2017: Reflections on another year in multiple sclerosis

Depending on how you see the world, i.e. through rose-tinted glasses, you may reflect on 2017 as being a landmark year for the field of MS.

Prof G's rose-tinted view of the world!

The following are 10 of my highlights, and a few lowlights, from 2017.

10 MS highlights from 2017 in descending order:

#10 - Length-dependent axonopathy hypothesis: The gradual acceptance of the length-dependent axonopathy hypothesis as a theoretical construct to view and treat MS. At the European Charcot Foundation (ECF) meeting in Baveno in November several senior, and well respected, MSologists mentioned the length-dependent axonopathy hypothesis during their presentations and stated it as fact. This is an indication that the concept is finally being accepted, which is critical for our #ThinkHand campaign. We have a lot planned in 2018 to celebrate and promote hand function in MS. DrK is in the final stages of preparing a grant application to test off-label cladribine in people with advanced MS (wheelchair users). The aim of the study is to assess whether, or not, subcutaneous cladribine can protect upper limb and hand function in advanced MS (Chariot MS Study). We are also lobbying Pharma to do similar trials.  2018 will be a success if we can get a DMT trial off the ground in wheelchair users.

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.

Dubuisson, et al. Disease modification in advanced MS: Focus on upper limb function. Mult Scler. 2017 Dec;23(14):1956-1957.

#9 - #BrainHealth: We now have over 45 international endorsements of the Brain Health Time Matters in MS policy document. The fact that so many international organisations are endorsing the principles in our policy statement means that we are finally getting somewhere about what the aims of MS treatment are in the modern era. I sincerely hope our follow-on activities, including the development of a Brain Health quality improvement tool and patient checklist, also get such a positive response.

Giovannoni et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016 Sep;9 Suppl 1:S5-S48.

#8 - Autologous haematopoietic stem cell transplantation (AHSCT): Submission of a grant to the NHIR (NHS equivalent of the NIH) to compare AHSCT to alemtuzumab in highly active MS. In addition to the grant submission more observational data emerged on the effectiveness of AHSCT in MS. We have had many debates on the Blog about the value of AHSCT as a treatment for MS. The fact that AHSCT is emerging as an accepted treatment option for MS in the UK is clearly an advance. What we need to find out is how effective is AHSCT compared to our other licensed very high efficacy DMTs and its relative safety profile.

Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469.

#7 - RIS: The observation that a proportion of people with radiologically isolated syndromes (asymptomatic MS) present later with primary progressive MS. This tells you that MS is one disease and that if we can diagnose and treat MS in the asymptomatic phase we may be able to delay the onset of PPMS.

Kantarci et al. Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome. Ann Neurol. 2016 Feb;79(2):288-94.

#6 - Plasma Neurofilament levels: A whole body of data emerged in 2017 of the potential utility of peripheral blood neurofilament levels as a biomarker of neuroaxonal damage MS. If this data holds up and can be confirmed it may replace CSF neurofilament analysis. This means phase 2 neuroprotective clinical trials could be done using peripheral blood neurofilament levels. Please watch this space. This is an example of technological innovation changing a field. Politicians should take note; they need to invest and reward innovation. This is not always that obvious in the NHS.

Novakova et al.  Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017 Nov 28;89(22):2230-2237.

#5 - Remyelination: When the second phase 2 study of opicinumab (anti-lingo-1), a remyelination therapy, was reported as being negative my heart sank. Could this be the end of neuro-restorative therapies in MS? However, when Biogen reanalysed the data they discovered a clear signal that a subgroup of study subjects responded to opicinumab. The responder subgroup is identifiable using MRI biomarkers and disease duration. Based on this Biogen have launched a further phase 2b study to look at opicinumab as an add-on therapy in MS. Many other companies would have canned this programme, but not Biogen. This may explain why Biogen has recently been rated as the world’s most innovative pharma company.

Source IdeaPharma

#4 - B cells: The publication of the observation that all effective DMTs seem to have an impact on the peripheral memory B cells. I am aware that this hypothesis is controversial, but at least it is starting a discussion on the central role B cells play in driving MS disease activity. The real question is how does the B-cell hypothesis fit in with other well-established observations about MS; for example the strong HLA association. The latter suggests T-cells must also be involved, but how?

Baker et al. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017 Feb;16:41-50.

Baker et al. Both cladribine and alemtuzumab may affect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 5;4(4):e360.

#3 - Paediatric MS: The reporting of the fingolimod in paediatric MS trial (Paradigms Study). This is the first positive-controlled trial of a DMT in the paediatric space. In summary, fingolimod reduced the annualised relapse rate in children with MS by 82% compared to intramuscular interferon-beta (Avonex). The relapse rate on fingolimod was 0.12 per annum vs. 0.68 on interferon-beta. The relative effectiveness of fingolimod surpassed my expectations and at least gives children with MS and their parents some confidence about the effectiveness of fingolimod (and it is an oral agent). With all the other DMTs we have to extrapolate from adult data, but not with fingolimod. Could this be the end of injectables for paediatric MS? Let's hope the EMA give fingolimod a 1st-line license for treating MS.

#2 - Oral Cladribine: The final licensing of oral cladribine (Mavenclad) as a treatment for relapsing MS. I have been intimately involved with the development of oral cladribine as a treatment of MS since 2002. Oral cladribine is the first selective immune reconstitution therapy (SIRT) and offers many advantages over other IRTs such as alemtuzumab and AHSCT. I think oral cladribine is going to really disrupt the MS space. Hopefully, a licensed formulation of cladribine will have a ‘halo effect’ and give neurologists working in resource-poor environments the confidence to prescribe off-label cladribine to their patients.

Alvarez-Gonzalez et al. Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis. Ann Clin Transl Neurol. 2017 May 17;4(7):506-511.

#1 - PPMS: Licensing of ocrelizumab as the first DMT for people with PPMS. I can’t stress how important this is to people with PPMS and the wider field of MS. The fact that PPMS is now modifiable changes the whole MS space and slays several dogmas that have crept into our psyche. I remain concerned, however, that NICE won’t greenlight the use of ocrelizumab in PPMS in the NHS.

Montalban et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220.

The following are some of my low-lights for 2017:

#4 - #MS-is-1-not-2-or-3-diseases: The failure of Barts-MS to get across the science of MS is being one disease and modifiable at all stages of the disease. At several key meetings in 2017 KoLs (key opinion leaders) were still talking about MS being several diseases. They are still classifying PPMS and SPMS as two different diseases. Then there is the concept that RRMS and SPMS are also different diseases. Help! How can we slay this dogma?

#3 - Diagnostic criteria for MS: I am very disappointed that the McDonald Diagnostic Criteria Committee did not include asymptomatic MS as part of the definition of MS. This means we cannot diagnose presymptomatic MS and hence we can’t treat it. This was an opportunity missed and we will have to now wait another 5-6 years before the next review of the diagnostic criteria occurs. In that time we may have the first positive clinical trials of DMTs in asymptomatic MS and we won’t be able to offer people with RIS (radiologically isolated syndromes) treatment for their MS. In general, Healthcare payers only cover the costs of treatment for a real disease, i.e. as defined by the experts.

Thompson et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2017 Dec 21. pii: S1474-4422(17)30470-2.

#2 - Brain atrophy: In the late-breaking session at ECTRIMS we saw that high-dose biotin had the opposite effect on brain atrophy to what we expected; study subjects treated with biotin had significantly more brain atrophy than study subjects on placebo. The investigators reported this as being a valid treatment effect and that shrinkage of the brain was due to normalisation of pathological enlarged brain volume. If this is the case it means brain atrophy cannot be used as an outcome measure in phase 2 neuroprotective clinical trials. More focus on the grey matter may be a solution.

Carassiti, et al. Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex. Neuropathol Appl Neurobiol. 2017 Apr 18. doi: 10.1111/nan.12405. 

#1 - Laquinimod: The failure of laquinimod to slow down disease progression in RRMS (Concerto Trial) and the failure of laquinimod show an effect on brain atrophy in PPMS (Arpeggio Trial). Laquinimod promised to be the first neuroprotective drug to be licensed in MS but failed to live up to its promise. Let’s hope other neuroprotective drugs emerge as potential add-on therapies for MS. Possibly ibudilast? However, unless ibudilast demonstrates a clinical signal, or a signal on peripheral blood neurofilament levels, over and above its effect on brain atrophy I will remain doubtful of its utility as a neuroprotective therapy in MS.

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