What needs to be done to tackle ‘progressive’ or more correctly ‘advanced’ MS? #ClinicSpeak #ThinkHand #ChariotMS
Summary: This post summarises what needs to be done to tackle more advanced MS including people with MS using wheelchairs. It makes the case for making several changes in the way we study advanced MS. What is needed now is a large injection of money to kick-start a trial in wheelchair users to delay loss of upper limb function. This post is an essential read for anyone who cares about people with more advanced MS.
Earlier this week I had a debate with a colleague about therapeutic targets and whether or not they are achievable. He thought NEDA was a crap target as most of our patients who achieve NEDA still have residual problems. Therein lies the rub. NEDA, or no evident disease activity, refers to evidence of ongoing inflammation. NEDA does not refer to previous damage, nor does it refer to the ongoing consequences of previous damage. You can only do so much with an anti-inflammatory agent, i.e. switch-off inflammation, and even then most anti-inflammatory agents we use don’t switch-off innate immunity within the CNS (hot microglia), nor do they purge the nervous system of plasma cells and oligoclonal immunoglobulins. In reality, we can only ask so much of our current DMTs. This is why we need combination therapy strategies.
The following are some points about progressive MS that needs repeating:
- We all need to accept that ‘progressive MS’ is a misnomer. Progression means improvement. At Barts-MS prefer the term ‘advanced MS’ this captures the associated disability that comes with this phase of the disease.
- We need to accept that the pathology that drives neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘advanced MS’) as being there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become physically disabled.
- MS is 1-disease and not 2-3-or-4-diseases. As I have said before the false division of MS into several diseases is not backed up by science, nor by philosophical arguments. This false division of MS into many diseases has become counter-productive to the field of MS. The division of MS into relapsing and progressive forms was Pharma-led to get MS defined as an orphan disease, which allowed interferon-beta-1b to get a license based on the results of one pivotal phase 3 study. It also allowed the company concerned to charge rather a lot of money for its product. Overall this has been good for MS in that it has attracted a lot of Pharma interest and has supercharged drug development in MS, but it is now slowing down drug development and making it very expensive. We need cheaper drugs for advanced MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for advanced MS need to be priced lower than those for relapsing forms of MS.
- Following on the point above the division between SPMS and PPMS is false. There is no pathological, genetic, imaging or other data that suggests these are different entities. We, therefore, should be doing trials in both populations simultaneously.
- 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 big part in driving advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.
- Accept that 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 refer to this as therapeutic-lag. These observations are explained by the length-dependent axonopathy hypothesis. This means that we will need to focus more on the arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0). This is what we are proposing to do in our CHARIOT study (parenteral cladribine).
- Challenge the dogma that once someone has lost lower limb function and is a wheelchair user that the 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.
- Accept that we will need to use combination therapies to make a real difference to more advanced MS. We are not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective 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.
- We need to ditch the EDSS as the primary outcome in advanced MS trials. The whole community 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 the disease. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more PROMS 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, including one from Barts-MS.
- 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 doesn’t like adaptive designs nor do the regulators. I do think we do need two phases to trials in more advanced MS, i.e. the standard head-to-head phase with a robust primary outcome, say a multi-outcome composite, 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).
- Acceptance of 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 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 have fully recruited our PROXIMUS trial and we have learned a lot in the process. For those of you new to this blog the PROXIMUS trial was 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’. Labelling eligible subjects as having early SPMS was a mistake. Nobody wants to be told they have SPMS, therefore their clinicians were reluctant to refer patients eligible for the study. My advice to anyone doing trials in this space is to avoid the term progressive.
- Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and have even written a paper on the so-called ‘Big Pharma Alternative’ to explain our thoughts on this.
- 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 drug x in combination with drug y 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 for example oncology.
- More detailed cost-effective models that focus on the loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the recent EU cost of MS study that costs soar as pwMS lose arm function.
- We also need to tackle ageing and its impact on worsening MS. The evidence that early, or premature, ageing from the reduced brain, and cognitive, reserve drives worsening of 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, similar to my colleague’s expectations. 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 axonal sprouting, synaptogenesis and plasticity mechanisms to restore function. This is not rocket science. If you are coming to ECTRIMS I will be giving a talk on this exaxt topic in a satellite symposium.
As you can see 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 in the points 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.
If there are any wealthy philanthropists out there? DrK (@KlausSchmierer) is looking for a large donation to support his application to the NIHR for the CHARIOT study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded.
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| DrK with a smile |
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.
Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.
CoI: multiple
Prof G what about Pharma? Are any of them prepared to do a trial in more advanced MS? Surely they would be the obvious solution to getting a trial done in wheelchair users?
Yes, I agree it would be better for them to do it. They have the DMTs, resources, etc. to make it happen. It is not for lack of trying. I have had discussions with several companies and make use of every opportunity I get to make the case for #ThinkHand campaign.
Thank god for Professor Coles. Instead of navel-gazing and blogging, actually getting on with a real trial (potential re- myelination):http://www.ms-uk.org/potential-myelin-repair-treatment-starts-clinical-trial Mouse will no doubt attempt to re-analyse the trial data in 15 years time (in his usual sour grapes way).
Good news indeed, let's hope for a positive result. I hope the good Professor Coles isn't too busy with this important trial to get on and publish the results of the CAM-THY trial, the results of which I suspect may be hugely revealing.BTW is it sour grapes to report "hidden" data? I think not, in fact the data has been very important in revealing the potential causes of autoimmunity and the central importance of the B cell in MS. Prof Larry Steinman (perhaps the most famous immunologist in the world) was very complimentary about this work "Gratitude is extended to Baker and coauthors1 for those careful measurements of immune cell repopulation after a successful therapy for MS and for their astute interpretation of the data, all emanating from an unwanted SAE. Their observations may kindle further advances in understanding how autoimmunity arises."http://jamanetwork.com/journals/jamaneurology/fullarticle/2630677Sour grapes can produce the finest wine 😉
That trial is fine if you have relapsing MS. Prof G is talking about people with advanced MS, a totally different scenario
Have we made the case for remyelination therapies in MS? Is there really a problem with lack of myelination in MS? Do we know how to do remyelination therapy trials? If you are interested in this topic I will post my presentation from ECTRIMS on the blog. There will also be some very nice new data presented from Biogen's opicinumab trial at ECTRIMS highlighting some interesting observations in this space. These observations, and others, are going to shake-up the field.
Please post of course
"Sour grapes can produce the finest wine ;-)" My fave comment ever! I'm gonna use it next time you tell me lol = lots of love, when you call me a black pot and a ranter 😀
I was quite proud of that one myself 😉
Navel grazing = self-indulgent or excessive contemplation of oneself or a single issue, at the expense of a wider view.Although my wife doesnt' think so…but maybe I can actually multi-task, blog and do two trials at once and do the invention that generated the trialSo what's my single issue?Patient safety is not worth mentioning and defending…..I guess.Also the idea of the remyelination trial is solely at the feet of Prof Franklin and Charles ffffffrench-constant. Rev Coles is the person who will try make someone else's ideas work. Let's hope it works.FYI. Prof Coles used to blog, but one of the last posts was to say that his last trial was terminated because it didn't work…the question is did it make things worse? I can ask him at ECTRIMS if he will talk to me:-(
News on the grapevine is that the CAM-THY trial actually increased autoimmunity post-alemtuzumab. Is that interesting?
Definitely.
What is your source? It is definitely interesting to me, we predicted that this was going to be the case based on the way T & B cell repopulate.If this is true….this is very different from "Failed to show a benefit of palifermin"
MD could you comment on the inflammatory penumbra and neuroprotection? You really should blow your trumpet more often;-)
I feel that much has been said about the need for neuro-protection but that on the whole, there is little proof that anything works substantially. Neuro-protective effects have been suggested in modafinil, interferon, idebenone, minocycline, alpha-lipoic acid, Vitamin D, lamotrigine, quetiapine, Resveratrol, Rosiglitazone, Pioglitazone, Troglitazone, Bezafibrate (PPARγ activator), rhBNDF, rhIGF-1, rhCNTF, etc., CERE-110 (AAV2-NGF), Phenitoin, Amiloride, Dimethyl-Fumarate, Resveratrol, Vitamin E, Vitamin C, Melatonin, Carnosine, Coenzyme-Q, Carotenoids, Memantine, Riluzole, BIIB003, Clemastine benztropine, miconazole, clobetasol, Epothilone B, BIIB003, GSK1223249, Caspase or calpain inhibitors, Glatiramer acetate, Fumarate, Dimethyl-Fumarate, Mesenchymal stem cells, Pentamidine, Methylthioadenosine and Fingolimod. It's small wonder that the community is scratching its head.On top of that you see people say that you shouldn't eat dairy, and you shouldn't eat gluten and you shouldn't eat animal fat, or that you should eat animal fat and that snake venom is good for you and that having a stent insterted into your neck is great news, and why not throw in a 2 for 1 offer on HSTC in Mexico while you are at it.So how do you even begin to test all these lovely agents above? Yes – pharma needs to step in. But I also think that there needs to be more proof that NFL in CSF correlates to progression: there seems to be a little conflicting data on all of this.Why alight on oxcarbazepine? Did Lamotrigine show conclusively that sodium channel blocking was the way forward? I don't think so.What about the stimulation of mitochondria to address neuro-degeneration? Is this a sticking plaster over a gaping wound?What about the use of alpha-lipoic acid to stop brain atrophy? The Phase II findings were really interesting, but this hasn't set this blog alight with excitement.To me the issue of neuro-protection has always been central to cracking the mystery of MS. Perhaps the MS community needs to tie up with the Alzheimers and the Parkinsons and others to really get to the core of why our neurons fail us… and how to stop that happening.I'd say look first at mitochondria preservation and see what stems from that.
You missed cannabinoids out from your list and the biology and animal studies shows they are undoubtedly neuroprotective. In a sub-set of pwMS at lower EDSS scores in the CUPID trial it was demonstrated that THC has a neuroprotective effect. Sadly when lumped together with all the other data this effect was swamped by negative data due to too many having an EDSS that is unlikely to change significantly during the course of the study."Why alight on oxcarbazepine? Did Lamotrigine show conclusively that sodium channel blocking was the way forward? I don't think so."Oxcarbazepine looks very promising in our mouse studies. The Lamotrigene trial was flawed, lessons have been learned."I'd say look first at mitochondria preservation and see what stems from that."Funny you should say that, we're working on this at the moment.https://www.ncbi.nlm.nih.gov/pubmed/26679998
It's a long time coming, but if the PPMS trial in Idebenone works, then perhaps this is the magic add-on…One day we might even get a situation where everyone with MS, upon diagnosis, is given Cladribine, then put on a Vit D3, Alpha Lipoic Acid and Idebenone treatment regime with a final as yet determined neuroprotective drug added on top….The issue of CSF analysis still concerns me. I want to see proof that a reduced NFL level correlates to reduced progression. Where's the evidence that this is the case?
Hopefully the PROXIMUS trial can provide some of that data.
Regarding THC, I live in a region that I could get a prescription for weed. Should I do that to have one joint on a Friday night for potential neuroprotection?
I'll leave you to make up your own mind on that one Aidan but there's plenty of supportive evidence for neuroprotective properties.
Frankly, whatever you say about experimenting w/ supplements, we all read these things and consider risks. What else can we do? So high dose r-lipoic-acid and Mito-Q for me until someone tells me something better or there is evidence of harm. My neuro said biotin for me for now. Also periodic fasting. I'll look into versions of THC that don't affect my cognition.
I'll look into versions of THC that don't affect my cognition.They are all linked the good and the bad.. so probably a futile search.
Thank you MouseDoctor.I meant to say above my neuro said **no** biotin for me right now. I am currently on a five-day fast per Valter Longo. I may try this more regularly and see if my naturopath will test my blood levels before and after. (The doses of biotin are too high if I plan to try for one more child.)
I am currently on a five-day fast per ValterNice, last month i was 90 hours only water and tea, blood sugar was 49, my brain was racingHow do you fell?Dont forget to refeedObrigadoHow do
MouseDoctor2Wednesday, September 20, 2017 3:37:00 pmI'll leave you to make up your own mind on that one Aidan but there's plenty of supportive evidence for neuroprotective properties.MouseDoctorWednesday, September 20, 2017 4:56:00 pmI'll look into versions of THC that don't affect my cognition.They are all linked the good and the bad.. so probably a futile search.can you also link the evidence? i think i have similar questions to aidan's
You guys are wasting your time trying to do this yourself. Get Pharma to do it. A positive trial won't lead to a drug license or adoption by the community. I think you know this already.
And if pharma refuse to do it, what do you do, give up?We're more tenacious than that and who knows, if nudge theory is correct, it might have an effect.
Pharma will only be interested in drugs with IP and the ability to make money. What about off-patent drugs and drugs with a limited patent-life span? This is why we have to press on and do what we need to do.
" He thought NEDA was a crap target"Is not the only one thinking that way"CONCLUSIONS AND RELEVANCENEDA is difficult to sustain long term even with treatment"Obrigadohttps://www.ncbi.nlm.nih.gov/pubmed/25531931
As sad as it is, pharma wont make money with edss »6.5And people with progressive disease are left aloneObrigado
NgR1 may regulate axo-myelin ultrastructure through Caspr-mediated adhesion, regulating the electrophysiological signature of myelinated axons of central nervous system (CNS). (2017 Aug 21)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567129/
If there was a drug/neuroprotectant that definitively was shown to slow progression, that was to be taken daily, let's say, then even at EDSS >6.5 it could/would be used and pharma could potentially make money from it. Unless of course the putative drug is off patent, when it becomes more complicated see cladribine.
Regarding point 6: reserve capacity aids recovery. Has there ever been an experiment to see what happens if a pwAMS is placed in a medical induced coma?Is it possible that taking the load of the network would allow that network to recover? Just a thought.
I can't imagine that would ever have been done for MS, though of course it is common in head trauma.
Few thoughts:If neuro-inflammatory agents have a therapeutic lag and length-dependant axonopathy, shouldn't researchers already be able to study those progressive patients previously treated with the powerful mitoxantrone or myeloablative HSCT already and look at the difference in those not treated with progressive MS? Shouldn't they have spared hand function or be clinically better off than those not treated?Imagine the outrageous and disgusting pricing currently for the neuro-inflammatory agents and then think we need to add on neuroprotective, remyelination and neurorestoration products. This will be unaffordable for any MS patient. The thought that "advanced" MS patients need to "dampen" expectations that they will get restored function or return to normal is unacceptable. Did Dr. G just mean currently or in the future? This will happen but not with the current false model of different divisions of MS (RRMS, SPMS and PPMS) created by profitable pharma teams where the neuro-inflammation model has taken the spotlight for decades and neuro-degeneration, remyelination and neuro-restoration has not been studied concurrently.
"Nissan GrifterWednesday, September 20, 2017 6:45:00 pmFew thoughts:If neuro-inflammatory agents have a therapeutic lag and length-dependant axonopathy, shouldn't researchers already be able to study those progressive patients previously treated with the powerful mitoxantrone or myeloablative HSCT already and look at the difference in those not treated with progressive MS? Shouldn't they have spared hand function or be clinically better off than those not treated?"No, because that's never been followed up. Instead, the various registries following people up only record number of relapses and progression. they don't record the type of progression v. what systems were affected beforehand and which ones afterwards.so much data could be collected but isn't it makes one want to cry.
Missing from your list – things won't change in the US until there's a healthcare system that decouples people's health insurance from their work, and there needs to be an MS scoring system that includes cognitive and mood effects, which start very, very early in the disease for many people. People who are newly diagnosed are afraid of the wheelchair but they should be afraid of losing brain.
While I agree with much of the info contained in this post, I'm still a little iffy on advanced MS (particularly PPMS) having an inflammatory component strong enough to make a difference if treated.I harken back to some of the HSCT longitudinal studies that clearly show people with relapsing MS doing far better than people with advanced ms. In one recent study, at the five year mark the difference is striking: approximately 75% of relapsing MS patients who underwent the procedure were progression free at five years, but only 35% of SPMS patients had that same kind of success.Here's the abstract to this study, which doesn't include a breakdown of the effectiveness by patient population. The full paper, however, does:https://www.ncbi.nlm.nih.gov/pubmed/28241268These numbers would certainly seem to indicate differences in neurodegenerative mechanisms of the different disease classifications, and that immune -related therapies, even as draconian as HSCT, hold much lesser promise for those with advanced ms.Certainly, patients with advanced MS should not be abandoned, and preserving upper limb function is vital. But all of this concentration on immune suppression/ablation seems to be a bit misguided when it comes to advanced ms. New strategies are desperately needed, above and beyond add-on neuroprotective agents.
WK the problem with both SPMS and PPMS is that they are on average 10 years older than the relapsing patients and are further down the EDSS slide; usually several points. This means less reserve, i.e. less ability to recover and fewer surviving axons. This is why they don't do as well, that is at least based on the EDSS that is mainly a lower limb impairment scale. The question is how do they do regarding upper limb function? It is clear the the biology of advanced MS is complex, but that does not mean we should not tackle it.
I started PPMS in my early twenties. Never had pronounced inflammation and I hardly recognise the MS that those with RRMS have as being the same disease. Speaking purely as a PPMSer, I find your theories a little hard to swallow. I certainly don't feel convinced enough to take on the side effects and risks of immunosuppression.
If Hsct is the most powefull Dmd ,and does´nt work very well for ppms or edss »6.5How could any order immunosupressive drug work in those patients?Obrigado
"No DMDs, including HSCT, work well in PPMS and MSers with an EDSS > 6.5."Why? Because they have lost too many axons in their spinal cords to show an effect in the lower limbs. But when you look at their arm and hand function it is a different story. It all about preservation of function and not restoration of function.
Thanks for replyDo you have had any experience treating those patients edss» 6.5 and restoring their hand function ?How manny years have they been treated? How are they now (edss)?Obrigado