Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Brown, J William L; Cunniffe, Nick; Prados, Ferrán; Kanber, Baris; Jones, Joanne L.; Needham, Edward; Georgieva, Zoya; Rog, David; Pearson, Owen; Overell, James; MacManus, David; Samson, R; Stutters, Jonathan; ffrench‐Constant, Charles; Wheeler-Kingshott, C; Moran, Carla; Flynn, Paul D; Michell, Andrew W.; Franklin, R. J. M.; Chandran, Siddharthan; Altmann, Daniel R.; Chard, Declan; Connick, Peter; Coles, Alasdair

doi:10.1016/s1474-4422(21)00179-4

Cited by 62 publications

(72 citation statements)

References 29 publications

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“…(A) Variation of lesion MTR increase (improvement) with patient age for the three regions with statistically significant increases in MTR 8 . The bexarotene group is shown in blue and placebo in red.…”

Section: Resultsmentioning

confidence: 99%

“…The full protocol and results from the CCMR One trial are published elsewhere 8 . Briefly, patients with relapsing remitting MS aged 18 to 50 with Expanded Disability Status Scale (EDSS) 0.0 to 6.0 were recruited at centers in Cambridge and Edinburgh.…”

Section: Methodsmentioning

confidence: 99%

“…Activation of retinoid‐X receptor (RXR) signaling can promote remyelination by stimulating OPC differentiation and clearance of myelin debris 6,7 . In a two‐center, randomized, double‐blind, placebo‐controlled, phase 2a trial, we recently showed that bexarotene, an RXR agonist, led to statistically significant improvements in the latency of the full‐field visual evoked potential (VEP), and of the MTR of gray matter (GM) lesions (deep and cortical) and brainstem lesions 8 . We hypothesized that the response to bexarotene would decline with age, and so investigated the effect of patient age on markers of remyelination in a post hoc analysis of the CCMR One trial (ISRCTN14265371).…”

Section: Introductionmentioning

confidence: 99%

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Remyelination in humans due to a retinoid‐X receptor agonist is age‐dependent

McMurran

Mukherjee

Brown

et al. 2022

Ann Clin Transl Neurol

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Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid-X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age-related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Remyelination in humans due to a retinoid‐X receptor agonist is age‐dependent

McMurran

Mukherjee

Brown

et al. 2022

Ann Clin Transl Neurol

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“…Second, promoting remyelination is another goal for successful treatment to regenerate and protect damaged axons in MS patients [21]. To observe remyelinating effects, current phase II clinical trials are testing, among others, bexarotene [32], opicinumab [33], erythropoietin [34] and clemastine fumarate [35] (see also [36] for an in-depth review on the topic). Importantly, most clinical trials assessing myelin regeneration focus on optic neuritis as a model system where demyelination and axonal degeneration can be assessed by visual evoked potentials and optical coherence tomography.…”

Section: Treatment Approaches In Patients With Progressive Multiple S...mentioning

confidence: 99%

Progression in multiple sclerosis – a long-term problem

Bittner

Zipp

2022

Current Opinion in Neurology

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Purpose of reviewDisability progression in multiple sclerosis (MS) is strongly linked to central nervous system (CNS)-specific pathological processes that occur throughout all disease stages, but that become clinically evident in later phases of the disease. We here discuss current views and concepts for targeting progressive MS.Recent findingsDetailed clinical assessment of MS patients has identified an even closer entanglement of relapse-remitting and progressive disease, leading to novel concepts such as ‘progression independent of relapse activity’. Evolving clinical concepts together with a focus on molecular (neurofilament light chain) and imaging (paramagnetic rim lesions) biomarkers might specifically identify patients at risk of developing progressive MS considerably earlier than before. A multitude of novel treatment approaches focus either on direct neuroaxonal protection or myelin regeneration or on beneficially modulating CNS-intrinsic or innate immune inflammation. Although some long-awaited trials have recently been unsuccessful, important lessons could still be drawn from novel trial designs providing frameworks for future clinical studies.SummaryTargeting progressive disease biology and repairing established damage is the current central challenge in the field of MS. Especially, the compartmentalized adaptive and innate CNS inflammation is an attractive target for novel approaches, probably as a combinatory approach together with neuroprotective or myelin regenerating strategies.

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“…However, in spite of promising preclinical data, such trials so far have not met their primary endpoint of improvement in clinical disability, even though subgroup analysis has shown some promise (e.g. MS-SMART 2 , Opicinumab 3 , Bexarotene 4 , Clemastine 5 ). This translational mismatch may result from the heterogeneity of the disease in people with MS.…”

Section: Introductionmentioning

confidence: 99%

Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

Macnair

Calini

Agirre

et al. 2022

Preprint

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The lack of understanding as to the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies and biomarkers. Here, to address this gap, we analysed 740,000 single nuclei RNAseq profiles of 165 samples of white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 55 MS patients and 28 controls. We find that gene expression changes in response to MS are highly cell-type specific in WM and GM lesions but are largely shared within an individual cell-type across lesions, following a continuum rather than discrete lesion-specific molecular programs. The major biological determinants of variability in gene expression in MS samples relate to individual patient effects, rather than to lesion types or other metadata. Using multi-omics factor analysis (MOFA+), we identify three subgroups of MS patients with distinct oligodendrocyte composition and WM glial gene expression signatures, suggestive of engagement of different pathological/regenerative processes. The discovery of these three patterns significantly advances our mechanistic understanding of progressive MS, provides a framework to use molecular biomarkers to stratify patients for best therapeutic approaches for progressive MS, and highlights the need for precision-medicine approaches to address heterogeneity among MS patients.

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Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study

Cited by 62 publications

References 29 publications

Remyelination in humans due to a retinoid‐X receptor agonist is age‐dependent

Remyelination in humans due to a retinoid‐X receptor agonist is age‐dependent

Progression in multiple sclerosis – a long-term problem

Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

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