Bexarotene came from studying remylination in cultures and experiments from beasties and this lead to a a trial. However many of the remylination studies find important molecules that have multiple functions throughout the body and so it should come as no surprise that when you manipulate these molecules they come with all sorts of unwanted side effects. The target for bearotene was all over the place and we predicted this could have unwanted effects and it did so much so that bexarotene study was not developed further. Now one may ask could you take a stort course to trigger remyelination and that may be possible but would need a study but it is clear long term treatment will not be tolerated for many.
Now this is only an opinion and my opinion and I have been chastised for making this view public. However it suggests that it is possible to do some good and promote repair.
Abstract Number: 218/O074 Abstract Number: 218/O074
Bexarotene-induced remyelination promotes neuroprotection in people with relapsing remitting multiple sclerosis
Gioia Riboni-Verri 1, Chris McMurran 1, J William L Brown 1, Alasdair Coles 1, Nick G. Cunniffe * Nick G. Cunniffe *
Introduction: The promotion of endogenous remyelination is a leading neuroprotective strategy in multiple sclerosis (MS). Change in full-field visual evoked potential (FF-VEP) peak time is commonly used to capture remyelination. However, whether remyelination is associated with neuroprotection remains uncertain. Neurofilament light chain (NfL) is an established blood biomarker of neuroaxonal damage. By correlating these two measures following treatment with a remyelinating therapy – such as bexarotene – we can see whether therapeutic remyelination is associated with neuroprotection.
Objectives/AimsWe aimed to investigate whether an improved FF-VEP peak time was associated with improved NfL levels in a cohort of relapsing-remitting MS (RRMS) participants treated with a remyelinating therapy. Methods: Methods: Between January 2017 and May 2019, 52 participants received 6 months of bexarotene (n=26) or placebo (n=26) under the phase IIa, randomised, double-blind, placebo-controlled CCMR-One trial conducted across Cambridge and Edinburgh. Blood serum at baseline and month 6 was collected from the Cambridge-based participants and immunoassayed for NfL levels via Neuro 4PLEX B on the Quanterix Simoa HDx platform. FFVEP peak time recordings were acquired with a Nicolet Synergy System (Optima Medical; Surrey, UK), as per ISCEV standards, at baseline and month 6.
Results: The blood biomarker cohort included a total of 15 participants randomised to bexarotene (53.3% female; 41.2 +/- 6.6 years) and 12 participants randomised to placebo (50% female; 38.5 +/= 6.9 years). Change in NfL did not differ between treated and placebo groups. However, treatment with bexarotene showed a significant correlation between improvement in NfL and improvement in FF-VEP P100 peak time, when analysing eyes with a prolonged (≥118 ms) baseline FF-VEP peak time (β = 2.29 ms/(pg/ml), p = 0.002), with a significant treatment group interaction (p = 0.002).
Conclusion: Our results suggest that remyelination, measured by change in VEP P100 peak time, is associated with neuroprotection following treatment with bexarotene. This aligns with previous findings showing an association between VEP latency and NfL levels in participants treated with clemastine. These conclusions support the role of blood-based neuroaxonal biomarkers for assessment of remyelinating therapies and neuroprotection across future clinical trials.
However I would say the best way to do this is to stop the damage occurring in the first place.
Abstract Number: 2025/P1453
Effect of Immunomodulatory Therapies on Imaging Measures of Remyelination in the ADVANCE and ASCEND Trials Effect of Immunomodulatory Therapies on Imaging Measures of Remyelination in the ADVANCE and ASCEND Trials Bastien Caba et al. Introduction: Remyelination is a critical yet unmet therapeutic need in multiple sclerosis (MS). Current immunomodulatory therapies primarily target immune dysfunction, but they may also influence remyelination.
Objectives/Aims: We aimed to assess the effect of peginterferon β-1a and natalizumab on tissue repair in chronic white matter lesions, as measured by changes in T1-weighted over T2-weighted ratio (T1w/T2w) derived from magnetic resonance imaging (MRI).
Methods: Brain MRI data from the phase-3 ADVANCE (1512 RRMS patients, NCT00906399) and ASCEND (889 SPMS patients, NCT01416181) trials were analyzed. Among supratentorial white matter voxels that were T2hyperintense at baseline, those located at least 3 millimeters away from any area of gadolinium enhancement (detected at baseline or follow-up) were selected. In selected voxels, after allowing for resolution of baseline sub-acute lesion activity, the change in T1w/T2w signal from week 24 to the last placebo-controlled study timepoint was measured. The effect of each therapy on MRI changes was assessed using a separate linear regression model, adjusted for subject age and gender, as well as for baseline lesional MRI signal and distance to the lateral ventricles.
Results: In ADVANCE, peginterferon β-1a promoted T1w/T2w signal recovery in chronic white matter lesions of RRMS subjects, relative to placebo (P=0.022). In ASCEND, natalizumab promoted T1w/T2w signal recovery in chronic white matter lesions of SPMS subjects, relative to placebo (P=0.046). Treatment effect was preferentially expressed in the deep white matter (WM) relative to juxtacortical and periventricular WM (P<0.03 in both trials). Treatment effect was also preferentially expressed in chronic lesion areas with a baseline T1-weighted signal intensity above the subject-level median (P<0.03 in both trials). Lastly, T1w/T2w recovery in chronic lesions treated with peginterferon β-1a was significantly greater in chronic lesions that were <1 year old relative to lesions that were >1 year old (P=0.002). This differential effect was greater in younger subjects (<34 years old) (P=0.043).
Conclusion: Current immunomodulatory therapies may promote remyelination in chronic white matter lesions. This effect is greatest in young chronic lesions showing less baseline T1-weighted signal abnormality, detected in the deep white matter of young MS patients.
Source: multiple-sclerosis-research.org