PMID- 37245350
OWN - NLM
STAT- MEDLINE
DCOM- 20230626
LR  - 20230626
IS  - 2211-0356 (Electronic)
IS  - 2211-0348 (Linking)
VI  - 75
DP  - 2023 Jul
TI  - Effects of baseline age and disease duration on the efficacy and safety of 
      siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.
PG  - 104766
LID - S2211-0348(23)00268-7 [pii]
LID - 10.1016/j.msard.2023.104766 [doi]
AB  - BACKGROUND: Older age and longer disease duration (DD) may impact the 
      effectiveness of disease-modifying therapies in patients with multiple sclerosis 
      (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the 
      treatment of active secondary progressive MS (SPMS) in many countries. The 
      pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS 
      population with both active and non-active disease. In this population, siponimod 
      demonstrated significant efficacy, including a reduction in the risk of 3-month 
      confirmed disability progression (3mCDP) and 6-month confirmed disability 
      progression (6mCDP). Benefits of siponimod were also observed across age and DD 
      subgroups in the overall EXPAND population. Herein we sought to assess the 
      clinical impact of siponimod across age and disease duration subgroups, 
      specifically in participants with active SPMS. METHODS: This study is a post hoc 
      analysis of a subgroup of EXPAND participants with active SPMS (>/= 1 relapse in 
      the 2 years before the study and/or >/= 1 T1 gadolinium-enhancing magnetic 
      resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or 
      placebo during EXPAND. Data were analyzed for participant subgroups stratified by 
      age at baseline (primary cut-off: < 45 year >/= 45 years; and secondary cut-off: 
      < 50 years or >/= 50 years) and by DD at baseline (< 16 years or >/= 16 years). 
      Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse 
      events (AEs), serious AEs, and AEs leading to treatment discontinuation. RESULTS: 
      Data from 779 participants with active SPMS were analyzed. All age and DD 
      subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod 
      versus placebo. Compared with placebo, siponimod significantly reduced the risk 
      of 3mCDP in participants aged >/= 45 years (hazard ratio [HR]: 0.68; 95% confidence 
      interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), >/= 50 years 
      (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 
      95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod 
      versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), 
      >/= 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 
      0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). 
      Increasing age or longer MS duration did not appear to increase the risk of AEs, 
      with an observed safety profile that remained consistent with the overall active 
      SPMS and overall SPMS populations in EXPAND. CONCLUSIONS: In participants with 
      active SPMS, treatment with siponimod demonstrated a statistically significant 
      reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not 
      every outcome reached statistical significance in the subgroup analyses (possibly 
      a consequence of small sample sizes), benefits of siponimod were seen across a 
      spectrum of ages and DD. Siponimod was generally well tolerated by participants 
      with active SPMS, regardless of baseline age and DD, and AE profiles were broadly 
      similar to those observed in the overall EXPAND population.
CI  - Copyright (c) 2023. Published by Elsevier B.V.
FAU - Hua, Le H
AU  - Hua LH
AD  - Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA. Electronic 
      address: hual@ccf.org.
FAU - Bar-Or, Amit
AU  - Bar-Or A
AD  - Department of Neurology and the Center for Neuroinflammation and Experimental 
      Therapeutics, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA.
FAU - Cohan, Stanley L
AU  - Cohan SL
AD  - Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, 
      Portland, OR, USA.
FAU - Lublin, Fred D
AU  - Lublin FD
AD  - Icahn School of Medicine at Mount Sinai, New York, NY, USA.
FAU - Coyle, Patricia K
AU  - Coyle PK
AD  - Department of Neurology, Stony Brook University, Stony Brook, NY, USA.
FAU - Cree, Bruce Ac
AU  - Cree BA
AD  - UCSF, Weill Institute for Neurosciences, Department of Neurology, University of 
      California San Francisco, San Francisco, CA, USA.
FAU - Meng, Xiangyi
AU  - Meng X
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
FAU - Su, Wendy
AU  - Su W
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
FAU - Cox, Gina Mavrikis
AU  - Cox GM
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
FAU - Fox, Robert J
AU  - Fox RJ
AD  - Mellen Center for Multiple Sclerosis Treatment and Research Neurological 
      Institute Cleveland Clinic, Cleveland, OH, USA.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
DEP - 20230516
PL  - Netherlands
TA  - Mult Scler Relat Disord
JT  - Multiple sclerosis and related disorders
JID - 101580247
RN  - 0 (Azetidines)
RN  - 0 (Benzyl Compounds)
RN  - RR6P8L282I (siponimod)
SB  - IM
MH  - Humans
MH  - *Azetidines/adverse effects
MH  - Benzyl Compounds/adverse effects
MH  - *Multiple Sclerosis/drug therapy
MH  - *Multiple Sclerosis, Chronic Progressive/drug therapy
OTO - NOTNLM
OT  - Active disease
OT  - Adverse events
OT  - Age subgroups
OT  - S1P modulator
OT  - Secondary progressive multiple sclerosis
OT  - Siponimod
COIS- Declaration of Competing Interest Le H Hua has received personal fees for 
      speaking, consulting and advisory board activities from Bristol Myers Squibb, EMD 
      Serono, Genentech, Genzyme, Novartis, TG Therapeutics, Horizon, Greenwich and 
      Alexion, and research support from Biogen paid to her institution. Amit Bar-Or 
      participated as a speaker in meetings sponsored by and received consulting fees 
      and/or grant support from Accure, Atara Biotherapeutics, Biogen, Bristol Myers 
      Squibb/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, 
      Merck/EMD Serono, Novartis, Roche/Genentech and Sanofi Genzyme, and has received 
      grant support to the University of Pennsylvania from Biogen Idec, 
      Roche/Genentech, Merck/EMD Serono and Novartis. Stanley L Cohan has received 
      speaker fees from Biogen, Bristol Myers Squibb, Novartis, Roche Genentech and 
      Sanofi Genzyme, and serves on advisory boards or as a consultant to AbbVie, 
      Biogen, Bristol Myers Squibb, EMD Serono, Novartis and Sanofi Genzyme. 
      Institutional research support (the Providence Brain and Spine Institute) was 
      received from AbbVie, Adamas, Biogen, EMD Serono, MedDay, Novartis, Roche 
      Genentech, Sage Bionetworks and Sanofi Genzyme. Fred D Lublin has participated in 
      consulting agreements, advisory boards and Data and Safety Monitoring Board 
      activities for Actelion/Janssen, Acorda, Apitope, Atara Biotherapeutics, Avotres, 
      Banner Life Sciences, Biogen, Brainstorm Cell Therapeutics, EMD Serono, GW 
      Pharma, Immunic, Jazz Pharmaceuticals, Labcorp Entelexo Biotherapeutics, Mapi 
      Pharma, Medday, MedImmune/Viela Bio/Horizon Therapeutics, Mylan, Neuralight, 
      Neurogene, Novartis, Orion Biotechnology, Population Council, 
      Receptos/Celgene/Bristol Myers Squibb, Roche/Genentech, Sanofi/Genzyme, Teva and 
      TG Therapeutics, acted as a speaker (non-promotional) for Sanofi, reports 
      research funding from Actelion, Biogen, Brainstorm Cell Therapeutics, National 
      Institutes of Health, Novartis, National Multiple Sclerosis Society and Sanofi, 
      and has stock options with Avotres and Neuralight. Patricia K Coyle has received 
      consulting fees from Accordant, Alexion, Bayer, Biogen, Celgene, Genentech/Roche, 
      Genzyme/Sanofi, GlaxoSmithKline, Mylan, Novartis, Serono and TG Therapeutics, and 
      research grants from Actelion, Alkermes, Corrona LLC, Genentech/Roche, MedDay, 
      NINDS, Novartis and PCORI. Bruce AC Cree has received personal compensation for 
      consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD 
      Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Neuron23, Novartis, Sanofi, Siemens, 
      TG Therapeutics and Therini and received research support from Genentech. Xiangyi 
      Meng, Wendy Su and Gina M Cox are employees of Novartis Pharmaceuticals 
      Corporation. Robert J Fox has received personal fees from Actelion, Biogen, 
      Celgene, EMD Serono, Genentech, Immunic, Novartis and Teva, grants from Novartis 
      and other support from Biogen and Novartis (clinical trial contracts).
EDAT- 2023/05/29 00:42
MHDA- 2023/06/19 13:08
CRDT- 2023/05/28 18:04
PHST- 2022/09/15 00:00 [received]
PHST- 2023/05/11 00:00 [revised]
PHST- 2023/05/15 00:00 [accepted]
PHST- 2023/06/19 13:08 [medline]
PHST- 2023/05/29 00:42 [pubmed]
PHST- 2023/05/28 18:04 [entrez]
AID - S2211-0348(23)00268-7 [pii]
AID - 10.1016/j.msard.2023.104766 [doi]
PST - ppublish
SO  - Mult Scler Relat Disord. 2023 Jul;75:104766. doi: 10.1016/j.msard.2023.104766. 
      Epub 2023 May 16.