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Phase 4 open-label study on dimethyl fumarate in MS investigating the dynamics of blood neurofilament as treatment response biomarker
Neurofilament light (NFL) is a cytoskeleton protein of myelinated axons and is one of the most studied biomarkers of disease activity and treatment response in patients with multiple sclerosis (MS), and the most promising biomarkers for the use in MS standard care. NFL levels increase in cerebrospinal fluid (CSF) and blood after axonal injury in MS and other neurological disorders, and the increase is proportional to the damage.1 The single molecule array (SIMOA) technology used to analyse NFL in the study by Sejbaek et al 2 is able to detect NFL at ultralow levels in the blood. This allows measuring NFL easily and regularly. The evidence for NFL as a disease activity and treatment response biomarker is increasing.3–5
The paper by Sejbaek et al 2 presents a prospective open-label phase 4 trial that enrolled newly diagnosed treatment-naïve patients with relapsing MS who started treatment with dimethyl fumarate (DMF). As the response to therapy, the dynamics of NFL concentrations in CSF, serum and plasma were examined. This study2 shows that the treatment with DMF reduces NFL in CSF and blood. This is a novel finding for this treatment and supports the use of blood NFL as a biomarker of treatment response. Previous studies showed similar reduction of NFL levels for other treatments.3–5 A significant reduction in NFL plasma concentration was observed after 6 and 12 months’ treatment with DMF. NFL concentration in the plasma of patients with MS became similar to healthy controls after 6 and 12 months’ treatment.2 Similarly, the phase 3 trials of fingolimod versus placebo, Efficacy and Safety of Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis (FREEDOMS), and interferon-β−1a, Efficacy and Safety of Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis with Optional Extension Phase (TRANSFORMS), showed a significant reduction in NFL levels after 6 and 12 months’ treatment with fingolimod and plasma NFL levels similar to healthy controls at the end of these studies.5
These two studies2 5 showed group-level changes, but there were missing larger studies showing NFL dynamics on an individual level. Despite the high sensitivity of SIMOA, a fraction of patients with MS showed increased NFL levels in CSF but normal NFL levels in blood.2 Thus, the assay needs further improvement of sensitivity.1 Further, studies on blood NFL measured by SIMOA published in recent years are not comparable due to the lack of standardisation.1
Another interesting finding is the relative larger reduction of NFL levels in serum than in plasma and that the NFL levels in paired samples are lower in plasma.2 More studies with parallel sampling of plasma and serum NFL are needed to confirm this finding. The therapeutic effect of DMT was not detected at months 1 and 3 in blood NFL. This might be affected by the treatment efficacy, and it can be hypothesised that treatment with higher efficacy may show the NFL reduction earlier. CSF NFL detect the axonal damage that occurred within the 3 months.6 However, the frequency of blood NFL measurement to detect the axonal injury in patients with MS needs to be further explored. Altogether, this study is a step towards using blood NFL as a biomarker in MS standard care.
Contributors The manuscript was written by LN.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.