Ocrelizumab reduces thalamic volume loss in patients with RMS and PPMS

Douglas L Arnold, Till Sprenger, Amit Bar-Or, Jerry S Wolinsky, Ludwig Kappos, Shannon Kolind, Ulrike Bonati, Stefano Magon, Johan van Beek, Harold Koendgen, Oscar Bortolami, Corrado Bernasconi, Laura Gaetano, Anthony Traboulsee, Douglas L Arnold, Till Sprenger, Amit Bar-Or, Jerry S Wolinsky, Ludwig Kappos, Shannon Kolind, Ulrike Bonati, Stefano Magon, Johan van Beek, Harold Koendgen, Oscar Bortolami, Corrado Bernasconi, Laura Gaetano, Anthony Traboulsee

Abstract

Background: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections.

Objective: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNβ1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570).

Methods: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model.

Results: Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen's d: RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNβ1a (p < 0.001) or placebo (p < 0.001).

Conclusion: Ocrelizumab effectively reduced thalamic volume loss compared with IFNβ1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.

Keywords: Ocrelizumab; atrophy; multiple sclerosis; thalamus; treatment outcome.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.L.A. has received consulting fees from Alkermes, Biogen, Celgene, Genentech/Roche, Frequency Therapeutics, Immunotec, Immune Tolerance Network, MedDay, Merck-Serono, Novartis, Pfizer, and Sanofi-Aventis. He has carried out contracted research for Novartis and Biogen. T.S.’s employer received compensation for speaking and advisory board/consulting activities from Actelion, Janssen, Eli Lilly, Merck-Serono, Roche, Novartis, Sandoz, Sanofi Genzyme, and Teva. A.B.-O. has received consulting fees from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi. He has carried out contracted research with Genentech, Merck/EMD Serono, and Biogen; and receives a salary from The University of Pennsylvania, Perelman School of Medicine. J.S.W. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alkermes, Avotres, Brainstorm Cell Therapeutics, Cleveland Clinic Foundation, EMD Serono, GW Pharma, MedDay, NervGen Pharma Corp, Novartis/Sandoz, Roche/Genentech, Sanofi Genzyme, and University of Alabama; royalties are received for out-licensed monoclonal antibodies through UTHealth from Millipore Corporation. L.K.s’ institution (University Hospital Basel) has received the following exclusively for research support: Steering committee, advisory board, and consultancy fees (Actelion, Bayer HealthCare, Biogen, BMS, Genzyme, Janssen, Merck, Novartis, Roche, Sanofi, Santhera, and TG Therapeutics); speaker fees (Bayer HealthCare, Biogen, Merck, Novartis, Roche, and Sanofi); support of educational activities (Allergan, Bayer HealthCare, Biogen, CSL Behring, Desitin, Genzyme, Merck, Novartis, Roche, Pfizer, Sanofi, Shire, and Teva); license fees for Neurostatus products; and grants (Bayer HealthCare, Biogen, European Union, InnoSwiss, Merck, Novartis, Roche, Swiss MS Society, and Swiss National Research Foundation). S.K. has received research support from Roche and Sanofi Genzyme; and consulting fees from Novartis. J.v.B. was an employee of F. Hoffmann-La Roche Ltd during the completion of the work related to this manuscript and is now an employee of Biogen (Cambridge, MA), which was not in any way associated with this study. U.B., S.M., H.K., and L.G. are employees and shareholders of F. Hoffmann-La Roche Ltd. C.B. and O.B. are contractors for F. Hoffmann-La Roche Ltd. A.T. has received research support from Sanofi Genzyme and Roche; has received consulting fees from Sanofi Genzyme, Roche, Teva Neuroscience, Novartis, Biogen, and EMD Serono; and has received honoraria for his involvement in speaker bureau activities for Sanofi Genzyme and Roche.

Figures

Figure 1.
Figure 1.
Associations between normalized thalamic volume and population characteristics at baseline. For continuous variables (i.e. age, disease duration, and T2w lesion volume), Spearman’s correlations were computed to assess the association with normalized thalamic volume. In this case, correlation coefficients andp values are reported. For categorical variables (i.e. sex, prior relapses, presence/absence of gadolinium-enhancing lesions), Wilcoxon rank-sum tests assessed the differences in normalized thalamic volume between groups and p values are reported.
Figure 2.
Figure 2.
Treatment effect on thalamic volume loss over time in the RMS (a) and PPMS (b) populations. BL, baseline; IFNβ1a, interferon β-1a; OCR, ocrelizumab; OLE, open-label extension; PBO, placebo; SE, standard error. Gray box in (b) represents the transition period of PPMS patients switching from placebo to ocrelizumab and entering the OLE from the extended controlled period. Percentage reductions reported in the figure were calculated as: 100 × (ocrelizumab adjusted mean—comparator arm adjusted mean)/(comparator arm adjusted mean).

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