Dataset Information

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

ABSTRACT:

Objectives

To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing-remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint.

Methods

Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2-year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2-year relapses and BVL explained by 6-month log-transformed NfL levels with the PTE explained by the number of active lesions over 6 months. We estimated sample size requirements for different treatment effects.

Results

At Month 6, blood NfL levels (pg/mL, median [range]) were lower in the fingolimod arm (fingolimod (n = 132) 18 [8-247]; placebo (n = 114) 26 [8-159], P < 0.001). NfL at 6 months correlated with number of relapses (r = 0.25, P < 0.001), 6-month CDW (hazard ratio 1.83, P = 0.012), active lesions (r = 0.46, P < 0.001), and BVL (r = -0.41, P < 0.001) at Month-24. The PTE (95% CI) on 24-month relapses and BVL explained by 6-month NfL was 25% (8-60%) and 60% (32-132%), and by 6-month active lesions was 28% (11-66%) and 45% (18-115%), respectively. Assuming a 20-40% treatment-related reduction in NfL levels, 143-28 patients per arm will be required.

Conclusions

Blood NfL may qualify as an informative and easy-to-measure endpoint for future Phase 2 clinical studies that captures both inflammatory- and noninflammatory-driven neuroaxonal injury in RRMS.

SUBMITTER: Sormani MP

PROVIDER: S-EPMC6562031 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

Sormani Maria Pia MP Haering Dieter A DA Kropshofer Harald H Leppert David D Kundu Uma U Barro Christian C Kappos Ludwig L Tomic Davorka D Kuhle Jens J

Annals of clinical and translational neurology 20190528 6

<h4>Objectives</h4>To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing-remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint.<h4>Methods</h4>Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2-year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume ...[more]

PMID: 31211172

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Project description:BackgroundBlood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease.MethodsWe did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF.FindingsBaseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=-0·374, p<0·0001; Stroop word reading r=-0·248, p=0·0033), total functional capacity (r=-0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=-0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48-7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001).InterpretationNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.FundingMedical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.

Dataset Information

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

Objectives

Methods

Results

Conclusions

Publications

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

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