Is the term ‘progressive MS’ a misnomer? In general, progression means improvement, not worsening. We have made the case for using the term ‘advanced MS’, which we think captures the disability that comes with the later stages of MS.
The neuroaxonal loss – the underlying element of ‘advanced MS’ – is there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become physically disabled. Do you agree?
MS is one disease and not two or three diseases. As we have said before, the division of MS into several diseases is not backed up by science. This false division of MS into several diseases has become counter-productive to the field of MS. The division of MS into multiple diseases was Pharma-led to get MS defined as an orphan disease. This helped in that it allowed interferon-beta-1b to get a licence based on the results of one pivotal phase 3 study.
Similarly, we believe the division between SPMS and PPMS is false. There are no pathological, genetic, imaging or other data that suggests these are different entities. We, therefore, propose doing trials in both populations simultaneously.
To slay the dogma that more advanced MS has reduced inflammation, or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a part in advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.
Reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we have referred to this as therapeutic-lag. These observations are explained by MS being a length-dependent axonopath. i.e. the longer nerve fibres, (to the legs) are more likely to be affected than shorter fibres, (those to the hands and arms). This means that we will need to focus more on arm-&-hand function as a primary outcome measure in clinical trials, in particular in pwMS who have lost too much function in their lower limbs (EDSS>=6.0).
We need to challenge the current view that once someone has lost lower limb function and is a wheelchair user that their disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in advanced MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign and plans to a trial in wheelchairs users (#Chariot-MS).
I think we also have to accept that we will need to use combination therapies to make a real difference to more advanced MS. I am not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective or remyelination therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms – for example, laquinimod which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.
Is it time to ditch the EDSS. The whole MS community, or almost, knows that the EDSS is not fit for purpose in more advanced MS. We need to get the regulators to accept this. We also need to work on a set of outcome measures that capture the whole impact of MS on someone with 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 patient-related outcome measures in the battery, in particular, a better hand-and-arm function PROM. We are aware that there are several out there and some are in development; these need to be validated and used in clinical trials.
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 don’t like adaptive designs nor do the regulators. We need to include two phases in trials of more advanced MS. For example, the standard head-to-head phase with a robust primary outcome, say the 9-HPT, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more advanced MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).
We also need 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/or blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. We are in the final stages of the PROXIMUS trial and we have learnt a lot in the process. The PROXIMUS trial is an add-on neuroprotective trial in which we add oxcarbazepine, a sodium channel blocker, on top of an existing DMT in subjects with ‘early SPMS’.
We also need to push for political change. We need true incentives for the repurposing of off-patent drugs. We have discussed this on this blog before and have written a paper on the so called ‘Big Pharma Alternative’ in which we propose potential solutions.
Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials. Some of my colleagues think this is a big issue. I don’t. If we do a trial and provide compelling data that a specific drug in combination with another drug delays, or stops, worsening disability in upper limb function in pwMS in wheelchairs they would be obliged to license the combination, provided it was safe. What we need from them, however, is to accept the need for combination therapies. MS is a complex disease and hence will need a complex solution to tackle it, i.e. combination therapies. This is not rocket science and happens all the time in other disease areas, like cancer.
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 recent EU health economic study that costs soar as pwMS lose arm function. Are you surprised? When you lose arm function you lose your independence.
We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing from reduced brain, and cognitive, reserve drives 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 advanced MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.
We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for me to falsely raise their hopes . To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote recovery mechanism (axonal sprouting, synaptogenesis and plasticity) to restore function.
As you can see at Barts0MS we are passionate about tackling more advanced MS. I personally think we have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted above. We need to start a serious debate about these issues and get on with the job of protecting arm and hand function in pwMS.
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.