Case study: unrealistic expectations
It is not good enough to simply target stabilisation or slowing down of disability worsening. I want to participate in a trial that offers an improvement in functioning.
Case study
I received an email from a middle-aged woman with MS who was recently turned down for the Metformin-Clemastine remyelination trial due to a history of worsening disability (ClinicalTrials.gov Identifier: NCT05131828). I suspect she was considered by the Cambridge team to have secondary progressive MS and therefore was not eligible for the trial. This patient has been on dimethyl fumarate for 7 years and is NEIDA (no evident inflammatory disease activity). I suggested she consider volunteering for our SIZOMUS trial (ClinicalTrials.gov Identifier: NCT03783416).
On reading about the study and watching my Youtube video of the trial she said no and made the following comment.
“The SIZOMUS trial is not appealing to me; it is not good enough to simply target stabilisation or slowing down of disability worsening. I want to participate in a trial that offers an improvement in functioning. I am particularly interested in volunteering for remyelination therapy trials.”
Prof G’s opinion
I can understand this woman’s frustration, but her level of expectation is potentially unrealistic considering the recent failure of several remyelination studies.
I sit on several steering committees and advisory boards for projects that are exploring remyelination or recovery of function as a treatment strategy in MS. This has prompted me to consider whether remyelination in MS is necessary or not. The question we need to ask ourselves is why have three recent remyelination trials and strategies failed? These trials include the following:
Primary outcome: The proportion of patients Improved on either the EDSS or 25TW
Secondary or remyelination outcome: Change in mean lesional MTR between month 0 and month 6 for lesions selected for each patient.
Primary outcome: Overall Response Score, a multicomponent score based on 4 components: EDSS, T25FW, 9HPT in the dominant hand and non-dominant hand.
Have we the MS community made a fundamental mistake in assuming that remyelination is an ongoing persistent problem that needs fixing in MS? Have we got the biology wrong? Are biotin-dependent mitochondrial dysfunction and biotin-dependent remyelination pathways a problem in MS? Is the activation of retinoid X receptors (RXRs), with bexarotene, to promote remyelination the correct target in MS? Is the inhibition of an inhibitor of remyelination with opicinumab (anti-LINGO-1) sufficient to promote remyelination across the central nervous system? At least with anti-LINGO-1 or opicinumab, there was proof of biology in pwMS, i.e. the drug did improve conduction speed in demyelinated optic nerves in the first phase 1 study (Cadavid et al. Lancet Neurol. 2017 Mar;16(3):189-199.).
Were the trial designs correct? For the high-dose biotin study, the population of pwMS was quite old with a lot of fixed disabilities (Cree et al. Lancet Neurol. 2020 Dec;19(12):988-997.). Maybe the population was too old and hence ageing mechanism prevented any recovery of function from being detected. Maybe there was too much axonal or nerve loss and hence remyelination was doomed to fail.
Maybe focusing on the individual MS lesion with bexarotene using MRI techniques is too fickle (Brown et al. Lancet Neurol. 2021 Sep;20(9):709-720.)? It is clear that in the bexarotene study there were too few new, presumably actively demyelinating, lesions to generate a positive signal.
The overall response score in the opicinumab trial may not be good enough to capture the recovery of function due to remyelination. The idea of using a composite score, with multiple components, to detect recovery of function makes clinical and biological sense. However, using the arms and legs as the main read-out may not be sensitive enough. What about vision, cognition, balance, bowels, bladder, fatigue, etc. Do we need a better outcome measure? Do we have to go back to the drawing board with our clinical outcome measures?
Or is the answer staring us in the face? When you treat MS early with the big guns, i.e. alemtuzumab or HSCT, it is quite remarkable how many pwMS have spontaneous recovery of function. Are alemtuzumab and HSCT doing something fundamental to the pathogenesis of MS that then allows for spontaneous recovery of function? Are we curing a proportion of people with MS with these treatments?
One of the latest theories that are being tested in MS is that because of premature ageing and senescence the oligodendrocyte precursors and oligodendrocytes (myelin-producing cells) can’t function properly. The solution is to reprogramme them, i.e. dial back the ageing clock by using diet (caloric restriction, intermittent fasting or ketosis) and/or medication (e.g. metformin or fumarates) before hitting them with drugs to stimulate myelin formation. The latter is backed by animal data, but will it work in MS? Possibly; however, this is based on the assumption that the tools we currently have for measuring remyelination in pwMS actually work.
The danger with all these strategies is tossing the baby out with the bathwater, i.e. once a trial is negative with a compound it is very rare that the community goes back to the compound or the biology to try again. So we need to be confident that our methods are sound and reliable. I am not sure we can be that confident after the three trial failures discussed above.
Another aspect that is lacking in all our trials is neurorehabilitation, i.e creating the biological stimulus to promote recovery of function. Nobody would perform a spinal cord injury recovery of function trial without active rehabilitation on top of the treatment being tested. The latter is backed up by sound science and compelling animal studies. Why do we in the MS community expect the spontaneous recovery of function without rehabilitation? If you don’t use it you lose it! To encourage the recovery of function you need to stress the pathway. I thought this concept would be a no-brainer, but I have yet to convince any of the Pharmaceutical companies I consult for to do a study on top of an active rehabilitation programme to promote recovery of function in pwMS.
Maybe instead of trying to promote remyelination and recovery of function in pwMS, our aim should be to treat MS effectively early on, i.e. to prevent the need for remyelination therapies in the first place? The question is how do we get the wider MS community to promote the use of alemtuzumab and HSCT, or similar agents, as the default first-line therapy for MS? Some of us have tried, including me, but have failed miserably with this seemingly easy task. By the time most pwMS get to alemtuzumab or HSCT, they have so much damage that they need restoration therapies.
As we think we now know the potential cause of MS trying to put out a fire without correcting the upstream pathology is folly. Therefore maybe we should only be trying remyelination and neurorestorative therapies in people who have stable fixed deficits, with no ongoing evidence of any inflammatory disease activity, post alemtuzumab or HSCT? The irony of letting pwMS become disabled before being treated with alemtuzumab or HSCT is inadvertently creating a trial-ready population of subjects for remyelination therapy trials.
I encourage thoughts or counterarguments on the above. We need to have an open discussion and debate on the points I have raised in this post. I think we need to answer some fundamental questions about remyelination and neurorestorative therapies before we spend more money on futile trials and throw the baby out with the bathwater.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry or Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
To prevent is always ‘easier’ and better than to cure. We should however leave no one behind. One of the biggest issues is that when medical MS interventions work in active inflammatory relapsing MS, they don’t work in progressive MS. The other way around is that successful progressive MS therapies do work in relapsing MS.
So why does the medical research establishment still focus on creating similar Disease Modifying Therapies addressing the immune system. Do we actually need more of the same therapies with a similar mode of action and effectiveness, but with different side effect profile or ‘novel’ route of administration? A paradigm shift in medical research is urgently needed to actually develop cures for all different types of People with MS.
Preventing cumulative neurological disability to eventually reach the level of Advanced Multiple Sclerosis should nowadays already be a tangible reality with several high efficacy Disease Modifying Therapies (IRT’s, alemtuzumab, etc) addressing the adaptive immune system attacking myelin in the Central Nervous System ultimately leading to neurodegeneration.
New treatments for Progressive MS addressing for instance the innate immune system (BTK, Mastinib, etc) and remyelination strategies (CNM-Au8, dendritic cells, NVG-291 etc) are also approaching the market in the next 5 to 10 years after decades of research if proved effective. The hope is this will halt progressing neurodegeneration atrophying the Central Nervous System.
To prevent MS (perhaps via a EBV vaccine) and halting its progressive course should be a more achievable goal in the next 5 to 10 years opposed to actually curing or at least improving cumulative neurological disability leading to advanced levels of MS. If we can prevent this devastating disease it will naturally disappear in time.
However currently the biggest unmet need lies with those people who experience daily struggles with varied advanced levels of disability and can even expect progressive worsening over time.
Remyelination strategies will only be effective if it is applied early in the disease course when there is active inflammation and for instance neurological reserve via neuroplasticity to compensate lost neurological function. Remyelination will not cure advanced progressive disease. It might slow down progression.
Other novel to be developed strategies are needed to improve or even reverse lost neurological function ultimately curing Advanced (progressive) MS.
In an acute MS lesion, the window of opportunity for both neuroprotection and remyelination may be relatively short. In other words, if you don’t protect and remyelinate damaged axons quickly, they may degenerate and hence remyelination therapies may fail. Also, some degree of neuroinflammation particularly of the regulatory type is beneficial for regenerative responses.
This so-called ‘window of opportunity’ has been referred to as the inflammatory penumbra and may limit the potential of remyelination therapies to a biological window of potentially weeks or possibly months. After acute optic neuritis retinal nerve fibre thinning or optic nerve atrophy may take somewhere between four to six months, respectively. It is therefore hard to imagine a treatment working beyond this window.
Improving or even reversing longstanding accumulated neurological disability is the biggest unmet need in the underserved Advanced (progressive) MS community.
It should, therefore, be abundantly clear to the Advanced (progressive) MS community that remyelination therapies alone will have no to limited effect due to the inflammatory penumbra. Only new acute inflammatory lesions are suitable for remyelination and neuroprotection.
Again, like with current DMT’s mainly (Early) Relapsing MS and early inflammatory progressive MS is addressed with remyelination and neuroprotection Research, and research to create adequate treatments for non-inflammatory and/or smouldering Progressive MS are still lacking.
I therefor do wonder why for instance the progressive MS Alliance and other national ms societies and foundations so strongly focus on myelin repair therapies for Progressive MS.
Cumulative neurological disability via axonal degeneration and CNS atrophy due to neurodegeneration and/or inflammation will not be adequately addressed with remyelination therapies alone. In best case scenario it will limited and/or prevent progression in (Advanced) Progressive MS.
At present PwMS, especially people with progressive MS, have unrealistically high expectations for potential remyelination therapies while those living with advanced levels of disability are likely to not benefit from them.
Therefore, we must manage the expectations to the underserved progressive MS patient community and explain the complexities and challenges posed by remyelination and neurorestorative therapies.
The way I see it, in 5 to 10 years’ time there will be roughly 2 types of MS patients.
1. Early MS diagnosis with a hit hard induction therapy or perhaps a virus (EBV?) vaccine in combination with possible remyelination medicines resulting in low EDSS and stable MS. (Remission / cure?)
2. MS Patients with cumulative acquired disability with hopefully CNS penetrable medical interventions (BTK? EBV vaccine? Temelimab? Etc) to address smouldering inflammation stopping progression and keeping them stable.
For those PwMS in the second group other novel medical interventions need to be developed next to remyelination alone to improve or even reverse longstanding accumulated neurological disability and improve quality of life. That’s the biggest unmet need for these patients who are effected the most by this gruesome and unforgiving disease.
As a 61 year old Secondary progressive M.S sufferer I am absolutely thrilled at the amazing news that M.S treatments are progressing so much I have two daughters whom I constantly worry will inherit this awful disease so as you can imagine any progress in treatments to start sooner is very well received. Now to risk offending others( not meaning to I promise and probably a bit selfish) while as I say quite honestly I am thrilled with all progress can I ask what's being done for those of us with established disabilities. From what I keep reading on your blogs and many others if I had been given treatments on diagnosis 15 years ago my disabilities may not have been so bad .My question therefore is. Is there anything that can be done to help those of us in this situation we seem to be the forgotten tribe and I can assure you I have put my name forward with my Neurologist and M,S nurse for any trials to have not been given the opportunity to try any.Therefore may I please inform you if you are looking for volunteers for ANY!! Trials look no further