Wednesday, 11 October 2017

Advanced MS

Summary: Our position, as formerly stated, on more advanced (formerly know as progressive) MS. 

Is the term ‘progressive MS’ a misnomer? In general, progression means improvement, not worsening. We have made the case for using the term ‘advanced MS’, which we think captures the disability that comes with the later stages of MS.


The neuroaxonal loss - the underlying element of ‘advanced MS’ - is there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become physically disabled. Do you agree?

MS is one disease and not two or three diseases. As we have said before, the division of MS into several diseases is not backed up by science. This false division of MS into several diseases has become counter-productive to the field of MS. The division of MS into multiple diseases was Pharma-led to get MS defined as an orphan disease. This helped in that it allowed interferon-beta-1b to get a licence based on the results of one pivotal phase 3 study.

Similarly, we believe the division between SPMS and PPMS is false. There are no pathological, genetic, imaging or other data that suggests these are different entities. We, therefore, propose doing trials in both populations simultaneously.

To slay the dogma that more advanced MS has reduced inflammation, or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a part in advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.

Reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we have referred to this as therapeutic-lag. These observations are explained by MS being a length-dependent axonopath. i.e. the longer nerve fibres, (to the legs) are more likely to be affected than shorter fibres, (those to the hands and arms). This means that we will need to focus more on arm-&-hand function as a primary outcome measure in clinical trials, in particular in pwMS who have lost too much function in their lower limbs (EDSS>=6.0). 



We need to challenge the current view that once someone has lost lower limb function and is a wheelchair user that their disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in advanced MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign and plans to a trial in wheelchairs users (#Chariot-MS).

I think we also have to accept that we will need to use combination therapies to make a real difference to more advanced MS. I am not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective or remyelination therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms - for example, laquinimod which targets hot microglia - with a classic anti-inflammatory against targeting adaptive immune mechanisms.

Is it time to ditch the EDSS. The whole MS community, or almost, knows that the EDSS is not fit for purpose in more advanced MS. We need to get the regulators to accept this. We also need to work on a set of outcome measures that capture the whole impact of MS on someone with MS. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more patient-related outcome measures in the battery, in particular, a better hand-and-arm function PROM. We are aware that there are several out there and some are in development; these need to be validated and used in clinical trials.

We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma don’t like adaptive designs nor do the regulators. We need to include two phases in trials of more advanced MS. For example, the standard head-to-head phase with a robust primary outcome, say the 9-HPT, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more advanced MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).

We also need more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and/or blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. We are in the final stages of the PROXIMUS trial and we have learnt a lot in the process. The PROXIMUS trial is an add-on neuroprotective trial in which we add oxcarbazepine, a sodium channel blocker, on top of an existing DMT in subjects with ‘early SPMS’.

We also need to push for political change. We need true incentives for the repurposing of off-patent drugs. We have discussed this on this blog before and have written a paper on the so called ‘Big Pharma Alternative’ in which we propose potential solutions.

Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials. Some of my colleagues think this is a big issue. I don’t. If we do a trial and provide compelling data that a specific drug in combination with another drug delays, or stops, worsening disability in upper limb function in pwMS in wheelchairs they would be obliged to license the combination, provided it was safe. What we need from them, however, is to accept the need for combination therapies. MS is a complex disease and hence will need a complex solution to tackle it, i.e. combination therapies. This is not rocket science and happens all the time in other disease areas, like cancer.

More detailed cost-effective models that focus on loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the recent EU health economic study that costs soar as pwMS lose arm function. Are you surprised? When you lose arm function you lose your independence.

We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing from reduced brain, and cognitive, reserve drives worsening MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in advanced MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.

We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for me to falsely raise their hopes . To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote recovery mechanism (axonal sprouting, synaptogenesis and plasticity) to restore function.


As you can see at Barts0MS we are passionate about tackling more advanced MS. I personally think we have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted above. We need to start a serious debate about these issues and get on with the job of protecting arm and hand function in pwMS. 

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

P.S. DrK (@KlausSchmierer) is looking for a large donation to support his application to the NIHR for the CHARIOT-MS study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded. Thank you. 

ProfG    

28 comments:

  1. DrK I need your 1-pager for the CHARIOT-MS study.

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  2. You say 'lost lower limb function and is a wheelchair user'.

    I cannot walk unaided, I must use a rollator, cannot stand for more than a 30 seconds unsupported but I am not a wheelchair user. i would much rather you said 'lost lower limb functionality' or 'extensive loss of lower limb functionality'

    Sorry if I sound picky but I really do value what independence I still have

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    1. Patrick, I am totally on board with your criticism here. I often think we do people a disservice by considering their lower limb function(ality) not useful just because you cannot walk unaided for any stretch. We need to bear in mind how important lower limb function remains even if walking is no longer possible. Whoever has made the experience of somebody trying to turn over in bed with "some" remaining leg functionality versus somebody with paraplegia (i.e. complete loss of lower limb function) say due to severe spinal cord injury knows the difference.

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  3. Not easy for sure to loose lower limb functionality but I can manage, already using a walking stick and I not afraid of the wheelchair. I am, however, terrified of loosing my hands and my voice. #ThinkHand from an advanced MSers.

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  4. Brilliant artical, how true it is that there is a feeling of hopelessness as the legs give up. This is especially so when you reach 60, which I have this year. Despite all naysayers, I just want to keep on keeping on. That's what I intend to do, despite my advanced ms and age .
    Thanks again for hitting the nail straight on the head, us oldies may have our uses yet!

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  5. "The division of MS into multiple diseases was Pharma-led to get MS defined as an orphan disease"

    Interesting, please explain?

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    1. ODA Orphan drug act provides incentives to develop agents for disease that may not normally be economically viable due to small
      numbers affected by disease.

      "The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug."

      Orphan designation qualifies the sponsor of the drug for various development incentives of the ODA, including tax credits for qualified clinical testing.

      https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/ucm2005525.htm

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    2. Back in the early 90's there were more than 200,000 pwMS in the USA. However, when you salami slice MS up into 3 or 4 diseases each slice was less than 200,000. Hence the one trial and the very high cost of interferon-beta.

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    3. In accordance to the reasoning above, current global MS research is Pharma-led, i.e, through university programs funding, clinical trials funding, MS societies, sponsoring, with the single aim of developing and marketing more drugs.

      In other words, MS research paths are not selected on strict scientific terms, they are chosen from a pool of Pharma sponsored ones.

      You are trying to make a difference by supporting the alternative EBV hypothesis or the B memory cell hypothesis, but you are still heavily Pharma-dependent for funding your department and your trials, so doubt remains whether this is the right research direction.

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  6. As a person with advanced MS and 53, I do feel like my options are non existent. The article is great, and I will share it with my neurologist. I hope that all you smart people find something that will work for us. Thank you!

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    1. RE: "...I will share it with my neurologist..."

      Please do. One of the aims of the blog and posts like this is to challenge the current dogma and get the community to think differently about advanced MS.

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  7. Wow!
    65, EDSS 8.5, 9HPT 180,260
    This so speaks to me.
    In an aged care home now but fighting to be allowed to live the next 20 years - the thought of which thrills me to the marrow.
    My consolation is my daily visit to the physio gym where I am clawing back my upper limb and core function.
    DMT's? 4AP - a repurposed potassium channel blocker that is known to lower the seizure threshold. Seizures scotched that one.
    My dream? To return to weight bearing transfers courtesy of full-leg prosthetics and the longest (11 meter) supported walk rails in the Southern Hemisphere

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    1. David, please don't give up. Withe rapid advancement in exoskeletons I suspect you will be mobile again quite soon. What we need to do is protect what you have left, this is what we are trying to do with our CHARIOT-MS study.

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  8. Great article. Thanks for posting.

    Regarding the "length dependent" observations, how does this apply to those of us who present with hemiparesis, where one side of our bodies are effected first, rather than the lower half. In my case my right arm and leg started deteriorating at the same time, and the deterioration advanced concurrently. My left side was left relatively unscathed for the first seven or eight years after my diagnosis, but now is unfortunately giving my left side a frighteningly good chase in the race towards quadriplegia.

    I understand that this presentation is rather unusual for MS patients, but I also know that it's certainly not unheard of and that there is a representative population of MS patients that do present with hemiparesis. Does the length dependent hypothesis not apply to us hemiparesis folks?

    In regards to an add-on neuroprotective therapy, just wanted to call your attention to some new research out of UCSF, which was recently published in The Lancet. Researchers used the over-the-counter antihistamine, clemastine fumerate on chronic MS patients and found a significant improvement in visual evoked potentials in treated patients, suggesting remyelination and possibly nerve regeneration. This was a phase 2 crossover trial conducted by well-respected researchers, so this finding could be of some significance.

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32346-2/fulltext?rss=yes

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    1. Re: "...hemiparesis..."

      The length-dependent hypothesis is based on the multi-hit model. i.e. assuming a random lesion development the longest pathways will acquire the greatest lesion load. From a statistical perspective a few people by chance will accumulate more lesions on one side of the body compared to the other. In addition, not all lesions are made equal in terms of their destructive ability. So if you have a larger more destructive lesion, that continues to expand (slowly expanding lesions) on one side it will present with a hemiparesis.

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    2. Re: UCSF clemastine study. We have invited the senior author, Ari Green, to do a guest post for us on the topic.

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  9. You mention the EMA. What about the FDA and other agencies?

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    1. I assume you came to post via Twitter (@GavinGiovannoni) in which I refer to the EMA only. The post actually refers to both.

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  10. "..neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we have referred to this as therapeutic-lag."

    How can you get any treatment effect at all if reserve capacity is exhausted..? There is no reserve to work with.
    Only way would be the brain were able to create more space through
    plasticity like a computer defragmentating itself.

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    1. You are right, it becomes more difficult to achieve an effect once a critical number of key structures (nerve cells & fibres, synapses) have been damaged or in fact lost. The point we're making is that if you want to treat MS, it always requires dealing with inflammation, whatever other mechanism you're targeting.

      I like the de-clutter/de-fragmenting idea, and you can view cognitive training exercises that way, repeating the same information using multiple modalities pushes intrusion by different (and not useful) information to the sidelines.

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  11. "We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound."

    Why can't DMTs flatline progression in the arms if they have sufficient reserve ? Are they really so ineffective that they can never flatline progression ?

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    1. As any treatment, success in stopping advanced MS not only depends on the intervention but also on the individual receiving it. If you are in your 20s and your MS has made you dependent on a wheelchair within 3 years, the likelihood (and size) of a treatment effect may be quite different from somebody in their 60s whose MS progressed over 30 years. We also need to remember that most disease modifying drugs don't enter the brain (including spinal cord), they act on the aberrant immunity in the blood stream. Particularly in later stage MS we believe you need the treatment to enter the brain and deal with the aberrant immunity there. This is why we are hopeful that our trial concept for people with advanced MS (#ChariotMS) could make a difference. I will post an update on this shortly.

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  12. "MS is one disease and not two or three diseases."

    Ok I'll buy it but why are some disease courses (ppms) so much very
    more damaging over time. Seems like many are walking after 24 years
    while the person below is bed bound. Why if it's all same disease
    are outcomes so different.

    "took 24 years but I'm finally bed bound. not bad no life left but I'm 51 so I guess i did alright :(
    Had ms for 24 years now."

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    1. One plausible theory is that ppms is really spms that had a clinically 'silent' rrms phase. PPMS appears worse but it really follows a long rrms phase where the inflammatory damage was done.

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    2. And another theory current with me, is that as most of my lesions are in my spinal cord, not my brain, I've never knowingly had a relapse - because my relapses were a loss of sensation in toes, etc. which is a lot less noticeable than, say, optic neuritis, for example. It's only when the lack of mobility started to manifest itself that it was noticeable and diagnosed.

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  13. "We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen."

    Really heartbreaking and difficult to accept. However, function does come back a bit with "really effective DMDs." You said so yourself when posting on HSCT, noting that other second line therapies could restore leg function that mimicked its impressive effects. The four different pattern types of lesions also suggest heterogeneous causes. I presented with tumefactive MS and was mis-dxed with a brain tumor. From all the literature that I've read, this actually portends a more favorable outcome, with a typical five year length of time between relapses (I am four years along with no relapses.) So, different causes/outcomes/possible interventions? While this may have little bearing on the RR/SP dichotomy and decision to treat, I would be careful in "lumping." Also, why a paucity of remyelnization research, especially because we've reached the ceiling of immunosuppression? When estrogen peaks on day 15, I do indeed feel "normal." 100%. I think clearly, run around, drive, the old me is back in spades! It is also heartbreaking because I think if, somehow, it was switched off I could have more normal days. Please keep researching and thanks for all you guys do.

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