Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trialsResearch in context
Amit Bar-Or,
Gian-Andrea Thanei,
Christopher Harp,
Corrado Bernasconi,
Ulrike Bonati,
Anne H. Cross,
Saloumeh Fischer,
Laura Gaetano,
Stephen L. Hauser,
Robert Hendricks,
Ludwig Kappos,
Jens Kuhle,
David Leppert,
Fabian Model,
Annette Sauter,
Harold Koendgen,
Xiaoming Jia,
Ann E. Herman
Affiliations
Amit Bar-Or
Center for Neuroinflammation and Experimental Therapeutics, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author. Multiple Sclerosis Division, Department of Neurology, 3400 Spruce Street–3 Dulles Building, Philadelphia, PA 19104, USA.
Gian-Andrea Thanei
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Christopher Harp
Genentech, Inc., South San Francisco, CA, USA
Corrado Bernasconi
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Ulrike Bonati
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Anne H. Cross
Washington University School of Medicine, St Louis, MO, USA
Saloumeh Fischer
Genentech, Inc., South San Francisco, CA, USA
Laura Gaetano
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Stephen L. Hauser
University of California, San Francisco, San Francisco, CA, USA
Robert Hendricks
Genentech, Inc., South San Francisco, CA, USA
Ludwig Kappos
Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital Basel and University of Basel, Switzerland
Jens Kuhle
Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital Basel and University of Basel, Switzerland
David Leppert
Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland; Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital Basel and University of Basel, Switzerland
Summary: Background: Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear. Methods: We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models. Findings: In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS. Interpretation: Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression. Funding: F. Hoffmann-La Roche Ltd.
