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.