Progressive MS – EAN 2020

Dr Wallace Brownlee, MS Specialist Neurologist, National Hospital for Neurology and Dr Kate Petheram, Consultant Neurologist, South Tyneside & Sunderland NHS Foundation Trust, discussed highlights from the EAN Conference regarding progressive MS.

Unsuccessful research in progressive MS (0.36)

Kate noted that often this area of research can be rather pessimistic; in this case there were two negative studies reported on at the conference and one positive which she summarised.

Kate gave an overview of the MESEMS study (fi 1) which was not successful in meeting its primary outcomes, although there was a trend towards a reduced relapse rate. Kate noted that it is clear that the treatment could not substitute disease-modifying therapies (DMTs) but could possibly be used as an adjunct treatment to support repair.

Wallace shared the opinion that this study is yet another failed trial to use Mesenchymal Stem Cells (MSC) to treat progressive MS and that perhaps it signals the need to cease this line of exploration. Kate agreed, adding that, whilst ‘safe’, it is an invasive treatment.

Summary findings from the MESEMS study

MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study: results from a multi-center, randomized, double blind, cross-over phase 2 Clinical Trial with autologous Mesenchymal Stem Cells (MSC) for the therapy of Multiple Sclerosis

– 127 patients.
– Aimed to look at safety and efficacy.
– Short trial – 24 weeks.
– No difference in adverse events.
– Didn’t meet primary outcomes for efficacy. No effect on GEL. No statistically significant difference in ARR but a trend towards reduced ARR at 24 weeks.
– Aim was to show biological effect on tissue repair.
– Don’t aim to substitute DMTs – look to be an add on treatment as tissue repair.

Uccelli A, Laroni A, Brundin L, et al. MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis. Trials. 2019;20(1):263. Published 2019 May 9. doi:10.1186/s13063-019-3346-z

Kate also summarised the MS-SPI 2 trial, an effort to replicate a successful phase 3 trial of MS-SPI 1 which took place amongst a small group of patients with non-active progressive MS.

• Unfortunately, examined on a larger scale, the primary aims were not met.
• 12% improvement with high-dose Biotin and 9% with a placebo.
• Wallace shared his disappointment in these results after the SPI1 study had seemed so promising.

Positive outcomes in recent progressive MS research (5.59)

The EXPAND studies have had some positive findings examining the effects of siponimod on reducing grey matter atrophy, something which is linked to the disease progression of MS.

• This particular study (fig 2) found that there was a significant decrease in cortical grey matter atrophy across all subgroups when treated with siponimod rather than a placebo
• 47% in the treatment group compared with 70% in the placebo group.

Both Kate and Wallace expressed positivity over these results, noting that they suggest that siponimod may have more impressive neuro-protective effects than first thought.

Summary findings from the EXPAND study element into grey matter atrophy in MS

Patterns of Grey Matter Atrophy in Patients With MS: A Multivariate Analysis Using Source-Based Morphometry

– CIS patients show grey matter atrophy compared with healthy controls in subcortical and cerebellar networks

– Suggest that cerebellar atrophy is a predictor of worse disability.

– All patients had worsening atrophy no matter what the phenotype was. But interestingly when they looked at the longitudinal data (comparison at 1 year follow up) there was no difference in the patterns of atrophy between patients who remained stable and those who clinically worsened.

– Clinical relevance:
– Further evidence that atrophy occurs early, supporting the early treatment paradigm.
– Perhaps the lack of difference in atrophy at 1 year in those who had worsened and those who hadn’t suggests that isn’t purely the rate of atrophy that drives worsening.

Valsasina P, Meani A, Gobbi C, Zecca C, Rovira A, Montalban X, Kearney H, Ciccarelli O, Matthews L, Palace J, ‘Patterns of grey matter atrophy in patients with MS: a multivariate analysis using source-based morphometry’, ECTRIMS Online Library. Valsasina P. 09/11/19; 278875; P515

Potential remyelination found by EXPAND sub-study (9.06)

Wallace explained that magnetisation transfer ratio (MTR) is a surrogate marker for myelination, and the EXPAND MRI substudy found that siponimod had a significant effect on it.

• Siponimod was found to attenuate the decline of MTR and grey matter.
• The study looked at people who had newly forming lesions over the study and examined the MTR within the lesions.
• They found that siponimod affected the MTR within newly formed lesions, suggesting that suppression of the inflammatory activity may promote remyelination.

Kate highlighted that, if NICE approves siponimod for use in the near future as is hoped, the treatment could be used in those who have been relapsing-remitting but are stopping DMTs due to continued disease progression.

Future developments (11.12)

Kate highlighted an abstract she had seen for a small study which viewed MRIs of expanding lesions in MS as an end-point for a trial. The small study looked at natalizumab and fingolimod in relation to this.

Wallace agreed that expanding lesions are an interesting and novel biomarker which might be linked to progression, and noted that he was interested to see this small study which at present is hypothesis-generating, and is an area to watch.

Kate echoed this, and shared her surprise that natalizumab did better, and noted that further work could be done into this line of investigation by using MRI scans which are already taking place.