think that we should test people taking teriflunomide for neuronal damage markers (in case this was not done yet) like nfl even if not validated yet. If it really has an impact on brain loss nfl should be low. As reported in your slides, I think we should also periodically check OCBs also in people taking high efficacy DMTs because there could be important information that we are missing with many DMTs. This OCB test in the slides makes me wonder why, ProfG, would you check OCBs? Do you suspect Teri does something to plasma cells?

    Why can’t people take a b cell depleting agent and Teri at the same time? One could do a combo trial and see if the effects on the decrease of BVL adds up. I think of a 3 arms study, one on teri alone, one on anti cd20 alone and the third on both where I would expect to see a difference between the combo arm with respect to mono treatment arms that should be comparable. In case they add up the mechanism could be likely different otherwise it may be a not saturated mechanism by single agents. If there is no increase than the mechanism is the same.

    A final question, teri is reported to stay in the body for up 2 years (!) after stopping. Where does it sit to take such a long time to be cleared?

    • “final question, teri is reported to stay in the body for up 2 years (!) after stopping” …..There is a rapid elimination protocol which can be administered to rid the body of the drug within days. However, I am told the process is not very pleasant.

  • Don’t lesions caused by relapses ultimately result in axon loss? The target maybe to limit brain and spinal cord atrophy but if relapses are left to run riot then it is not much consolation for the patient on Teri or am I missing something here?

    • My concern too.

      I’m worried about taking anti-cd20 forever. Agree that it can’t be good.

      Am also worried that the progression (deterioration) will kick in

      But all that is in the future.
      At the moment everything is good, and has been so for years.
      A return to relapses absolutely the last thing I want

  • Prof G, I think you hit the nail on the head! Of my 950 MS patients here in the USA, I have about 220 on Teriflunomide( Aubagio ). As my MS patients age, with senescing immune systems, and the end organ is atrophying, I have transitioned them off the “job well done” immunosurpressive antiinflammatories for the 12-15 years of the relapses and hot MRI activity, which is not the “Real MS”, as per your mantra. I was invited by Genzyme ( Aubagio’s manufacturer ) to Advisory Board Meetings 11/2/19 in Phoenix Arizona and Virtually, several months ago. I espoused to them exactly what you just said, with my adding in the Asclepios Ofatumumab vs Teriflunomide comparable brain atrophy data. I strongly suggested to the Genzyme upper brass attending that Genzyme market Aubagio for the 1 million aging MS patients we have in the USA as a safe, immunomodulatory, cytostatic, broad antiviral, small CNS penetrant molecule. Subsequently they did not go for my argument, I guess, perhaps, with generics looming in the near future, but many in the company, and the MS docs, bought my argument. Lastly, EBV infected B cells cannot be happy and become immortalized. The only time B cells can present antigen to naive T cells, without T cell help, is in a smoldering, low grade in flammatory environment. Could this be the “inside out” pathophysiology of MS? A smoldering EBV CNS infection turning glia and neurons into “non self antigens”, carried by EBV infected B cells to naive T cells in deep cervical nodes, via the lymphatics or CSF, and set up the trafficking MS clone forever after?

    Clifford Reed

  • Prof. G – I am concerned these treatment approaches may not work when an individual’s disease course is “highly active.” See my comments under the following post: https://multiple-sclerosis-research.org/2020/11/chariotms-is-on-a-roll/

    This is why we need to initiate aggressive (individualized) combination treatments EARLY. If only there were more forward-thinking visionaries like yourself in the MS field……we might actually be able to slow this horrible disease down.

    Sorry for my less than positive tone. I have been in a horrible relapse over the past few weeks, which has left me with a baseline pain level of 8/10. Please keep advocating for change, so future pwms do not have to suffer as much as the previous generation. Being < 40yr old and left with a baseline 8 pain level for the rest of the life is a difficult pill to swallow.

    Glad to see your recovery is going better than expected. Although, I am not surprised, as healthy individuals with a positive attitude and strong support system tend to heal faster than expected.

  • Would you suggest to use teriflunomide as a continuation therapy after immune reconstitution therapy to protect end organ damage even though IRT’s can result in NEDA. If so what would the criteria be to start using teriflunomide after IRT’s and Neda. Brain atrophy and / Or other biomarkers? Would the new BTK inhibitors even be better to address innate immune system inflammation than teriflunomide also after IRT treatment?

    • I wanted to write a post about BTK inhibition and Teri… I remember that leflunomide is the active form Teri is converted to. I found a paper saying that a metabolite analogue of leflunomide has some btk inhibition activity although I cannot access full paper so I really can’t tell more. In case, would this be a possible explanation for teriflunomide effects?

  • “Anti-CD20 agents are also anti EBV”; “Teriflunomide is clearly doing something at the level of the end-organ that anti-CD20 therapies are not, cause Teri is anti-EBV”.

    These two statements don’t add-up. Axon atrophy is a delayed measure related to relapses or lesions, so a two-year trial will never show the real deal. If your findings do not take time since onset as well as timing of treatment into consideration they can be very inaccurate.

  • Nice thought.

    We are the only dudes in the mix NOT prescribing combination therapies. The concept has been, perhaps, floated a long time ago but there appear to be NO takers.

    When none of the anti-CD20 stuff gets into the brain and anti-CD52 is equally bad at getting in, why not use something like Ozanimod that gets in but AFTER the disease has been ‘silenced’ for 6-12 months ? Or, use them concomitantly and d/c the MAb after 12 mo ?

    Of course, everything has to be done in a clinical trial but if IRBs allow this to occur with a lightning fast review, proof of concept studies can be done using a collaborative design between Universities.

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