TY - JOUR
T1 - Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis
T2 - Results From the Phase 3 ASCLEPIOS I and II Trials
AU - Ziemssen, Tjalf
AU - Arnold, Douglas L.
AU - Alvarez, Enrique
AU - Cross, Anne H.
AU - Willi, Roman
AU - Li, Bingbing
AU - Kukkaro, Petra
AU - Kropshofer, Harald
AU - Ramanathan, Krishnan
AU - Merschhemke, Martin
AU - Kieseier, Bernd
AU - Su, Wendy
AU - Häring, Dieter A.
AU - Hauser, Stephen L.
AU - Kappos, Ludwig
AU - Kuhle, Jens
N1 - Funding Information:
RW, BL, PK, HK, KR, MM, WS, and DH are employed by Novartis. This study was funded by Novartis Pharma AG, Basel, Switzerland. Novartis Pharma AG supported the development of this manuscript, provided data analyses according to the direction of the authors, and paid for medical writing support.
Funding Information:
The authors thank the participants for their involvement in and commitment to the ASCLEPIOS trials and the clinical study team for the conduct of the study. The authors are grateful to Vimal Kumar Muthyala and Anuja Shah (Novartis Healthcare Pvt. Ltd., Hyderabad, India) for providing medical writing support. These services were sponsored by Novartis Pharma AG.
Publisher Copyright:
Copyright © 2022 Ziemssen, Arnold, Alvarez, Cross, Willi, Li, Kukkaro, Kropshofer, Ramanathan, Merschhemke, Kieseier, Su, Häring, Hauser, Kappos and Kuhle.
PY - 2022/3/31
Y1 - 2022/3/31
N2 - Objective: This 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). Background: Previous 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/Methods: In 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. Results: High 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. Conclusion: This 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.
AB - Objective: This 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). Background: Previous 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/Methods: In 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. Results: High 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. Conclusion: This 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.
KW - MS disease activity
KW - brain atrophy
KW - lesion formation
KW - prognostic biomarker
KW - serum neurofilament light chain
UR - http://www.scopus.com/inward/record.url?scp=85128432186&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2022.852563
DO - 10.3389/fimmu.2022.852563
M3 - Article
C2 - 35432382
AN - SCOPUS:85128432186
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 852563
ER -