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Krzysztof Selmaj - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis radiance a multicentre randomised 24 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Jeffrey A Cohen, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Giancarlo Comi, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus Interferon Beta-1a in individuals with relapsing multiple sclerosis. Methods We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18–55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0–5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation. Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months. The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , NCT02047734 , and EudraCT, 2012-002714-40. Findings Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to Interferon Beta-1a) and 1138 (86·7%) completed 24 months of treatment. Adjusted ARRs were 0·17 (95% CI 0·14–0·21) with ozanimod 1·0 mg, 0·22 (0·18–0·26) with ozanimod 0·5 mg, and 0·28 (0·23–0·32) with Interferon Beta-1a, with rate ratios versus Interferon Beta-1a of 0·62 (95% CI 0·51–0·77; p Interpretation In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular Interferon Beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis sunbeam a multicentre randomised minimum 12 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Giancarlo Comi, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular Interferon Beta-1a in participants with relapsing multiple sclerosis. Methods SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18–55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0–5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , number NCT02294058 and EudraCT, number 2014–002320–27. Findings Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or Interferon Beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the Interferon Beta-1a group). Adjusted ARRs were 0·35 (0·28–0·44) for Interferon Beta-1a, 0·18 (95% CI 0·14–0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41–0·66] vs Interferon Beta-1a; p Interpretation In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than Interferon Beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • consistent efficacy of daclizumab Beta across patient demographic and disease activity subgroups in patients with relapsing remitting multiple sclerosis
    Multiple sclerosis and related disorders, 2017
    Co-Authors: John W. Rose, Ludwig Kappos, Gavin Giovannoni, Krzysztof Selmaj, Heinz Wiendl, Ralf Gold, Eva Havrdova, Jun Zhao, Katherine Riester, Claire L Tsao
    Abstract:

    Abstract Background Daclizumab Beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab Beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) Interferon Beta-1a. Objectives To determine if the efficacy of daclizumab Beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. Methods In the SELECT study, patients received daclizumab Beta 150 or 300 mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab Beta 150 mg administered subcutaneously every 4 weeks for 96–144 weeks, and were compared with patients who received IM Interferon Beta-1a 30 µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous Interferon Beta-1a use. Results Treatment with daclizumab Beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with Interferon Beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab Beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab Beta treatment compared with placebo or Interferon Beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). Conclusions These findings suggest that treatment with daclizumab Beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS.

  • p 1 effect of ocrelizumab on magnetic resonance imaging markers of neurodegeneration in patients with relapsing multiple sclerosis analysis of the phase iii double blind double dummy Interferon Beta 1a controlled opera i and opera ii studies
    Clinical Neurophysiology, 2017
    Co-Authors: T Ziemssen, Ludwig Kappos, Amit Baror, Krzysztof Selmaj, Stephen L Hauser, Fred D. Lublin, Douglas L Arnold, H P Hartung, G Comi, Anthony Traboulsee
    Abstract:

    Background Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+B cells. The pathogenesis of multiple sclerosis (MS), including neurodegeneration, is thought to be influenced by B cells. Volumetric magnetic resonance imaging (MRI) measurements can be used to assess neurodegeneration. Objective To evaluate the effect of OCR vs Interferon Beta-1a (IFN β -1a) on brain MRI markers of neurodegeneration in patients with relapsing MS enrolled in two identical Phase III, randomised, double-blind, double-dummy trials (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomised (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44  μ g three-times weekly over 96 weeks. MRI endpoints thought to be related to neurodegeneration included the change in whole brain volume, change in cortical grey matter volume and change in cerebral white matter volume. Results Compared with IFN β -1a, OCR reduced the rate of whole brain volume loss from baseline to Week 96 by 23.5% ( p p  = 0.0001), and from Week 24 to Week 96 by 22.8% ( p  = 0.0042) and 14.9% ( p  = 0.0900) in OPERA I and OPERA II, respectively. OCR-treated patients showed a smaller mean percentage of cortical grey matter volume loss compared with IFN β -1a from baseline to Week 96, with a mean difference of 0.273% ( p  = 0.0005) in OPERA I and 0.516% ( p β -1a from baseline to Week 96, with a mean difference of 0.261% ( p  = 0.0024); in OPERA II, there was no difference ( p  = 0.2748) in cerebral white matter volume loss in patients treated with OCR compared with IFN β -1a from baseline to Week 96. Conclusion The rate of neurodegeneration as measured by whole brain, cortical grey and cerebral white matter volume loss on MRI was reduced by OCR compared with IFN β -1a in patients with relapsing MS over 96 weeks. This study is sponsored by F. Hoffmann-La Roche Ltd.

  • ocrelizumab versus Interferon Beta 1a in relapsing multiple sclerosis
    The New England Journal of Medicine, 2017
    Co-Authors: Stephen L Hauser, Hans-peter Hartung, Bernhard Hemmer, Amit Baror, Gavin Giovannoni, Xavier Montalban, K Rammohan, Fred D. Lublin, Giancarlo Comi, Krzysztof Selmaj
    Abstract:

    BackgroundB cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. MethodsIn two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous Interferon Beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with ocrelizumab than with Interferon Beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with Interferon Beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disabilit...

Douglas L Arnold - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis sunbeam a multicentre randomised minimum 12 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Giancarlo Comi, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular Interferon Beta-1a in participants with relapsing multiple sclerosis. Methods SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18–55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0–5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , number NCT02294058 and EudraCT, number 2014–002320–27. Findings Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or Interferon Beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the Interferon Beta-1a group). Adjusted ARRs were 0·35 (0·28–0·44) for Interferon Beta-1a, 0·18 (95% CI 0·14–0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41–0·66] vs Interferon Beta-1a; p Interpretation In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than Interferon Beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis radiance a multicentre randomised 24 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Jeffrey A Cohen, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Giancarlo Comi, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus Interferon Beta-1a in individuals with relapsing multiple sclerosis. Methods We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18–55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0–5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation. Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months. The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , NCT02047734 , and EudraCT, 2012-002714-40. Findings Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to Interferon Beta-1a) and 1138 (86·7%) completed 24 months of treatment. Adjusted ARRs were 0·17 (95% CI 0·14–0·21) with ozanimod 1·0 mg, 0·22 (0·18–0·26) with ozanimod 0·5 mg, and 0·28 (0·23–0·32) with Interferon Beta-1a, with rate ratios versus Interferon Beta-1a of 0·62 (95% CI 0·51–0·77; p Interpretation In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular Interferon Beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • trial of fingolimod versus Interferon Beta 1a in pediatric multiple sclerosis
    The New England Journal of Medicine, 2018
    Co-Authors: Tanuja Chitnis, Gavin Giovannoni, A Ghezzi, Douglas L Arnold, Brenda Banwell, Wolfgang Bruck, Benjamin Greenberg, Lauren B Krupp, Kevin Rostasy, Marc Tardieu
    Abstract:

    Abstract Background Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with Interferon Beta-1a ...

  • p 1 effect of ocrelizumab on magnetic resonance imaging markers of neurodegeneration in patients with relapsing multiple sclerosis analysis of the phase iii double blind double dummy Interferon Beta 1a controlled opera i and opera ii studies
    Clinical Neurophysiology, 2017
    Co-Authors: T Ziemssen, Ludwig Kappos, Amit Baror, Krzysztof Selmaj, Stephen L Hauser, Fred D. Lublin, Douglas L Arnold, H P Hartung, G Comi, Anthony Traboulsee
    Abstract:

    Background Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+B cells. The pathogenesis of multiple sclerosis (MS), including neurodegeneration, is thought to be influenced by B cells. Volumetric magnetic resonance imaging (MRI) measurements can be used to assess neurodegeneration. Objective To evaluate the effect of OCR vs Interferon Beta-1a (IFN β -1a) on brain MRI markers of neurodegeneration in patients with relapsing MS enrolled in two identical Phase III, randomised, double-blind, double-dummy trials (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomised (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44  μ g three-times weekly over 96 weeks. MRI endpoints thought to be related to neurodegeneration included the change in whole brain volume, change in cortical grey matter volume and change in cerebral white matter volume. Results Compared with IFN β -1a, OCR reduced the rate of whole brain volume loss from baseline to Week 96 by 23.5% ( p p  = 0.0001), and from Week 24 to Week 96 by 22.8% ( p  = 0.0042) and 14.9% ( p  = 0.0900) in OPERA I and OPERA II, respectively. OCR-treated patients showed a smaller mean percentage of cortical grey matter volume loss compared with IFN β -1a from baseline to Week 96, with a mean difference of 0.273% ( p  = 0.0005) in OPERA I and 0.516% ( p β -1a from baseline to Week 96, with a mean difference of 0.261% ( p  = 0.0024); in OPERA II, there was no difference ( p  = 0.2748) in cerebral white matter volume loss in patients treated with OCR compared with IFN β -1a from baseline to Week 96. Conclusion The rate of neurodegeneration as measured by whole brain, cortical grey and cerebral white matter volume loss on MRI was reduced by OCR compared with IFN β -1a in patients with relapsing MS over 96 weeks. This study is sponsored by F. Hoffmann-La Roche Ltd.

  • efficacy of ocrelizumab in patients with relapsing multiple sclerosis pooled analysis of two identical phase iii double blind double dummy Interferon Beta 1a controlled studies s49 003
    Neurology, 2016
    Co-Authors: Stephen L Hauser, Hans-peter Hartung, Amit Baror, Krzysztof Selmaj, Fred D. Lublin, Giancarlo Comi, Douglas L Arnold, Anthony Traboulsee, Gaelle Klingelschmitt, Donna Masterman
    Abstract:

    Objective To evaluate the efficacy of ocrelizumab compared with Interferon Beta-1a (IFNβ-1a) through pooled analysis of efficacy in OPERA I and OPERA II. Background MS pathogenesis is understood to involve two distinct, but overlapping mechanisms, with early inflammation and concurrent or subsequent neurodegeneration. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20 + B cells, was superior in reducing annualized relapse rate (ARR) vs IFNβ-1a in OPERA I and OPERA II, two identical Phase III, randomized, double-blind, double-dummy trials in relapsing MS. Methods Pooled analyses of OPERA I and OPERA II efficacy were considered to be valid if treatment differences between the ocrelizumab and IFNβ-1a groups for ARR through week 96 and ≥12-week confirmed disability progression (CDP) were broadly consistent between the two studies; i.e. p>0.1 for study-by-treatment group interaction or p≤0.1 for study-by-treatment group interaction and both within-study treatment differences point to the same direction. Pre-specified pooled analyses included ≥12-week and ≥24-week CDP and ≥12-week confirmed disability improvement (CDI) through week 96. Results Consistency of baseline characteristics and treatment effects across both studies met pre-determined criteria for pooled efficacy analysis. Compared with IFNβ-1a, ocrelizumab showed a 47[percnt] reduction in adjusted ARR (p<0.0001) and reduced the risk of 12-week CDP by 40[percnt] (p=0.0006) and 24-week CDP by 40[percnt] (p=0.0025). In pooled analyses, the proportion of ocrelizumab-treated patients that achieved CDI at 12 and 24 weeks was 20.7[percnt] and 15.6[percnt] vs 15.6[percnt] and 11.6[percnt], respectively, for IFNβ-1a-treated patients, representing a 33[percnt] and 36[percnt] relative improvement (relative risk 1.33 [p=0.0194] and 1.36 [p=0.0343]), respectively. Ocrelizumab showed an 18.8[percnt] reduction in brain atrophy vs IFNβ-1a (p=0.0015). Conclusions Pooled analyses of OPERA I and OPERA II efficacy endpoints showed that ocrelizumab significantly suppressed disease progression and increased the proportion of patients with disability improvement over 96 weeks compared with IFNβ-1a. Supported by F. Hoffmann-La Roche Disclosure: Dr. Hauser has received personal compensation for activities with Annexon, Symbiotix, Bionure as a scientific advisory board member and from F. Hoffmann-La Roche Ltd. Dr. Arnold holds stock and/or stock options in NeuroRx Research, which sponsored research in which Dr. Arnold was an investigator. Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly as a consultant, speaker and advisory board member. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Almirall, and Serono Symposia International Foundation. Dr. Hartung has received personal compensation for activities with from Bayer, Biogen, GeNeuro, Genzyme as speaker, committee member, consultant. Dr. Lublin has received personal compensation for activities with Acorda Therapeutics, Inc., Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Inc.,Genzyme, Sanofi, Celgene, Cognition Pharmaceuticals, Inc., Elsevier, NIH, and NMSS. Dr. Selmaj has received personal compensation for activities with Biogen Idec, Novartis, TEVA Pharmaceuticals, Roche Diagnostics Corporation, Genzyme, Synthon, Receptos, and Bayer for serving on the Scientific Advisory Board. Dr. Traboulsee has received personal compensation for activities with Genzyme and Roche. Dr. Traboulsee has received research support from Genzyme, Roche, Chugai. Dr. Klingelschmitt holds stock and/or stock options in F. Hoffmann-La Roche, Ltd., which sponsored research in which Dr. Klingelschmitt was involved as an investigator. Dr. Masterman holds stock and/or stock options in Genentech, which sponsored research in which Dr. Masterman was involved as an investigator. Dr. Fontoura has received personal compensation for activities with.F. Hoffmann-La Roche as an employee. Dr. Chin has received personal compensation for activities with Genentech, Inc. as an employee. Dr. Garren has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Kappos9s institution (University Hospital Basel) has received royalty payments from Neurostatus Systems GmbH.

Ludwig Kappos - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis sunbeam a multicentre randomised minimum 12 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Giancarlo Comi, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular Interferon Beta-1a in participants with relapsing multiple sclerosis. Methods SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18–55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0–5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , number NCT02294058 and EudraCT, number 2014–002320–27. Findings Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or Interferon Beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the Interferon Beta-1a group). Adjusted ARRs were 0·35 (0·28–0·44) for Interferon Beta-1a, 0·18 (95% CI 0·14–0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41–0·66] vs Interferon Beta-1a; p Interpretation In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than Interferon Beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • consistent efficacy of daclizumab Beta across patient demographic and disease activity subgroups in patients with relapsing remitting multiple sclerosis
    Multiple sclerosis and related disorders, 2017
    Co-Authors: John W. Rose, Ludwig Kappos, Gavin Giovannoni, Krzysztof Selmaj, Heinz Wiendl, Ralf Gold, Eva Havrdova, Jun Zhao, Katherine Riester, Claire L Tsao
    Abstract:

    Abstract Background Daclizumab Beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab Beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) Interferon Beta-1a. Objectives To determine if the efficacy of daclizumab Beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. Methods In the SELECT study, patients received daclizumab Beta 150 or 300 mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab Beta 150 mg administered subcutaneously every 4 weeks for 96–144 weeks, and were compared with patients who received IM Interferon Beta-1a 30 µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous Interferon Beta-1a use. Results Treatment with daclizumab Beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with Interferon Beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab Beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab Beta treatment compared with placebo or Interferon Beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). Conclusions These findings suggest that treatment with daclizumab Beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS.

  • p 1 effect of ocrelizumab on magnetic resonance imaging markers of neurodegeneration in patients with relapsing multiple sclerosis analysis of the phase iii double blind double dummy Interferon Beta 1a controlled opera i and opera ii studies
    Clinical Neurophysiology, 2017
    Co-Authors: T Ziemssen, Ludwig Kappos, Amit Baror, Krzysztof Selmaj, Stephen L Hauser, Fred D. Lublin, Douglas L Arnold, H P Hartung, G Comi, Anthony Traboulsee
    Abstract:

    Background Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+B cells. The pathogenesis of multiple sclerosis (MS), including neurodegeneration, is thought to be influenced by B cells. Volumetric magnetic resonance imaging (MRI) measurements can be used to assess neurodegeneration. Objective To evaluate the effect of OCR vs Interferon Beta-1a (IFN β -1a) on brain MRI markers of neurodegeneration in patients with relapsing MS enrolled in two identical Phase III, randomised, double-blind, double-dummy trials (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomised (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44  μ g three-times weekly over 96 weeks. MRI endpoints thought to be related to neurodegeneration included the change in whole brain volume, change in cortical grey matter volume and change in cerebral white matter volume. Results Compared with IFN β -1a, OCR reduced the rate of whole brain volume loss from baseline to Week 96 by 23.5% ( p p  = 0.0001), and from Week 24 to Week 96 by 22.8% ( p  = 0.0042) and 14.9% ( p  = 0.0900) in OPERA I and OPERA II, respectively. OCR-treated patients showed a smaller mean percentage of cortical grey matter volume loss compared with IFN β -1a from baseline to Week 96, with a mean difference of 0.273% ( p  = 0.0005) in OPERA I and 0.516% ( p β -1a from baseline to Week 96, with a mean difference of 0.261% ( p  = 0.0024); in OPERA II, there was no difference ( p  = 0.2748) in cerebral white matter volume loss in patients treated with OCR compared with IFN β -1a from baseline to Week 96. Conclusion The rate of neurodegeneration as measured by whole brain, cortical grey and cerebral white matter volume loss on MRI was reduced by OCR compared with IFN β -1a in patients with relapsing MS over 96 weeks. This study is sponsored by F. Hoffmann-La Roche Ltd.

  • daclizumab hyp versus Interferon Beta 1a in relapsing multiple sclerosis
    The New England Journal of Medicine, 2015
    Co-Authors: Ludwig Kappos, Krzysztof Selmaj, John W. Rose, Heinz Wiendl, Eva Havrdova, Douglas L Arnold, Alexey Boyko, Michael Kaufman, Steven J Greenberg, Marianne T Sweetser
    Abstract:

    BackgroundDaclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders. MethodsWe conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing–remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with Interferon Beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with daclizumab HYP than with Interferon Beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower w...

  • daclizumab hyp reduced brain mri lesion activity compared with Interferon Beta 1a results from the decide study p7 252
    Neurology, 2015
    Co-Authors: John W. Rose, Ludwig Kappos, Krzysztof Selmaj, Heinz Wiendl, Eva Havrdova, Douglas L Arnold, Alexey Boyko, Michael Kaufman, Steven Greenberg, Marianne T Sweetser
    Abstract:

    OBJECTIVE: To evaluate the impact of treatment with daclizumab high-yield process (DAC HYP) versus Interferon Beta-1a (IFNβ-1a) on brain magnetic resonance imaging (MRI) lesion activity in patients with relapsing-remitting multiple sclerosis (RRMS). BACKGROUND: In the 52-week SELECT study, subcutaneous DAC HYP 150mg every 4 weeks significantly reduced clinical multiple sclerosis disease activity and brain MRI activity compared with placebo in patients with RRMS. DESIGN/METHODS: DECIDE was a randomized, double-blind, Phase 3 study of subcutaneous DAC HYP 150mg once every 4 weeks versus intramuscular IFNβ-1a 30mcg once weekly for 96 to 144 weeks in RRMS patients. Prospective brain magnetic resonance imaging (MRI) endpoints included: numbers of new/newly-enlarging T2 hyperintense lesions, gadolinium-enhancing lesions, or new T1 hypointense lesions; volume of T2 hyperintense lesions and T1 hypointense (black hole) lesions; and change in whole brain volume over 96 weeks. RESULTS: 1841 patients were randomized and treated (DAC HYP, n=919; IFNβ-1a, n=922). At Week 96, DAC HYP treatment versus IFNβ-1a resulted in 54[percnt], 65[percnt], and 52[percnt] reductions in the number of new/enlarging T2 hyperintense lesions, gadolinium-enhancing lesions, and new T1 hypointense (black holes) lesions (all P P P P P =0.03) and Weeks 24 to 96 (0.52 vs 0.56; P <0.0001). CONCLUSIONS: DAC HYP reduced focal inflammatory lesions and brain atrophy over a 2-3 year treatment period compared with IFNβ-1a. Study Supported by: Biogen Idec and AbbVie Biotherapeutics. Disclosure: Dr. Weindl has received personal compensation for activities with Bayer HealthCare, Biogen Idec, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, and Novartis. Dr. Arnold has received personal compensation for activities with Acorda, Bayer Healthcare, Biogen Idec, Merck Serono, Genentech, Genzyme, GlaxoSmithKline, Medimmune, Novartis, Receptos, Inc., Roche, Sanofi-Aventis, and Teva. Dr. Kappos has received personal compensation for activities with Actelion Pharmaceuticals. Dr. Havrdova has received research support from the Czech Ministries of Education and Health. Dr. Selmaj has received personal compensation for activities with Genzyme Corporation, Novartis, Ono Pharmaceutical, Roche Diagnostics Corporation, Synthon, Teva Neuroscience, and Biogen Idec. as a consultant and/or speaker. Dr. Boyko has received personal compensation for activities with Bayer Schering, Merck Serono, Teva, Novartis, Biogen Idec, Nycomed, Genzyme, and Sanofi-Aventis as a consultant and/or speaker. Dr. Kaufman has received personal compensation for activities with Biogen Idec, Acorda Therapeutics, Genzyme, Novartis, and Teva. Dr. Rose has received research support from Biogen Idec, AbbieVie, Teva Neuroscience, Cumming Foundation, National Multiple Sclerosis Society, Veterans Affairs, and the National Institutes of Health. Dr. Greenberg holds stock and/or stock options in AbbVie. Dr. Sweetser holds stock and/or stock options in Biogen Idec. Dr. Riester has received personal compensation for activities with Biogen Idec as an employee. Dr. Elkins holds stock and/or stock options in Biogen Idec.

Eva Havrdova - One of the best experts on this subject based on the ideXlab platform.

  • treatment response score to glatiramer acetate or Interferon Beta 1a
    Neurology, 2020
    Co-Authors: Francesca Bovis, Fred D. Lublin, Eva Havrdova, Maria Trojano, Tomas Kalincik, Gary Cutter, Charles B Malpas, Dana Horakova, Alexandre Prat, Marc Girard
    Abstract:

    OBJECTIVE: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular Interferon Beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments. METHODS: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. RESULTS: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity p < 0.0001). CONCLUSIONS: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.

  • treatment response score to glatiramer acetate or Interferon Beta 1a
    Neurology, 2020
    Co-Authors: Francesca Bovis, Fred D. Lublin, Eva Havrdova, Maria Trojano, Tomas Kalincik, Gary Cutter, Charles B Malpas, Dana Horakova, Alexandre Prat, Marc Girard
    Abstract:

    Objective To compare the effectiveness of glatiramer acetate (GA) vs intra-muscular Interferon Beta-1a (IFNBeta-1a)), we applied a previously published statistical method, aimed at identifying patients9 profiles associated with efficacy of treatments. Methods Data from 2 independent multiple sclerosis datasets, a randomized study (the CombiRx trial, evaluating GA vs IFNBeta-1a and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. Results The overall ARR ratio of GA vs IFNBeta-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration and EDSS) detected differential response of GA vs IFNBeta-1a: in the trial, patients with the largest benefit from GA vs IFNBeta-1a (lower score quartile) had an ARR ratio of 0.40 (95%confidence interval [CI] = 0.25–0.63), those in the 2 middle quartiles of 0.90 (95% CI = 0.61–1.34) and those in the upper quartile of 1.14 (95%CI = 0.59–2.18) (heterogeneity p = 0.012); this result was validated on MSbase, with the corresponding ARR ratios of 0.58 (95% CI = 0.46–0.72), 0.92 (95% CI = 0.77–1.09) and 1.29 (95% CI = 0.97–1.71); heterogeneity p Conclusions We demonstrate the possibility of a criterion, based on patients9 characteristics, to choose whether to treat with GA or IFNBeta-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis sunbeam a multicentre randomised minimum 12 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Giancarlo Comi, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular Interferon Beta-1a in participants with relapsing multiple sclerosis. Methods SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18–55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0–5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , number NCT02294058 and EudraCT, number 2014–002320–27. Findings Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or Interferon Beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the Interferon Beta-1a group). Adjusted ARRs were 0·35 (0·28–0·44) for Interferon Beta-1a, 0·18 (95% CI 0·14–0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41–0·66] vs Interferon Beta-1a; p Interpretation In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than Interferon Beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis radiance a multicentre randomised 24 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Jeffrey A Cohen, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Giancarlo Comi, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus Interferon Beta-1a in individuals with relapsing multiple sclerosis. Methods We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18–55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0–5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation. Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months. The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , NCT02047734 , and EudraCT, 2012-002714-40. Findings Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to Interferon Beta-1a) and 1138 (86·7%) completed 24 months of treatment. Adjusted ARRs were 0·17 (95% CI 0·14–0·21) with ozanimod 1·0 mg, 0·22 (0·18–0·26) with ozanimod 0·5 mg, and 0·28 (0·23–0·32) with Interferon Beta-1a, with rate ratios versus Interferon Beta-1a of 0·62 (95% CI 0·51–0·77; p Interpretation In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular Interferon Beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • consistent efficacy of daclizumab Beta across patient demographic and disease activity subgroups in patients with relapsing remitting multiple sclerosis
    Multiple sclerosis and related disorders, 2017
    Co-Authors: John W. Rose, Ludwig Kappos, Gavin Giovannoni, Krzysztof Selmaj, Heinz Wiendl, Ralf Gold, Eva Havrdova, Jun Zhao, Katherine Riester, Claire L Tsao
    Abstract:

    Abstract Background Daclizumab Beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab Beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) Interferon Beta-1a. Objectives To determine if the efficacy of daclizumab Beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. Methods In the SELECT study, patients received daclizumab Beta 150 or 300 mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab Beta 150 mg administered subcutaneously every 4 weeks for 96–144 weeks, and were compared with patients who received IM Interferon Beta-1a 30 µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous Interferon Beta-1a use. Results Treatment with daclizumab Beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with Interferon Beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab Beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab Beta treatment compared with placebo or Interferon Beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). Conclusions These findings suggest that treatment with daclizumab Beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS.

Hans-peter Hartung - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis radiance a multicentre randomised 24 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Jeffrey A Cohen, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Giancarlo Comi, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus Interferon Beta-1a in individuals with relapsing multiple sclerosis. Methods We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18–55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0–5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation. Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months. The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , NCT02047734 , and EudraCT, 2012-002714-40. Findings Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to Interferon Beta-1a) and 1138 (86·7%) completed 24 months of treatment. Adjusted ARRs were 0·17 (95% CI 0·14–0·21) with ozanimod 1·0 mg, 0·22 (0·18–0·26) with ozanimod 0·5 mg, and 0·28 (0·23–0·32) with Interferon Beta-1a, with rate ratios versus Interferon Beta-1a of 0·62 (95% CI 0·51–0·77; p Interpretation In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular Interferon Beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • safety and efficacy of ozanimod versus Interferon Beta 1a in relapsing multiple sclerosis sunbeam a multicentre randomised minimum 12 month phase 3 trial
    Lancet Neurology, 2019
    Co-Authors: Giancarlo Comi, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Xavier Montalban, Krzysztof Selmaj, Eva Havrdova, Douglas L Arnold, Lawrence Steinman, Bruce A.c. Cree
    Abstract:

    Summary Background Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular Interferon Beta-1a in participants with relapsing multiple sclerosis. Methods SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18–55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0–5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular Interferon Beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov , number NCT02294058 and EudraCT, number 2014–002320–27. Findings Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or Interferon Beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the Interferon Beta-1a group). Adjusted ARRs were 0·35 (0·28–0·44) for Interferon Beta-1a, 0·18 (95% CI 0·14–0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41–0·66] vs Interferon Beta-1a; p Interpretation In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than Interferon Beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis. Funding Celgene International II.

  • Cladribine tablets in the ORACLE-MS study open-label maintenance period: analysis of efficacy in patients after conversion to clinically definite multiple sclerosis (CDMS) (P6.349)
    Neurology, 2017
    Co-Authors: Giancarlo Comi, Hans-peter Hartung, Mark S Freedman, Thomas Leist, Bruce A.c. Cree, Patricia K. Coyle, Patrick Vermersch, Doris Damian, Fernando Dangond
    Abstract:

    Objective: To assess annualized relapse rate (ARR) and lymphopenia during the OLMP of the ORACLE-MS study. Background: In the ORACLE-MS study in patients with a first demyelinating event, cladribine tablets (3.5 and 5.25 mg/kg) significantly reduced risk of conversion to clinically definite MS (CDMS) vs placebo. If CDMS occurred in the initial double-blind treatment period (DBTP), patients entered an open-label maintenance period (OLMP) and received Interferon-Beta 1a. Design/Methods: Participation in the OLMP was dependent upon the clinical course of the patient’s disease in the DBTP. Patients in ORACLE-MS who converted to CDMS (Poser criteria) during the DBTP entered the OLMP and received subcutaneous Interferon-Beta 1a (titrated over 4 weeks to 44 mcg) 3 times/week. Results: 109 ORACLE-MS patients converted to CDMS in the DBTP and received ≥1 dose of Interferon-Beta 1a. Median time on Interferon-Beta 1a was 56.0 weeks. Estimated ARR in the OLMP was 0.14 (95% confidence interval [CI] 0.00–0.27) for patients (n=25) originally treated with cladribine tablets 3.5 mg/kg; 0.24 (95% CI 0.07–0.40) for patients (n=24) treated with 5.25 mg/kg, and 0.42 (95% CI 0.28–0.56) for patients (n=60) who received placebo in the DBTP. Conclusions: A durable treatment effect of cladribine tablets given in the DBTP was observed in patients who converted to CDMS and switched to treatment with a different disease modifying drug (Interferon Beta-1a). Patients treated with cladribine tablets during the DBTP who converted to CDMS had a lower ARR during the OLMP than those given placebo during the DBTP. The incidence of lymphopenia was low in patients switched from cladribine tablets after conversion to CDMS and treated with Interferon-Beta, even if given within 10 months of the last cladribine tablet dose. The durable efficacy of cladribine tablets in the ORACLE-MS OLMP is consistent with the results of other clinical studies of cladribine tablets. Disclosure: Prof. Comi has received personal compensation for activities with Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion Sano as a speaker, consultant or participating on an advisory board. Dr. Leist has received personal compensation for activities with EMD Serono, Teva Neuroscience, Biogen, Bayer, Pfizer as a consultant. Dr. Leist has received research support from EMD Serono, Teva Neuroscience, Bayer, ONO, Novartis, Daiichi, and Acorda. Dr. Freedman has received personal compensation for activities with Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation, Chugai, Merck Serono, Novartis, Opexa for honoraria, consulting or participating on a advisory board. Dr. Cree has received personal compensation for activities with AbbVie, Biogen, EMD Serono, Novartis and Shire as a consultant. Dr. Coyle has received personal compensation for activities with AbbVie, Accordant, Acorda, Bayer, Biogen Idec, Genentech/Roche, Genzyme/Sanofi, Mallinckrodt, Novartis, Serono, and Teva as a consultant. Dr. Hartung has received personal compensation from Bayer, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Roche, and Sanofi Genzyme as a speaker and consultant. Dr. Vermersch has received personal compensation for activities with Biogen, Roche, Merck, Teva, Sanofi Genzyme, and Almirall. Dr. Vermersch has received research support from Roche, Biogen and Sanofi Genzyme. Dr. Damian has received personal compensation for activities with EMD Serono, Inc as an employee. Dr. Dangond has received personal compensation for activities with EMD Serono, Inc. as an employee.

  • ocrelizumab versus Interferon Beta 1a in relapsing multiple sclerosis
    The New England Journal of Medicine, 2017
    Co-Authors: Stephen L Hauser, Hans-peter Hartung, Bernhard Hemmer, Amit Baror, Gavin Giovannoni, Xavier Montalban, K Rammohan, Fred D. Lublin, Giancarlo Comi, Krzysztof Selmaj
    Abstract:

    BackgroundB cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. MethodsIn two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous Interferon Beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with ocrelizumab than with Interferon Beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with Interferon Beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disabilit...

  • efficacy of ocrelizumab in patients with relapsing multiple sclerosis pooled analysis of two identical phase iii double blind double dummy Interferon Beta 1a controlled studies s49 003
    Neurology, 2016
    Co-Authors: Stephen L Hauser, Hans-peter Hartung, Amit Baror, Krzysztof Selmaj, Fred D. Lublin, Giancarlo Comi, Douglas L Arnold, Anthony Traboulsee, Gaelle Klingelschmitt, Donna Masterman
    Abstract:

    Objective To evaluate the efficacy of ocrelizumab compared with Interferon Beta-1a (IFNβ-1a) through pooled analysis of efficacy in OPERA I and OPERA II. Background MS pathogenesis is understood to involve two distinct, but overlapping mechanisms, with early inflammation and concurrent or subsequent neurodegeneration. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20 + B cells, was superior in reducing annualized relapse rate (ARR) vs IFNβ-1a in OPERA I and OPERA II, two identical Phase III, randomized, double-blind, double-dummy trials in relapsing MS. Methods Pooled analyses of OPERA I and OPERA II efficacy were considered to be valid if treatment differences between the ocrelizumab and IFNβ-1a groups for ARR through week 96 and ≥12-week confirmed disability progression (CDP) were broadly consistent between the two studies; i.e. p>0.1 for study-by-treatment group interaction or p≤0.1 for study-by-treatment group interaction and both within-study treatment differences point to the same direction. Pre-specified pooled analyses included ≥12-week and ≥24-week CDP and ≥12-week confirmed disability improvement (CDI) through week 96. Results Consistency of baseline characteristics and treatment effects across both studies met pre-determined criteria for pooled efficacy analysis. Compared with IFNβ-1a, ocrelizumab showed a 47[percnt] reduction in adjusted ARR (p<0.0001) and reduced the risk of 12-week CDP by 40[percnt] (p=0.0006) and 24-week CDP by 40[percnt] (p=0.0025). In pooled analyses, the proportion of ocrelizumab-treated patients that achieved CDI at 12 and 24 weeks was 20.7[percnt] and 15.6[percnt] vs 15.6[percnt] and 11.6[percnt], respectively, for IFNβ-1a-treated patients, representing a 33[percnt] and 36[percnt] relative improvement (relative risk 1.33 [p=0.0194] and 1.36 [p=0.0343]), respectively. Ocrelizumab showed an 18.8[percnt] reduction in brain atrophy vs IFNβ-1a (p=0.0015). Conclusions Pooled analyses of OPERA I and OPERA II efficacy endpoints showed that ocrelizumab significantly suppressed disease progression and increased the proportion of patients with disability improvement over 96 weeks compared with IFNβ-1a. Supported by F. Hoffmann-La Roche Disclosure: Dr. Hauser has received personal compensation for activities with Annexon, Symbiotix, Bionure as a scientific advisory board member and from F. Hoffmann-La Roche Ltd. Dr. Arnold holds stock and/or stock options in NeuroRx Research, which sponsored research in which Dr. Arnold was an investigator. Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly as a consultant, speaker and advisory board member. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Almirall, and Serono Symposia International Foundation. Dr. Hartung has received personal compensation for activities with from Bayer, Biogen, GeNeuro, Genzyme as speaker, committee member, consultant. Dr. Lublin has received personal compensation for activities with Acorda Therapeutics, Inc., Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Inc.,Genzyme, Sanofi, Celgene, Cognition Pharmaceuticals, Inc., Elsevier, NIH, and NMSS. Dr. Selmaj has received personal compensation for activities with Biogen Idec, Novartis, TEVA Pharmaceuticals, Roche Diagnostics Corporation, Genzyme, Synthon, Receptos, and Bayer for serving on the Scientific Advisory Board. Dr. Traboulsee has received personal compensation for activities with Genzyme and Roche. Dr. Traboulsee has received research support from Genzyme, Roche, Chugai. Dr. Klingelschmitt holds stock and/or stock options in F. Hoffmann-La Roche, Ltd., which sponsored research in which Dr. Klingelschmitt was involved as an investigator. Dr. Masterman holds stock and/or stock options in Genentech, which sponsored research in which Dr. Masterman was involved as an investigator. Dr. Fontoura has received personal compensation for activities with.F. Hoffmann-La Roche as an employee. Dr. Chin has received personal compensation for activities with Genentech, Inc. as an employee. Dr. Garren has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Kappos9s institution (University Hospital Basel) has received royalty payments from Neurostatus Systems GmbH.