Saturday, 2 June 2018

Cladribine for People with Progressive MS.There are options available

Today we provide further evidence that people with Progressive MS can respond to DMT

MS is neurodegenerative from day one to the last day and is also inflammatory from day one to the last day.

Why don't we do something about the inflammation in MS in every one?. 
The simple answer is due to cost-effectiveness. 

The powers that be have decided that it is not cost-effective to use high cost treatments in people with progressive/Advanced MS.

Will this change with the demonstration that orelizumab is useful in PPMS.

We have been using generic cladribine, which is a potent DMT at a fraction of the cost of other MS drugs. 

Disease activity can be seen on MRI scans.

In this study we have used neurofilaments, as a biomarker of ongoing nerve damage, to help inform on people who may respond to DMT treatment. People treated have shown a marked decrease in neurofilament loss, so the treatment is blocking the processes that lead to nerve damage.

Disease activity in progressive multiple sclerosis can be effectively reduced by cladribine


O. Yildiz, Z. Mao, A. Adams, N. Dubuisson, K. Allen-Philbey, G. Giovannoni, A. Malaspina, D. Baker, S. Gnanapavan, K. Schmierer



Highlights

  • People with advanced (“progressive”) MS (pwPMS) currently have only one licensed disease modifying treatment (DMT) option (ocrelizumab), and this option is highly restricted to a specific MS subpopulation living in high cost economies
  • The cerebro-spinal fluid (CSF) neurofilament light chain (NfL) level is a sensitive index of ongoing neuro-axonal damage
  • pwPMS who had significantly elevated NfL levels alongside MRI detectable disease activity, were treated using off-label injectable cladribine
  • Cladribine was well tolerated without any side effects and led to reduction of disease activity as indicated by a substantial drop in CSF NfL concentration alongside reduction in active MRI lesions, whilst total lymphocyte counts remained within the normal reference range.

Abstract




Background

Evidence suggests people with non-relapsing deteriorating (“progressive”) multiple sclerosis (pwPMS) may benefit from disease-modifying immune therapy (DMT). However, only one such treatment (ocrelizumab) has been licensed and is highly restricted to pwPMS suffering from the primary progressive phenotype. The difficulties assessing treatment outcome in pwPMS is one important reason for the lack of respective DMT. The concentration of neurofilaments in the cerebrospinal fluid (CSF) provides a biomarker of neuro-axonal damage, and both neurofilament light (NfL) and heavy chain (NfH) levels have been used as outcome indices and to guide treatment choices.



Methods

We report on two pwPMS, who were treated with off-label subcutaneous cladribine undergoing CSF NfL testing, alongside MRI and clinical follow-up, before and after treatment.



Results

Cladribine treatment was well tolerated without any side effects. CSF NfL after treatment revealed significant reduction (by 73% and 80%, respectively) corroborating the MRI detectable drop in disease activity. Disability mildly progressed in one, and remained stable in the other pwPMS.



Conclusions

pwPMS with detectable disease activity (MRI, elevated NfL) should be considered for DMT. NfL appears to be a sensitive index of treatment effect in pwPMS, and may be a useful outcome in clinical trials targeting this patient group. Over and above its licensed indication (relapsing MS), cladribine may be an effective treatment option for pwPMS.

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CoI This is work by DrK and other members of the Team

32 comments:

  1. Two people? Two.

    And it says little / nothing about pathology - in some people, inflammation may drive neurodegeneration to a relatively high degree, in others, inflammation may be more of a secondary process - we still don't know.

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    1. Yes we do, get rid of cells entering the CNS and attacks go down. This total protective inflammation idea is tosh. If so drugs like natalizumab would be making people seriously worse.

      However, Inflammation is a two part process protect and repair it is destructive to start and then it beneficial and a secondary process.

      Delete
    2. We have treated two hundred people with generic cladribine...yes two hundred.

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    3. If you have treated 200 why publish on 2? Something doesn't add up..

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    4. Simply Time...

      We are publishing the work in the order that it was done by our doctors. Furthermore, many of these people have not been followed for that long.

      We do have another paper in press on price comparisons and another under consideration on about the first 50-70 pwMS,

      We will do another audit and publish the next experience in due course, but we need hands to do this.

      In our experience we have about 1-2% with grade 3-4 lymphopenia verses 6% in the CLARITY mavenclad study at year 1 and 85% with alemtuzumab. The key is what happens after first cycle where mavenclad induced about 25% grade 3/4 lymphopenia.

      Delete
    5. Thank you for response, MD. I don't think I articulated myself well, what I mean is that this paper doesn't seem to say much about the long term impact of Cladribine on progression, or that MS is not actually about neurodegeneration in the _first instance_ (e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673225/). So, whilst Cladribine may well be a boon to those with pms who continue to have strong "relapse" activity, I don't think it's necessarily anything exciting for progression. We still don't know enough, and the studies aren't long enough.

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    6. I dont think I can much about the long term impact.

      However, we have made the point that to deal with progressive MS we need a layer cake and on the bottom we need something to deal with the issues that we know we can deal with, which is lymphocytic based disease activity.

      I am sure there will be people who will continue to worsen on cladribine, just like they would on HSCT etc. There is more to progression.

      We need an audit of CSF to see what has happen to oligoclonal bands. Has anything happened to them?.

      Have enough people volunteered for serial lumbar punctures?

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    7. "get rid of cells entering the CNS and attacks go down"

      Can NFLs get released in CSF without immune cell inter mediation, by pure mechanics only?
      Or axons always degenerate with immune system help?

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    8. A simple explanation of the NFL reduction is this: Demyelinated axons that would otherwise disintegrate into NFLs via immune cell intervention remain as they are, because cladribine inhibits normal immune cell behavior.

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    9. MouseDoctor says "Have enough people volunteered for serial lumbar punctures?".

      Well, I'm receiving s.c. cladribine at Barts and no one has asked me if I'd be wiling to do this. Depending on how often you'd want these, I'd probably be wiling to do this (as long as atraumatic needles were used!)

      Delete
  2. Great work Team G!

    Some questions-

    1. Did you or the patients detect improvement in anything other than neuro-filament levels? In symptoms, in fatigue, or in anything else

    2. With just two patients, can you really conclude that cladribine reduces disease activity in progressive MS?

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    1. The point is there are pw progressive MS that will clearly get some benefit from using current DMT. People dont get access to these because they cost too much money. If there is a cost-effective alternative then why not use it.

      If you remember we also published on a person with 48 lesions pre treatment. There has been alot more than two people on the drug, but we have to wait to see how our experience develops. There are people who will continue to worsen on treatment, this is true of all DMT.

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    2. P.S. This is teamK, DrK has been the lead on this as ProfG was conflicted with his involvement with the oral variant.

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  3. Disability still progressed? This seems like it's a waste of time

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    1. Would disbability progress at a faster rate without treatment?
      Remember we also have to bring in the concept of therapeutic lag as it may take some time for the treatment to show benefit

      Delete
  4. Great work!
    Great news!
    Thanx for sharing the full text

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  5. Maybe I missed the reason but why s.c. cladribine over oral cladribine? Is it because there are generics that are only s.c.?

    ReplyDelete
    Replies
    1. The generics are subcutaneous or intravenous. Subcutaneous is easier to
      administer. 10mg generic = £65, 10mg oral = £2,000.

      Delete
    2. P.S. Oral variant is licenced for highly-active rlapsing MS.

      Delete
  6. Doesn't this study have a methodological problem since at progressive MS both MRI activity and NFL levels can disappear on their own? How can you know that it was the drug and not the disease?

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    Replies
    1. You are correct, that is why we want to do proper trials.

      We have been attempting to do them for along time, but without the funding we can't do them. In the interim we are being as pro-active as we can.

      Delete
  7. Thanks for the post TeamK - really great work on many levels. As a UK tax payer I'm especially glad that low cost routes to the same medicine are being explored - wonderful example of value for money in the NHS.

    However, I should declare a vested interest here; I am one of the patients receiving this treatment at Barts. Its early days for me but below are three observations I'd like to share on the blog - please don't read too much into these as they are personal observations that are not based on empirical data - just comments about how I have felt. We'll have to wait for additional results down the line from TeamK to show how it is doing for a larger number of patients.

    1. I personally did not have any problems with the injections, in fact, I was amazed at how quickly and efficiently this was done by Maria and the team. I guess this is what would be considered as "well tolerated" in the paper above; I had no immediate issues and experienced similar levels of discomfort as having a blood sample taken.

    2. I personally noted a short term increase in fatigue levels immediately following treatment lasting a week or so (maybe longer, but definitely no longer than 2 weeks). However, this may not be just down to the treatment as I had long journeys each day to get to London and back - this certainly contributed to elevated fatigue levels.

    3. I personally have not noticed any immediate change in my condition - mobility is the pretty much the same as before, no better, no worse, and still having relatively good days and relatively bad days. My expectations are realistic and I am not expecting short term miracles; my objective is trying to slow down and preferably halt long term progression rather than fixating on short term trends and correlating that directly with s.c. cladribine treatment.

    Overall, very happy with this treatment and especially happy to have had the chance to have this. Hopefully we won't have to wait long for further publications showing how treatment works for a wider range of patients based on the work TeamK are doing.

    A. Nonny-Moose

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    1. Wondering if anyone else on Cladribine treatment has experienced increasing hair thinning as weeks go by along with trouble sleeping/horrible nightmares and anxiety?? I must admit I also feel a deeper depression since starting the tablets but I guess the disrupted sleep may be largely responsible for that. However, the nausea and tummy discomfort have been relatively mild so grateful for that and much prefer taking tablets to injections every day.

      Delete
    2. Anonymous (Sunday, june 03, 2018: 7.06.00 pm) - I think you misunderstand the frequency of s.c. cladribine injections outlined in the research - this is not daily. According to the paper:

      "Treatment was as follows: week 1 administration of cladribine 10 mg on three consecutive days; week 4 confirmation of normal blood counts (including total lymphocyte count); week 5 administration of cladribine 10 mg on three consecutive days" -

      That's it for the first year, repeat after 12 months.

      Delete
  8. If both cladribine and ocrelizumab became available for people with progressive MS based on side effects particularly cancer which one would be preferred?. Ocrelizumab is a continuous treatment whereas cladribine is not and is given more like alemtuzumab?
    If either proved ineffective for a patient which one is easier to follow with an alternative treatment?

    ReplyDelete
    Replies
    1. This is hypothetical.
      Ocrelizumab has positive phase III trial data, cladribine doesn't so it won't be available in the near future.

      Based on the data we have published ocrelizumab may like cladribine have induction therapy potential like mavenclad and alemtuzumab

      Delete
  9. Thanks for the free access :)

    Are nf levels dynamic ie nf constantly being shed and tidied up by phages (whatever they're called in csf?) So if levels are high in MS it means nf shedding faster than being cleared up? Wonder what causes nf shedding in healthy people? Aging?

    Presumably can't expect nfl to ever drop to normal in MS unless also treat with the add-on pyramid layers?

    But these cases sound encouraging 1700 to 500 (patient 1) and 10,000 to 2000 (patient 2) ain't bad! Isn't patient 2 due another LP? Would be interesting to publish a follow-up....


    Ps surprised to see TeamK have dutifully checked levels of Tcell CD8 and CD4 but left Bcells as one lot?? ;-)



    ReplyDelete
    Replies
    1. We'll try follow up and get another CSF...

      B cell subsets still not routine, we're trying to raise the funds for it.

      Delete
  10. If your neuro filaments level is normal and you have no active disease does that mean the MS is stable?

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  11. No, not necessarily. This is the frontier for combination treatments that target different mechanisms. Though even in those with normal NfL and stable MRI we cannot be absolutely certain inflammation is quiescent.

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  12. With the recent announcement of the Oratorio trial for wheelchair users there is obviously belief that it could help progressive MS and if this proves to be the case why would anyone want to use cladribine subcutaneous at the current strength other than because it is or easily available?

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