Effect of siponimod on cortical grey matter and thalamic volume in patients with secondary progressive multiple sclerosis - results of the EXPAND study
ECTRIMS Online Library. Arnold D. 09/11/19; 278743; P382
Dr. Douglas L Arnold
Dr. Douglas L Arnold
Contributions Biography
Abstract

Abstract: P382

Type: Poster Sessions

Abstract Category: Clinical aspects of MS - Progressive MS

D.L. Arnold1,2, R. Fox3, A. Bar-Or4, B.A.C. Cree5, G. Giovannoni6, R. Gold7, P. Vermersch8, D. Piani Meier9, S. Arnould9, S. Ritter10, F. Dahlke9, D. Tomic9, L. Kappos11

1Montreal Neurological Institute, McGill University, 2NeuroRx Research, Montreal, QC, Canada, 3Mellen Center for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland, OH, 4Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 5UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States, 6Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 7Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany, 8University Lille, INSERM U995, CHU Lille, Lille, France, 9Novartis Pharma AG, Basel, Switzerland, 10Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 11Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland

Background: Grey matter (GM) volume loss is associated with cognitive decline and physical disability in multiple sclerosis (MS) patients. In the Phase 3 EXPAND study, siponimod significantly reduced disability progression, cognitive decline and whole brain volume loss versus placebo in patients with secondary progressive MS (SPMS). There is limited data reporting the effect of sphingosine-1-phosphate modulating drugs on cortical GM (cGM) and thalamic volume loss in patients with SPMS.
Objective: To compare changes in cGM and thalamic volume in SPMS patients treated with siponimod or placebo in the EXPAND study.
Methods: Two magnetic resonance imaging (MRI) datasets from the EXPAND study population were pooled and included 583 patients who participated in a high resolution T1 MRI sub-study and 1062 patients who underwent conventional MRI. Structural volume loss was analysed at a central reading centre using Paired Jacobian Integration. Analysis included the intent-to-treat population who received ≥1 dose of the study drug (full analysis set, FAS) and the per-protocol set (PPS; excluding subjects who switched treatments or had major protocol deviations). Adjusted mean percent changes from baseline in cGM and thalamic volumes were assessed at Month (M) 12 and M24. Changes in brain structure volumes were analysed using a mixed model for repeated measures adjusted for the respective structural volume at baseline.
Results: The pooled MRI dataset (FAS/PPS) presented here comprised 1315/1029 patients for the analysis of cGM volume and 1329/1038 patients for thalamic volume. In the FAS, adjusted mean percent change in volume from baseline with siponimod versus placebo at M12 and M24, respectively, were −0.07 versus −0.59 (88% reduction vs placebo, p< 0.0001) and −0.51 versus −0.90 (43% reduction; p< 0.0001) for cGM; −0.54 versus −1.01 (47% reduction; p< 0.0001) and −1.20 versus −1.74 (31% reduction; p=0.0001) for the thalamus. Corresponding PPS values were 0.01 versus −0.60 (100% reduction; p< 0.0001) and −0.39 versus −1.04 (63% reduction; p< 0.0001) for cGM; −0.47 vs −0.94 (50% reduction; p< 0.0001) and −1.02 versus −1.77 (42% reduction; p< 0.0001) for the thalamus.
Conclusions: Siponimod significantly reduced cGM and thalamic volume loss compared with placebo in patients with SPMS. This effect on measures of neuroaxonal damage, an important substrate of motor and cognitive disability, supports the value of siponimod as a treatment of patients with SPMS.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland.
Douglas L. Arnold received honoraria from Acorda, Biogen Idec, Genentech, Genzyme, Novartis, F. Hoffmann-La Roche and Sanofi-Aventis; research support from Novartis and Biogen; and has an equity interest in NeuroRx Research, which performed the MRI analysis for the trial.
Robert Fox has received compensation for serving as a consultant or speaker from Allozyne, Avanir, Biogen, Novartis, Questcor and Teva Pharmaceutical Industries. He, or the institution he works for, has received research support from Novartis.
Amit Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from: Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MAPI, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme.
Bruce Cree has received personal compensation for consulting from Abbvie, Akili, Alexion, Biogen, EMD Serono, Novartis, Sanofi Genzyme and TG Therapeutics.
Gavin Giovannoni is a steering committee member on the daclizumab trials for AbbVie, the BG12 and daclizumab trials for Biogen, the fingolimod and siponimod trials for Novartis, the laquinimod trials for Teva and the ocrelizumab trials for Roche. He has also received consultancy fees for advisory board meetings for oral cladribine trials for Merck KGaA, Genzyme-Sanofi, and in relation to DSMB activities for Synthon BV, as well as honoraria for speaking at the Physicians' summit and several medical education meetings. He is also the Co-Chief Editor of Multiple Sclerosis and Related Disorders (Elsevier).
Ralf Gold has received compensation for serving as a consultant or speaker from Bayer HealthCare, Biogen, Merck, Novartis and Teva. He, or the institution he works for, has received research support from Bayer HealthCare, Biogen, Merck, Novartis and Teva; he has also received honoraria as a Journal Editor from SAGE and Thieme Verlag.
Patrick Vermersch has received honoraria and consulting fees from Biogen, Sanofi, Teva, Novartis, Merck and Almirall, and research support from Biogen, Sanofi, Bayer, and Merck.
Ludwig Kappos has received no personal compensation. Ludwig Kappos' institution (University Hospital Basel) has received the following exclusively for research support: Steering committee, advisory board and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB and Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi and Teva); support for educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi and Teva); licence fees for Neurostatus products; and grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society and Swiss National Research Foundation).
Daniela Piani Meier, Sophie Arnould, Shannon Ritter, Frank Dahlke and Davorka Tomic are employees of Novartis. All authors would like to acknowledge Dieter A. Häring for his support on data analysis.

Abstract: P382

Type: Poster Sessions

Abstract Category: Clinical aspects of MS - Progressive MS

D.L. Arnold1,2, R. Fox3, A. Bar-Or4, B.A.C. Cree5, G. Giovannoni6, R. Gold7, P. Vermersch8, D. Piani Meier9, S. Arnould9, S. Ritter10, F. Dahlke9, D. Tomic9, L. Kappos11

1Montreal Neurological Institute, McGill University, 2NeuroRx Research, Montreal, QC, Canada, 3Mellen Center for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland, OH, 4Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 5UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States, 6Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 7Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany, 8University Lille, INSERM U995, CHU Lille, Lille, France, 9Novartis Pharma AG, Basel, Switzerland, 10Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States, 11Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland

Background: Grey matter (GM) volume loss is associated with cognitive decline and physical disability in multiple sclerosis (MS) patients. In the Phase 3 EXPAND study, siponimod significantly reduced disability progression, cognitive decline and whole brain volume loss versus placebo in patients with secondary progressive MS (SPMS). There is limited data reporting the effect of sphingosine-1-phosphate modulating drugs on cortical GM (cGM) and thalamic volume loss in patients with SPMS.
Objective: To compare changes in cGM and thalamic volume in SPMS patients treated with siponimod or placebo in the EXPAND study.
Methods: Two magnetic resonance imaging (MRI) datasets from the EXPAND study population were pooled and included 583 patients who participated in a high resolution T1 MRI sub-study and 1062 patients who underwent conventional MRI. Structural volume loss was analysed at a central reading centre using Paired Jacobian Integration. Analysis included the intent-to-treat population who received ≥1 dose of the study drug (full analysis set, FAS) and the per-protocol set (PPS; excluding subjects who switched treatments or had major protocol deviations). Adjusted mean percent changes from baseline in cGM and thalamic volumes were assessed at Month (M) 12 and M24. Changes in brain structure volumes were analysed using a mixed model for repeated measures adjusted for the respective structural volume at baseline.
Results: The pooled MRI dataset (FAS/PPS) presented here comprised 1315/1029 patients for the analysis of cGM volume and 1329/1038 patients for thalamic volume. In the FAS, adjusted mean percent change in volume from baseline with siponimod versus placebo at M12 and M24, respectively, were −0.07 versus −0.59 (88% reduction vs placebo, p< 0.0001) and −0.51 versus −0.90 (43% reduction; p< 0.0001) for cGM; −0.54 versus −1.01 (47% reduction; p< 0.0001) and −1.20 versus −1.74 (31% reduction; p=0.0001) for the thalamus. Corresponding PPS values were 0.01 versus −0.60 (100% reduction; p< 0.0001) and −0.39 versus −1.04 (63% reduction; p< 0.0001) for cGM; −0.47 vs −0.94 (50% reduction; p< 0.0001) and −1.02 versus −1.77 (42% reduction; p< 0.0001) for the thalamus.
Conclusions: Siponimod significantly reduced cGM and thalamic volume loss compared with placebo in patients with SPMS. This effect on measures of neuroaxonal damage, an important substrate of motor and cognitive disability, supports the value of siponimod as a treatment of patients with SPMS.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland.
Douglas L. Arnold received honoraria from Acorda, Biogen Idec, Genentech, Genzyme, Novartis, F. Hoffmann-La Roche and Sanofi-Aventis; research support from Novartis and Biogen; and has an equity interest in NeuroRx Research, which performed the MRI analysis for the trial.
Robert Fox has received compensation for serving as a consultant or speaker from Allozyne, Avanir, Biogen, Novartis, Questcor and Teva Pharmaceutical Industries. He, or the institution he works for, has received research support from Novartis.
Amit Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from: Atara Biotherapeutics, Biogen Idec, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MAPI, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme.
Bruce Cree has received personal compensation for consulting from Abbvie, Akili, Alexion, Biogen, EMD Serono, Novartis, Sanofi Genzyme and TG Therapeutics.
Gavin Giovannoni is a steering committee member on the daclizumab trials for AbbVie, the BG12 and daclizumab trials for Biogen, the fingolimod and siponimod trials for Novartis, the laquinimod trials for Teva and the ocrelizumab trials for Roche. He has also received consultancy fees for advisory board meetings for oral cladribine trials for Merck KGaA, Genzyme-Sanofi, and in relation to DSMB activities for Synthon BV, as well as honoraria for speaking at the Physicians' summit and several medical education meetings. He is also the Co-Chief Editor of Multiple Sclerosis and Related Disorders (Elsevier).
Ralf Gold has received compensation for serving as a consultant or speaker from Bayer HealthCare, Biogen, Merck, Novartis and Teva. He, or the institution he works for, has received research support from Bayer HealthCare, Biogen, Merck, Novartis and Teva; he has also received honoraria as a Journal Editor from SAGE and Thieme Verlag.
Patrick Vermersch has received honoraria and consulting fees from Biogen, Sanofi, Teva, Novartis, Merck and Almirall, and research support from Biogen, Sanofi, Bayer, and Merck.
Ludwig Kappos has received no personal compensation. Ludwig Kappos' institution (University Hospital Basel) has received the following exclusively for research support: Steering committee, advisory board and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB and Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi and Teva); support for educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi and Teva); licence fees for Neurostatus products; and grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society and Swiss National Research Foundation).
Daniela Piani Meier, Sophie Arnould, Shannon Ritter, Frank Dahlke and Davorka Tomic are employees of Novartis. All authors would like to acknowledge Dieter A. Häring for his support on data analysis.

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