8 picograms

What does your DMT say on the tin? 

Some advice on what to say to your neurologist, or HCP, the next time you see them; “I now know why I am not expecting to get anything more out of this DMT than what it says on the tin”

Our current crop of DMTs can only do what they are designed for, i.e. stopping the focal inflammatory activity or new lesions from forming.  They are not designed to switch-off smouldering MS, restore neurological function or scrub the brain clean of the damaging B-cells and plasma cells. Based on this we need to readjust our treatment goals for DMTs. 

This is why one of my #ECTRIMS2019 highlights was as a post-hoc analysis that showed the best predictors of treatment response to natalizumab was (1) MRI activity (Gd-enhancing lesions and new T2 lesions),  (2) neurofilament levels and (3) relapses. All the other factors did not contribute anything to predicting treatment response. Why not? The answer lies in the biology of MS. Relapses, focal MRI activity and raised neurofilament levels are the triumvirate of inflammatory disease activity

Calabresi et al. Disease control beyond NEDA: The value of non-clinical disease activity measures to determine treatment response to natalizumab. ECTRIMS Online Library. Calabresi P. Sep 13, 2019; 278615; P1415

Based on the analyses in this poster our treatment goal with anti-inflammatory DMTs should be NEDA based on these three variables. All the other factors (EDSS, 9HPT, 25TW, BVL, PASAT) that we analysed added zero to the predictive model. The reason for this is that all these additional variables measure disability worsening or end-organ damage that is the consequence of the previous inflammatory activity. 

This is why we should not expect our DMTs to do more than what they are designed to do. If you want to prevent worsening from occurring you have to get your MS treated early and effectively and prevent the accrual of early damage. 

Another message from this analysis is that relapses were the weakest member of the triumvirate; MRI and NFL levels trumped relapses. The implications of this are that you need to have your disease activity monitored; yes, measured on a regular basis. If your neurologist suggests that you don’t need an MRI, or in the future peripheral blood NFL measurements, can I suggest you tell them they are wrong? 

Another implication of this study is potentially a cut-off for what is an acceptable peripheral blood neurofilament level, i.e. you need your NFL levels kept below 8pg/mL. This cut-off will separate the ‘men from the boys’; the only DMTs that are effective enough to reduce average levels consistently below this point are the high efficacy DMTs. 

One final message. Natalizumab continues to teach us about MS. It is the one drug that has transformed MS in so many ways and it has taught me more about MS than anything else. As I have said before there are two phases to the history of MS; the phase before natalizumab and the phase after natalizumab

CoI: multiple

36 thoughts on “8 picograms”

  1. Prof G what about the ofatumumab results; surely these were the highlight of ECTRIMS? Clearly more important than a post-hoc analysis of the AFFIRM study?

    1. I will get to them in time. But to be honest they were to be expected and slightly disappointing in terms of BVL and disability progression. I heard one neurologist make a comment at how good it made Teriflunomide look. Anti-CD20 therapies do what they do and little more. They are not the holy grail of MS therapy.

  2. What about the #AttackMS trial? Are you still planning to do this study? You could use the triumvirate as the outcome of the trial.

    1. Yes, ProfK and I are working on a protocol. Good idea to use the triumvirate for the primary outcome. At the moment we plan to target AUC of serial NFL measurements.

    1. At the moment peripheral blood NFL levels is still a research test, unlike CSF levels. There is an international consortium trying to validate the Quanterix platform so that we can use NFL levels clinically. However, the Quanterix platform is too expensive and temperamental and is unlikely to get adopted. The good news is that Siemens and Biogen and hopefully Roche Diagnostics are working on getting NFL measurements onto standard diagnostic platforms. Once this happens NFL measurements will become routine.

  3. Prof G,

    You are now pretty clear in your view that MS is not about focal inflammation (seen as relapses and MRI activity). MS is a smouldering disease / slowly expanding lesions causing end organ damage, neurodegeneration and disability). I have had one of the highly effective time anti inflammatory treatment (Lemtrada) to stop relapse / MRI activity [and it has]. I have two simple questions and would be grateful for straightforward answers. 1 – is there any therapy I can take to limit / stop the smouldering disease / slowly expanding lesions? 2 – are there any therapies in the pipeline to limit / stop the smouldering disease / slowly expanding lesions which I should be looking out for (either to get on them as soon as they are licensed or to get on a trial? I have found your latest position quite discouraging as I took a highly effective treatment on the basis that it might put the disease into long term remission and am now being told that relapses / MRI activity don’t mean much as MS is really a neurodegenerative disease from the outset. I wish you guys could make your minds up as it’s just a roller coaster ride for MSers – building up hope and then knocking it down!

    1. Unfortunately, none of our current treatments works on smouldering MS. This is why we need add-on treatments. Who knows the slowly expanding lesions may be due to a viral infection and what we need to tackle them are anti-virals.

      1. Not a dig at you, but some observations:
        50+ years of MS research and the disease is now (after all this time) primarily neurodegenerative and not inflammatory.
        EBV has been a chief suspect for c.30+ years and the researchers are still to definitively confirm this.
        The notion of add on therapies has been banded about for the last 15 or so years and still we have nothing.
        If MS research was a school pupil my report would be: disappointing performance, changes mind frequently, full of ideas but fails to translate them into practical use, has failed to live up to early promise.

    2. Although focal activity is not MS, we have to assume that it is in response to what is MS (or what is causing the disease). Therefore, focal activity is still a good treatment target. In other words if you are not treating MS inflammatory activity will continue to occur.

  4. How about the updated mavenclad data 75% of patient free of progression 5 years after end of treatment seems quite impressive?

    1. From reading Prof G’s comments, am I right in thinking that smouldering MS is probably still going on underneath the surface so worsening will eventually happen at some point in the future? Is the Mavenclad data misleading and giving false hope?

  5. Hi Prof G, thanks for this info (as always)

    I have been seeing NFLs mentioned more and more over the past few years – I have always been curious of my own levels esp when I feel like I am relapsing

    Is there anywhere I can get tested on this (im London based) and will this become more common as part of patient monitoring do you believe?

    1. Get your neurologist to contact d.w.holden@qmul.ac.uk or NDG this can be tested as part of NHS service.

      On another issue I wonder if it is time to re stratify NEDA. Relapses and MRI lesions and it seems neurofilament are all surrogates of disease activity. However disease progression is not. It is a measure of inflammatory damage relating to the measures above, however it is also a measure of progression so it is detecting two processes one of which may not be responding to the DMT blocking activity

      1. Yes, time to create different treatment targets for different treatment strategies.

        NEDA = NEIDA (no evident inflammatory disease activity)

  6. I have personal experience as a few of these are my patients and they are doing remarkably well considering that they all had very active MS, with a poor prognostic profile, prior to alemtuzumab treatment. The real question on everyone’s lips is are these MSers cured of their disease? When will be confident enough to claim victory? Most in the field don’t like using the C-word (C = cure) as it raises false expectations. My argument is if we don’t define and look for a cure we will never find it. In addition, the only reason why some MSers want alemtuzumab, or induction therapies in general, is because of the potential for a cure. Why would you take the risks if not for a cure?

    This is from one of your posts in 2015 and it was reading your views on Alemtuzumab that strongly underpinned my decision to seek it as my treatment option (meeting the NHS criteria, of course) When I received my infusions in 16/17 I was under no illusions that MS remains a degenerative condition for which there is no cure. I understood that I may require additional treatment at some future point. What I had anticipated was the benefits of disease activity suspension, for whatever period, meaning that my disability accumulation was stalled , again for whatever period – time is brain etc.

    Since last year there has been a strong emphasis in your posts on smouldering disease and progression despite being NEDA. All of this seems to be a long way from reference to induction therapies and the word cure in the same breath. As someone who I think I accurately perceived as very pro Alemtuzumab four years ago, will you kindly provide us with your current position statement on the induction therapies as treatment for MS.

      1. Thanks.
        I have read these, but it’s been useful to re-read them in the context of today’s post.

    1. “Why would you take the risks if not for a cure?”

      This cure potential talk started just a year or 2 ago, when long term efficacy figures were being pushed out.

      Are you saying that your patients (and others) chose to take the risk blindly before then? i.s. was the risk reward curve asymmetric until recently and has somehow fixed itself since?

      The take-up figures of alemtuzumab have certainly not “spiked” since those figures were published (read about the GCVRZ lawsuit if interested)…. so something does not tie up well here.

      1. If IRTs such as alemtuzumab and HSCT simply converts relapsing-MS into PPMS then we would see an increasing number of treated MSers coming back with SPMS. This does not seem to be happening in a lot of treated patients. However, the earlier you treat the less damage has accrued the longer it will take to see non-relapsing SPMS emerge. I have set the bar at 15 years for pragmatic reasons. We are not yet at 15 years so let’s be patient.

      2. Aren’t we beyond 15ys with Natalizumab already?

        Certainly if counting from pre-marketing…

      3. Yep, but Biogen stopped their post-marketing surveillance programme (STRATA Study) at 8 years. I have about 10 AFFIRM/STRATA patients who are 17+ years on natalizumab and are still stable, but I also have some who have worsened. The latter could be early ageing and comorbidities. Overall the veteran natalizumabers are doing remarkably well.

        How many swallows does it take to make a summer?

      4. Doesn’t this argue against your ‘Field Hypothesis’? If they are stable on natalizumab for 17+ years it would indicate that the disease is driven from the periphery.

      5. Yes and no! Yes, in the sense you need a immune surveillance for whatever is causing MS to manifest. No, in that whatever is causing MS can live symbiotically with the nervous system without causing any problems. The clue is when you remove the natalizumab break and see rebound; it is awful and several patients have died from natalizumab rebound.

  7. “This is why one of my #ECTRIMS2019 highlights”

    Its one of my PAPERS

    Isto e ser juiz em causa propria 🙁 this is being both judge and jury

    But i guess you do this over and over again

    Who know maybe you need to 🙁

    1. It is the data that is important not the authorship. There is only one AFFIRM trial and it is how you use the insights from the trial to understand MS that is important. You can always ignore what I have to say if you don’t like it 😉

      1. We do plenty wrong; for example not referring our patients for HSCT first-line or at least supporting their requests for 1st-line HSCT. 🙁

  8. So NFL blood tests can also help predict Alzheimer’s, in my family both Alzheimer’s and MS are a curse. If this blood test were available for those family members with these links, ( I won’t say genetic as we can’t be sure) it would help with early treatments for neurological disease. I’ve a sister with MS, both of us diagnosed before anything would make a difference. My father, his siblings, and mother all have/ had Alzheimer’s. I’d love to think We could offer my children some protection, with early interventions if they developed either of these. Which means early diagnosis. Simpler diagnostic tools too.

    1. But why would you want to know that you had early Alzheimer’s disease? There is no treatment for dementia. At least with MS you could opt for a treatment; that’s if you can find someone to prescribe a treatment for it and for your insurance to pay for it. At the moment I doubt any insurance company will cover asymptomatic MS.

      1. I suspect it won’t be long before we can treat RIS or asymptomatic MS. Why wouldn’t we? This is provided we get the diagnosis right.

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