Abstract
Background and purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662). Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0–6.5) were investigated in ORATORIO and MSBase. Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31–0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: −4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years. Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
| Original language | English |
|---|---|
| Pages (from-to) | 1082-1090 |
| Number of pages | 9 |
| Journal | European Journal of Neurology |
| Volume | 29 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2022 |
Keywords
- disease progression
- ocrelizumab
- primary progressive multiple sclerosis
- wheelchair
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In: European Journal of Neurology, Vol. 29, No. 4, 04.2022, p. 1082-1090.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Risk of requiring a wheelchair in primary progressive multiple sclerosis
T2 - Data from the ORATORIO trial and the MSBase registry
AU - Butzkueven, Helmut
AU - Spelman, Tim
AU - Horakova, Dana
AU - Hughes, Stella
AU - Solaro, Claudio
AU - Izquierdo, Guillermo
AU - Kubala Havrdová, Eva
AU - Grand'Maison, Francois
AU - Prat, Alexandre
AU - Girard, Marc
AU - Hupperts, Raymond
AU - Onofrj, Marco
AU - Lugaresi, Alessandra
AU - Taylor, Bruce
AU - the MSBase Study Group
AU - Giovannoni, Gavin
AU - Kappos, Ludwig
AU - Hauser, Stephen L.
AU - Montalban, Xavier
AU - Craveiro, Licinio
AU - Freitas, Rita
AU - Model, Fabian
AU - Overell, James
AU - Muros-Le Rouzic, Erwan
AU - Sauter, Annette
AU - Wang, Qing
AU - Wormser, David
AU - Wolinsky, Jerry S.
N1 - Funding Information: This work was financially supported by F. Hoffmann‐La Roche Ltd., Basel, Switzerland for the study and publication of the article. Funding Information: Eleanor Foy (Articulate Science, UK) drafted the manuscript based on input from the authors, funded by F. Hoffmann–La Roche Ltd. The authors had full editorial control of the manuscript and provided final approval. The authors thank all patients, their families, and the investigators who participated in the ORATORIO trial and MSBase registry. Funding Information: institution (Monash University) has received funding from Biogen, F. Hoffmann‐La Roche Ltd., Merck. and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann‐La Roche Ltd., and Biogen; has taken part in speakers' bureaus for Biogen, Genzyme, F. Hoffmann‐La Roche Ltd., and Merck; and has received personal grants from Oxford PharmaGenesis and Biogen (prior to June 30, 2018). has received compensation for serving on steering committees and advisory boards from Biogen. received compensation for travel, speaker honoraria. and consultant fees from Biogen, Novartis, Merck, Bayer, Sanofi, Roche, and Teva; as well as support for research activities from Biogen. She was also supported by the Czech Ministry of Education project Progress Q27/LF1. S.H. has received previous travel/conference support and speaking honoraria from Biogen, Sanofi‐Genzyme, Merck, Novartis, and Roche. has received honoraria/research support from Biogen, Merck Serono, Novartis, Roche, Almirall, Amgen, and Teva; and has been supported by the Italian MS Foundation. has received personal fees from Bayer, Biogen‐IDec, Novartis, Sanofi, Merck Serono, Roche, Actelion, Celgene, and Teva. has received honoraria/research support from Biogen, F. Hoffmann‐La Roche Ltd., Merck Serono, Novartis, Sanofi Genzyme, and Teva; has served on advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and has been supported by the Czech Ministry of Education project Progress Q27/LF1. received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. does not declare any competing interests. received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis, and EMD; and has also received a research grant from Canadian Institutes of Health Research. received research grants from Merck, Biogen, and Sanofi; and received honoraria from Merck, Roche, and Sanofi for invited speaker's activities. does not declare any competing interests. has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme, and Teva. Her institutions have received research grants from Novartis (in the last 4 years). received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen, and Novartis; and has served on advisory boards for Biogen, Novartis, Roche, and CSL Australia. received personal compensation in the past for serving as a consultant for AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi Genzyme, Genentech, GlaxoSmithKline, Merck Serono, Novartis, Roche, and Teva; has received personal compensation from Elsevier for serving as an editor on ; and has received financial support for research activities from Biogen, Roche, Merck, Merck Serono, Novartis, Sanofi Genzyme, and Takeda. institution (University Hospital Basel) received in the last 3 years and used exclusively for research support at the department: steering committee, advisory board, and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df‐mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, F. Hoffmann‐La Roche Ltd., Sanofi‐Aventis, Santhera, Teva, and Vianex; and license fees for Neurostatus‐UHB products; the Research of the MS Center in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, Innoswiss, the European Union, and Roche Research Foundations. serves on the board of trustees for Neurona and on scientific advisory boards for Alector, Annexon, Bionure, and Molecular Stethoscope; and has received travel reimbursement and writing assistance from F. Hoffmann‐La Roche Ltd. and Novartis for CD20‐related meetings and presentations. has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Genzyme, Immunic, Medday, Merck, Mylan, Nervgen, Novartis, Roche, Sanofi‐Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF, and NMSS. is an employee of F. Hoffmann‐La Roche Ltd. is an employee of F. Hoffmann‐La Roche Ltd. is an employee and shareholder of F. Hoffmann‐La Roche Ltd. is currently an employee and shareholder of F. Hoffmann‐La Roche Ltd. During his previous employment he received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva, Biogen, Celgene, EMD Serono, MedDay, Novartis, Roche, Sanofi Genzyme, WebMD Global, and Allergan. His research and department were supported by grants from Sanofi Genzyme, Biogen, Novartis, and Roche. is an employee and shareholder of F. Hoffmann‐La Roche Ltd. is an employee and shareholder of F. Hoffmann‐La Roche Ltd. is an employee of F. Hoffmann‐La Roche Ltd. is an employee of Novartis and shareholder of F. Hoffmann‐La Roche Ltd. and Novartis. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda Therapeutics, Alkermes, Brainstorm Cell Therapeutics, EMD Serono, GeNeuro, GW Pharma Ltd., MedDay Pharmaceuticals, NervGen Pharma Corp, Novartis, Roche/Genentech, and Sanofi Genzyme; royalties are received for out‐licensed monoclonal antibodies through UTHealth from Millipore Corporation. H.B.'s T.S. D.H. C.S. G.I. E.K.H. F.G. A.P. M.G. R.H. M.O. A.L. B.T. G.G. Multiple Sclerosis and Related Disorders L.K.'s S.L.H. X.M. L.C. R.F. F.M. J.O. E.M.‐L.R. A.S. Q.W. D.W. J.S.W. Publisher Copyright: © 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2022/4
Y1 - 2022/4
N2 - Background and purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662). Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0–6.5) were investigated in ORATORIO and MSBase. Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31–0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: −4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years. Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
AB - Background and purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662). Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0–6.5) were investigated in ORATORIO and MSBase. Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31–0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: −4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years. Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
KW - disease progression
KW - ocrelizumab
KW - primary progressive multiple sclerosis
KW - wheelchair
UR - https://www.scopus.com/pages/publications/85105017493
U2 - 10.1111/ene.14824
DO - 10.1111/ene.14824
M3 - Article
C2 - 33724638
AN - SCOPUS:85105017493
SN - 1351-5101
VL - 29
SP - 1082
EP - 1090
JO - European Journal of Neurology
JF - European Journal of Neurology
IS - 4
ER -