Author Of 2 Presentations
LB01.02 - Phase 2 clinical trial evidence that a retinoid-X receptor agonist promotes remyelination in people with relapsing-remitting multiple sclerosis
Abstract
Background
Retinoid acid X receptor [RXR] gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination following experimental demyelination.
Objectives
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.
Methods
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.
Results
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 [2], 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).
Conclusions
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.
PS07.03 - Predicting disability progression and cognitive worsening in multiple sclerosis with gray matter network measures
Abstract
Background
In multiple sclerosis (MS), MRI measures at a whole and regional brain level have proven able to predict future disability, albeit to a limited degree. Their modest prognostic ability may reflect how cognitive and neurological functions are served by distributed networks rather than by single brain regions.
Objectives
We aimed to identify data-driven MRI network-based measures of covarying gray matter (GM) volumes that can predict disability progression.
Methods
We used baseline MRI and longitudinal clinical data from 988 patients with secondary progressive MS (SPMS) from a randomized, double-blind, placebo-controlled, multicenter trial (ASCEND). We applied spatial-ICA to baseline structural GM probability maps to identify co-varying GM regions. We computed correlations between the loading of our ICA components and expanded disability status scale (EDSS), 9 hole peg test (9HPT), and symbol digit modalities test (SDMT) scores. We estimated the progression of the EDSS confirmed at 3 months, 6 months, and 1 year, and respectively the 20% and 10% worsening of 9HPT and SDMT. We used Cox proportional hazard models to determine the prognostic value of our ICA-components and conventional MRI measures (whole and deep GM volumes, and white matter lesion load).
Results
We identified 15 networks of co-varying GM patterns that were clinically relevant. At baseline, SDMT and 9HPT scores correlated more strongly with ICA-components than the conventional MRI measures. The highest correlations were with a mainly basal ganglia component (encompassing the thalamus, caudate, putamen, frontal and temporal lobe). EDSS correlated more closely with an ICA-component involving cerebellum, brainstem, temporal and parietal lobes (r= -0.11, p<0.001). Prognostically, the baseline volume of caudate predicted EDSS progression confirmed at 3 months (HR= 0.81, 95%CI [0.68: 0.98], p<0.05), while some GM network-based measures outperformed conventional MRI measures in predicting SDMT and 9HPT worsening. SDMT progression was predicted by 6 ICA-components (component 8 (HR= 1.26, 95% CI [1.08-1.48], p< 0.005, and component 13 (HR= 1.25, 95% CI [1.07:1.46], p<0.005)). Two ICA-components were predictors of 9HPT worsening (HR=1.30, 95% CI [1.06:1.60], p<0.01; and HR= 1.21, 95%CI [1.01:1.45], p<0.05).
Conclusions
Data-driven MRI network-based measures of covarying GM volumes predict disability progression better than volumetric measures of GM and white matter lesion loads. ICA of MRI shows promise as a method that could enrich clinical MS studies with patients more likely to show a treatment response.
Author Of 1 Presentation
P0072 - Effect of switching disease modifying drugs on relapse rate in stable relapsing remitting multiple sclerosis patients planning for pregnancy. (ID 580)
Abstract
Background
The decision to have children is complex for multiple sclerosis patients due to the range of aspects that affect it. One of the most important aspects is the use of disease modifying drugs (DMDs) when planning or during pregnancy and how continuing, stopping or switching them may affect the disease course. It is always better to avoid the use of medications during pregnancy but in patients with severe disease stopping their medium or high potency medications imposes high risk of disease recurrence, rebound or Immune Reconstitution Inflammatory Syndrome (IRIS),specifically when stopping Natalizumab (NTZ) or Fingolimod. Switching to another medication that can be used up to conception and even during pregnancy which are either Glatiramer acetate (GA) or Interferons (IFNs) may be an option.
Objectives
To review available evidence on the effect of different switching strategies in stable relapsing remitting MS (RRMS) patients on clinical and radiological disease activity.
Methods
We searched MEDLINE, EMBASE, EMCARE, CINAHL, SCOPUS, Cochrane Library up to March 2020. No limits or restrictions on time or study design were applied, but only papers written in English were included. We used the revised Cochrane risk of bias tool for randomized trials (ROB2), and national heart, lung and blood institute (NIH) quality assessment tool for before-after (pre-post) with no control group cohort studies.
Results
Seven articles that matched the inclusion criteria were included: 4 cohorts, 2 case reports and one RCT. Results were synthesized narratively and Meta-analysis was not possible due to high heterogeneity (limited treatment overlap) between the studies. Four different switching strategies were identified, the first three were considered de-escalation from high to low potency DMDs, (NTZ to GA), (NTZ to monthly methylprednisolone for three months then GA) which is called (bridging) and (NTZ to IFN). All studies measured the mean change in annualized relapse rate after switching as disease activity measure. These switches showed some protection from rebound and IRIS but not from disease recurrence. The fourth strategy IFN to GA (switching between first line injectables), showed disease stability in two case reports.
Conclusions
Evidence on switching strategy effect on disease course in stable RRMS patients is scarce, available data suggests partial activity in case of de-escalation, and stability in case of switching between first line injectables.