Neurofilament Light Chain Levels and Disease Activity During Long-Term Treatment of Relapsing Multiple Sclerosis with the Bruton's Tyrosine Kinase Inhibitor Evobrutinib
Jens Kuhle1, Ludwig Kappos2, Xavier Montalban3, Pascal Benkert4, Ying Li5, Karthinathan Thangavelu5, Yann Hyvert6, Davorka Tomic7
1Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, and University of Basel, 2Departments of Medicine, Clinical Research and Biomedical Engineering, Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, and University of Basel, 3Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, 4Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, 5EMD Serono, 6The healthcare business of Merck KGaA, Darmstadt, Germany, 7Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany
Objective:
To evaluate neurofilament light chain (NfL) levels, a biomarker of neuroaxonal damage, as a prognostic and a potential surrogate marker of evobrutinib treatment response (MRI and relapse outcomes) in patients with relapsing multiple sclerosis (PwRMS).
Background:
Evobrutinib is a highly selective, CNS-penetrant Bruton’s tyrosine kinase inhibitor, currently in Phase III for RMS. The efficacy of evobrutinib (MRI and clinical outcomes) observed in double blind phase (DBP) of a Phase II trial (NCT02975349) in PwRMS was maintained in the open-label extension (OLE; beginning at Week [W] 48 from DBP baseline). Previous analyses of the Phase II trial showed sustained reductions in NfL levels with evobrutinib up to W144.
Design/Methods:
NfL levels were measured over time in the pooled OLE safety population and reported as control-adjusted NfL Z-scores (expression of standard deviations [SDs] away from mean NfL level in a control population [participants without evidence of CNS disease]). The number of T1 Gd+ and new/emerging T2 lesions at W96 and W144 and qualified relapses over W96-144 were assessed, stratified by W96 NfL Z-scores (<1; ≥1 [Z-score 1 being one SD above the control mean]). MRI outcomes at W48 and W96 and relapses over W48-96 were also assessed using stratified W48 NfL Z-scores [<1; ≥1].
Results:
Stratified by W96 Z-scores (<1[N=66]; ≥1[N=34]), the proportion of patients with no T1 Gd+ lesions, no new/enlarging T2 lesions (both at W144) and no relapse between W96-144 were 84.5% (n=49/58) vs 57.1% (n=16/28), 65.5% (n=38/58) vs 28.6% (n=8/28) and 95.4% (n=62/65) vs 94.1% (n=32/34), respectively. Similar findings were observed in patients stratified by W48 Z-scores (<1[N=84]; ≥1[N=40]).
Conclusions:
Evobrutinib reduced NfL levels in a sustained manner (up to W144). Low NfL levels were associated with improved MRI and relapse outcomes, supporting the role of NfL as a prognostic marker of disease activity and a potential surrogate marker for evobrutinib’s treatment effect.