Friday, 26 December 2014

What does the future hold for PPMS?

Do we need to rethink PPMS?  #MSBlog #MSResearch

“Now that the INFORMS (fingolimod) PPMS trial was negative we will have to rethink PPMS. It is clear that fingolimod, which is an anti-inflammatory with a potential neuroprotective effect, was not good enough. Is this because PPMS is not inflammatory? No, PPMS is very inflammatory; I have previously discussed the post-mortem findings of PPMS in comparison to SPMS. However, the type of inflammation in PPMS may be qualitatively different; i.e. the contribution of focal inflammatory lesions that cause relapses and new MRI lesions is less important in PPMS. What may be more relevant is the downstream activation of innate immunity, in particular microglia and macrophages; the hot microglial hypothesis."

"I hypothesise that we will need to tackle PPMS with combination therapies; i.e. a combination of drugs that tackle focal inflammation (e.g. fingolimod), innate immune activation (e.g. laquinimod), a neuroprotective (e.g. oxcarbazepine) and possibly a drug that targets anti-ageing mechanisms (e.g. simvastatin). Why anti-ageing? Age is the most powerful predictor of the onset of non-relapsing progression in MS. There is evidence that inflammation in the brain and spinal cord cause premature ageing and that what we are seeing clinically is age-related neurodegeneration. If this is the case we will need a whole new approach to progressive MS. The MS-STAT trial was very informative; it showed a positive impact of simvastatin in non-relapsing SPMS with a signal that was present in year 1 and year 2 of similar magnitude. If Simvastatin was working on MS-related mechanisms I would have anticipated a therapeutic lag, i.e. no or little impact in year 1 and a larger impact in year 2. The fact that no therapeutic lag was observed suggests the statin is working on non-MS mechanisms; i.e. on other disease-related mechanisms for example secondary vascular pathology. If I was running a drug development programme for a Pharma company I would seriously looking at these results and thinking how can we develop a combination pill to tackle non-relapsing progressive MS? I am also seriously considering starting taking the polypill, a cocktail of drugs that includes simvastatin, to prevent vascular disease and implementing all the other lifestyle changes to promote brain health."

"If you have PPMS please try and not get despondent; the INFORMS trial may have been negative but we will learn from it and move forward. The next results to report will be the ocrelizumab PPMS trial and following that the laquinimod PPMS trial. Ocrelizumab is likely to be a more potent anti-inflammatory than fingolimod and it is more likely to target the B cell response within the brain and spinal cord. Some in the field feel that the latter is one of the biggest drivers of progressive MS. Laquinimod is a very interesting drug and targets the hot microglia. The question is will ocrelizumab and laquinimod be good enough as monotherapies? I sincerely hope they are; PPMSers need a break.”



CoI: multiple, I sit on the steering committees of both the ocrelizumab and laquinimod PPMS trials.

6 comments:

  1. Prof G it is good to hear you are still alive. I thought you had decided to desert us. I hope you are having a well deserved rest over the holidays. Wishing you and your team happy holidays and every success in the New Year.

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  2. I'm curious - what is the method of action of laquinimod? And, if the inflammatory aspect was already switched off in rrms (eg Alemtuzumab or BMT) would laquinimod be an induction or a maintenance therapy, to switch off microglia. If the latter, is there any induction therapy that would hit microglia?

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    Replies
    1. One mechanism is that it inhibits NF kappa B so it will inhibit cytokines and microglia

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  3. "PPMSers need a break"
    Hear, hear - I wholeheartedly second that motion

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  4. I got PPMS AT 26. I was young, not old.

    I don't think that PPMS will be cracked, not as long as it's considered as straight-forward MS. It's a different disease with its own pathology.

    As long as neurologists deem PPMS as MS it will always be the unworthy relative. Give a new name and an entirely new school of approaches to treatment. Rename it. If it is labelled as MS the advances in success will be slow and rubbish.

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  5. You say : "PPMS is very inflammatory "and "Ocrelizumab is likely to be a more potent anti-inflammatory than fingolimod " so why there is no trial with HSCT and PPMS ?
    I thought HSCT is the most powerful anti inflammatory therapy.

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