#Smouldering-MS: the BTK inhibitor race is on

Barts-MS rose-tinted-odometer: ★★★

Mouse Doctor studied zoology and as a result, he tends to use animal analogies to describe various phenomena. In the past, he has been known to use his favourite invertebrates to describe some neurologists or even groups of neurologists. Why invertebrates? If anyone comes up with the correct answer I will send you an MRI scanner lego set as a prize. 

Another animal he loves are lemmings, which he uses to describe the behaviour of pharmaceutical companies, i.e. they tend to follow each other by running off a cliff together. The question on everyone’s mind is how will the BTK (Bruton Tyrosine Kinase) inhibitor MS race turnout; will it be mass suicide with them failing as a class or will they usher in the next generation of innovative MS treatments? 

Our interest with BTK inhibitors started about 5 years ago when the Mouse Doctor and I almost managed to get Abbvie to fund an investigator-led study of Ibrutinib in MS. However, it was not to be as Abbvie’s partner Janssen blocked the grant. Janssen was concerned that it was too risky to test Ibrutinib in MS because of the off-target effects of Ibrutinib and its potential for serious adverse events.  I suspect they were right as Ibrutinib is a dirty drug and not a very selective BTKi as it also inhibits several other kinases.

Our hypothesis was simple; we wanted a CNS penetrant drug to target B-cells and plasma cells in the CNS of pwMS. We were buoyed by the observation that several people with CNS B-cell lymphomas were having dramatic responses to Ibrutinib. Although it was never to be we continued our search for a CNS penetrant anti-B-cell and anti-plasma cell agent and eventually, we managed to convince Takeda to fund a trial of their CNS penetrant second-generation proteasome inhibitor Ixazomib in MS. This study was meant to start earlier this year and has been unfortunately delayed by COVID-19 (we are now recruiting and are due to start very soon). 

Despite our failure to get Ibrutinib, a first-generation BTK-inhibitor, into MS Pharma has taken up the challenge and there are now four companies with BTKi programmes in MS (Merck KGaA, Sanofi-Genzyme, Roche and Biogen). 

BTKi’s will work in MS because they inhibit B-cell activation. There is phase 2 data for two of these agents confirming this (Merck and Sanofi-Genzyme). However, most people are not aware that BTKi also inhibits macrophage and microglial activation via the  Fc receptor (FcR) signalling pathway.  Therefore CNS penetrant BTK inhibitors, which applies to at least three of the four BTKi’s referred to above, will also target the so-called ‘hot’ or activated microglial response and test the hypotheses whether or not this response is favourable in MS.

The problem will be dissecting-out the anti-B-cell response from the anti-microglial response in terms of efficacy. Clearly, this will be important in view of some of the issues I raised yesterday around the ‘hot microglial’ response being potentially beneficial in the pathogenesis of MS. I envisage BTKi being very effective in stopping relapses and focal MRI activity the big question will be about the impact of BTKi on the smouldering component of MS. BTKi’s may have no effect on this component of MS, improve it or even make it worse. 

I note that many of the phase 3 studies will be testing BTKi against teriflunomide. Clearly, BTKi’s are likely to beat Teri in terms of their impact on relapses and focal MRI activity, but Pharma (or the lemmings) may be taking a chance of beating Teri in terms of its impact on the end-organ or the smouldering component of MS. Don’t forget ofatumumab and teriflunomide had the same effect on brain volume loss when they were compared head-2-head in the ASCLEPIOS I and ASCLEPIOS II studies despite ofatumumab being clearly superior to teriflunomide in suppressing relapses and focal MRI activity. 

It is clear to me that BTK is a very important treatment target in MS and the phase 3 trials will provide additional evidence beyond the B-cell on whether or not we should be targeting macrophage and microglial activation via their Fc-receptors. Whether or not this class of treatments will fail, i.e. fall of the cliff waits for the outcomes of the phase 3 trials. 

For once I going to be an optimist and give this new class of treatment a 65% chance of success, mainly due to their anti-B-cell effects, and only a 30% chance of failure, due to their microglial inhibition and yet to be identified off-target effects. What is important is that we are testing a hypothesis about the smouldering component of MS, which I consider to be the real MS and why I am so excited to be part of the story.

CoI: I sit on two BTKi phase-3 trial steering committees.

Twitter: @gavinGiovannoni                  Medium: @gavin_24211

33 thoughts on “#Smouldering-MS: the BTK inhibitor race is on”

  1. Interesting that you should refer to The MDs Zoological knowledge re Lemmings You will find that the Lemmings running off a cliff is a myth, which became popularised by a Disney film. Lemmings in real life don’t do anything of the sort!

    How many myths are still lurking around the world of multiple sclerosis? Now that would make a stimulating paper, and perhaps come up with the new approaches the recent MSers so frequently hope for. Perhaps ‘autoimmunity and MS’ would be a good leader of the pack?

    1. Re: “Lemmings in real life don’t do anything of the sort!”

      I am fully aware that it is a myth, but the saying ‘like lemmings running off a cliff’ captures the image very well and we actually use the phrase all the time. It also shows you how powerful a story can become 😉

      1. Yes of course, mythical pictures are useful but just occasionally its good to remember that some are so frequently and thoughtlessly repeated that they imperceptibly take on the distinction of fact……….and I suspect that there are not a few of these about in MS activities, as has always been the case. What a joker!

    2. Re: “How many myths are still lurking around the world of multiple sclerosis? Now that would make a stimulating paper, and perhaps come up with the new approaches the recent MSers so frequently hope for. Perhaps ‘autoimmunity and MS’ would be a good leader of the pack?”

      I couldn’t agree with you more. As you know I am not convinced MS is an autoimmune disease either.

      1. Prof G,

        I was thinking about your final comment here re (not an) autoimmune disease last night. I saw it days ago but couldn’t remember exactly which post it was on. Have you written elsewhere about this point of view? I’d like to read more about it. Thanks!

    3. Lemmings have become the subject of a widely popular misconception that they are driven to commit mass suicide when they migrate by jumping off cliffs. It is not a deliberate mass suicide where the animal voluntarily chooses to die, but rather a result of their migratory behavior (source Wikipedia).

    1. Yes, or at least the effect of EBV on B-cell signalling. BTK is downstream of EBV’s LMP2A; therefore BTKi’s may nullify EBV-related B-cell survival signals.

  2. Prof G,
    Since my diagnosis 18 years ago, I’ve lost count of the different drugs trialled for MS and the different targets of these drugs eg:
    T cells
    B cells
    If BTK inhibitors do not deliver (against Macrophages and Microglia), have we not reached the end of the road? How many more targets can MSologists / researchers identify? Or do we just go back to the theories of the 40s, 50s and 60s and try again with up to date drugs?
    My best animal analogy for MSologists / researchers is the Groundhog, whose activities have led to the term Groundhog Day “a situation in which a series of unwelcome or tedious events appear to be recurring in exactly the same way.” Every year MSers get excited by the prospect of treatments which either stop MS in its tracks or help the body to repair previous damage. Every year the MSologists / researchers fail to deliver. The same excuses are used: wrong target; wrong drug; wrong dosage of drug; wrong trial design; too many trial participants withdrew; drug had too many serious side effects (eg recent Bexarotene trial). Please break this cycle with BTK inhibitors!

  3. Thanks this is fascinating. These drugs have been a game changer in oncology hopefully they can do the same for ms!

  4. I hope you are successful 😎
    Guessing Neurologists equivalent invertebrate would be a Sponge.
    Every generation breaking the old thinking.
    I can’t understand your explanation but you clearly have a Spine and not just another sponge 🌹

  5. Good to hear the trial on ixazomib is starting. I would try to enrol if I lived in UK. Just a curiosity, when do you define a drug as BBB penetrant?
    I think BTKi may put the disease in standby. If they effectively suppress B-cell and microglia activation they are the “perfect” drug: no relapses, no or little smouldering. Pills to be taken for life. Of course assuming hot microglia inhibition is positive. I am not saying this is bad! It would be a huge step forward in treating the disease.
    But if we think that the hypothesis that OCBs drive microglia activation is correct, then depleting plasma cells and their B-cell precursors will put the disease in the stop position because in turn this treatment will inhibit microglia. If it doesn’t there are still BTKi to use. Also we will know that OCB are not a driver of the disease, but given the number of reports on OCB presence in MS I find hard to believe in this. BTKi will likely not stop antibody production otherwise they would be very dangerous drugs. OCB will probably stay… can they drive damage via complement activation?
    To me the future of MS treatment is to give the right drugs in the correct order to deal with all MS mechanisms.

    1. “To me the future of MS treatment is to give the right drugs in the correct order to deal with all MS mechanisms“…….Well said Fabio! I completely agree. The sad part is that it does not not have to be the future, we have the knowledge and tools to archive this goal now! Maybe not a cure, but more positive outcomes for sure.

      Attack early and aggressive. Better diagnostics, wide acceptance and use of bio markers, and a individualized treatment regiment based on a pwms specific genetic make up. Patient care should be driven by science, forward thinking, and compassion. Not broken norms and big pharma.

      1. Easier said than done 🙁
        I think many neurologists are scared of side effects more than patients. Also, it is not easy to treat with not authorized procedures. There is ethics, funding etc. If it is difficult to have a pharma start a monotherapy trial imagine how hard it can be to do a combination of two drugs from different companies or even three.
        Concerning the biomarkers and so on, it was already discussed here: the science is slow. If we want faster science we need to push on our neuros.

        But I can tell that for one patient pushing there are 9 that feel safe with CRAB drugs and happy to switch between them instead to get some risk and possibly a cure.

  6. And there is another point I forgot to mention in my post… we need also to understand why lemtrada can put the disease in remission and make this finding fit into the b cell plasma cells microglia story. It is quite hard if we don’t say that lemtrada effectively kills young plasma cells in the brain in recently diagnosed patients. Yet there are reports of people not losing their ocb on alemtuzumab.

  7. I would postulate that Mouse Dr. refers to some groups of MS Neurologists as invertebrates because they have no spines. If right, I can’t wait to get my Lego set, even if my MS disabilities will prevent me from building it myself.
    As another commenter asked, how does masitinib relate to the crop of BTK inhibitors now being trialed? I understand that masitinib is a TK inhibitor, meaning that it is far less targeted than the BTK inhibitors. Still, the masitinib phase 2/3 trial results appeared quite impressive, and even indicated some reversal of disability in progressive ms patients.
    I would love to get my hands on some of the stuff. I realize the side effect profile isn’t great, but at this point in my MS journey it’s any port in a storm. If only I were a UK based Labrador Retriever…

    1. Isn’t this why we have laws protecting compassionate use drugs and the Right to Self Determination? Drugs are still unavailable that we may opt to try to improve our life. It hurts.

  8. Prof G – I’m curious: if there is a 65% chance of success, mainly due to anti-B-cell effects, and only a 30% chance of failure, what is there a 5% chance of? A 5% chance that the numbers don’t add up?!?

    1. Instead of. It makes no biological sense to use an anti-CD20 therapy in combination with a BTKi. Maybe sequentially, i.e. start with an anti-CD20 and then sequence onto a BTKi.

      1. Thanks ProfG. I remember this from your iTeri and iBruT posts. This research blog has been really useful, in that my wife started on ocrevus as soon as she was diagnosed a few months ago. Young neuro who also was keen on high efficacy straight away. Doc said yes to tracking brain volume loss and no to serum NFL (“still done only in clinical trials”) for tracking progression. Doc is a glial researcher and had optimistic things to say about BTKs. This blog helped us ask the right questions. Thank you.

  9. If one doesn’t buy into MS is autoimmune, why would one believe in more potent IRT treatments like Cladribine, Alemtuzumab, aHSCT and especially Double dosed Ocrelizumab, which only potential benefit from DD OCR is CD20 depletion in CNS?

    1. All these DMTs are anti-EBV and the more you deplete and route out the various compartments that hide EBV the more likely you are to get on top of the disease and cure it.

    2. Whist MS is not a classical autoimmune disease as the antigen has never been identified, immune infiltrates into the CNS are undoubtedly damaging and so need to be suppressed.

      1. I can understand MS is not a classical autoimmune disease, but still largely autoimmune, otherwise the proportion of PPMS patients would have a higher male to female ratio – the male patients who do not present autoimmune reactions at disease onset, would be more than females. Didn’t know DMT’s has anti-EBV characteristics (even the anti-CD20 agents Ocrelizumab and Rituximab?)

      2. Sorry about double posting – Maybe only look into PPMS patients who never had a clinical relapse for the hot-microglia theory?

      3. 1. “Real MS” is not autoimmune, possibly driving by EBV or HERV.
        2. Risk of infecting EBV or HERV is the same for males and females.
        3. MS is one disease.
        4. More females with relapsing symptoms caused by autoimmune reactions to the “Real MS”. (Fact, about 1:3 male to female)
        —-> if 1-3 also true, there should be more males showing PPMS symptoms.
        5. PPMS Male to Female is 1:1 (Fact)

        In conclusion: something is wrong with points 1-3.

  10. Neurologists that bury their head in the sand.
    The Sea Mouse is a type of marine worm and lives buried head first in the sand.

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