REVIEW ARTICLE Real-world evaluation of ocrelizumab in multiple sclerosis: A systematic review Xavier Montalban1, Paul M. Matthews2, Alex Simpson3, John L. Petrie4, Cormac Sammon4, Sreeram Ramagopalan3, Giulio Disanto5 & Jens Kuhle6,7 1 Department of Neurology, Centre d’Esclerosi Mu tiple de Catalunya (Cemcat), Barcelona, Spain 2 Department of Brain Sciences, UK Dementia Research Institute Centre at Imperial College London, London, UK 3 F. Hoffmann-La Roche, Global Access, Basel, Switzerland 4 PHMR Ltd, Berkley Grove, London, UK 5 Ente Ospedaliero Cantonale (EOC), Lugano, Ticino, Switzerland 6 Department of Neurology, University Hospital, University of Basel, Basel, Switzerland 7 Departments of Biomedicine and Clinical Research, Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital, University of Basel, Basel, Switzerland Correspondence Abstract Alex Simpson, F. Hoffmann-La Roche, Grenzacherstrasse, Basel, Switzerland. Across its clinical development program, ocrelizumab demonstrated efficacy in +41798825367; E-mail: improving clinical outcomes in multiple sclerosis, including annualized relapse alex.simpson.as1@roche.com rates and confirmed disability progression. However, as with any new treat- ment, it was unclear how this efficacy would translate into real-world clinical Received: 21 September 2022; Revised: 19 practice. The objective of this study was to systematically collate the published December 2022; Accepted: 19 December real-world clinical effectiveness data for ocrelizumab in relapsing remitting mul- 2022 tiple sclerosis and primary progressive multiple sclerosis. A search strategy was Annals of Clinical and Translational developed in MEDLINE and Embase to identify articles reporting real-world Neurology 2023; 10(3): 302–311 evidence in people with relapsing remitting multiple sclerosis or primary pro- gressive multiple sclerosis receiving treatment with ocrelizumab. The search doi: 10.1002/acn3.51732 focused on English language articles only but was not limited by the country in which the study was conducted or the time frame of the study. Additional manual searches of relevant websites were also performed. Fifty-two studies were identified reporting relevant evidence. Real-world effectiveness data for ocrelizumab were consistently favorable, with reductions in relapse rate and dis- ease progression rates similar to those reported in the OPERA I/OPERA II and ORATORIO clinical trials, including in studies with more diverse patient popu- lations not well represented in the pivotal trials. Although direct comparisons are confounded by lack of randomization of treatments, outcomes reported suggest that ocrelizumab has a similar or greater efficacy than other therapy options. Initial real-world effectiveness data for ocrelizumab appear favorable and consistent with results reported in clinical trials, providing clinicians with an efficacious option to treat patients with multiple sclerosis. Current therapies have had a major impact on the Introduction management of RRMS through reduction or elimination Multiple sclerosis (MS) is an immune-mediated demyeli- of relapses. However, disease progression independent of nating neurodegenerative disease reported to affect 2.8 relapses often continues and current medicines are less million people worldwide in 2020.1 The International efficacious in people with PPMS or SPMS.3 Ocrelizumab Advisory Committee on Clinical Trials of MS defined is a humanized monoclonal antibody, the mechanism of four MS phenotypes: clinically isolated syndrome (CIS), action for which is based on the selective depletion of relapsing remitting MS (RRMS), primary progressive MS CD20+ B-cells. In two Phase III clinical trials of ocre- (PPMS), and secondary progressive MS (SPMS).2 lizumab versus interferon beta-1a (OPERA I and OPERA 302 ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. X. Montalban et al. Real-world evaluation of ocrelizumab II), ocrelizumab significantly lowered annualized relapse Results rate (ARR) compared to interferon beta-1a in RRMS patients.4 The proportion of patients at 12 and 24 weeks In total, 52 relevant studies that were consistent with the with confirmed disability progression (CDP) also was sig- scope were included (Fig. 1). A summary of included nificantly lower for patients treated with ocrelizumab. study characteristics are provided in the data supplement The ORATORIO trial found ocrelizumab to be associated (Table S2). Full text articles were available for 23 (44%) with lower rates of confirmed disability progression com- of the studies, while only conference abstracts were avail- pared to placebo in patients with PPMS at 12 and able for the remainder. Studies varied widely by geo- 24 weeks.5 graphical region; 33 reported real-world outcomes in Although randomized controlled trials (RCTs) are typi- Europe,7–39 seven in the United States,40–46 two in the cally considered the most reliable source of evidence on Middle East,47,48 three in various geographical regions,49–51 new treatments, patients enrolled in RCTs are not neces- one in South America,52 and six did not report the coun- sarily representative of patients in real-world clinical prac- try in which the study was conducted.53–58 The most fre- tice. Therefore, to have a fuller understanding of the quently reported study populations included combined impact of ocrelizumab, it is important to consider real- populations of RRMS, PPMS, and SPMS patients for world evidence alongside the results of RCTs. Here, we which data were not stratified by type of MS (n = 20). report results from a systematic literature review (SLR) to Where reported, mean/median age ranged from 35 to 62, identify and summarize published literature reporting on mean/median disease duration ranged from 2.8 to the real-world effectiveness of ocrelizumab in RRMS and 18.7 years, and mean expanded disability status scale PPMS. (EDSS) ranged from 2 to 6.5 at baseline (Table S3). Methods Clinical relapse A search strategy with no time period restriction was The proportion of patients experiencing a clinical relapse developed in MEDLINE and Embase to identify articles following initiation of ocrelizumab treatment was low reporting real-world evidence relating to clinical effective- across the studies; all studies reported relapse in fewer ness and health-related quality of life (HRQoL) in people than 20% of patients at follow-up times ranging from 3 with RRMS or PPMS receiving treatment with ocre- to 30 months, with the majority of studies reporting lizumab. The search strategies broadly included terms to relapse in fewer than 10% of patients (Table S4). One search for the health condition of interest (“relapsing study performed statistical analysis on relapse versus base- remitting multiple sclerosis,” “RRMS,” “primary progres- line and reported a statistically significant decrease in sive multiple sclerosis,” and “PPMS”) and terms to search relapse activity in RRMS patients treated with ocre- for the intervention of interest (“ocrelizumab” and “Ocre- lizumab for a minimum of 12 months (patients with vus”). The search included English language articles only relapse in the 12 months prior to receiving ocrelizumab: but did not limit by country in which the study was con- 32 [62%], patients with relapse after at least 12 months ducted or the time frame of the study. The search cap- of ocrelizumab [mean number of cycles received, 3.6]: 8 tured full peer-reviewed articles and conference abstracts [15%], P = 0.01).59 Two studies performed statistical published before 22nd March 2022, when searches were analysis of relapse data between RRMS patients receiving run. The full search strategy is provided in the data sup- different disease-modifying therapies (DMTs) and both plement (Method S1). reported significantly fewer relapses in ocrelizumab- Study selection was performed using Covidence soft- treated patients.8,39 ware (www.covidence.org). Screening was performed by two independent reviewers against the Population, Inter- Time to relapse vention, Comparison, Outcomes, and Study (PICOS) scope for applicability to the research questions.6 The Six studies assessed time to first relapse in patients trea- PICOS is provided in the data supplement (Table S1). ted with ocrelizumab, with patient numbers ranging For studies where the applicability was not certain, a third from 33 to 11048,18,28,34,39,51,58 (Table S5). Median time reviewer (JLP) performed additional evaluation and a to first relapse following treatment initiation with ocre- consensus decision was made through discussion between lizumab ranged from 52.5 days (411 RRMS patients the reviewers. Where sufficient information was provided, switching to ocrelizumab following fingolimod treat- included studies were checked for duplication of reported ment)51 to 8.7 months (66 RRMS and PPMS patients data (e.g., abstracts and full texts reporting the same switching to ocrelizumab following natalizumab treat- data). ment).58 In the study reporting the shortest time to ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 303 Real-world evaluation of ocrelizumab X. Montalban et al. Figure 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram. relapse, patients switching from fingolimod to ocre- shorter time to relapse, as the study also reported that lizumab had relatively longer washout periods, possibly relapse incidence during washout was significantly as a result of prescribers choosing to wait for lympho- higher in patients with longer washout periods, as was cyte counts to recover following fingolimod treatment relapse incidence up to 1 year following ocrelizumab before initiating ocrelizumab. This may account for the initiation.51 304 ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. X. Montalban et al. Real-world evaluation of ocrelizumab (Table S8). One study assessed change in EDSS scores in Annualized relapse rate different ethnicities exposed to ocrelizumab and found Fourteen studies, with patient numbers ranging from 29 they remained stable across ethnic groups.40 Based on to 1104, assessed the change in ARR compared to baseline change in EDSS score, CDP in RRMS patients was and all reported a numerical decrease in ARR following reported in 12 studies, with patient numbers ranging ocrelizumab initiation (Table S6). Three studies per- from 5 to 946 (Table S9): 11 studies reported CDP in formed statistical analysis comparing follow-up to base- fewer than 10% of patients (ranging from 0% to line and all found the decrease in ARR to be statistically 9.5%)8,13,17,23,28,30,31,39,47,51,52 and one study reported CDP significant.31,33,52 Two studies evaluated effects of ocre- in 20% of patients at a mean follow-up of 5.6 months.26 lizumab and other DMTs on ARR; ocrelizumab-treated In PPMS patients, the rates of CDP were generally higher; patients experienced significantly greater reductions in the study by Sempere et al reported CDP in 5% (1/21) of ARR compared with fingolimod-treated patients (ocre- patients with a mean follow-up of 17 months31 and the lizumab: 0.12 vs fingolimod: 0.41, P = 0.04)8 and had an remaining six studies, in which patient numbers ranged estimated 51% lower risk of ARR compared with patients from 16 to 48 and follow-up ranged from 6 months to receiving cladribine (ExpB: 0.485, 95% CI: 0.264–0.893, 2 years, reported CDP in 20.5%–37.5% of P = 0.02).39 patients,13,15,17,28,52,57 but the majority of patients in these studies experienced either improvement or no change in EDSS score. One study performed statistical analysis of Magnetic resonance imaging activity changes in disability progression in RRMS and PPMS Studies reporting magnetic resonance imaging (MRI) patients treated with ocrelizumab for a minimum of activity are summarized in the data supplement 12 months; compared to the proportion of patients expe- (Table S7). Statistical analysis of MRI activity compared riencing EDSS progression in the year prior to receiving with baseline was reported in two studies; Rojas et al ocrelizumab (RRMS patients: n = 21 [40.4%], PPMS reported a statistically significant decrease in the number patients: n = 19 [65.5%]), a smaller proportion of of RRMS patients with T2 MRI activity following patients progressed (RRMS patients: n = 2 [4%], PPMS 12 months of ocrelizumab treatment (baseline: n = 41 patients: n = 9 [31%]), although no significant changes [79%], 12 months: n = 18 [35%], P = 0.001)52 and Sem- were reported in either patient group.52 pere et al reported statistically significant decreases in the number of ocrelizumab-treated patients with gadolinium- Evidence of disease activity enhancing lesions at 4–6 months (n = 1 [1%]) and 12 months (n = 0 [0%]) relative to baseline (n = 40 Four studies, with patient numbers ranging from 33 to [57%], P < 0.001 for both).31 Significantly fewer 93, reported the proportion of patients with no evidence ocrelizumab-treated patients had new T2 lesions 3– of disease activity (NEDA): >50% of patients treated with 6 months following treatment initiation compared with ocrelizumab for up to 2 years were classified as fingolimod-treated patients (ocrelizumab: n = 0 [0%], fin- NEDA13,17,31,47 (Table S10). Regarding evidence of disease golimod: n = 5 [17%], P = 0.02)8 and ocrelizumab activity (EDA), significantly fewer patients exhibited EDA patients also had a lower risk of MRI activity at 12 months when switched from natalizumab to ocrelizumab (n = 5 compared with patients receiving cladribine (ExpB: 0.248, [15%]) compared with patients switched to fingolimod 95% CI: 0.065–0.948, P = 0.04).39 (n = 24 [56%], P < 0.001).8 Expanded disability status scale Health-related quality of life Studies reporting EDSS data are summarized in the data Three of the studies included presented HRQoL out- supplement (Tables S8 and S9). Where reported, EDSS comes, with patient numbers ranging from 93 to was assessed either by the treating neurologist or chart 3559,20,44 (Table S11). In the only study that carried out review. Five studies, in which patient numbers ranged statistical tests of differences in HRQoL in ocrelizumab- from 35 to 110, performed statistical analysis of changes treated patients between baseline and subsequent time in absolute EDSS scores compared to baseline after receiv- points, the Modified Fatigue Impact Scale (MFIS) sug- ing ocrelizumab; three reported no significant change at gested improvement with a mean change of 3.7 time points ranging from 6 months33,56 to 1 year,10 one (p = 0.02) at 1 year.44 No change in the Beck Depression reported significant improvement at 1 year,21 and one Inventory-II (BDI-II) was observed.44 In other studies, reported progression in PPMS patients, but not RRMS MFIS, BDI-II, and the EuroQol-5 Dimension Index patients, at a median follow-up time of 2.09 years19 (EQ-5D) measure acquired at baseline and at 6 months ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 305 Real-world evaluation of ocrelizumab X. Montalban et al. remained stable,9 while the Multiple Sclerosis Quality of n = 35 in the expanded group). In general, the real-world Life-54 (MSQoL-54) measure was found to remain stable studies identified by this SLR included fewer treatment- from baseline to 1 year.20 na€ıve patients, and several studies reported on study pop- ulations with a higher mean age, compared with the piv- otal clinical trials (Figs. 2 and 3). Included studies also Discussion spanned various geographical regions and likely therefore This SLR collates real-world effectiveness evidence for included study populations of varying races and ethnici- ocrelizumab in RRMS and PPMS across 52 studies, sum- ties, although this information was not specifically marizing data supporting the real-world effectiveness of reported in the vast majority of studies. Despite the diver- ocrelizumab for these indications. sity of the real-world study populations, effectiveness out- Across most of the real-world studies, baseline ARR comes appear similar to the OPERA and ORATORIO and EDSS values and ARR and CDP outcomes following trials. Three studies noted the similarity of clinical out- periods of ocrelizumab treatment were of similar magni- comes in real-world settings with clinical trials in the dis- tude to those reported by the pivotal OPERA I,4 OPERA cussion of their results,40,48,52 although comparisons II,4 and ORATORIO5 trials (Figs. 2 and 3). Only the real- between real world and clinical trial populations should world study by Rojas et al52 reported an ARR numerically be treated with caution. greater than that observed in the OPERA trials (0.23 vs In addition to demonstrating favorable real-world effec- 0.16) (Fig. 2). However, in this study, ARR values at base- tiveness that appear to be consistent with clinical trial line were slightly higher than in the trial and there was data, this SLR highlights other important aspects of real- considerable uncertainty associated with the ARR estimate world ocrelizumab use in RRMS and PPMS patients; due to the small number of patients included and the rel- three studies report stable or improving HRQoL following atively short follow-up time (1 year). Similarly, the stud- up to 1 year of ocrelizumab treatment,9,20,44 five studies ies by Neo et al26 and Fernandez-Diaz et al17 were the reported on the clinical effectiveness of switching to ocre- only ones reporting higher levels of CDP than in the lizumab from natalizumab,8,25,36,39,58 and three further RRMS trials and PPMS trials, respectively (Fig. 3). In studies described the effective and safe transition to ocre- both cases, these studies had higher baseline EDSS value lizumab from other DMTs,16,18,27 highlighting ocre- than the trials and the other real-world studies and the lizumab as a suitable option for previously treated confidence intervals spanned the trial outcomes. These patients that can mitigate the risk of disease reactivation. studies serve to illustrate how clinical outcomes in real- Only six studies captured outcome data for both ocre- world study populations can vary in relation to clinical lizumab and other treatments, which included rituximab, trial cohorts. cladribine, fingolimod, dimethyl fumarate, natalizumab, In the studies by Frahm et al18 and Bigaut et al,8 a low and teriflunomide.7–9,35,37,39 Two of the comparative stud- ARR at baseline relative to the trial and other real-world ies reported significantly superior clinical outcomes in studies was observed, which may be driven partly by the ocrelizumab-treated patients; Bigaut et al reported signifi- absence of treatment-na€ıve patients in these studies. Nota- cantly fewer relapses, a greater reduction in ARR, fewer bly, in the studies by Frahm et al and Bigaut et al, which patients with new T2 lesions, and fewer patients with capture patient groups that differ to those in the pivotal EDA when treated with ocrelizumab compared with fin- trials, ARR values following ocrelizumab were numerically golimod8 and Zanghi et al reported significantly fewer lower than at baseline and of a similar magnitude to relapses compared to rituximab- and cladribine-treated those in the other real-world studies and the trials. patients, decreased risk of ARR and MRI activity com- The study by Pereira-Coutinho et al attempted to pared to cladribine-treated patients only, and similar rates directly assess the applicability of ocrelizumab clinical trial of infection and adverse events across all treatment data to a real-world setting by splitting their retrospective groups.39 However, all of the comparative studies are rela- cohort into a “control group” that mirrored the clinical tively small and may be impacted by bias, particularly trial cohorts (aged 18–55 years, baseline EDSS 3–6.5, due to residual confounding. For example, in the study symptom duration of less than 15 years for a baseline by Bigaut et al, which compared DMTs following natal- EDSS>5 or less than 10 years if baseline EDSS<5) and an izumab cessation, time on natalizumab was longer in the “expanded group” which consisted of patients that did ocrelizumab-treated group and patient follow-up times not meet these criteria.57 The study found no significant varied in the study by Zanghi et al. Rituximab-treated differences in EDSS progression, time until EDSS progres- patients also had a higher mean number of prior DMTs sion, or secondary outcomes (timed-25-foot-walk, 9-hole- compared to ocrelizumab patients (1.7 vs 1.3) in the peg test, and MRI activity) between the groups, although study by Zanghi et al, which may account for the better sample size was small (n = 16 in the control group and relapse outcome with ocrelizumab, although the 306 ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. X. Montalban et al. Real-world evaluation of ocrelizumab Number Disease ARR Age No prior Time Study of duration Mean (mean) DMT (%) point patients (mean, y) (SD) RRMS OPERA I 410 37.1 6.7 73.8 Baseline 1.31 (0.65) b 96 weeks 0.16 (0.41) OPERA II 417 37.2 6.7 72.9 Baseline 1.32 (0.69) b 96 weeks 0.16 (0.42) Bigaut (2022) 102 48.0 13.5 0 Baseline 0.15 (0.36) 1 year 0.12 (0.39) a a Braune (2020) 352 41.7 10.8 NR Baseline 0.61 (0.82) a 1 year 0.13 (0.34)b Butzkueven (2019) 882 42.8a 9.7 11.2 Baseline 0.51 (0.74) Follow−up 0.08 (0.30)b Butzkueven (2021) 748 42.7a 12.4 13.0 Baseline 0.50 (0.69) Follow−up 0.07 (0.21)b Cellerino (2021) 17 36.9 9.3 NR Baseline 0.78 (0.70) 1 year 0.04 (0.18) 2 years 0.04 (0.21) Coban (2021) 59 38.0 7.6 42.0 Baseline 1.40 (0.90) Follow−up 0.15 (NR) Fernandez−Diaz (2021) 144 39.5 7.3 25.0 Baseline 1.12 (0.77) 10 months a 0.10 (0.40)b Frahm (2022) 2536 41.8 NR 0 Baseline 0.32 (NR) Follow−up 0.15 (NR) Pontieri (2022) 946 41.4 10.8 12.5 Baseline 0.63 (0.71)b 6 months 0.16 (0.63)b Rojas (2021) 52 37.8 8.8 14.0 Baseline 1.40 (0.70) >1 year 0.23 (0.40) Sempere (2020) 49 39.2 7.7 20.0 Baseline 1.30 (0.65) 2 years 0.02 (0.14) a Smoot (2021) 278 NR 12.0 21.5 Baseline 0.34 (0.42) 2 years 0.09 (NR) 0 0.4 0.8 1.2 1.6 2 2.4 ARR Figure 2. Annualized relapse rate in RRMS: clinical trials versus real-world studies. Colors indicate comparable time points as indicated by the key. aMedians provided in figure as means not reported. bStandard deviations for ARR in OPERA I and II, Braune et al,11 Butzkueven et al,49,50 Fernandez-Diaz et al,17 and Pontieri et al28 were back-calculated from confidence intervals. ARR, annualized relapse rate; DMT, diseasemodifying therapy; EDSS, expanded disability status scale; NR, not reported; RRMS, relapsing remitting multiple sclerosis; SD, standard deviation. ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 307 Real-world evaluation of ocrelizumab X. Montalban et al. Figure 3. Percentage of patients with confirmed disability progression (CDP): clinical trials versus real-world studies. Confidence intervals for con- firmed disability progression percentages were calculated by assuming that the data follow a binomial distribution, except for Sempere et al,31 in which the rule of three was used. aMedians provided in figure as means not reported. CDP, confirmed disability progression; DMT, disease- modifying therapy; EDSS, expanded disability status scale; NR, not reported; PPMS, primary progressive multiple sclerosis; RRMS, relapsing remit- ting multiple sclerosis. difference in number of prior DMTs was not statistically improvements in outcome, and the lack of studies com- significant. Other studies have reported varying results paring ocrelizumab with other DMTs. The limited infor- comparing rituximab with ocrelizumab, with some mation reported in some studies also precludes a reporting lack of non-inferiority of rituximab versus ocre- thorough deduplication of studies, as such some studies lizumab60 and others reporting no significant difference capturing overlapping patient populations may have been in clinical outcomes.7 As a result, comparative effective- included. While these issues render comparisons across ness conclusions are difficult to confidently draw from studies challenging, the consistency of results observed is these studies or from real-world studies in general. In notable. In order to facilitate future syntheses of real- order to best support patients and healthcare profession- world evidence on ocrelizumab, future studies should seek als in selecting an optimum therapeutic approach in to use standardized outcome definitions and publish RRMS and PPMS, further work is needed to generate evi- results in accordance with relevant reporting standards. dence on the comparative effectiveness of the available To conclude, this SLR demonstrates that initial real- therapies in the form of prospective comparative cohort world effectiveness data for ocrelizumab appear favorable studies with matched pairs.61 Any such work should seek and similar to the results reported in the OPERA I/ to utilize best practices in the design and execution of OPERA II and ORATORIO clinical trials, including in real-world studies. studies with relatively diverse patient populations across Challenges encountered in synthesizing the literature different geographical locations where baseline disease include heterogeneity in study design, study populations characteristics differed to the pivotal clinical trials. and outcome definitions, lack of information available in Although direct comparisons may be confounded by lack conference abstracts, the lack of statistical tests for of randomization or patient matching, outcomes reported 308 ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. X. Montalban et al. Real-world evaluation of ocrelizumab suggest that ocrelizumab has a similar or greater efficacy Novartis. The submitted work is not related to these than other therapy options. However, the majority of agreements. Jens Kuhle received speaker fees, research studies identified reported outcomes based on ocre- support, travel support, and/or served on advisory boards lizumab exposure times of 1 year or less. Therefore, fur- by Swiss MS Society, Swiss National Research Foundation ther work will be required to monitor the long-term (320030_189140/1), University of Basel, Progressive MS impact of ocrelizumab in RRMS and PPMS patients as Alliance, Bayer, Biogen, Bristol Myers Squibb, Celgene, larger, comparative real-world studies with longer follow- Merck, Novartis, Octave Bioscience, Roche, and Sanofi. up are published. References Author Contributions 1. Multiple Sclerosis International Federation. Atlas of MS Sreeram Ramagopalan, Cormac Sammon, and Donna 3rd edition 2020. Fountain PhD (employee of PHMR Ltd) were responsible 2. Lublin FD, Reingold SC, Cohen JA, et al. Defining the for study conception and design. John L Petrie, Alexandra clinical course of multiple sclerosis: the 2013 revisions. Ellicott MPH (employee of PHMR Ltd), and Emily Neurology. 2014;83(3):278-286. Robertshaw MSc (employee of PHMR Ltd) performed 3. Hauser SL, Cree BAC. Treatment of multiple sclerosis: a screening of studies and data extraction. Emily Robert- review. Am J Med. 2020;133(12):1380-90.e2. shaw also performed data visualization for Figures 2 and 4. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus 3. John L Petrie and Cormac Sammon drafted the manu- interferon Beta-1a in relapsing multiple sclerosis. N Engl J script. All authors reviewed and edited the manuscript. Med. 2017;376(3):221-234. 5. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Acknowledgements Engl J Med. 2017;376(3):209-220. 6. Counsell C. Formulating questions and locating primary This study was funded by F. Hoffmann-La Roche. F. studies for inclusion in systematic reviews. Ann Intern Hoffmann-La Roche contributed to the study conception, Med. 1997;127(5):380-387. study design, and editing of the manuscript. 7. Alcala C, Quintanilla-Bordas C, Gascon F, et al. Effectiveness of rituximab vs. ocrelizumab for the Conflict of Interest treatment of primary progressive multiple sclerosis: a real- world observational study. J Neurol. 2022;269:3676-3681. Xavier Montalban has received speaking honoraria and 8. Bigaut K, Kremer L, Fabacher T, et al. Ocrelizumab versus travel expenses for participation in scientific meetings, has fingolimod after natalizumab cessation in multiple been a steering committee member of clinical trials or sclerosis: an observational study. J Neurol. 2022;269:3295- participated in advisory boards of clinical trials in the 3300. past years with Abbvie, Actelion, Alexion, Biogen, Bristol- 9. Bossart J, Kamm CP, Kaufmann M, et al. Real-world Myers Squibb/Celgene, EMD Serono, Genzyme, disease-modifying therapy usage in persons with relapsing- Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, remitting multiple sclerosis: cross-sectional data from the Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, swiss multiple sclerosis registry. Mult Scler Relat Disord. Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, 2022;60:103706. Excemed, MSIF, and NMSS. Paul Matthews has received 10. Braune S, Bluemich S, Bruns C, et al. Real world consultancy fees from Novartis and Biogen. He has experience with ocrelizumab in patients with primary received honoraria or speakers’ fees from Novartis and progressive multiple sclerosis: insights from the German Biogen and has received research or educational funds neuro trans data registry. Mult Scler J. 2021;27(2 from Biogen, Novartis, Merck, and Bristol Myers Squibb. Suppl):210-211. Alex Simpson is an employee of F Hoffmann-La Roche. 11. Braune S, Heer Y, Tozzi V, et al. Real-world experience John Petrie and Cormac Sammon are employees of with ocrelizumab in the German neurotransdata registry. PHMR Ltd, which received financial support from F Mult Scler J. 2020;26(3 Suppl):69-70. Hoffmann-La Roche for the work, including the develop- 12. Buttmann M, Meuth S, Weber M, et al. The effectiveness of ment of the literature review and preparation of the ocrelizumab in real-world patients with relapsing multiple manuscript. Sreeram Ramagopalan is an employee of F sclerosis over 18 months-interim analysis of the Hoffmann-La Roche. Ente Ospedaliero Cantonale (em- CONFIDENCE study. Mult Scler J. 2021;27(2 Suppl):684-685. ployer) received compensation for Giulio Disanto: finan- 13. Cellerino M, Boffa G, Lapucci C, et al. Predictors of cial support for speaking, educational, or travel grants ocrelizumab effectiveness in patients with multiple from Biogen Idec, Sanofi Genzyme, Roche, Merck, and sclerosis. Neurotherapeutics. 2021;18(4):2579-2588. ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 309 Real-world evaluation of ocrelizumab X. Montalban et al. 14. Cellerino M, Mancuso E, Boffa G, et al. Effect of suppression and clinical outcomes. Mult Scler J. 2020;26(3 ocrelizumab treatment on retinal atrophy: preliminary Suppl):185-186. results from a single-center prospective observational 27. Pasanisi MB, Vercellino M, Schillaci V, et al. Switching to study. Mult Scler J. 2021;27(2 Suppl):501-502. ocrelizumab from other second line treatments in 15. Daniels K, van der Nat PB, Frequin S, et al. Real-world relapsing-remitting multiple sclerosis: a single center results of ocrelizumab treatment for primary progressive cohort. Mult Scler J. 2020;26(3 Suppl):311-312. multiple sclerosis. Mult Scler Int. 2020;2020:5463451. 28. Pontieri L, Blinkenberg M, Bramow S, et al. Ocrelizumab 16. Ellwardt E, Rolfes L, Klein J, et al. Ocrelizumab initiation treatment in multiple sclerosis: a Danish population-based in patients with MS: a multicenter observational study. cohort study. Eur J Neurol. 2022;29(2):496-504. Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e719. 29. Prockl V, Nickel FT, Utz KS, et al. Real world application 17. Fernandez-Diaz E, Perez-Vicente JA, Villaverde-Gonzalez of ocrelizumab in multiple sclerosis: single-center R, et al. Real-world experience of ocrelizumab in multiple experience of 128 patients. J Neurol Sci. 2020;415:116973. sclerosis in a Spanish population. Ann Dent. 2021;8 30. Rolfes L, Pawlitzki M, Pfeuffer S, et al. Ocrelizumab (2):385-394. extended interval dosing in multiple sclerosis in times of 18. Frahm N, Fneish F, Ellenberger D, et al. Therapy switches COVID-19. Neurol Neuroimmunol Neuroinflamm. 2021;8 in fingolimod-treated patients with multiple sclerosis: (5):e1035. long-term experience from the German MS registry. 31. Sempere AP, Berenguer-Ruiz L, Borrego-Soriano I, et al. Neurol Ther. 2022;11(1):319-336. Ocrelizumab in multiple sclerosis: a real-world study from 19. Guerra T, Caputo F, Bollo L, Iaffaldano P, Paolicelli D, Spain. Front Neurol. 2020;11:592304. Trojano M. Effectiveness and safety of ocrelizumab in a 32. Signoriello E, Bonavita S, Di Pietro A, et al. BMI real-world setting: A single center experience from influences CD20 kinetics in multiple sclerosis patients southern italy. Journal of the Neurological Sciences. treated with ocrelizumab. Mult Scler Relat Disord. Conference: World Congress of Neurology (WCN 2021); 2020;43:102186. Rome Italy; 429 Supplement; 2021. 33. Signoriello E, Lus G, Bonavita S, et al. Switch from 20. Impellizzeri M, Moiola L, Robotti M, et al. A 1 year follow- sequestering to anti-CD20 depleting treatment: disease up study of an italian cohort of primary progressive activity outcomes during wash-out and in the first 6 months multiple sclerosis (PPMS) patients treated with of ocrelizumab therapy. Mult Scler. 2022;28(1):93-101. ocrelizumab: changes of clinical, radiological, psychological 34. Toorop AA, van Lierop ZYGJ, Strijbis EMM, et al. The and biological markers. Eur J Neurol. 2019;26(Suppl 1):662. wearing-off phenomenon of ocrelizumab in patients with 21. Lanzillo R, Carotenuto A, Moccia M, et al. Ocrelizumab multiple sclerosis. Mult Scler Relat Disord. treatment in multiple sclerosis: Prospective real world 2022;57:103364. observational multi-center study in Campania, Italy. 35. Treffts J, Van Kesteren Y, Thiel S, et al. Short term relapse Journal of the Neurological Sciences. Conference: World risk after switching from natalizumab to ocrelizumab or Congress of Neurology (WCN 2021); Rome Italy; 429 cladribine-An international cohort study. Neurology Supplement; 2021. Conference: 73rd Annual Meeting of the American 22. Lopez Ruiz R, Dotor Garcia-Soto J, Hiraldo JDG, et al. Academy of Neurology, AAN; 2021;96(15 Suppl 1). Real world experience with ocrelizumab in patients with 36. Tsantes E, Curti E, Fiore A, Bazzurri V, Granella F. primary progressive multiple sclerosis. Mult Scler J. Ocrelizumab as exit strategy from natalizumab: results 2020;26(3 Suppl):301-302. from a clinical series. Mult Scler J. 2020;26(3 Suppl):294. 23. Lopez Ruiz R, Eichau S, Guerra Hiraldo JD, Dotor Garcia- 37. Van Kesteren Y, Treffts J, Thiel S, et al. Short term relapse Soto J, Ruiz De Arcos M, Ruiz-Pena JL. Real world data risk after switching from fingolimod to ocrelizumab on the use of ocrelizumab. Incidence of lymphopenia, B- orcladribine-An international cohort study. Neurology cell and immunoglobulins evolution. Mult Scler J. 2021;27 Conference: 73rd Annual Meeting of the American (2 Suppl):631. Academy of Neurology, AAN; 2021;96(15 Suppl 1). 24. Magyari M, Pontieri L, Blinkenberg M, et al. Early 38. van Lierop ZYGJ, Toorop AA, van Ballegoij WJC, et al. experience with ocrelizumab in Denmark. A population- Personalized B-cell tailored dosing of ocrelizumab in based registry study. Mult Scler J. 2020;26(3 Suppl):530- patients with multiple sclerosis during the COVID-19 531. pandemic. Mult Scler J. 2022;28(7):1121-1125. 25. Mancinelli CR, Scarpazza C, Cordioli C, et al. Switching 39. Zanghi A, Gallo A, Avolio C, et al. Exit strategies in to ocrelizumab in RRMS patients at risk of PML natalizumab-treated RRMS at high risk of progressive previously treated with extended interval dosing of multifocal leukoencephalopathy: a multicentre comparison natalizumab. Mult Scler. 2021;27(5):790-794. study. Neurotherapeutics. 2021;18(2):1166-1174. 26. Neo C, Singh-Curry V, Nandoskar A, et al. Real-world 40. Coban H, Germaine S, Dimaandal I, et al. Real-world data on the use of ocrelizumab, among MS patients: B-cell experience of ocrelizumab initiation in a diverse multiple 310 ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. X. Montalban et al. Real-world evaluation of ocrelizumab sclerosis population. Mult Scler Relat Disord. 52. Rojas JI, Patrucco L, Fruns M, et al. Real-world experience 2021;53:103021. of ocrelizumab in multiple sclerosis patients in Latin 41. Fan J, Bilello M, Shinohara R, Bar-Or A, Schindler M. America. Arq Neuropsiquiatr. 2021;79(4):305-309. Ocrelizumab infusion delays and radiologic relapse in 53. Miscioscia A, Puthenparampil M, Pengo M, Miante S, multiple sclerosis. Mult Scler J. 2021;27(2 Suppl):691-692. Gallo P. Optical coherence tomography in primary 42. Geils H, Stribling I, Katz J, Lathi E, Douglas E, Bouley A. progressive multiple sclerosis: INL thinning as a possible Acapella: real-world experience with ocrelizumab: an biomarker of response to ocrelizumab. Mult Scler J. observational study evaluating safety in patients with 2021;27(2 Suppl):503. relapsing and progressive ms year three. Mult Scler J. 54. Moss BP, Utigard E, Baldassari LE, Cohen JA, Ontaneda 2020;26(3 Suppl):256. DD. Real-world experience with ocrelizumab. Mult Scler J. 43. Smoot K, Chen C, Lucassen E, Stuchiner T, Grote L, 2019;25(Suppl 1):69-70. Cohan S. Utilization, safety and tolerability of 55. Novi G, Cellerino M, Nesi L, et al. Ocrelizumab in an ocrelizumab: year 1 data from the Providence ocrelizumab expanded cohort of primary progressive MS patients: registry. Mult Scler J. 2018;24(2 Suppl):288. safety outcomes and clinical/ paraclinical follow-up. Mult 44. Smoot K, Chen C, Stuchiner T, Lucas L, Grote L, Cohan Scler J. 2018;24(2 Suppl):901-902. S. Clinical outcomes of patients with multiple sclerosis 56. Ozakbas S, Ozcelik S, Kaya E, Ozdogar AT, Sagici O, Baba treated with ocrelizumab in a US community MS center: C. Early treatment response of ocrelizumab in persons an observational study. BMJ Neurol. 2021;3(2):e000108. with multiple sclerosis: six-month results. Mult Scler J. 45. Vollmer B, Ijadi N, Declusin A, et al. Two-year real-world 2021;27(2 Suppl):278. experience with ocrelizumab in the treatment of patients 57. Pereira Coutinho M, Leitao L, Ladeira F, et al. with multiple sclerosis. Mult Scler J. 2021;27(2 Suppl):595- Ocrelizumab-time to expand borders? Eur J Neurol. 596. 2021;28(Suppl 1):916. 46. Vollmer B, Nair K, Sillau S, Corboy J, Vollmer T, Alvarez 58. Smoot K, Gervasi-Follmar T, Marginean H, Chen C, E. Ocrelizumab real-world safety and effectiveness in the Zhang HJ, Repovic P. Evaluating the efficacy and safety of one year treatment of multiple sclerosis compared to other transitioning patients from natalizumab to ocrelizumab. disease modifying therapies. Mult Scler J. 2019;25(Suppl Mult Scler J. 2021;27(2 Suppl):653. 2):747-748. 59. Rojas J, Patrucco L, Fruns M, et al. Real-world experience 47. Garcia-Canibano B, Ouanes S, Ganesan GS, et al. Real- of ocrelizumab in multiple sclerosis patients in Latin world experience of ocrelizumab in multiple sclerosis in America. Mult Scler J. 2020;26(3 Suppl):548. an Arab population. J Drug Assess. 2021;10(1):106-113. 60. Roos I, Hughes S, Macdonell G. A non-inferiority study of 48. Yousuf W, Ganesan GS, Humos B, Baig T, Canibano B, rituximab versus ocrelizumab in relapsing-remitting Deleu D. Real-world experience with Ocrelizumab in multiple sclerosis. 2022 ECTRIMS Congress; October 26–28; multiple sclerosis patients: two years follow up in Qatar. Amsterdam, Netherlands; 2022. Neurology Conference: 73rd Annual Meeting of the 61. Habs M. Prospective, comparative cohort studies and their American Academy of Neurology, AAN; 2021;96(15 Suppl contribution to the benefit assessments of therapeutic 1). options: heart failure treatment with and without hawthorn 49. Butzkueven H, Spelman T, Ozakbas S, et al. Real-world special extract WS 1442. Forsch Komplementarmed Klass experience with ocrelizumab in relapsing multiple Naturheilkd. 2004;11(Suppl 1):36-39. sclerosis: insights from the MSOCR-R cohort, an MS Base registry sub-study. Mult Scler J. 2021;27(2 Suppl):104-106. 50. Butzkueven H, Spelman T, Patti F, et al. Real-world Supporting Information experience with ocrelizumab in the MSBase registry. Mult Additional supporting information may be found online Scler J. 2019;25(Suppl 2):539-540. in the Supporting Information section at the end of the 51. Zhong M, van der Walt A, Stankovich J, et al. Prediction article. of multiple sclerosis outcomes when switching to ocrelizumab. Mult Scler J. 2021;28:958-969. Table S1 ª 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 311