Efficacy of Siponimod on Disability Progression in SPMS Patients With and Without On-Study Relapses
ECTRIMS Online Library. Kappos L. Oct 26, 2017; 200437; P782
Prof. Dr. Ludwig Kappos
Prof. Dr. Ludwig Kappos
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Abstract

Abstract: P782

Type: Poster

Abstract Category: Therapy - disease modifying - 31 Treatment of progressive MS

Background: In EXPAND, a randomised, double-blind, parallel-group, placebo-controlled, variable-treatment duration study in patients with secondary progressive multiple sclerosis (SPMS), siponimod reduced the risk of 3-month (3m) and 6-month (6m) confirmed disability progression (CDP) by 21% (p=0.013) and 26% (p=0.006), respectively. Siponimod also reduced the annualised relapse rate by 55.5%. However, on-study relapses (OSRs) may impact CDP results. Analyses for the subgroups of non-relapsing (n=1430) and relapsing (n=215) patients classified by occurrence of OSR favoured siponimod over placebo for 3mCDP and 6mCDP. However, subgroup analyses based on on-study findings may be confounded since the allocation to such subgroups may be affected by treatment effects.
Objective: To investigate the impact of OSRs on CDP in patients with SPMS receiving siponimod.
Methods: Impact of OSR on CDP was explored by an exploratory multi-state time-to-event model. In the model all patients start in a Baseline state. From there CDP may be reached without prior OSR or with ≥1 OSRs preceding CDP. Treatment effects were evaluated in terms of risk reductions for (1) transitioning from Baseline to CDP without prior OSR, (2) transitioning from Baseline to OSR without prior CDP, and (3) transitioning to CDP following OSR.
Results: Annualised transition rates (number of transitions divided by number of patient-years of follow-up for the respective transition) were calculated. The transition rate to 3mCDP without prior OSR was 0.20 for placebo and 0.17 for siponimod patients. For transition from Baseline to OSR state, the rates were 0.14 for placebo and 0.07 for siponimod patients. For transition from OSR to 3mCDP in these relapsing patients, rates of 0.74 for placebo and of 0.48 for siponimod patients were found. Similar results were observed for 6mCDP. Based on the model, siponimod reduced the risk of 3mCDP and 6mCDP in patients with OSR by 31% and 19%, respectively, and by 13% and 22% in patients without OSR, respectively. The risk reduction for 6mCDP in patients without OSR reached nominal statistical significance (HR 0.78 [95%CI (0.61; 0.98)]).
Conclusions: The exploratory multi-state model indicates that siponimod reduces the risk of CDP independently from OSRs. For both, 3mCDP and 6mCDP, HRs for CDP without prior OSR favoured siponimod over placebo.
Disclosure: Funding source: This study was funded by Novartis Pharma AG, Basel, Switzerland.
Ludwig Kappos has received no personal compensation. Ludwig Kappos' institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees from 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 from Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; license fees for Neurostatus products and grants from Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, and the Swiss National Research Foundation.
Patrick Vermersch has received honoraria and consulting fees from Biogen Idec, Genzyme-Sanofi, Bayer, Novartis, Merck Serono, GSK, Almirall, and Servier; research support from Biogen Idec, Genzyme-Sanofi, Bayer, and Merck Serono.
Amit Bar-Or has received personal compensation for consulting, serving on scientific advisory boards, and/or speaking activities from Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly, F. Hoffmann-La Roche Ltd., Genentech, GlaxoSmithKline (GSK), Guthy-Jackson/GGF, Merck Serono, Novartis, Ono Pharmacia, Sanofi-Aventis, Teva Neuroscience, and Wyeth.
Ralf Gold has received compensation for serving as a consultant or speaker from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience, and he or the institution he works for has received research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience; he has also received honoraria as a Journal Editor from SAGE and Thieme Verlag.
Robert Fox has received compensation for serving as consultant or speaker from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva Pharmaceutical Industries. He or the institution he works for has received research support from Novartis.
Bruce Cree has received personal compensation for consulting from Abbvie, Biogen Idec, EMD Serono, and Novartis.
Baldur Magnusson, Nicolas Rouyrre, Ana de Vera and Frank Dahlke re employees of Novartis.
Christian Wolf is a partner at Lycalis sprl. He is serving as a consultant to Novartis and has also received compensation for serving as a consultant for to-BBB, Desitin, Investitionsbank Berlin, Keyrus, Synthon, Mylan, ICON and Teva.
Gavin Giovannoni is a steering committee member on the daclizumab trials for AbbVie, the BG12 and daclizumab trials for Biogen-Idec, 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-Serono, 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).

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