I spent most of last week at the annual Association of British Neurologists (ABN) meeting in Brighton. I chaired two debates, presented 4 posters and was co-presenter on another 2 posters. I also networked and met many young neurologists and saw some old friends.
Debate 1: ‘Was the NICE mandate that pwMS should have annual cognitive assessments appropriate or not?’
There were too few voters to really assess which way this debate went, but the debate generated lively discussions. I concluded that this debate needs a larger audience and should include people with the disease. I wonder if NICE asked MSers their opinion before recommending annual cognitive assessments?
Debate 2: ‘To manage MS properly we need a new MS disease activity score or DAS’
As chairman I set the scene drawing on the experience of rheumatolgists who have been using the RA DAS (disease activity scale) for decades. In RA a DAS score is used as a metric to treat-2-target. The RA-DAS semi-objectively measures how active RA is and allows rheumatologists to assess how effective their DMARDs (disease-modifying antirheumatic drugs) are at controlling RA. The RA-DAS has been instrumental the paradigm of treating-2-target that underpins what we are trying to copy and promote in MS.
I am of the opinion that a new MS-DAS is essential; we need it to get wide adoption of the treat-2-target approach of NEDA. Its development would clearly need careful consideration and multi-stakeholder input if it had any chance of being adopted. I personally would argue for it to include a PROM (patient-related outcome measure). A PROM will at least get the individual with MS engaged with the process of monitoring their own disease activity. The latter aspect may be why the RA-DAS has been so successful as a change agent in the management of RA. As I have said before patient-engagement is a no-brainer and one of the most underused therapeutic interventions we have. A MS-DAS could also be used as a driver of quality. If your neurologist refused to use the MS-DAS you may be tempted to find another neurologist who did. Now wouldn’t that be something worth talking about? I am aware from comments on this blog that some of you have done this already and moved neurologists simply to get annual MRI scans.
Although the posters were up for most of the meeting we had just over an hour to stand by the posters to field questions from the attendees. This caused me problems although I had three posters in a row the fourth poster was in another location so I had to split my time between the two locations. It was a pity because the data in all my posters was worth talking about. The isolated poster showed that disability improvement on alemtuzumab occurs across most functional systems of the EDSS and is not simply limited to one functional system. On reflections isn’t amazing that with the more effective DMTs we can now expect disability improvement? Interestingly, we are seeing disability improvement occurring in years 3 and 4 and not just in year 1 and 2 post-alemtuzumab. This challenges the dogma about recovery mechanisms in the central nervous system and finally buries the dogma that the EDSS progression is a one-way street. Disability improvement, or the promise of disability improvement, is in itself proof of how far we have come with the treatment of MS. For the cynics and nihilists out there ‘eat your hat’.
Another ground-shifting poster was the ORATORIO study results (ocrelizumab in PPMS). This study is the first study to show a DMT slowing the rate of disability progression in PPMS. This is has to be one of the most significant things to happen in the field of MS in the last 10 years. Despite this I am concerned that NICE may not view ocrelizumab as a treatment for PPMS very favourably. NICE always assesses cost-effectiveness using an incremental cost model. For PPMS the cost-effectiveness of ocrelizumab will be compared to what is out there already, i.e. best supportive care. The latter will cause problems because ocrelizumab will presumably be licensed for RRMS where the comparison will be with existing DMTs that are high-cost. So the cost per QALY for treating RRMS will command a higher price than that for PPMS. Will this be the opportunity for NICE to demand differential pricing? Will the NHS pay less for ocrelizumab in PPMS compared to RRMS? Differential pricing of this nature is called value-based pricing whereby healthcare payers pay for what they get. In reality this is the system that airlines use for booking flights and what Uber use in the APP with surge pricing. Why shouldn’t we bring value-based, or surge, pricing to the field of MS? Comments; I am particularly interested to hear Pharma’s perspective on this.
I also presented two posters on daclizumab. One was on NEDA rates in the phase 3 study and the other the effectiveness of daclizumab in study subjects in the extension study of the phase 2b, SELECT-SELECTION, study, appropriately called the SELECTED study. Please note that although I sat on the steering committee of the SELECT and SELECTION studies I had nothing to do with their names. There is a whole field dedicated to the naming of clinical trials; if you get the acronym right the study develops a life of its own. Not unexpectedly in the phase 3 ??? study the chances of NEDA were higher on daclizumab than interferon-beta. In the extension, or SELECTED, study the relapse rate appeared to continue to go down, hinting that the efficacy of daclizumab may increase with time. We actually saw the evidence for the ramping up of efficacy in the original SELECT study on MRI. Despite the daclizumab efficacy data, I spent most of my time at the daclizumab posters enthusing over daclizumab’s mode of action or MOA. Dac’s MOA challenges the core immunological dogma around the pathogenesis of MS. As I have said many times before daclizumab is not an immunosuppressive drug and it works by subtly changing the IL2 (interleukin 2) signaling pathways diverting IL2 away from activated T cells and T-reg cells towards the CD56-bright NK cell population. The expansion of this latter cell population seems to be closely linked to Dac’s efficacy. What is more the number of T-reg cells go down; this contrary to what we have been told by immunologists that MS is a immune mediated disease that is linked to abnormally regulated T-cells. An interesting discussion will be where Dac fits into the current treatment paradigm; I have thoughts on this but this will be a discussion for another time.
My ABN highlight:
The real highlight of the meeting was Prof. Compston’s ABN gold medal acceptance speech. It was about his medical life from the time he entered medical school up until the present and his current retirement plans writing historical books. He summarised his career as a neurologist covering his research into the genetics and treatment of MS, his time as an editor of Brain (one of the premier neurology journals, or argubly the premier neurology journal) and his legacy – a large number of his trainees now head-up neurology departments across the UK. He voice broke a few times during his talk as it was clearly very emotional speech. Getting to an end of such a glittering career and reflecting on it must be very nostalgic. I personally find nostalgia one of the most powerful of emotions; it is not necessarily a sad, or happy, emotion, but it somehow brings tears to my eyes. At the end of the talk he was given a standing ovation; the first time I have experienced this at an ABN gold medal ceremony.
Some reflections after the meeting:
Many times we the community are criticised for not making progress in MS research. The problem is we tend to look at what happens from year to year. When you look at it from Professor Compston’s perspective and take a 40-year view of the field you realise that so much has changed. It is simply quite incredible what has happened to MS in the last 40 years. We now have treatments that render MSers with NEDA, i.e. putting some of them into long-term remission with the promise of a cure in a proportion of them. With ocrelizumab we now have a DMT that has been shown to be effective in PPMS. We have refined our diagnostic criteria and are better at excluding MS mimics from being inappropriately diagnosed as having MS. We know so much more about the causal pathway of MS and are beginning to use this knowledge to discuss and design MS prevention studies. Are there really some humbugs out there who still think we have made so little progress in MS research? If there are I suggest they take a 40 year helicopter view of the field rather than a very short-sighted one, or two, year view of the field. Another option who be to spend an afternoon discussing MS research with Professor Compston.