Are IRTs ahead of their time?

A

I am beginning to think that immune reconstitution therapies or IRTs are ahead of their time. Many neurologists, people with MS (pwMS), payers – particularly fee-for-service insurance companies – and the regulators are unable to get their heads around how these agents work. In addition, a few recent review articles, written by colleagues, cast doubt on this treatment strategy and the terminology we use. 

IRTs are the only treatments that are addressing the cause of MS and hence have the potential to cure MS. We will know in the near future how many pwMS in very long-term remission post -alemtuzumab, -HSCT or -cladribine are truly MS free. This information is critical to convince a sceptical field of the value of these treatments.

The mortality associated with HSCT makes people shudder. Although the risk of dying from one of the complications of HSCT is quoted as being between one of 1 in 333 (0.3%) to 1 in 50 (2%) many pwMS are taking this risk in the UK or abroad. Despite HSCT being a viable treatment option for pwMS in England and now Scotland many UK MSologists don’t routinely put this option on the table when discussing switching treatments with their patients who are failing other high-efficacy therapies. Why?

Even going to the easy-to-use, easy-to-monitor, oral cladribine option we are seeing slow adoption. Why? I am now convinced HCPs don’t understand IRTs, in particular, the concepts of frontloading of risk and long-term remission.

The study below shows that patients failing alemtuzumab in year one after the first course of five infusions, do very well after receiving their second course. Despite these patients having more active disease and early breakthrough activity, they do very well longterm with high chances of being rendered NEDA and experiencing disability improvement and having brain volume loss that slows markedly – into the normal range – after year 2.

DMTs are about protecting the end-organ or brain and keeping it as healthy as possible so that pwMS can live a normal life as possible and have the necessary reserve to deal with ageing when it sets in.  Is this message difficulty to communicate? Knowing this brain volume data why wouldn’t we want to at least offer an IRT to all our patients with active disease and I mean first, second or third line? It is clear the sooner you are treated with an IRT the better you do. 

I am now planning to do a series of online lectures on IRTs to explain why they should be so appealing as a treatment strategy for pwMS. Would you be interested in watching? 

I also have a vested interest in getting IRTs adopted. We want to use them as induction agents in more advanced MS to be followed by maintenance therapies that target the processes within the brain and spinal cord to address smouldering MS. 

Van Wijmeersch et al. Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies. Mult Scler. 2019 Nov 1:1352458519881759

BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.

OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).

METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.

RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%).

CONCLUSION: Early relapsers’ outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.

CLINICALTRIALS.GOV REGISTRATION NUMBERS: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

CoI: multiple

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.

32 comments

  • I wonder if you have muddied the waters a bit with recent posts about smouldering MS and slowly enhancing lesions? I am c.14 years post my first Alemtuzumab infusion and still doing well (long term remission). I was happy to take the risks attached to Alemtuzumab given the possibility of putting the disease in remission. However, I was very shaken by your recent post that an IRT such as Alemtuzumab might just be converting RRMS to PPMS. You also noted your view that relapses and MRI activity are not MS. IRTs will only take off big time when (1) MSers realise how bad MS is, (2) IRTs can, for most, put MS into remission for 20 years plus, (3) the side effects can be better managed, and (4) IRTs are shown to have an impact on the real MS (not just relapses and MRI activity).

    • Although smouldering MS is a real entity it is likely to be triggered by innate immunity inflammation, which builds up over time. Hence the earlier you treat MS the less innate immune activation occurs and hence the less likely you are to see and experience smouldering MS. This is why we keep beating the early-effective treatment drum!

      • If I’m not mistaken, Cladribine is referred to as selective because it leaves much of the innate immune system intact.

        Does this mean that it is not as effective as, lets say alemtuzumab, in preventing smouldering MS?

        • We have insufficient evience , but I suspect that they could be comparable or cladribine could be better, why because cladribine can enter the CNS and one suspects alemtuzumab does not get in. Why is alemtuzumab seen to be better, becuase of the atrophy data, but study 2 year posrt diagnosis is not going to be the same as 9 years post diagnosis but if you look at ORACLE hidden in supplementary data is the atrophy data and it shows it is similar to alemtuzumab. This an experiment I would do, do a trial in early MS and show it works first line and it works on atrophy. You are correct alemtuzumab has a transient effect on monocytes, cladribine does not

  • I would be very interested in knowing long-term for Cladribine and SpMS users . After one year and half after first dose of Cladribine I believe things are slowing down now yes I do believe in an induction time to see any good affects time will tell ..

    • Prof K and the team have some very good clinical, MRI and neurofilament data to support cladribine’s effectiveness in more advanced MS. This has been presented at several meetings.

  • Hi Prof G,

    Long-time reader, first-time commenter here.

    I’m a scientist (marine ornithologist) and last year (during the final year of my PhD!) was diagnosed with RRMS. Currently, on tech but have a new lesion so trying to get my head around the literature in order to inform my choice on next DMT.

    Please, can you provide the links to the “few recent review articles”, so I can take a look at them?

    Thanks for the excellent and honest blog.

    • These are 3 general articles to start with:

      1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol. 2018 Jun;31(3):233-243.
      2. Giovannoni et al.Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015 Jul;4(4):329-33.
      3. Giovannoni et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016 Sep;9 Suppl 1:S5-S48.

  • “We want to use them as induction agents in more advanced MS to be followed by maintenance therapies that target the processes within the brain and spinal cord to address smouldering MS”

    I am confused. Could you please point me towards publications that shows any evidence that suppressing the adaptive peripheral immunity works on progression independent of relapses or deleterious innate immunology changes?

    In other words, how does alemtuzumab, cladribine, or HSCT work to slow down the “smouldering MS” changes caused by A1 astrocytes, hot microglia, oligodendrocyte changes or neuron death/mitochondrial dysfunction?

    Do you believe these medications act on EBV controlled memory B-cells in clusters in meninges of the brain thereby indirectly suppressing the adverse changes in the innate immune system?

    By this thought process, wouldn’t HSCT be expected to have the greatest outcome on inhibiting the slow burn/progression as it is used in treatment of B-cell multiple myeloma of the CNS and is CNS penetrant? Why no trials on HSCT in progressive MS then? Isn’t Dr. Pender’s primed CD8 T-cells against EBV controlled B-cells doing just this?

    Also by this logic, cladribine is CNS penetrant and would be the second best choice? Wouldn’t alemtuzumab or even ocrezulimab have the lowest or minimal effect as it is mainly not CNS penetrant?

    • You have to get on top of both adaptive and innate immune function and other processes as well. Cladribine, for example, will target both peripheral and central T and B cells and then the maintenance therapy will be used to target innate and other processes within the CNS. In other words, the IRTs will be the platform on which you build the sandwich (neuroprotection, remyelination and neurorestoration).

    • A good article to start with is the following showing that parenteral cladribine may, in about 50% of treated patients, clear the CSF of OCBs.

      Rejdak et al. Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study. Mult Scler Relat Disord. 2019 Jan;27:117-120. doi: 10.1016/j.msard.2018.10.006. Epub 2018 Oct 10.

      BACKGROUND: There has been long-term interest in cladribine as a drug for the treatment of MS. The current study focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years.

      METHODS: 29 treatment-naive subjects with RRMS were prospectively enrolled and received induction therapy with subcutaneous parenteral cladribine (at a cumulative dose of 1.8 mg/kg; divided into 6 courses every 5 weeks given for 4-6 days, depending on patients’ body weight). Selected patients received maintenance doses in the follow-up period.

      RESULTS: Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB. There were no significant differences in Expanded Disability Status Scale scores at baseline and at the end of treatment cycle between OCB-positive vs. OCB-negative subgroups. At the last follow-up, OCB-negative patients had lower disability compared to OCB-positive patients (p = 0.03).

      CONCLUSION: Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.

      • Thanks for your thoughts and publication.

        Do you expect the CNS penetrant cladribine to have the biggest effect on both adaptive and innate processes of all the dmd currently available, excluding HSCT?

  • Hi,

    Highly appreciate your blog.

    A couple of quick questions;
    – can you explain why drugs like Ocrelizumab Rituximab are not listed as (S)IRTs? How does their MoA differ from drugs like cladribine and alemtuzemab, which does not put them on this list?
    – will repetitive cycles of cladribine increase the probability of (near) complete IR? I.e. being a less potent drug than alemtuzemab, can this be alternative approach to reaching a similar effect?

    Regards,
    Sondre

    • Yes, we think anti-CD20 therapy could be used as an IRT, which is why we have proposed the ADIOS trial. I am convinced that adverse events will emerge with time that will force us to use anti-CD20 therapies as IRTs or induction agents, i.e. to be followed by safer maintenance therapies.

      • Thank you for replying so fast 🙂

        Do you also have a reply for my second bullet point? (I have already read the post on Cladribine re-treatment, which was excellent).

        As an end-note, I hope there soon will be more directions on how to monitor treatment effect (e.g. from cladribine) as a way of knowing when to re-treat, and also what types of drugs can be used after the Year 2 cycle as a maintenance therapy. Going 3 years without any treatment except cladribine IR scares me…. (despite the data from the trials).

        Sondre

      • Again, thank you for replying.

        Still a bit curious about the answer to the question in my second bullet point though;

        “– will repetitive cycles of cladribine increase the probability of (near) complete IR? I.e. being a less potent drug than alemtuzemab, can this be alternative approach to reaching a similar effect?”

        Sondre

        • Repetitive cycles increase the risk of lymphopenia similar to alemtuzumab, but you dont need this if memory cells are the inportant target as you can achieve the depletion without the depletion of other cells seen with alemtuzumab

          • I apologize, I don’t mean to be rude, and I may be a bit slow, but what exactly do you mean by: «you don’ need this if….» what exactly is it someone don’t need? Repetitive cycles of cladribine?

            If I understand this correctly you are referring to a hypothesis that memory (B?) cells are the once which need to be depleted as means to achive the desired effect, and that this is done successfully by cladribine without depleting other cells which may be unnecessary? (Like alemtuzemab does)

          • Yes you got it

            It may be that the cells are gone and once a cell is dead it stays dead and is not there. This will occur for some people with ocrelizumab that they get a dose at 6 months but there are no B cells for it to kill. The same will hold true for cladribine

      • but we kinda do, albeit not on such.large scale as it would be if they didn’t needlessly pull the plug. You have to count all the patients on generic cladribine! Is anyone collecting the data on those?

  • The more I read about Lemtrada/HSCT the more I want the opportunity to go that route and wish they’d been an option earlier. I understand the risks of each from a laypersons standpoint but ironically, I have to get worse before I qualify for either.

    Has anyone had any luck getting their neurologist on board with switching if you are slowly but not majorly getting worse? Even from a financial perspective to the NHS, they’d beat my Tecfidera in the long run.

    • Grateful to say that in Canada it was a fairly quick and painless process switching from a first line DMT to Lemtrada….though it still involved a massive degree of self advocacy and determination. RRMS diagnosis sept 2018 with a trial of Ocrevus over the past year and then a quick transition to Lemtrada in September after a minor relapse. Feeling grateful for the system in place here and a neurologist who supported my decisions.

      I do feel the weight of inequity in this privileged access., especially in light of some of prof G’s recent posts. Disheartening that treatment with effective medications is not a human right globally. Once again I wear my white middle class western badge somewhat shamefully with an uncomfortable mix of gratitude and shame.

  • Thank you for very interesting posts on an excellent blog!

    Some months ago I received HSCT. Recovering from chemotherapy is harder than I expected, but there being a chance of long-term remission or cure makes it worth the struggle. I was diagnosed with RRMS two years ago, but I have had the disease for much longer. Whether I have smouldering lesions, I do not know, but you suggest that IRT should be followed by maintenance therapies that target the processes within the brain and spinal cord to address smouldering MS (neuroprotection, remyelination and neurorestoration). Are there any such therapies available today, or are these for the future? My neurologist is forward-leaning, so I am sure that he would prescribe.

    Since you mentioned the dangers of HSCT, I would like to share my experience. I went to India for treatment, but in spite of very competent haematologists, it was a very bumpy ride with lots of procedural hygiene issues. If it hadn’t been for my wife – she is an MD – overseeing every detail, chances are that I would not be here today. It was extremely devastating, heart breaking and frightening to hear while we were there that another patient receiving HSCT became septicemic and passed away. Hospitals in India offer HSCT at low cost, but I would strongly recommend seeking help elsewhere.

  • “ I am now planning to do a series of online lectures on IRTs to explain why they should be so appealing as a treatment strategy for pwMS. Would you be interested in watching? ”

    I would be very interested in watching.

    I have started a Dutch foundation to inform patients about scientific insights (focusing on the very hot topic HSCT at the moment). The foundation is http://www.msinbeeld.nl (some pages are available in English). I would be happy to help you in any way I could, I am a PhD, MS patient, had HSCT due to lymphoma in 2017. For my work (educating people about HSCT and alternatives, IRTs are a big (and complicated) topic) I compile information, spend time on creating informative graphics and slides and I create video’s about this. Just shoot me an email when I can help you with anything.

  • So to wrap it up, all the folks who turned out to be JCV+ on diagnosis and offered Lemtrada are the lucky ones after all!

  • Yes, I would certainly be interested in watching. Critically appraising papers is time consuming stuff! On that subject, do you think we could ever cover competing theories around the pathogenesis of MS sometime? I spend too long on this site and I’ve been taking all this functional reserve stuff, and naughty B and T cells and their migroglia mates, as gospel and forgetting it’s theory (less likely or more likely). What about neuromeningeal inflammation and the like? There are people, myself included, that have brains that look like a car wreck on an MRI with spinal cords that still seem to hold together (definitely fewer there neurons, though I’m no neuroscientist) and yet we get by even in old age. We spend a lot of time understanding how conditions might work through drug mechnisms of action and it hasn’t worked out that well with psychotropics and mental health. Any info here would be great because it’s a complex beast.

  • As a pharmaceutical professional who has worked with alemtuzumab and cladribine I agree that the uptake of these innovative agents has been slow. The early IRT’s such as alemtuzumab presented major challenges to the MS service from both a financial and safety/monitoring perspective and although the more recent introductions such as cladribine have to a major extent overcome the safety/monitoring challenges there are still significant obstacles to overcome.

    My experience suggests that the two key obstacles are :

    – an inherent conservatism within certain sections of the clinical community
    -a failure to convince commissioners of the long-term value of early treatment with IRT’s

    It is difficult to fully understand why clinical conservatism is more significant in some medical specialities and individuals however it is clear that overall numbers of UK patients on treatment and receiving the latest MS therapies tend to lag behind comparable nations.

    The failure to convince commissioners of the value of investing in IRT’s could perhaps be addressed by better communicating the burden of illness resulting from MS and also improvements in the systematic collection and analysis of patient outcome data.

    Ideally,a coalition of manufacturers,clinical leaders and patient organisations need to come together to focus on how access to these life changing treatments can be improved.

By Prof G

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