Monday, 18 January 2016

Saving Upper Limb Function-Should we Go for it? Can we afford not to try?

Previously posted as "It may not be all doom and gloom" following our decision to stop trying to get funding for a trial in RRMS...

Currently, Big Pharma is mainly interested in Relapsing MS. Academia, at least in the UK, are focussing their effort on ambulatory people with MS.

Can we do something for the forgotten thousands, those with deteriorating MS who are wheel chair users most or all of the time?

We know that 
  • MS is associated with the accumulation of damaging white blood cells (lesions) within the CNS.
  • Lesions in people with relapsing and deteriorating ("progressive") MS are similar.
  • People with deteriorating MS (pwDMS) have inflammatory and smouldering lesions.
  • Modulation of the peripheral immune response blocks relapsing MS and the formation of new lesions.
  • Many pwDMS develop new lesions and have relapses.
  • pwDMS who display disease activity on MRI respond to peripheral immunomodulation with current DMT.
  • pwDMS may respond to central neuroprotection.
  • Optimum therapy will likely mean control of immunity plus neuroprotection and repair.
Current DMT are too expensive and are not considered cost-effective for pwDMS and so DMT are withdrawn, or not even started.
  • Current trials in pwDMS are focussed (fixated?) on the EDSS as an outcome. This non-linear scale is heavily biased towards lower limb function.
  • Deteriorating MS as measured by EDSS due to smouldering lesions is not responsive to peripheral immunomodulation by the time it is tested.
  • pwDMS have evidence of B cell activity within their brains that may cause grey matter lesions. They can produce antibodies that may be damaging in MS. No current drug works in the CNS to tackle this problem.
  • Most importantly: pwDMS who have lost most or all of their lower limb function, will wish to maintain their upper limb function for mobility and other things!
    "Save the Hands"
Picture drawn by MD over 30 years ago (found yesterday when having a clear out) based on original by Patrick Woodroofe

pwDMS who are in wheel chairs 

(i)  have virtually no access to DMT and 
(ii) are excluded from clinical trials of drugs against deteriorating ("progressive") MS.

They are the forgotten thousands.  People in wheel chairs have active lesions and progress and loose upper limb function.
  • Many pwDMS in wheelchairs may indeed respond to DMT.
  • As their neural reserve of lower limb function may be lost pwDMS may not respond in terms of EDSS to peripheral immunomodulation with DMT.
  • However, upper limb function is vital to everyone with MS, including those in wheelchairs and we should try saving this neural reserve.
  • Upper limb function may still respond to potent peripheral DMT:
The data from the ASCEND trial provide evidence that upper limb deterioration can be halted in pwDMS, whilst lower limb function continued to deteriorate. Other studies may not have shown this because DMT are not good enough to stop active disease at this disease stage.
  • Most companies making peripheral DMT have been burned by failures in progressive MS and may not risk further trials.
  • People in wheelchairs are ignored as far as DMT goes.
  • If this appeals please contact us.
Cladridine inhibits Active Lesion Formation: 
Gadolinium enhancing lesions drop by over 90%. 
Fewer lesions means less damage and reduced risk of deterioration

Cladribine inhibits Relapses (annual relapse rate decreased to about 0.1 = one every ten years). Fewer relapses means less damage and reduced risk of deterioration.

Cladribine induces NEDA-3 in nearly 50% of people with a 1 year course of treatment.

Cladribine will be of value to slow the accumulation of damage in anyone with active MS... This means it should be of value for everyone with MS.

A cost-effective drug means everyone with active MS could have access to treatment.

                                      Missed the video?

Cladribine may have the potential to save upper limb function via inhibition of peripheral immunity as it probably is as active as Natalizumab.

Cladribine enters the central nervous system and can kill dividing and non-dividing white blood cells, and it can kill plasma cells and could potentially get rid of oligoclonal antibody bands. If these are causing grey matter lesions or even deterioration, it will target these mechanisms unlike any other MS drugs, including Ocrelizumab.

Cladribine is an induction treatment, thus it can act as a platform for layering on neuroprotection and repair agents. 

Are you interested in a study for pwDMS, who are wheel chair users? 

If so, what should we call the trial?

This will again mean writing grants to support the study and it will not be quick, but we are willing to give it a go.


  1. Last week Panorama ran a story about the wonders of HSCT: autologous haematopoietic stem cell transplant.

    'Remarkable' was a headline that the BBC news-site used:

    We have also seen much noise made about the potential of Ocrelizumab.

    Two things, though. The first is that HSCT is a very aggressive treatment. The second is that Ocrelizumab is (likely) going to be very expensive.

    But Cladribine... it seems that the data suggests that it is as effective, or more, than all the current NICE treatments. It is far cheaper than Ocrelizumab ever will be (and so you won't have to fight a financial battle with your NHS trust to get treatment). And it seems to be pretty safe (the cancer scare appears to have been proven a false one).

    We know that MS is degenerative. We know that smouldering lesions might cause damage far down the line. We know that cognitive impairment and other burdens effect even those with 'benign' MS.

    Cladribine appears - and believe me I have done the reading - to be a really, really good alternative. So much so that I chose to go on it recently and, to be frank, the results have been wonderful. My limp has gone. My brain fog has cleared. My eyesight has improved. For the first time in a long time I feel 'normal'.

    I have one regret - that I didn't get offered this treatment 5 years ago.

    We don't know how bad our MS will get. But we should, as patients, be aware that it can get very bad. That degeneration might be happening even as we feel able to function. When is too late to start treatment? Perhaps never. When is too early to start treatment? Perhaps diagnosis.

    Cladribine seems to be a drug that works. It seems to be a drug that is cheap. It seems to be a drug that is safe (or, at least, worth the risk).

    Have a chat with your neurologist about it. I chose it above Campath. Above Tysabri. And I have felt better now than I have in 5 years.

    1. Thanks for sharing your personal account. Though I agree individual experience can be interpreted (and mis/represented) in many ways, the discussion about Cladribine currently lacks this type of "grounding" in somebody's life. Simple reason being as an off-lable drug it is not widely prescribed. It makes a difference to hear from somebody who has actually taken the drug.

    2. Question for Iain O
      Is your MS RRMS, or PPMS, or have you moved from RR to SPMS?

  2. "Last week Panorama ran a story about the wonders of HSCT"
    It's tonight/

    "And I have felt better now than I have in 5 years".

    I am happy that you are feeling good, but please remember every one that each persons journey is an anecdote, others may have a different experience.

    cladribine is not a licenced treatment

    1. Agree MD, but personal experience is what is lacking in the current discussion, so I really appreciate Iain sharing his albeit quite recent.

  3. How do you test for upper limb function?

    1. This neurological examination demonstration may answer your question.

    2. Several tests & questionnaires, we're currently reviewing best options for the trial.

  4. Thank you for the clarity that this post provides. The first time I have read such a good synopsis of the situation for people with progressive MS such as I.

  5. klausy you are going to get knighted for this!! smartest neurologist ever!

  6. I am not sure you can make the claim that 'cladribine is probably as active as natalizumab'. I am not aware of any head to head studies comparing these agents. Can I suggest you stick to the evidence, or you risk destroying your reputation and the reputation of this blog. Cladribine is effective but any claims of relative efficacy need to be backed up with data.

    1. Agree there has been no direct comparison, however some modelling suggesting similar efficacy: In JCV negative patients I'm very happy using Natalizumab - when I'm allowed to use it in line with NHS England cost-effectiveness criteria.

  7. This all is a really complex and difficult discussion.

    Cladribine lets say is as effective or more so and safer than existing therapies. Its costing is much less. Pharma is in the business of making money and while they make significant revenues a good portion of revenues go back into research. That research may be for Lupus or other conditions. Its not strictly bound to MS. The MS market for Pharma is already risky.

    Risky in that MS research makes real gains reported much more so than other chronic disorders. A product like Ocrelizumab might just kill whatall, Tysabri or TikFedera. Thats business. The fact BioGen has been smashed by statistically by a very small set of people who experienced PML sends waves through all areas of the new generation med's in profit risks.

    If 4 people driving a Saab car had the wheels fall off resulting in PML one would not expect Saab to loose 50% of its market valuation. Its caused BioGen to back off MS research some and release a good portion of staff. They stated they will be shifting focus.

    Now a affordable Med like Cladribine enters the scene and its effective would Pharma shift focus to PPMS? Maybe. Probably not due to market size. Alot of the gains in learning of SPMS/PPMS come from the education learned in RRMS.

    This linkage poses advancement problems. Money unfortunately, very unfortunately is in the arena in all respects from research through delivery to market.

    Here in the USA prices of the DMT's in MS, crazy. Meds that not long ago such as Copaxone have priced up to equal that of new DMT's as is the case with interferons. Why? Part of it is insurers. They dont want insurers to say, "We offer you the cheapest and thats it. Doesnt work? Next cheapest" and thats what would happen. There exists this funky sort of rebate system here people are completely unaware of in the USA. We had no idea until a former assistant state attorney general who has MS told us the lay of that land.

    If Cladribine went into say India where there is nothing and its costing is low and efficacy great word does "get out"... fast in fact. So many people here in the USA will go, "I want that".

    To sum it up, there is doing what is RIGHT for people but as history shows not only in disease but literally all across the boards such as our processed foods, genetically altered fruits, Twinkees when buried in dumps that appear to have a better half life than my car, money drives and steers.

    The problem in pharmacological areas is that its health and people held hostage to access based on cost. The same exists in housing, a new automobile, quality foods and more.

    I do not know the answers. Wish I did. There SHOULD be some form of happy medium to be sure.

    Thus, just a suggestion as you all know how these systems work far better than I, perhaps Cladribine needs be examined in a different angle along with DMT's. Something along the lines of "flat rate" costing no matter which DMT and the consumer has choice based on doctors inputs or a scaled system even. So the meds showing less efficacy cost less than those showing high efficacy. Again, thats unfair but its better than no access based on costing. Like I an buy a cheap car or a safer car, a Mercedes.

    Trying to push "Money" to alter its curve along with the resultant matters if they did... Trying to push government to act in peoples best interests .vs. money are really difficult walls to breach. Finding new mechanisms that afford all parties towards a better way, even if imperfect might be a better course?

  8. How about calling the trial CLIMB?
    Very simple: Cladribine preserving upper LIMB function (with a nod to ASCEND)

    1. Too Long Dont Read....what use is this? The suggestions need to be better than this.

    2. "Again, thats unfair but its better than no access based on costing. Like I an buy a cheap car or a safer car, a Mercedes."

      While I agree with most of what you said, I think we can do better than this. I don't think we'll advance as a species until we can find some way to decouple human need from human greed.

  9. Aidan28 December 2015 at 14:19
    Not been able to come up with anything original:



    Anonymous28 December 2015 at 17:15

    CLAdribine for MS HELL

    Though the regulators might find this a bit flippant :(


    Klaus Schmierer29 December 2015 at 09:17
    Thanks. Working on design, will put draft on blog in next few days. Full title might spark further ideas.

  10. Spoke to DrK today plan is to do a combination anti-inflammatory plus neuroprotective

    1. Is that a combo only offer, is it a case of no clap without the shot? (Clapshot.) Or can you just get the one, not the other if you want?

  11. If the trial is going to include PwS/PPMS with EDSS >6.5 and is going to include neuroprotective why not call the trial INCLUDE - title could be something like:

    Integrated Neuroprotectiveand CLadribine to prevent Upper body Disability


    Immuno-suppressive and Neuro-protective Combination to prevent Loss of Upper-limb function unDetected by Edss

    or similar, there's lots of scope with these letters.

  12. "If this appeals please contact us." Do you mean PwMS interested in the drug? If so, which e-mail address should one use? I'm sure Prof. Giovannoni receives about 300 e-mails every minute.

    1. All our emails are on the blog if you look at the tab "About" and "BartsMS team" and you will find DrK's email there.

      I met the first pioneer at the weekend


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