Summary: This post makes a case for a new treatment philosophy at Barts-MS based on the principle that “It’s never too early, nor too late, to treat MS”. The post also describes the influence of the London Underground, or tube, on our thinking about MS. This post is longer than usual and no summary can do it justice so please take the time to read it in full. Thank you.
What has the tube, or London Underground, have to do with MS? My rendition of London Underground map to explain the MS journey should come to mind. I was recently told that my published, earlier, version has achieved iconic status as it is frequently used by other people in their presentations. It is a pity because things have moved on since I created the published version. Firstly, it depicts MS as a one-way journey that starts in the at-risk period and terminates in death valley. Another negative is that it is an all or nothing picture; it is not layered, it is not subtle. You may have noticed that I often show the MS tube map with a cut onion; if you peel an onion too fast it is going to make you cry. My ultimate aim is to produce a fold-out MS tube map that will allow you to unfold the journey one segment at a time. In this way, you can look at one part of the MS journey at a time. Secondly, my latest version of the map has become very dense with many additional lines and one line that is still under construction. This under construction line, or the dotted grey line, is the one that leads to long-term remission, a cure and normal ageing. It is under construction because the data is yet to emerge showing we can cure MS. I added this line to give people with MS hope and to make the point that the journey is not necessarily a one-way journey. Other add-ons to the map that I am particularly proud of include the co-morbidity, lifestyle and wellness lines. These illustrate the importance of managing MS holistically. Despite its limitations and criticisms, I maintain that the MS tube map creates a framework for laying out what MS is for people with the disease. Healthcare professionals can also use the map as a reference point to help them pigeonhole their knowledge and for explaining MS to their patients.
What about the criticisms? The cynics, and trolls, never miss an opportunity to take a punt at me and say that I created the MS tube map on behalf of Pharma to promote the prescribing of DMTs. The truth is that Pharma has never had a say in its content. The only reasons DMTs are a large part of the map is because there has been an explosion in the number of DMTs available to treat MS and with this, the complexity of treating MS has increased.
Please note the MS tube map will never be complete. It needs to evolve and improve. So if you have any ideas about improving it please drop me an email (email@example.com).
The real reason for penning this post is that DrK and I had a discussion on the tube last night about MS (yes, DrK and I are typical Londoners – we commute to and from work on the underground). Our discussion revolved around the observation that we as a group at Barts-MS are pushing two messages that may seem incongruent. (1) To treat early to prevent damage from occurring in the first place, but also (2) to treat late as there is always some neurological function to preserve. This led us to come up with a new slogan:
What do we mean by this? It is clear that people with active MS do better with early access to treatment compared to delayed access to treatment. Similarly, people with MS treated with highly-effective treatments early (rapid-escalation or flipping the pyramid) do better than those who are started on less effective treatments first and escalated if necessary to highly effective therapies later (slow stepwise approach). However, even the former approach may not be early enough. We know that a significant number of people presenting with clinically isolated syndromes (CIS) already have substantial damage. Therefore we really need to define early, as being even earlier, and try and identify people in the asymptomatic phase of the disease, or in the at-risk period of MS, and treat them to prevent them getting MS in the first place. I am also very keen that we expand the diagnostic criteria of MS to include RIS (radiologically isolated syndrome) as part of the treatable MS spectrum. Approximately, 25% of RIS patients already have significant cognitive impairment. Why would we not want to treat these patients and prevent further damage?
It is never too late. At the moment all the trials that have led to licensed DMTs have excluded patients who are wheelchair users. The consequences of this are that many international guidelines, including NHS England guidelines, require us to stop DMTs once a patient reaches EDSS 7.0. We know this is wrong. We have emerging evidence that treatments still work in more advanced MS and slow down the progression of the disease in neuronal systems that still have reserve capacity, for example, the arms, speech and swallowing. Our #ThinkHand campaign’s main aim is to raise awareness about this issue and to get the MS community to take the preservation of upper limb function seriously. What we need is class 1 evidence (randomised-controlled trials) of the effect of DMTs on upper limb function in people with more advanced MS. This is why we are trying to get funding in place for our CHARIOT-MS study. The CHARIOT-MS study will tell us if subcutaneous cladribine, given to patients with more advanced MS (EDSS 6.0 to 8.0), will delay the inevitable loss of function of the upper limbs. Please note that Pharma has no interest in funding this trial; the liquid formulation of cladribine is generic and hence there is no financial incentive in place for them to do this trial. You may ask what about Mavenclad, the licensed oral formulation of cladribine? Unfortunately, the patent life on the oral formulation is too short; by the time a study in more advanced MS is done Mavenclad is likely to be generic.
In parallel to the CHARIOT-MS trial, we will continue to lobby Pharma. In my opinion, the four best agents, apart from Mavenclad, to test in more advanced MS are natalizumab, alemtuzumab, ocrelizumab and ofatumumab. Please note these are all high efficacy therapies. Insights that have led us to design the CHARIOT-MS study come from the ASCEND (natalizumab in SPMS) and ORATORIO (ocrelizumab in PPMS) trials. These studies indicate that we probably need a high efficacy therapy to make a difference in advanced MS. We are aware that Genzyme is developing a follow-on anti-CD52 monoclonal to replace alemtuzumab and Novartis have ofatumumab in phase 3 trials in RRMS. Therefore, which of the big guns, Genzyme, Biogen, Roche or Novartis are prepared to be bold and take-up the challenge of testing their drugs in more advanced MS? If anyone from one of these companies is reading this post can you please forward our message to the decision-makers in your companies?
Life tends to reward the bold, the risk-takers, and people who care. Which one of you cares enough about MS to take-up the challenge? The rewards of doing a study of this nature go way beyond economics. Can you imagine what the MS community will say about you as a company if you challenge the current dogma that ‘advanced MS is not modifiable’? One of the reasons for inviting so many company people as co-authors on our length-dependent axonopathy paper was to try and catalyse a change of thinking within your companies. We sincerely hope this is happening.
A softer and possibly easier option is to dig deep into your pockets and to make a large donation to DrK’s (@KlausSchmierer) CHARIOT-MS project. DrK 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.