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
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.
LB01.04 - Brain microstructural and metabolic alterations detected in vivo at the onset of the first demyelinating event.
In early multiple sclerosis, a clearer understanding of normal-brain tissue microstructural and metabolic abnormalities will provide valuable insights into its pathophysiology. Here, we studied the brain of patients with their first demyelinating episode using neurite orientation dispersion and density imaging (NODDI), for information about neuro-axonal density and spatial distribution, and 23Na MRI, for total sodium concentration reflecting neuro-axonal metabolic dysfunction and loss.
To detect, using a multi-parametric quantitative MRI approach, clinically relevant alterations in the brain of early patients not captured by conventional MRI.
We enrolled 42 patients with clinically isolated syndrome or multiple sclerosis within 3 months from the onset and 16 healthy controls. We assessed physical and cognitive scales. On a 3T scanner, we acquired brain and spinal cord structural scans, and brain NODDI. Thirty-two patients and 13 healthy controls also underwent brain 23Na MRI. In the brain normal-appearing white matter, white matter lesions, and grey matter, we measured, from NODDI, the neurite density index (NDI), a marker of neuro-axonal density, and the orientation dispersion index (ODI), reflecting the fanning and crossing of neurites, and, from 23Na MRI, the TSC. We used linear regression models, adjusted for brain parenchymal fraction and lesion load, and Spearman correlation tests. For robust regression estimates, we used a p≤0.01.
Patients showed higher ODI in normal-appearing white matter, including the corpus callosum, where they also showed lower NDI and higher TSC, compared with controls. In grey matter, compared with controls, patients had lower ODI in frontal, parietal and temporal cortex; lower NDI in parietal, temporal and occipital cortex; and higher TSC in limbic and frontal cortex. Brain volumes did not differ between patients and controls. In patients, higher ODI in corpus callosum was associated with worse performance on timed walk test (p=0.009, B=0.01, 99% Confidence Interval=0.0001-0.02), independent of brain and lesion volumes. Higher TSC in left frontal middle gyrus was associated with higher disability on Expanded Disability Status Scale (rs=0.5, p=0.005).
We found increased axonal dispersion in normal-appearing white matter, particularly corpus callosum, where we found also reduced axonal density and total sodium accumulation suggesting that this structure can be early affected by neurodegeneration. The association between increased axonal dispersion in the corpus callosum and worse walking performance implies that morphological and metabolic alterations in this structure may contribute to disability in multiple sclerosis. Brain volumes were neither altered nor related to disability in patients, so these two advanced MRI techniques can be more sensitive at detecting clinically relevant pathology in very early multiple sclerosis.