Author Of 1 Presentation
LB01.02 - Phase 2 clinical trial evidence that a retinoid-X receptor agonist promotes remyelination in people with relapsing-remitting multiple sclerosis
Retinoid acid X receptor [RXR] gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination following experimental demyelination.
To assess the safety and efficacy of bexarotene, a non-specific RXR agonist licensed for cutaneous T-cell lymphoma, as a remyelinating therapy in people with relapsing remitting multiple sclerosis.
In a double-blind, placebo-controlled, phase 2a trial (Cambridge Centre for Myelin Repair: CCMR-One), participants aged 18-50 years with relapsing remitting multiple sclerosis, stable on dimethyl fumarate for at least 6 months, were randomised to bexarotene 300mg/m2 or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions whose baseline MTR was below the median lesional MTR for that patient. The secondary efficacy outcome was change in full-field visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy (baseline latency >118ms). We analysed by intention to treat.
52 patients were randomised 1:1 to receive six months of bexarotene or placebo. Two placebo patients withdrew before receiving study drug and one bexarotene patient withdrew consent during the trial. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]) and hypertriglyceridaemia (24 [92%, mean maximum of 6.79 mmol/L ,SD 4.4]; as well as rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo because of adverse events and five discontinued bexarotene because of rash , neutropenia, triglyceridaemia and mood disturbance. The primary efficacy outcome was negative (mean submedian lesion MTR change was 0.25pu in the bexarotene group versus 0.09pu in the placebo group, p=0.54), but in an exploratory, lesion-level analysis, though treatment difference in submedian lesions was too small to achieve significance, it was statistically significantly greater than in supermedian lesions (p=0·007). This suggests that bexarotene has a biological effect on MTR and that this effect is dependent on baseline lesional MTR. This interpretation is supported by the finding that bexarotene treatment reduced full field visual evoked potential latency compared to placebo in the 52 eyes with delayed VEPS at baseline, by 4·66 ms/eye (95% CI -8·38 -0·93; p=0·014) and in all eyes, by a per-protocol analysis, by 4.02ms/eye (P=0.015).
Despite a negative primary efficacy outcome, evidence from both magnetisation transfer ratio imaging and visual evoked potentials suggest that a retinoic X receptor agonist, bexarotene, promotes remyelination in people with multiple sclerosis. We have also a heterogeneous response of MS lesions to a drug promoting remyelination. Although bexarotene’s safety profile precludes its widespread use, these data support efforts to develop a selective RXR-gamma agonist.
Author Of 4 Presentations
LB1155 - Vitamin D levels in the UK MS population and COVID-19 susceptibility (ID 1116)
Despite the well-described association between vitamin D and MS, little is known about current behaviours surrounding vitamin D and the corresponding vitamin D status in this group at a population level across the UK. During the COVID-19 pandemic, interest in the role that vitamin D might play in reducing susceptibility to and severity of COVID-19 has come to the foreground.
To determine the vitamin D status of the UK MS population, understand the factors that influence it, and examine how vitamin D supplementation affects the risk of COVID-19.
A cohort study using the UK MS Register was performed. Self-reported data surrounding vitamin D and remotely collected biological samples were collected. 1768 people with MS (pwMS) completed a questionnaire regarding vitamin D-influencing behaviours; dried blood spots were collected from 388 of these pwMS and 309 matched controls, and serum 25(OH)D was measured. Subsequently, 592 participants from this MS cohort prospectively completed questionnaires evaluating symptoms suggestive of COVID-19.
Marked differences were observed between supplementation behaviours with pwMS more likely to take supplements (72% vs 26% controls, p<0.001), and at higher doses (median 1600 IU/day vs 600 IU/day in controls, p<0.001). Serum levels of 25(OH)D were higher in pwMS than controls (71nmol/L, IQR 48 vs 49nmol/L, IQR 27, p<0.001). People with MS who did not supplement had lower serum 25(OH)D levels than non-supplementing controls (median 38 nmol/L, IQR 35 vs 44 nmol/L, IQR 21, p<0.001). 71% of those self-diagnosed with COVID-19 reported taking vitamin D vs 72% without COVID-19. Median dose for those with COVID-19 was reported as 1000 IU/day vs 2000 IU/day in those without (p=0.682).
pwMS living in the UK are more likely to have adequate levels of vitamin D than controls, and is driven by the higher rate and dose of supplementation across this population. This has implications on the design and interpretation of any future clinical trials with vitamin D in this population. In addition, we found no evidence that vitamin D supplementation had an impact on susceptibility to COVID-19 in this population.
P0196 - Cladribine to halt deterioration in people with advanced multiple sclerosis (ChariotMS) (ID 585)
Whilst the introduction of disease modifying treatments (DMTs) has transformed the management of people with early/relapsing MS (pwRMS), the use of DMTs in people with MS who are largely or completely wheel chair-dependent (EDSS>6.5) remains controversial. Evidence suggests that slowing or stopping disease deterioration is possible even past this arbitrary (loss of ambulatory function) threshold. Pathology and anecdotal clinical data support the hypothesis that even at an advanced stage of MS (AMS) inflammatory activity is a key driver of functional decline and that effective immunotherapy may halt this process. Cladribine tablets are a highly effective and central nervous system (CNS) penetrant DMT for people with highly-active RMS. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control in MS. Evidence, suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limb functions and (ii) longer axons are more vulnerable to the effects of focal inflammatory demyelination than shorter ones, corroborate our hypothesis that upper limb function can be protected even beyond EDSS=6.5.
Primary Objective: To investigate whether cladribine tablets over 24 months is an effective DMT in people with AMS (pwAMS; EDSS=6.5-8.5) as measured using the 9-hole peg test (9HPT) peg speed.
Secondary Objectives: To establish whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in (i) blood/serum biomarkers of inflammation (lymphocyte subsets) and/or neurodegeneration (neurofilament light chain), (ii) MRI loss of brain volume and spinal cord cross sectional area, (iii) T2 lesion burden, (iv) hypo-intense lesions on T1 weighted scans, (v) quality of life, and (vi) whether cladribine is a cost-effective treatment for pwAMS.
Randomised, double-blind, placebo-controlled phase IIb trial. To detect a 15% treatment effect in 9HPT peg speed with 90% power at 5% significance and 20% drop-out over 104 weeks n=200 pwAMS will be recruited across 20 UK MS centres.
Protocol and ancillary documents have been submitted for ethics approval. So far 17 centres have agreed to recruit pwAMS for ChariotMS. Due to the COVID-19 pandemic start of recruitment has been deferred to 04 Jan 2021.
ChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for add-on therapies.
P0671 - Exploring the gut microbiome in multiple sclerosis via the international MS Microbiome Study (iMSMS) (ID 1532)
- S. Singh
- M. Mendoza
- R. Baumann
- J. Landefeld
- P. Casaccia
- I. Katz Sand
- Z. Xia
- H. Weiner
- T. Chitnis
- S. Chandran
- P. Connick
- D. Oteagui
- T. Castillo-Trivino
- S. Caillier
- A. Santaniello
- G. Ackermann
- G. Humphrey
- L. Negrotto
- M. Farez
- R. Hohlfeld
- A. Pröbstel
- X. Jia
- J. Graves
- A. Bar-Or
- H. Wekerle
- J. Oksenberg
- T. West
- J. Correale
- B. Cree
- S. Hauser
- R. Knight
- S. Baranzini
The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.
The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.
A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.
This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.
Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.
P0777 - High-content drug screening in human iPSC-derived oligodendrocytes identifies novel pathways to promote oligodendrocyte differentiation (ID 340)
Oligodendrocytes provide vital support to axons via their myelin sheath however these cells are disrupted in multiple sclerosis (MS) causing demyelination; this eventually results in degeneration. Oligodendrocyte progenitor cells (OPCs) are found throughout the central nervous system (CNS), including MS lesions, and are able to differentiate into oligodendrocytes to remyelinate axons. OPCs may therefore be a potential therapeutic target to stimulate remyelination and slow the progression of MS.
Our aim is to identify novel compounds which promote oligodendrocyte differentiation from OPCs to mature, myelinating oligodendrocytes.
Human induced pluripotent stem cells were differentiated into oligodendrocytes (Magnani et al., Methods Mol Biol. 2019) for high-content screening of a drug library of epigenetic regulators at a final concentration of 1μM. Cells were stained for Myelin Basic Protein (MBP) and then imaged on a Molecular Devices ImageXpress; MBP fluorescence was analysed using MetaXpress analysis software. Explants isolated from new-born mouse cerebellum and attached hindbrain were allowed to myelinate normally over 21 days in vitro before being demyelinated with lysophosphatidyl choline (LPC). They were treated with vehicle and compounds and allowed to remyelinate over 14 days post-LPC.
This high-content screening assay was able to identify one compound that increased the number of MBP-positive oligodendrocytes significantly compared to a vehicle (DMSO) control (Z-score = 3.86). Confirmation, in dose-response, determined the EC100 to be 300nM (p=<0.0001, n=3). Oligodendrocyte lineage profiling showed that the compound acted on oligodendrocyte progenitor cells (p=0.02, n=4) and immature oligodendrocytes (p=0.001, n=4) but not neural progenitor cells (p=0.28, n=4). This increased remyelination was also observed in the mammalian ex vivo model (p=0.0118, N=6).
Our drug screening assay was able to identify a compound which promotes oligodendrocyte differentiation via a potentially novel pathway that has not yet been reported in the literature. This compound was found to act on OPCs, and initial target validation was performed using a mammalian ex vivo model and target analogues.