During my physical rehabilitation exercise session yesterday I realised that I have not reflected on the New Year from an MS or personal perspective be it MS research, MS clinical practice or my personal life. I suspect I have been distracted by my injuries and recovery and that the COVID-19 pandemic has pushed the New Year transition into the future. The political mayhem across the world has also hijacked my attention and as a result, I have wasted many unproductive hours reading, listening to and watching the news. Putting these issues aside there are several MS-related questions that I have asked myself that we need to address in 2021.
Do my posts still need a rose-tinted-odometer?
We now live in a world where information is walled-in and that most people only consume information, which is consistent with their worldview – the so-called echo-chamber phenomenon. People with MS who read this blog should be able to handle any type of post; they come here to hear what we have to say, be it sugar-coated or not. I am therefore ditching the odometer. I hope you agree!
Should we continue to challenge the dogma?
As with any specialist field, multiple sclerosis is wrapped in a cloak of dogma that largely dictates the research agenda. It is always important to challenge the prevailing dogma and to think laterally. The latter is particularly important when it comes to preventing MS. Yes, I do think MS is caused by EBV and there is now a groundswell of people within the MS community who think so as well. So this year will be one in which we focus on EBV and how we can target it to treat and prevent MS.
Another theory that we actively promote is the memory B-cell hypothesis, which overlaps with EBV biology. The B cell hypothesis is not new and underpins many of our current DMTs and a potential new class of treatment, namely the BTK inhibitors (BTKi). The CNS penetrant BTKi also inhibit activated microglia and macrophages and hence may help address the ‘hot microglial’ hypothesis of progressive MS. The latter hypothesis is based on the observation that people with progressive MS have extensive activation of the innate immune system in their brains and spinal cords, which may be responsible for the neurodegeneration that characterizes progressive MS. I have previously argued that this may not necessarily be the case as innate immune responses may be secondary to what is causing MS and may be part of repair response. The good news is that three phase-3 trial programmes of BTKi in MS have already started. This is also an acknowledgement by Big Pharma that we need to go beyond our current DMTs. In other words, there is still a lot to do when it comes to managing MS optimally.
Smouldering MS is a rebranded old hypothesis that will continue to dominate MS debates this year. Essentially it states that focal inflammation is not MS, but rather the immune system’s response to what is causing MS and that our therapeutic targets should include the processes that are downstream of inflammation that have been identified to drive smouldering disease.
In 2021 we will continue to promote and investigate smouldering disease and help develop the therapeutic paradigm for testing add-on or combination therapies. The hurdles or obstacles to making this a reality are not insurmountable, but we clearly need a consensus from all MS stakeholders that this is what we want to do and to get the regulators on board.
Will we be able to close the loop on several hypotheses we have been pushing?
The short answer is yes for some and no for others. Getting funding, setting-up, starting and then completing clinical trials takes time. The good news is that as part of our #ThinkHand campaign the ORATORIO-HAND or O’HAND study (ocrelizumab in PPMS) started last year and despite some delays in recruitment due to COVID-19 should fully recruit this year. Prof K tells me that first-patient for the CHARIOT-MS trial should be randomised in the first quarter of this year.
Some other good news is that our Under&Over remote hand rehabilitation trial will start in the next few weeks. This is will be testing whether a simple, but engaging, dexterity task can maintain or improve hand-function in people with late-stage MS. This study will be testing the ‘use it or lose it’ hypothesis, something I now know from personal experience to be true.
Other studies that we are involved in that will start this year includes STAR-MS, which compare HSCT to alemtuzumab or ocrelizumab. This study may help address the B-cell versus T&B-cell hypothesis, which I support; i.e. it is not enough to target B-cells only. To manage MS you need to target both B and T cells.
We will watch on the sidelines to see how the DELIVER-MS and TREAT-MS trials recruit. In DELIVER-MS (NCT03535298) subjects are being randomized either to a maintenance-escalation or an early high-efficacy treatment approach (flipping the pyramid). In comparison, TREAT-MS (NCT03500328) is evaluating subjects with higher and lower risks of disability accumulation whether an escalation approach or early highly effective therapy (flipping the pyramid) influence disability. TREAT-MS is also comparing disability risk between individuals who switch from a first-line medication to a highly effective medication (escalation) versus those who switch to another first-line therapy (horizontal switching or cycling).
We designed a NEDA trial back in 2014 to test treat-2-target of NEDA versus standard of care but soon realised that at Barts-MS we didn’t have equipoise and felt it would not be ethical to randomise our patients to a trial of this nature, which is why we personally didn’t progress the trial. We think the data is so compelling in relation to rapid vertical escalation or flipping-the-pyramid, compared to the ‘standard step-care’ approach, that pwMS should be given a choice in how they want their MS to be treated.
In 2021 I would argue that in most MS centres the ‘step-care’ or ‘slow-escalation’ approach to DMTs is not standard of care anymore. Rapid vertical escalation or flipping-the-pyramid in the context of informed- and/or guided-choice is the new ‘standard-of-care’ when it comes to treating active MS.
Clearly, as our ideas have evolved since 2014 I would argue that the new frontier is going beyond NEIDA (no evident inflammatory disease activity) and targeting the end-organ. Normalising brain and spinal cord volume loss and protecting the reserve capacity of the CNS for healthy normal ageing should become our new treatment target. This is why we have extended our MS Brain Health campaign to the general population, i.e. #ThinkBrainHealth.
Why did MS remyelination trials fail?
2020 saw the failure of three remyelintion strategies; high-dose biotin, bexarotene and opicinumab (anti-LINGO-1). Most people have dismissed the high-dose biotin trial as targeting people with MS in whom the MS pathology was too advanced to modify; most of the subjects in the trial had an EDSS or 6.0 (unilateral support to walk 100m) or 6.5 (bilateral support to walk 10m). The bexarotene trial was negative, but a per protocol subgroup analysis showed a positive treand, but was underpowered. Despite this weak efficacy signal the drug had too many adverse events to be taken forward. The opicinumab or anti-LINGO-1 trial was the most dissappointing as it was backed by good science, a positive proof of biology and a phase 2 study that suggested a sweet spot for remyelination, i.e. patients who were disabled by MS, but not too disabled, and had MRI evidence of demyelination. We really need to look at the opicinumab study results in greater detail to find out why the study failed. Was it the biology (wrong target), the molecule (non-CNS penetrant), the population (too old or not disabled enough) or the trial design (wrong outcome measure)? If we don’t learn from these negative studies we won’t progress the field and are likely to make the same mistakes again in the future.
The question we need to ask ourselves in the MS community is whether or not persistent demyelination is a problem in MS? Just maybe the dogma is wrong and remyelination is not necessary in MS. When you suppress ongoing inflammation in people with active MS the lesions remyelinate spontaneously. Yes, we know that the remyelination processes slow down and eventually fail with increasing age.
Ageing is the next biological frontier in MS and other fields; we may have to reverse the biology of senescence with dietary manipulations or drugs (e.g. metformin) and to then repeat the remyelination experiment. So this year we will hopefully see a phase 2 combination therapy trial of metformin (anti-ageing) and clemastine a centrally-acting anticholinergic remyelination therapy start.
We will also see phase 2 results of the elezanumab (ABT-555) trial reported this year. Elezanumab is a monoclonal antibody that inhibits or blocks the repulsive guidance molecule A (RGMa). Inhibiting RGMa promotes remyelination, axonal sprouting and synapse formation. The basic science underlying RGMa, particularly from spinal cord injury models, is very compelling. Will the elezanumab trial be able to answer the fundamental question about whether or not remyelination and neurorestoration are realistic treatment target in MS? I would give the odds of this trial being positive at slightly over 50%; maybe 55%.
Why are social determinants of health so important?
I have personally been interested in the social determinants of health (SDoH) for several years and I am convinced they affect MS outcomes. To that effect, we have produced some preliminary evidence from our own centre showing that social capital, one of the SDoH, improves MS outcome. We have therefore been fortunate to get funding for a PhD student to study the impact that our public engagement programme has on social capital in our own patients. I see a future when social prescribing will be part of the service we provide to pwMS to improve their longterm disease outcomes.
It is clear that inequality, one of the major SDoH, explains a lot when it comes to health outcomes and mortality. It is worth noting that COVID-19 pandemic has exposed the brutality of inequality in our societies and this will hopefully be a turning point for politicians to do something about this scourge. When the dust settles post-COVID-19 and the data comes in I am confident that we will see the impact inequality has had on pwMS during the pandemic.
So yes, 2021 will be the year when our #ThinkSocial campaign will be given some teeth.
Can we listen, watch, experience or do and learn?
I think most readers have heard enough about my accident, resuscitation, acute management, inpatient stay, rehabilitation and now my recovery. The reason for publising my story was to help raise money for our Barts-MS COVID-19 antibody study. To this aim the information campaign was a great success and I would like to thank you once again for generously donating money towards our study.
However, my brush with mortality and exposure to the NHS as a patient has taught me that healthcare services need to learn from each other. What can we adopt from acute medicine and surgery services and their service design to improve what we have to offer pwMS? This is something I will try and do once I am back at work next month.
My COVID-19 prehabilitation programme was one of the reasons I got so lucky and I am convinced is one of the reasons why I am recovering so well after the accident. I am confident that by the end of the month my physical rehabilitation will be sufficient enough for me to go back to work in February.
When I wrote about prehabilitation early during the COVID-19 pandemic it was to try and get the wider MS community to improve their general health so as to maximize their chances of doing well in the event of them getting COVID-19. As a result of my prehabilitation post, I decided to walk-my-talk. This motivated me to get physically fit, yes marathon fit, lose weight and in general optimise my sleep, diet, blood pressure, etc. I even experimented with biohacking, i.e. trying a low carbohydrate ketogenic diet and intermittent fasting. I am now a biohacking convert and think we need to study ketogenesis as a potential DMT in pwMS.
Finally, what has allowed me to do this was time; not travelling, spending quality time at home and thinking. Hopefully, my musings and reflections will allow me to focus on the research questions above and make the many changes I have made to my life during the pandemic a habit.
I also want to thank the Barts-MS team who have been quite amazing in rising the unique clinical and research challenges last year threw at us. We have not come out unscathed, but I think we will be leaner and wiser when we tackle the challenges of 2021.
Happy New Year.