Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry

Helmut Butzkueven, Tim Spelman, Dana Horakova, Stella Hughes, Claudio Solaro, Guillermo Izquierdo, Eva Kubala Havrdová, Francois Grand'Maison, Alexandre Prat, Marc Girard, Raymond Hupperts, Marco Onofrj, Alessandra Lugaresi, Bruce Taylor, MSBase Study Group, Gavin Giovannoni, Ludwig Kappos, Stephen L Hauser, Xavier Montalban, Licinio Craveiro, Rita Freitas, Fabian Model, James Overell, Erwan Muros-Le Rouzic, Annette Sauter, Qing Wang, David Wormser, Jerry S Wolinsky, Helmut Butzkueven, Tim Spelman, Dana Horakova, Stella Hughes, Claudio Solaro, Guillermo Izquierdo, Eva Kubala Havrdová, Francois Grand'Maison, Alexandre Prat, Marc Girard, Raymond Hupperts, Marco Onofrj, Alessandra Lugaresi, Bruce Taylor, MSBase Study Group, Gavin Giovannoni, Ludwig Kappos, Stephen L Hauser, Xavier Montalban, Licinio Craveiro, Rita Freitas, Fabian Model, James Overell, Erwan Muros-Le Rouzic, Annette Sauter, Qing Wang, David Wormser, Jerry S Wolinsky

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.

Keywords: disease progression; ocrelizumab; primary progressive multiple sclerosis; wheelchair.

Conflict of interest statement

H.B.'s 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). T.S. has received compensation for serving on steering committees and advisory boards from Biogen. D.H. 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. C.S. has received honoraria/research support from Biogen, Merck Serono, Novartis, Roche, Almirall, Amgen, and Teva; and has been supported by the Italian MS Foundation. G.I. has received personal fees from Bayer, Biogen‐IDec, Novartis, Sanofi, Merck Serono, Roche, Actelion, Celgene, and Teva. E.K.H. 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. F.G. received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. A.P. does not declare any competing interests. M.G. 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. R.H. received research grants from Merck, Biogen, and Sanofi; and received honoraria from Merck, Roche, and Sanofi for invited speaker's activities. M.O. does not declare any competing interests. A.L. 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). B.T. 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. G.G. 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 Multiple Sclerosis and Related Disorders; and has received financial support for research activities from Biogen, Roche, Merck, Merck Serono, Novartis, Sanofi Genzyme, and Takeda. L.K.'s 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. S.L.H. 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. X.M. 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. L.C. is an employee of F. Hoffmann‐La Roche Ltd. R.F. is an employee of F. Hoffmann‐La Roche Ltd. F.M. is an employee and shareholder of F. Hoffmann‐La Roche Ltd. J.O. 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. E.M.‐L.R. is an employee and shareholder of F. Hoffmann‐La Roche Ltd. A.S. is an employee and shareholder of F. Hoffmann‐La Roche Ltd. Q.W. is an employee of F. Hoffmann‐La Roche Ltd. D.W. is an employee of Novartis and shareholder of F. Hoffmann‐La Roche Ltd. and Novartis. J.S.W. 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.

© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Figures

FIGURE 1
FIGURE 1
Patient disposition in the ORATORIO study period. †Forty‐seven patients (19.3%) entered safety follow‐up from DBP. ‡Seventy‐five patients (15.4%) entered safety follow‐up from DBP. §One patient (0.6%) completed the DBP+ECP but did not enter the OLE period. ¶Six patients (1.6%) completed the DBP+ECP but did not enter the OLE period. DBP, double‐blind period; ECP, extended controlled period; OCR, ocrelizumab; OLE, open‐label extension; PBO, placebo
FIGURE 2
FIGURE 2
(a) Time to 24‐week confirmed EDSS ≥7.0 during the DBP+ECP.† (b) Time to 24‐week confirmed EDSS ≥7.0 extrapolation. Hazard ratios were estimated by Cox regression, stratified by geographical region (United States vs. ROW) and age (≤45 vs. >45 years). Patients with missing baseline EDSS (n = 1) were excluded from the analysis. Patients with a post‐baseline EDSS ≥7.0 that is sustained for at least 24 weeks are considered as having an event. Patients with EDSS ≥7.0 at the time of treatment discontinuation with no further EDSS score are imputed as having an event. Parameters of the Weibull distribution were estimated based on the observed ORATORIO‐DBP+ECP data, and these parameters applied to the extrapolated curve to enable estimation of the survival function beyond the observation period. †Data cutoff for DBP+ECP in ORATORIO: February 2017. ‡The preferred model is the one with the minimum AIC value. AIC, Akaike information criterion; CI, confidence interval; DBP, double‐blind period; ECP, extended controlled period; EDSS, Expanded Disability Status Scale; HR, hazard ratio; OCR, ocrelizumab; ROW, rest of world
FIGURE 3
FIGURE 3
Time to 24‐week confirmed EDSS ≥7.0 in MSBase† and the ORATORIO DBP+ECP+OLE,‡ superimposed onto extrapolated results. Patients with a post‐baseline EDSS ≥7.0, which is sustained for at least 24 weeks, are considered as having an event. Patients with EDSS ≥7.0 at the time of treatment discontinuation with no further EDSS score are imputed as having an event in ORATORIO but are not imputed in MSBase. †Patients with PPMS with baseline EDSS 3.0–6.5 (N = 775). ‡Data presented up to 312 weeks; OLE data cutoff from January 2019. In ORATORIO, patients with missing baseline EDSS (n = 1) were excluded from the analysis. §Results extrapolated from the DBP+ECP, data cutoff from February 2017. DBP, double‐blind period; ECP, extended controlled period; EDSS, Expanded Disability Status Scale; N/A, not applicable; OCR, ocrelizumab; OLE, open‐label extension; PBO, placebo; PPMS, primary progressive multiple sclerosis

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