Lab Lessons – Page 6 – Prof G's MS Blog Archive

Fallers

Barts-MS rose-tinted-odometer: ★

Mrs P came for her annual follow-up appointment. She has had MS for 12 years, was NEDA on dimethyl fumarate and had an EDSS of 4.0. She had fatiguable foot drop on the right; after walking for about 20 minutes her right leg would start dragging and her foot would catch on uneven surfaces. Does this symptom sound familiar?

Fatiguable foot drop in MS is very common and indicates that the pyramidal nerve fibre tract or motor pathway, in Mrs P case to the right leg, has lost reserve and is vulnerable to slow degeneration of the sort that is associated with worsening MS or secondary progressive MS.

Towards the end of the consultation, almost in passing, Mrs P told me that during the summer, whilst on holiday she had tripped and twisted her right ankle and had fractured her fibula (one of the long bones in the lower leg that helps support the ankle). Fortunately, the fracture was mild and not unstable and she was managed with a soft foot splint. Although the fracture had healed her foot was still swollen and stiff. Interestingly, she had not been referred to physiotherapy for an exercise programme to advise her on a sensible rehabilitation programme. I said it was never too late to start rehabilitation.

As a reader of this blog, you must be aware that pwMS are at increased risk of falls and fractures, which is one of the most common causes of unscheduled or emergency hospital admissions for pwMS. A fractured neck of femur or femur is one of the reasons why pwMS end-up in a wheelchair and never mobilise again.

In a Barts-MS audit Dr Ruh several years ago we showed that the best predictor of falls was the need or potential need for a walking aid, i.e. a foot splint, a foot-up, FES device (functional electric nerve stimulator), walking stick or sticks, walking frame etc.

Another issue that is closely related to falls is bone health. PwMS are more likely to have thin bones (osteopaenia) and osteoporosis for multiple reasons, which also increases the risk of fractures, which is why we recommend bone density or DEXA scans in all of our patients at risk of falls. In addition, to a bone health screen, we try and get these vulnerable patients into a falls prevention clinic. The latter doesn’t always work as there is a shortage of physiotherapists in the NHS and the wait for falls clinics can be many months.

We tried to address this problem by setting up a group falls prevention clinic a few years ago, but because of a lack of funding and a shortage of physiotherapy time within our NHS trust, we couldn’t make the clinic sustainable. This is a great pity as every year several patients under my care, such as Mrs P, fall and have fractures, which impacts on their quality of life and their MS. I often ask how many of these predictable fractures could have been prevented?

The study below shows that you can use technology, i.e. sensors to detect falls. A system like this could be embedded into a well-designed self-management or self-prevention application to tackle falls prevention and bone health at a population level. This is yet another example of technology showing great potential to improve preventive medicine, but as usual, there is no clear path on how to incorporate this type of innovation into routine clinical care. This is why my recent post on rethinking healthcare is so timely. As a MS HCP, I want an easy and well-oiled or frictionless system for testing these type of innovations in the NHS. Is that too much to ask for?

Do you use, or potentially need, a walking aid? Have you had any falls or near falls (trips)? If yes, you need to have the state of your bone health assessed and referred to a falls prevention clinic. Believe me when I say bone fractures are unpleasant; they are. I am typing this post supine with a painful fractured pelvis and a fractured cervical spine and a foggy head from the analgesics I am on to manage my pain. Although fractures heal they can leave behind residual deficits that could impact on your quality of life.

If any of you are having falls and have been on a falls prevention programme please feel free to share your experience.

Mosquera-Lopez et al. Automated Detection of Real-World Falls: Modeled from People with Multiple Sclerosis. J Biomed Health Inform. 2020 Nov 27;PP. doi: 10.1109/JBHI.2020.3041035.

Falls are a major health problem with one in three people over the age of 65 falling each year, oftentimes causing hip fractures, disability, reduced mobility, hospitalization and death. A major limitation in fall detection algorithm development is an absence of real-world falls data. Fall detection algorithms are typically trained on simulated fall data that contain a well-balanced number of examples of falls and activities of daily living. However, real-world falls occur infrequently, making them difficult to capture and causing severe data imbalance. People with multiple sclerosis (MS) fall frequently, and their risk of falling increases with disease progression. Because of their high fall incidence, people with MS provide an ideal model for studying falls. This paper describes the development of a context-aware fall detection system based on inertial sensors and time of flight sensors that is robust to imbalance, which is trained and evaluated on real-world falls in people with MS. The algorithm uses an auto-encoder that detects fall candidates using reconstruction error of accelerometer signals followed by a hyper-ensemble of balanced random forests trained using both acceleration and movement features. On a clinical dataset obtained from 25 people with MS monitored over eight weeks during free-living conditions, 54 falls were observed and our system achieved a sensitivity of 92.14%, and false-positive rate of 0.65 false alarms per day.

CoI: multiple

Twitter: @gavinGiovannoni

Medium: @gavin_24211

Teriflunomide’s secrets

Barts-MS rose-tinted-odometer: ★★★★★

What should be our therapeutic target in MS? Reducing relapses and MRI activity, NEDA (no evident disease activity) or saving the end-organ (brain volume loss)?

I have been pushing the for the latter, i.e. the most important treatment target must be protecting the end-organ and saving or protecting as many neurons, axons and synapses as possible in people with MS (pwMS) so that can age normally and live as near normal life as possible. To achieve this we need to diagnose and treat MS as effectively as possible (Time is Brain) and to promote a brain-healthy lifestyle and to treat MS holistically (minimal gains hypothesis).

This principle of protecting the end-organ is not new and was probably first promulgated by the kidney doctors in relation to loss of kidney function in chronic kidney disease; every nephron (the kidney’s equivalent of a neuron) is sacred. Every neuron is sacred! The difference between kidney doctors and neurologists is that they can always put their patients on dialysis and offer them kidney transplants. We, neurologists, don’t have that luxury and what awaits our patients with progressive loss of end-organ (brain atrophy) is unemployment, worsening cognitive impairment and physical disabilities and the consequences (bladder, bowel, falls, walking aids, wheelchairs, dementia, etc).

What is interesting is that not all DMTs are made equal when it comes to protecting the end-organ. At the top of the rankings are HSCT and alemtuzumab followed by natalizumab and then there are the also-rans. What is interesting is the impact on brain volume loss is not necessarily linked to the DMTs ability to switch of focal lesions (relapses and MRI activity). A good example of this is teriflunomide, which has only a modest effect on relapses (~35% reduction in relapse rate) compared to say anti-CD20 therapies, which after 6 months of treatment almost completely stop relapses and MRI activity, but these two classes of therapy have a similar impact on slowing down brain volume loss.

Teriflunomide is clearly doing something at the level of the end-organ that anti-CD20 therapies are not. This study below in subjects with CIS shows that teriflunomide works very well, on the end-organ, even early on in the disease, but not all subjects are responders. This begs the question; what is it about teriflunomide’s mode of action that explains its remarkable effects on brain atrophy? I have hypothesised in the past about teriflunomide’s broad-spectrum anti-viral effects and have proposed doing the iTeri study, i.e. using an anti-CD20 or other depleting DMT as true induction therapy and then using teriflunomide (or another DHODH inhibitor) as the maintenance therapy. The hypothesis is to allow peripheral B-cell reconstitution or recovery to occur in the presence of anti-EBV agents, which will prevent EBV-infected autoreactive (MS causing) B-cells returning. The problem we are having with the iTeri study is trial design; i.e. how do you design a trial that will convince the regulators of its efficacy and get the drug licensed as a maintenance therapy? Would the regulators accept non-inferiority or safety design? Another reason for this study design is to derisk anti-CD20 therapies. The doubting Thomas in me is saying there is no way someone with MS can stay on an anti-CD20 therapy indefinitely.

Maybe I am wrong, but let’s not stick our heads in the sand. Relapses and focal MRI activity are not MS. The real MS is smouldering MS and all the processes that cause accelerated brain volume loss. Let’s focus on smouldering MS and ask questions about what needs to be done to tackle these processes. What is ot about HSCT, alemtuzumab, natalizumab and possible teriflunomide that differentiates the DMTs into two classes. For example, could it be the T-cell?

Zivadinov et al. Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS. Ther Adv Neurol Disord. 2020 Nov 11;13:1756286420970754.

Background: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS).

Methods: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2.

Results: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy versus placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; p = 0.0359) and 28.6% (WB; p = 0.0286); month 24, 40.2% (CGM; p = 0.0416) and 43.0% (WB; p < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (p = 0.0004) and 47.3% (p < 0.0001) during years 1-2, respectively, and 6.6% (p = 0.0570) and 35.9% (p = 0.0250) during years 1-5. In patients with the least (bottom quartile) versus most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; p = 0.0024) and 58% (WB; p = 0.0028) during years 1-2, and 42% (CGM; p = 0.0138) and 29% (WB; p = 0.1912) during years 1-5.

Conclusion: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.

If you enjoy reading this blog you may want to support Prof G’s challenge

After his recent accident in which he sustained a broken pelvis and cervical spine, he has set himself a rehab challenge to walk 5 km unsupported by the end of the year (‘Prof G’s bed to 5km Challenge’). He is raising money for Queen Mary University of London to support Dr Ruth Dobson and Dr Angray Kang’s COVID-19 MS Antibody Study. So please donate if you can, every little helps and will get this study completed on time.

CoI: multiple

Twitter: @gavinGiovannoni

Medium: @gavin_24211

Progressive multiple sclerosis is a misnomer

Barts-MS rose-tinted-odometer: ★

In my opinion, the term ‘progressive multiple sclerosis’ is a misnomer. In general, progression means improvement, which is one of the reasons I prefer the term ‘late-stage MS’, which not only differentiates the terminologies but captures the associated disability that comes with this phase of the disease.

It is important to stress that the pathologies that drive neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘late-stage MS’) are there from the earliest stages of MS; even when people have asymptomatic MS. This means the neurodegenerative phase of MS is present prior to pwMS becoming 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.

One could argue that this has been good for MS in that it has attracted a lot of Pharma investment and has supercharged drug development in MS. However, MS as three or four disease entities is now slowing down drug development and making it very expensive. We need more affordable DMTs for late-stage MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for late-stage MS need to be priced lower than those licensed for earlier or 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 late-stage MS populations simultaneously.

Slay the dogma that more late-stage MS has reduced inflammation or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a big part in driving late-stage MS. Therefore not to target more late-stage 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, i.e. surviving and functioning axons, 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 arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0).

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 late-stage 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 late-stage MS. I am 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, which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.

We need to ditch the EDSS. The whole community knows that the EDSS is not fit for purpose in more late-stage MS. We need to get the regulators to accept this. We also need to use 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 PROMS in the battery, in particular, ones that capture hand-and-arm function, cognition and quality of life.

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 necessarily like adaptive designs nor do the regulators. I do think we do need two phases to trials in more late-stage 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 late-stage 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.

Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and we even wrote 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, newer outcome measures and combination therapy approach.

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 health economic data that the costs associated with managing MS increase as disability advances.

We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing as a result of reduced brain and cognitive reserve underpins 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 late-stage 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 us 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.

As you can see we are passionate about tackling more late-stage MS. 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 a serious debate about these issues and get on with the job of protecting cognition, arm, hand and bulbar function in people with more late-stage MS. The good news is that we now have licensed therapies for both primary and secondary progressive disease that can act as the platform on which to build our pyramid and to tackle MS holistically to improve longterm outcomes.

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
Twitter: @gavinGiovannoni Medium: @gavin_24211

Swiss Neurologists Challenge Lublin

Barts-MS rose-tinted-odometer: ★

I have just been chastised by someone from a Swiss Pharma company for suggesting that siponimod is a cul-de-sac DMT. Why can’t someone who is diagnosed and labelled as having SPMS who is started on siponimod be switched to any other DMT? I agree, but the absurdity of the situation arises because of the rigidity of the Lublin classification of MS (see below) and the salami-slicing of MS into multiple disease entities.

The cul-de-sac is based on the assumption that once you have progressive MS, either primary progressive or secondary progressive MS, you can’t become unprogressive and be subsequently re-diagnosed as having relapsing-remitting MS. This is explicit in the Lublin classification system that defines the clinical course of MS. According to Lublin progressive MS is a one-way street.

The reason we find ourselves in this ridiculous situation is that MS was salami-sliced up into three and four diseases in the 1990s to allow interferon-beta to get licensed under the US Orphan Drug Act. The Orphan Drug Act states that to be an orphan disease there have to be fewer than 200,000 US citizens with the disease. There are clearly more than 200,000 people with MS in the US, but there were less than 200,000 people with relapsing-remitting MS, secondary progressive MS or primary progressive MS in the 1990s. Subsequently, a fourth category was added to the classification system of clinically-isolated syndrome (CIS). Fortunately, CIS is gradually disappearing as the McDonald criteria are gradually nibbling away at this pseudo-category of MS.

Few people are aware of the history of MS becoming four diseases, but the consequences of this to the field have been enormous. For one it means that Pharma has had to do trials in all four ‘pseudo-MS disease states’ at great expense to the field. It has had major psychological effects on people with the disease. When you tell people they have SPMS it is like telling them they have a second disease that until recently was unmodifiable.

The other consequence of MS being three or four diseases is that once you have been diagnosed as having SPMS we are mandated under NHS England guidelines to stop DMTs. This is why most neurologists in the UK avoid labelling their patients as having SPMS.

The Lublin classification system is based on a clinico-radiological worldview of MS and is not underpinned by biology. If you take a biological worldview of MS, which is the correct philosophy based on our current thinking of what constitutes a disease, then MS is one disease and not three or four diseases.

Interestingly, I have been asked by the CONY Virtual Conference organisers to give a keynote plenary lecture on this exact topic, which I recorded yesterday.

The good news is that this Pharma Executive tells me that the Swiss Neurologists have decided that the Lublin classification system is incorrect and that according to the Swiss it will be fine to reverse out of the secondary-progressive cul de sac and to relabel their patients as having relapsing MS and to be able to switch their patients from siponimod to ofatumumab once it is licensed in Switzerland. I sincerely hope the Swiss neurologists publish their new classification system of MS, or MS roadmap, as the Lublin one is out-of-date. More importantly, will the Swiss neurologists be prepared to convince the NHS of their wisdom?

Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014 Jul 15;83(3):278-86.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Anti-CD20 Derisk Study

Barts-MS rose-tinted-odometer: ★★★★★

Did you watch the anti-CD20 debate on the triMS-online platform yesterday? The question that was asked was ‘Can we use anti-CD20 therapies as immune reconstitution therapies rather than maintenance therapies?’. I am not sure the debaters answered the question.

When I asked Anders Svenningsson, who is probably the world’s biggest adopter of anti-CD20 therapy as a treatment for MS, whether or not someone with MS could stay on anti-CD20 for life, he hesitated before saying ‘YES and NO’. His reason? SAFETY. He described things they were doing to try and reduce the risk of hypogammaglobulinaemia and infections in their patients on longterm anti-CD20 therapy. I am not sure it will work. Interestingly, he suggested stopping anti-CD20 therapy when pwMS get to 55-60 years of age when the risks of treatment outweigh the benefits. In other words, Anders Svenningsson is saying we can’t leave pwMS on anti-CD20 lifelong.

I have been making this exact point on this blog for several years and that is why I have proposed the ADIOS and iTeri studies as ways to derisk long-term anti-CD20 therapies. However, I have been thinking are there any other DMTs we could use after anti-CD20 that would potentially work to derisk the hypogammaglobulinaemia and tackle the cause of MS. I suspect yes. Fumarates, as monotherapy, or in combination with a neuroprotective therapy, also makes sense. The difficulty is what will be the primary outcome of such a trial and how would you do power calculations?

Maybe we could use a non-inferiority design and make safety the primary outcome. Would regulators buy that in addition to non-inferiority as a secondary outcome?

There are not many companies who have the resources, motivation and know-how to do such a study. Roche-Genentech and Novartis would not as this would eat into their franchise. In my opinion, the only company with big enough bollocks and know-how to take this on would be Biogen. Would they be interested?

This is potentially an opportunity for them to come up with a new combination pill of one of their fumarate formulations with an add-on neuroprotective. DMF will maintain MS in remission post-anti-CD20 and the neuroprotective will tackle smouldering MS, which is something anti-CD20 therapies don’t do. A fumarate-neuroprotection combination may actually not only show improved safety but superiority on end-organ damage markers (brain volume loss etc.).

The hypothesis is that if B-cells and in particular memory B-cells are driving MS then starting DMF for example before memory B-cell reconstitution occurs may actually make MS more responsive to fumarates. Add in a combination, to generate new intellectual property (Biogen need this as their fumarate patents are being challenged) and you have a new DMT.

If successful this new combination pill will probably become the most prescribed DMT in MS. Why? To quote Anders Svenningsson you can’t really remain on anti-CD20 lifelong so if you have to derisk an anti-CD20 at some stage. So why not do it before you develop hypogammaglobulinaemia? As more than 50% of MS patients will be treated with anti-CD20 therapy in the near future this combination therapy could potentially capture more than 50% of the market.

If you are on an anti-CD20 therapy (ocrelizumab, rituximab or ofatumumab) would you volunteer to participate in the DERISK study below?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Are you a super-responder?

Barts-MS rose-tinted-odometer: ★★

For every DMT there are patients who respond and there are those who don’t respond. Trying to predict who will be a responder and non-responder is not possible upfront. This is why we talk in averages, i.e. what happens to populations of patients and extrapolate backwards to the individual. If only we have individualised or personalised prediction tools.

The study below shows a cohort of glatiramer acetate super-responders who are doing as well a group of patients on fingolimod when it comes to the end-organ, i.e. losing brain volume loss. Could you imagine a world when we didn’t have to gamble with time and we could select the treatment that will do the job we want it to in terms of protecting your brain for when you get older?

In my talk at the MSVirtual2020 meeting this year I try and communicate these concepts using an actuarial approach. Is it understandable? As it is your brain what have you done?

<iframe width="560" height="315" src="https://www.youtube.com/embed/owhRLn3XwCs" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture" allowfullscreen></iframe>

Honce et al. Brain Atrophy Rates for Stable Multiple Sclerosis Patients on Long-Term Fingolimod versus Glatiramer Acetate. Frontiers in Neurology 2020 Sep 23;11:1045.

Background: Clinically stable multiple sclerosis (MS) patients on long-term therapy often have negligible acute inflammation on MRI. Brain atrophy may provide insight into subclinical disease progression in such populations. Objective: This study aims to compare brain atrophy for age- and gender-matched MS patients treated for >2 years with fingolimod (FTY) or glatiramer acetate (GA), examining brain volume, cognition, and patient-reported outcomes (PROs).

Methods: Stable relapsing-MS patients, age 18-60, on FTY or GA for >2 years were followed up for 2 years. MRI brain and lesion volumes, cognitive measures, and PROs were collected at baseline and annually.

Results: Forty-four FTY and forty-three GA patients completed baseline and year 2 visits. No differences in age, gender, or education were observed. Median EDSS was 2.0GA and 2.5FTY (p = 0.22). Treatment duration was longer for GA, 6.50GA vs. 3.73FTY years (p < 0.001). Baseline geometric mean T2LV were different, GA = 1,009.29 cm3 vs. FTY = 2,404.67 cm3 (p = 0.0071). Baseline brain volumes were similar, GA = 1,508 cm3 vs. FTY = 1,489 cm3 (p = 0.2381). Annualized atrophy rates, adjusted for baseline and at mean baseline value, were GA = -0.2775% vs. FTY = -0.2967% (p = 0.7979). No differences in cognitive measures or PROs were observed.

Conclusions: Stable MS patients on long-term treatment with FTY and GA have similar brain volume loss rates. Differences in baseline disease severity may suggest patients with more aggressive disease treated with FTY may achieve similar brain volume loss rates as patients with milder baseline disease on GA.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#BlackSwan: anecdotal evidence we can’t ignore

Barts-MS rose-tinted-odometer: ★★★★★

What is a black swan event?

“The black swan theory or theory of black swan events is a metaphor that describes an event that comes as a surprise, has a major effect, and is often inappropriately rationalised after the fact with the benefit of hindsight”. (Source Wikipedia)

The case study below is another example of a mounting number of case studies of patients with MS being treated with antivirals, with activity against EBV, doing well. We now need to do properly powered randomised controlled trials to test the EBV causation of MS hypothesis definitively.

Prof. Julian Gold and I launched the Charcot Project in 2012 to investigate the viral aeitology of MS. We tried on numerous occasions to get trials funded to test this hypothesis and have failed. We managed to test one anti-retroviral in a small proof-of-concept study, which was negative. Since then we have managed to get funding to see if famciclovir is capable of suppressing EBV shedding in the saliva. This study should have been completed by now, but we had to delay its start because of the COVID-19 pandemic.

We have also managed to show that teriflunomide is anti-EBV in that it reduces EBV viral shedding in the saliva of people with MS. I suspect this is a very relevant an important observation and underpins the iTeri study, i.e. to use a B-cell depleting agent as induction therapy and teriflunomide or related compound as a maintenance therapy to prevent EBV reinfecting B-cells during the B-cell reconstitution phase.

Life is short and I started working on EBV as a cause of MS way back in 2005 and feel like I am treading water. The evidence that EBV is the cause of MS is so overwhelming that we really can’t afford to ignore it any longer. What we need is a substantial investment from the major funding agencies, MS charities, wealthy philanthropists and Pharmaceutical companies with antiviral drugs in their portfolio to prove (or disprove) that EBV is the cause of MS.

When you apply Bradford-Hill’s causation theory to EBV being the cause of MS there is only one criterion out of nine that still needs to be ticked and that is experimental evidence. What we need are therapeutic interventional trials targeting EBV to complete the proof.

Torkildsen et al. Tenofovir as a treatment option for multiple sclerosis. Mult Scler Relat Disord 2020 Oct 7;46:102569. doi: 10.1016/j.msard.2020.102569.

Some antiretroviral medications are also inhibitors of EBV. We describe a patient with highly active MS who was infected with HIV and started HIV-treatment containing tenofovir alafenamide (TAF), a potent inhibitor of EBV lytic reactivation. Her MS was in complete remission during this treatment, and she had new radiological disease activity again after switching to tenofovir disoproxil fumarate, an HIV drug with less potent activity against EBV replication. Based on the recently detected mechanism of TDF and TAF, we suggest that further studies on these drugs in MS are warranted.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#Smouldering-MS: the BTK inhibitor race is on

Barts-MS rose-tinted-odometer: ★★★

Mouse Doctor studied zoology and as a result, he tends to use animal analogies to describe various phenomena. In the past, he has been known to use his favourite invertebrates to describe some neurologists or even groups of neurologists. Why invertebrates? If anyone comes up with the correct answer I will send you an MRI scanner lego set as a prize.

Another animal he loves are lemmings, which he uses to describe the behaviour of pharmaceutical companies, i.e. they tend to follow each other by running off a cliff together. The question on everyone’s mind is how will the BTK (Bruton Tyrosine Kinase) inhibitor MS race turnout; will it be mass suicide with them failing as a class or will they usher in the next generation of innovative MS treatments?

Our interest with BTK inhibitors started about 5 years ago when the Mouse Doctor and I almost managed to get Abbvie to fund an investigator-led study of Ibrutinib in MS. However, it was not to be as Abbvie’s partner Janssen blocked the grant. Janssen was concerned that it was too risky to test Ibrutinib in MS because of the off-target effects of Ibrutinib and its potential for serious adverse events. I suspect they were right as Ibrutinib is a dirty drug and not a very selective BTKi as it also inhibits several other kinases.

Our hypothesis was simple; we wanted a CNS penetrant drug to target B-cells and plasma cells in the CNS of pwMS. We were buoyed by the observation that several people with CNS B-cell lymphomas were having dramatic responses to Ibrutinib. Although it was never to be we continued our search for a CNS penetrant anti-B-cell and anti-plasma cell agent and eventually, we managed to convince Takeda to fund a trial of their CNS penetrant second-generation proteasome inhibitor Ixazomib in MS. This study was meant to start earlier this year and has been unfortunately delayed by COVID-19 (we are now recruiting and are due to start very soon).

Despite our failure to get Ibrutinib, a first-generation BTK-inhibitor, into MS Pharma has taken up the challenge and there are now four companies with BTKi programmes in MS (Merck KGaA, Sanofi-Genzyme, Roche and Biogen).

BTKi’s will work in MS because they inhibit B-cell activation. There is phase 2 data for two of these agents confirming this (Merck and Sanofi-Genzyme). However, most people are not aware that BTKi also inhibits macrophage and microglial activation via the Fc receptor (FcR) signalling pathway. Therefore CNS penetrant BTK inhibitors, which applies to at least three of the four BTKi’s referred to above, will also target the so-called ‘hot’ or activated microglial response and test the hypotheses whether or not this response is favourable in MS.

The problem will be dissecting-out the anti-B-cell response from the anti-microglial response in terms of efficacy. Clearly, this will be important in view of some of the issues I raised yesterday around the ‘hot microglial’ response being potentially beneficial in the pathogenesis of MS. I envisage BTKi being very effective in stopping relapses and focal MRI activity the big question will be about the impact of BTKi on the smouldering component of MS. BTKi’s may have no effect on this component of MS, improve it or even make it worse.

I note that many of the phase 3 studies will be testing BTKi against teriflunomide. Clearly, BTKi’s are likely to beat Teri in terms of their impact on relapses and focal MRI activity, but Pharma (or the lemmings) may be taking a chance of beating Teri in terms of its impact on the end-organ or the smouldering component of MS. Don’t forget ofatumumab and teriflunomide had the same effect on brain volume loss when they were compared head-2-head in the ASCLEPIOS I and ASCLEPIOS II studies despite ofatumumab being clearly superior to teriflunomide in suppressing relapses and focal MRI activity.

It is clear to me that BTK is a very important treatment target in MS and the phase 3 trials will provide additional evidence beyond the B-cell on whether or not we should be targeting macrophage and microglial activation via their Fc-receptors. Whether or not this class of treatments will fail, i.e. fall of the cliff waits for the outcomes of the phase 3 trials.

For once I going to be an optimist and give this new class of treatment a 65% chance of success, mainly due to their anti-B-cell effects, and only a 30% chance of failure, due to their microglial inhibition and yet to be identified off-target effects. What is important is that we are testing a hypothesis about the smouldering component of MS, which I consider to be the real MS and why I am so excited to be part of the story.

CoI: I sit on two BTKi phase-3 trial steering committees.

Twitter: @gavinGiovannoni Medium: @gavin_24211

Smouldering MS: Is 20 years a long time?

Barts-MS rose-tinted-odometer: zero stars or one ★ depending on your disposition

I prepared this post not knowing that Prof. Laura Airas has submitted a guest post in response to a request from the Mouse Doctor. Before reading this post please make sure you read her blog post first. It provides an important counterbalance to my contrarian view below. Thank you.

More than 20 years ago, when I was a junior researcher, doing my PhD, I started a research collaboration with Dr Richard Banati, who worked in the Queen Square Brain Bank and the Imperial College PET imaging unit. Richard was investigating activated microglia in multiple sclerosis. The collaboration was very fruitful and led to the very first study of an imaging molecule called PK11195 that could label activated microglia.

In the study (see below), we elegantly showed that people with MS (pwMS) had widespread microglial activation in their brains. Their brains, in fact, lit up like Christmas trees with so-called ‘hot’ or activated microglia. The assumption, which is now dogma, from this and other studies is that these microglia must be bad for pwMS. This has led to many research and drug discovery programmes to find treatments to switch off hot microglia.

PK11195 labelling hot microglia. From Banati et al.

Now dial forward 20 years and finally, a follow-up study from Finland that shows that pwMS with a lit Christmas tree in their heads do worse in the longterm, i.e. pwMS with more microglial activation as determined by PK11195 staining had more disease progression that was independent of relapses. The implication is that PK11195 is a good marker of smouldering MS and if we switch off this marker we will improve long-term outcomes.

In an email exchange with colleagues, I challenged this thinking. Is the PK11195 signal, or hot microglial response, the chicken or the egg? The microglial response may not be causal but simply associated with a worse outcome in MS. Just maybe the microglia are responding to what is causing MS and are not the primary drivers of the MS pathology. Therefore if you switch off the microglial response you may not improve MS outcomes but actually make them worse.

I even provided some early odds of this happening. I predicted that a drug that switches off the microglial response had only about a 20% chance of improving MS outcomes. I balanced this by saying that I thought that a microglial inhibitor had about a 60% chance of actually making MS worse. I was then challenged that these odds were simply a guess; like an unskilled poker player. I disagree. Firstly, poker is a game of skill and the most skilled poker players make a relatively decent living from their skills. Secondly, there is a scientific process behind making accurate predictions (see post-script), which I try to apply. Finally, we need to apply science to the microglial prediction at hand.

The Science: In the smouldering or slowly expanding MS lesion the hot microglia are lined up like soldiers fighting an enemy at the edge of the lesion. They remind me of a Greek phalanx.

These microglia are not malignant cells, which makes me think they are simply doing their job. Now what if these microglia are responding to something in the surrounding tissue, for example, a slow viral infection? Switching them off may actually make the slow viral infection worse. In addition, microglia have very important function clearing up debris in the nervous system and maintaining the health of synapses and neurons in general.

Figure 1 (from Frischer et al., Ann Neurol 2015): (A, B) Early active plaques (EAL) were defined by macrophages immunoreactive for minor myelin proteins (MOG positive macrophages right insert in A) as well as major myelin proteins (PLP positive macrophages left insert in A). (C, D) Smoldering plaques (also called slowly expanding plaques) typically showed a rather inactive centre with no or few macrophages, surrounded by a rim of activated microglia. Only few of these macrophages or microglia cells contained early myelin degradation products. Inserts depict plaque edge. (E, F) Inactive plaques revealed a sharp plaque border without or only few macrophages or activated microglia (insert). (G, H) Completely remyelinated plaques typically containing few macrophages without early myelin degradation products were classified as shadow plaques. Shadow plaques presented with a sharp plaque edge and were associated with fibrillary gliosis.

More Science: Importantly, defects in the signalling pathway of CSF-1 (colony-stimulating factor 1), which is also known as macrophage colony-stimulating factor (M-CSF), cause progressive dementia and disease of the cerebral white matter called a leukoencephalopathy. CSF-1 is a microglial stimulant. This is a warning that inhibiting microglia indiscriminately is unlikely to be good for the brain and particularly a damaged MS brain. This is why I have given greater odds to a microglial inhibitor making MS worse than making MS better.

I am also aware that there are different types of microglia, different types of microglial responses and hence we may have to be more selective in how we target microglia in MS. Despite this, I think we as an MS community need to take a step back and challenge the current dogma that the microglial response in MS is necessarily bad. If we don’t we may be unpleasantly surprised and disappointed with the outcome of clinical trials targeting hot microglia and smouldering MS.

P.S. If you are interested in reading about the science of prediction I would recommend ‘Superforecasting: The Art and Science of Prediction’ by Dan Gardner and Philip Tetlock; a remarkable book that provides important insights and lessons to avoid unconscious biases and it teaches you a little poker as well 😉

Sucksdorff et al. Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis. Brain, awaa275, https://doi.org/10.1093/brain/awaa275 Published: 02 October 2020.

Overactivation of microglia is associated with most neurodegenerative diseases. In this study we examined whether PET-measurable innate immune cell activation predicts multiple sclerosis disease progression. Activation of microglia/macrophages was measured using the 18-kDa translocator protein (TSPO)-binding radioligand 11C-PK11195 and PET imaging in 69 patients with multiple sclerosis and 18 age- and sex-matched healthy controls. Radioligand binding was evaluated as the distribution volume ratio from dynamic PET images. Conventional MRI and disability measurements using the Expanded Disability Status Scale were performed for patients at baseline and 4.1 ± 1.9 (mean ± standard deviation) years later. Fifty-one (74%) of the patients were free of relapses during the follow-up period. Patients had increased activation of innate immune cells in the normal-appearing white matter and in the thalamus compared to the healthy control group (P = 0.033 and P = 0.003, respectively, Wilcoxon). Forward-type stepwise logistic regression was used to assess the best variables predicting disease progression. Baseline innate immune cell activation in the normal-appearing white matter was a significant predictor of later progression when the entire multiple sclerosis cohort was assessed [odds ratio (OR) = 4.26; P = 0.048]. In the patient subgroup free of relapses there was an association between macrophage/microglia activation in the perilesional normal-appearing white matter and disease progression (OR = 4.57; P = 0.013). None of the conventional MRI parameters measured at baseline associated with later progression. Our results strongly suggest that innate immune cell activation contributes to the diffuse neural damage leading to multiple sclerosis disease progression independent of relapses.

Banati, …., Giovannoni,….et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000 Nov;123 ( Pt 11):2321-37. doi: 10.1093/brain/123.11.2321.

This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Beyond NEDA: protecting the end-organ or your brain

Barts-MS rose-tinted-odometer: zero-★’s

It became clear to me at least 6 years ago that we need to go beyond NEDA (no evident disease activity) when treating MS and we have to focus on protecting the end-organ, i.e. normalising the brain volume loss that occurs in people with MS (pwMS). To do this you really need to diagnose and treat MS as effectively as possible early on. From a research perspective, this means a focus on smouldering MS and the mechanisms responsible for the smouldering disease or the ‘real MS’.

This study below is another study showing a link between brain atrophy and cognitive impairment and supports the therapeutic strategy above. The criticism that is alway levelled at the flipping-the-pyramid argument is that too many pwMS will end up on high-efficacy DMTs and then what? My response to this is that if the majority of pwMS end-up on high-efficacy DMTs eventually is a testament to fact that the majority of pwMS need high-efficacy DMTs and hence it is best to get them there as soon as possible (#TreatMSASAP).

This #TreatMSASAP principle underpins our #AttackMS trial design of using natalizumab ASAP after presentation and is aping the management of stroke.

Another argument about flipping the pyramid is safety, i.e. we are putting pwMS at risk of severe adverse events. Yes, we are, but we can derisk a lot of the anticipated adverse events, i.e. the known-knowns and the unknown-knowns (anticipated AEs based on the mode-of-action of DMTs). In any event it is not for the neurologist or HCP to make the call on risk; surely it is up to the person with the disease to make the call?

The following is a recording of my presentation from ACTRIMS-ECTRIMS 2020 that discusses these issues. Please note the presentation is targeting HCPs, but most pwMS should understand it.

Golan et al. The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis. Brain Cogn 2020 Sep 11;145:105614. doi: 10.1016/j.bandc.2020.105614. Online ahead of print.

Background: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated.

Objective: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS.

Methods: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual-spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software.

Results: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing-remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores.

Conclusion: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

CoI: multiple Twitter: @gavinGiovannoni Medium: @gavin_24211