Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials

Abstract

ObjectiveThis study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).BackgroundPrevious post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.Design/MethodsIn this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup.ResultsHigh versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, −0.32% vs. −0.24%, p=0.044, and teriflunomide, −0.43% vs. −0.29%, p=0.002), thalamic volume (−0.56% vs. −0.31%, p=0.047 and −0.94% vs. −0.49%, p<0.001), and WM volume (−0.30% vs. −0.19%, p=0.083 and −0.38% vs. −0.18%, p=0.003) but not of cGM volume (−0.39% vs. −0.32%, p=0.337 and −0.49% vs. −0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients.ConclusionThis study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients.

Association between Serum Biomarker Profile and Real-World Evidence of Disability in Multiple Sclerosis

“…Blood biomarkers could potentially aid MS monitoring. [8][9][10][11] Serum neurofilament light chain (sNEFL) and glial fibrillary acidic protein (sGFAP) are well-studied blood biomarkers of MS. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] NEFL and GFAP are neuron-specific and astrocyte-derived intermediate filament cytoskeletal proteins, respectively. 12,18 Blood NEFL (e.g., sNEFL) has potential clinical applications in monitoring neuroaxonal damage associated with inflammatory disease activity (i.e., clinical and/or neuroimaging relapse), short-term disability worsening, and treatment response, though its utility to inform long-term disability remains unsettled.…”

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis

“…We here investigated whether different levels of sNfL influence MSrelated MRI measures and disability worsening in pwMS. We show that a single time point peak in sNfL above the 33th percentile of our MS cohort had a distinct effect on BV loss over a median follow-up time of 3.8 years, and repeated (2×) higher sNfL levels were associated with a greater risk of disability worsening irrespective of disease A few other reports have also shown that especially high sNfL levels are related to a more severe disease course [1,[3][4][5][30][31][32][33][34][35].…”

“…A few other reports have also shown that especially high sNfL levels are related to a more severe disease course [1, 3–5, 30–35]. sNfL levels ranging above the 80–95 percentile of healthy subjects were predictive of brain atrophy in pwMS during a follow‐up time of 5 years [5].…”

Neuroaxonal and Glial Markers in Patients of the Same Age With Multiple Sclerosis

“…43 Nevertheless, earlier studies have also showed the ability of NfL to predict WM atrophy, a result which we cannot confirm in our cohort. 44,45 Remarkably, the multivariable logistic regression model with sNfL and sGFAP had an explained variance in the same range as the model including MRI measures only. This suggests that the easily accessed biomarkers NfL and GFAP may have comparable accuracy with neuroimaging biomarkers when assessing advanced disability.…”

“… 43 Nevertheless, earlier studies have also showed the ability of NfL to predict WM atrophy, a result which we cannot confirm in our cohort. 44 , 45 …”