What needs to be done to tackle 'progressive' or more correctly 'advanced' MS? #ClinicSpeak #ThinkHand #ChariotMS
Summary: This post summarises what needs to be done to tackle more advanced MS including people with MS using wheelchairs. It makes the case for making several changes in the way we study advanced MS. What is needed now is a large injection of money to kick-start a trial in wheelchair users to delay loss of upper limb function. This post is an essential read for anyone who cares about people with more advanced MS.
Earlier this week I had a debate with a colleague about therapeutic targets and whether or not they are achievable. He thought NEDA was a crap target as most of our patients who achieve NEDA still have residual problems. Therein lies the rub. NEDA, or no evident disease activity, refers to evidence of ongoing inflammation. NEDA does not refer to previous damage, nor does it refer to the ongoing consequences of previous damage. You can only do so much with an anti-inflammatory agent, i.e. switch-off inflammation, and even then most anti-inflammatory agents we use don't switch-off innate immunity within the CNS (hot microglia), nor do they purge the nervous system of plasma cells and oligoclonal immunoglobulins. In reality, we can only ask so much of our current DMTs. This is why we need combination therapy strategies.
The following are some points about progressive MS that needs repeating:
- We all need to accept that ‘progressive MS’ is a misnomer. Progression means improvement. At Barts-MS prefer the term ‘advanced MS’ this captures the associated disability that comes with this phase of the disease.
- We need to accept that the pathology that drives neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘advanced MS’) as being there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become 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. It also allowed the company concerned to charge rather a lot of money for its product. Overall this has been good for MS in that it has attracted a lot of Pharma interest and has supercharged drug development in MS, but it is now slowing down drug development and making it very expensive. We need cheaper drugs for advanced MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for advanced MS need to be priced lower than those for 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 populations simultaneously.
- 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 big part in driving advanced MS. Therefore not to target more advanced 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 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 the arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0). This is what we are proposing to do in our CHARIOT study (parenteral cladribine).
- 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 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.
- Accept that we will need to use combination therapies to make a real difference to more advanced MS. We are 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 - for example, laquinimod which targets hot microglia - with a classic anti-inflammatory against targeting adaptive immune mechanisms.
- We need to ditch the EDSS as the primary outcome in advanced MS trials. The whole community 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 the disease. 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, a better hand-and-arm function PROM. We are aware that there are several out there and some are in development, including one from Barts-MS.
- 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 like adaptive designs nor do the regulators. I do think we do need two phases to trials in more advanced 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 advanced 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. We have fully recruited our PROXIMUS trial and we have learned a lot in the process. For those of you new to this blog the PROXIMUS trial was 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’. Labelling eligible subjects as having early SPMS was a mistake. Nobody wants to be told they have SPMS, therefore their clinicians were reluctant to refer patients eligible for the study. My advice to anyone doing trials in this space is to avoid the term progressive.
- Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and have even written 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. Some of my colleagues think this is a big issue; I don’t. If we do a trial and provide compelling data that drug x in combination with drug y 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 for example oncology.
- More detailed cost-effective models that focus on the loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the recent EU cost of MS study that costs soar as pwMS lose arm function.
- We also need to tackle ageing and its impact on worsening MS. The evidence that early, or premature, ageing from the reduced brain, and cognitive, reserve drives worsening of 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, similar to my colleague's expectations. 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 axonal sprouting, synaptogenesis and plasticity mechanisms to restore function. This is not rocket science. If you are coming to ECTRIMS I will be giving a talk on this exaxt topic in a satellite symposium.
As you can see 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 in the points 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.
If there are any wealthy philanthropists out there? DrK (@KlausSchmierer) is looking for a large donation to support his application to the NIHR for the CHARIOT study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded.
|DrK with a smile|
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.
Labels: #ChariotMS, #ClinicSpeak, #ThinkHand, advanced MS, chronic progressive MS, philanthropists, primary progressive, Secondary progression