Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis

Fox, Robert J.; Raska, Paola; Barro, Christian; Karafa, Matthew; Konig, Victoria; Bermel, Robert; Chase, Marianne; Coffey, Christopher S.; Goodman, Andrew; Klawiter, Eric C.; Naismith, Robert T.; Kuhle, Jens

doi:10.1177/1352458520986956

Cited by 36 publications

(25 citation statements)

References 25 publications

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“…Daclizumab was also shown to significantly decrease the number of new contrast-enhancing lesions and CSF NfL levels 353 . In contrast to the previously mentioned DMTs, treatment with ibudilast had no significant effect on the baseline and endpoint CSF and serum NfL levels between individuals receiving therapy and placebo 354 . Similarly, no evidence of therapeutic effect concerning NfL concentration was observed in SPMS patients receiving simvastatin or placebo 324 .…”

Section: Other Therapiescontrasting

confidence: 76%

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: a Comprehensive Review of the Literature with a Focus on Neurofilaments and Therapeutic Considerations

Biernacki¹,

Kokas²,

Sandi³

et al. 2022

Preprint

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Introduction: multiple sclerosis (MS) is the most common immune-mediated chronic neurodegenerative disease of the central nervous system (CNS), affecting young people. Due to the permanent disability, cognitive impairment, and the enormous detrimental impact MS can exert on the patients’ health-related quality of life. It is of great importance to recognise it in time and commence adequate treatment at an early stage. The currently used disease-modifying therapies (DMT) aim to reduce disease activity and thus halt disability development, which in current clinical practice are monitored by clinical and imaging parameters but not by biomarkers found in blood and/or the cerebrospinal fluid (CSF). Both clinical and radiological measures routinely used to monitor disease activity lack information on the fundamental pathophysiological features and mechanisms of MS. Furthermore, they lag behind the disease process itself. By the time a clinical relapse becomes evident or a new lesion appears on the MRI scan, potentially irreversible damage has already occurred in the CNS. In recent years several biomarkers that previously have been linked to other neurological and immunological diseases have received increased attention in MS. Additionally, other novel, potential biomarkers with prognostic and diagnostic properties have been detected in the CSF and blood of MS patients. Areas covered: in this review, we summarise the most up to date knowledge and research conducted on the already known and most promising new biomarker candidates found in the CSF and blood of MS patients. Author commentary: the current diagnostic criteria of MS rely on three pillars; MRI imaging, clinical events and the presence of oligoclonal bands in the CSF (which was reinstated into the diagnostic criteria by the most recent revision). Even though the most recent McDonald criteria made the diagnosis of MS faster than the prior iteration, it is still not an infallible diagnostic toolset, especially at the very early stage of clinically isolated syndrome. Together with the gold standard MRI and clinical measures, ancillary blood and CSF biomarkers may not just improve diagnostic accuracy and speed but very well may become agents to monitor therapeutic efficacy and make even more personalised treatment in MS a reality in the near future. The major disadvantage of these biomarkers in the past has been the need to obtain CSF to measure them. However, the recent advances in extremely sensitive immunoassays made their measurement possible from peripheral blood even when present only in minuscule concentrations. This should mark the beginning of a new biomarker research and utilisation era in MS.

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Section: Other Therapiescontrasting

confidence: 76%

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: a Comprehensive Review of the Literature with a Focus on Neurofilaments and Therapeutic Considerations

Biernacki¹,

Kokas²,

Sandi³

et al. 2022

Preprint

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“…31 There was, however, no significant difference between the treatment groups in either serum or CSF NfL. 9 Although ibudilast is likely to have pleotropic effects (such as modulation of CNS innate immunity through inhibition of phosphodiesterases, macrophage migration inhibitory factor, and Toll-like receptor 4), like simvastatin, it is not thought to be systemically immunomodulatory. 32 NfL has shown utility as a biomarker of treatment with fingolimod, siponimod, natalizumab, and ocrelizumab in PMS cohorts.…”

Section: Discussionmentioning

confidence: 99%

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis

Williams

Holdsworth

Nicholas

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

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“…Ibudilast also prevented Aβ1–42 induced memory impairments and reduced neuroinflammation and apoptotic responses (Wang et al, 2014 ). Ibudilast has been investigated in clinical trials for multiple sclerosis without any significant effects (Wang et al, 2014 ; Fox et al, 2021 ; Goodman et al, 2021 ). A promising novel Aβ antibody drug, aducanumab, received FDA approval under the accelerated approval pathway.…”

Section: Discussionmentioning

confidence: 99%

Alcohol-Induced Neuroinflammatory Response and Mitochondrial Dysfunction on Aging and Alzheimer’s Disease

León

Kang

Franca-Solomon

et al. 2022

Front. Behav. Neurosci.

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Mitochondria are essential organelles central to various cellular functions such as energy production, metabolic pathways, signaling transduction, lipid biogenesis, and apoptosis. In the central nervous system, neurons depend on mitochondria for energy homeostasis to maintain optimal synaptic transmission and integrity. Deficiencies in mitochondrial function, including perturbations in energy homeostasis and mitochondrial dynamics, contribute to aging, and Alzheimer’s disease. Chronic and heavy alcohol use is associated with accelerated brain aging, and increased risk for dementia, especially Alzheimer’s disease. Furthermore, through neuroimmune responses, including pro-inflammatory cytokines, excessive alcohol use induces mitochondrial dysfunction. The direct and indirect alcohol-induced neuroimmune responses, including pro-inflammatory cytokines, are critical for the relationship between alcohol-induced mitochondrial dysfunction. In the brain, alcohol activates microglia and increases inflammatory mediators that can impair mitochondrial energy production, dynamics, and initiate cell death pathways. Also, alcohol-induced cytokines in the peripheral organs indirectly, but synergistically exacerbate alcohol’s effects on brain function. This review will provide recent and advanced findings focusing on how alcohol alters the aging process and aggravates Alzheimer’s disease with a focus on mitochondrial function. Finally, we will contextualize these findings to inform clinical and therapeutic approaches towards Alzheimer’s disease.

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Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis

Cited by 36 publications

References 25 publications

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: a Comprehensive Review of the Literature with a Focus on Neurofilaments and Therapeutic Considerations

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: a Comprehensive Review of the Literature with a Focus on Neurofilaments and Therapeutic Considerations

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis

Alcohol-Induced Neuroinflammatory Response and Mitochondrial Dysfunction on Aging and Alzheimer’s Disease

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