Tweet
Long-term Effect of Siponimod on MRI Outcomes in SPMS: Analyses from the EXPAND Study up to 5 Years
Douglas L. Arnold1,2, Ludwig Kappos3, Patrick Vermersch4, Ralf Gold5, Amit Bar-Or6, Gavin Giovannoni7, Bruce A.C. Cree8, Daniela Piani Meier9, Shannon Ritter10, Goeril Karlsson9, Frank Dahlke9, Thomas Hach9, Robert J. Fox11
1Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada, 2NeuroRx Research, Montreal, Quebec, Canada, 3Neurologic Clinic and Policlinic and Research Center for Clinical Neuroimmunology and Neuroscience, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland, 4Univ. Lille, Inserm UMR U1172 LilNCog, CHU Lille, FHU Imminent, Lille, France, 5Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany, 6Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 7Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, 8UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA, 9Novartis Pharma AG, Basel, Switzerland, 10Novartis Pharmaceutical Corporation, East Hanover, NJ, USA, 11Mellen Center for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland, OH, USA
Objective:
To evaluate the long-term effect of siponimod on volume loss (VL) of whole brain, cortical grey matter (cGM) and thalamus, and changes in T2 lesion volume (T2LV) and cumulative number of new/enlarging T2 (neT2) lesions in the Phase 3 EXPAND extension study.
Background:
In the EXPAND core study, siponimod compared with placebo significantly reduced disability progression, cognitive decline, MRI measures of focal inflammation, and global and regional brain VL, in SPMS patients.
Design/Methods:
Of 1651 patients randomized and completing EXPAND core (median 21 months [M]), 1224 entered the 7-year, open-label extension study. Changes in MRI outcomes from EXPAND core baseline to M60 were compared between continuous (siponimod in core/extension) and switch (placebo in core/siponimod in extension) groups. Furthermore, within group comparisons for annualized rate of brain atrophy [ARBA]), and yearly T2LV change and neT2 counts in extension versus core were assessed. Data were analyzed using non-parametric methods and models for repeated measures.
Results:
At M60, treatment effects on VL of whole brain (-1.62% vs -1.76%, p<0.05) and thalamus (-2.68% vs -3.48%, p<0.0001) were more pronounced in the continuous versus switch group; cGM VL was low in both groups (-1.42% vs -1.43%). T2LV change and neT2 counts were reduced in the continuous versus switch group (326 vs 870 mm3 and 3.4 vs 9.3, both p<0.0001). Within-group comparison of extension versus core phase: the switch group recapitulated the pronounced reductions in VL of whole brain (58.1%), cGM (85.4%), and thalamus (58.3%), and yearly T2LV change (94.3%) and neT2 counts (72.8%) on starting siponimod (all, p<0.0001); low ARBA/lesion activity was maintained in the continuous siponimod group.
Conclusions:
Siponimod treatment showed sustained efficacy on MRI measures, including GM atrophy over the long-term, and benefit upon switching from placebo. Persistent differences between continuous and switch groups in measures of brain tissue integrity highlight the importance of early treatment initiation.
Douglas L. Arnold1,2, Ludwig Kappos3, Patrick Vermersch4, Ralf Gold5, Amit Bar-Or6, Gavin Giovannoni7, Bruce A.C. Cree8, Daniela Piani Meier9, Shannon Ritter10, Goeril Karlsson9, Frank Dahlke9, Thomas Hach9, Robert J. Fox11
1Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada, 2NeuroRx Research, Montreal, Quebec, Canada, 3Neurologic Clinic and Policlinic and Research Center for Clinical Neuroimmunology and Neuroscience, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland, 4Univ. Lille, Inserm UMR U1172 LilNCog, CHU Lille, FHU Imminent, Lille, France, 5Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany, 6Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 7Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, 8UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA, 9Novartis Pharma AG, Basel, Switzerland, 10Novartis Pharmaceutical Corporation, East Hanover, NJ, USA, 11Mellen Center for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland, OH, USA
Objective:
To evaluate the long-term effect of siponimod on volume loss (VL) of whole brain, cortical grey matter (cGM) and thalamus, and changes in T2 lesion volume (T2LV) and cumulative number of new/enlarging T2 (neT2) lesions in the Phase 3 EXPAND extension study.
Background:
In the EXPAND core study, siponimod compared with placebo significantly reduced disability progression, cognitive decline, MRI measures of focal inflammation, and global and regional brain VL, in SPMS patients.
Design/Methods:
Of 1651 patients randomized and completing EXPAND core (median 21 months [M]), 1224 entered the 7-year, open-label extension study. Changes in MRI outcomes from EXPAND core baseline to M60 were compared between continuous (siponimod in core/extension) and switch (placebo in core/siponimod in extension) groups. Furthermore, within group comparisons for annualized rate of brain atrophy [ARBA]), and yearly T2LV change and neT2 counts in extension versus core were assessed. Data were analyzed using non-parametric methods and models for repeated measures.
Results:
At M60, treatment effects on VL of whole brain (-1.62% vs -1.76%, p<0.05) and thalamus (-2.68% vs -3.48%, p<0.0001) were more pronounced in the continuous versus switch group; cGM VL was low in both groups (-1.42% vs -1.43%). T2LV change and neT2 counts were reduced in the continuous versus switch group (326 vs 870 mm3 and 3.4 vs 9.3, both p<0.0001). Within-group comparison of extension versus core phase: the switch group recapitulated the pronounced reductions in VL of whole brain (58.1%), cGM (85.4%), and thalamus (58.3%), and yearly T2LV change (94.3%) and neT2 counts (72.8%) on starting siponimod (all, p<0.0001); low ARBA/lesion activity was maintained in the continuous siponimod group.
Conclusions:
Siponimod treatment showed sustained efficacy on MRI measures, including GM atrophy over the long-term, and benefit upon switching from placebo. Persistent differences between continuous and switch groups in measures of brain tissue integrity highlight the importance of early treatment initiation.