RESEARCH ARTICLE OPEN ACCESS Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis Stephen L. Hauser, MD, Ludwig Kappos, MD, Xavier Montalban, MD, PhD, MBA, Licinio Craveiro, MD, PhD, Correspondence Cathy Chognot, PhD, Richard Hughes, MD, Harold Koendgen, MD, PhD, Noemi Pasquarelli, PhD, MSc, Dr. Hauser Ashish Pradhan, MD, Kalpesh Prajapati, MSc, MPhil, and Jerry S. Wolinsky, MD stephen.hauser@ucsf.edu ® Neurology 2021;97:e1546-e1559. doi:10.1212/WNL.0000000000012700 Abstract RELATED ARTICLE Background and Objectives Editorial To report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple Longer-term Safety of sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or B-Cell Therapy With Ocrelizumab in Multiple treated in real-world postmarketing settings. Sclerosis Methods Page 751 Safety analyses are based on integrated clinical and laboratory data for all patients who received MORE ONLINE OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, Class of Evidence OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), Criteria for rating additional postmarketing data were used. Incidence rates of serious infections (SIs) and ma- therapeutic and diagnostic lignancies were contextualized using multiple epidemiologic sources. studies NPub.org/coe Results At data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data. Discussion Continuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population. Classification of Evidence This analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls. From the Department of Neurology (S.L.H.), University of California, San Francisco; Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering (L.K.), Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Switzerland; Department of Neurology-Neuroimmunology (X.M.), Multiple Sclerosis Centre of Catalonia (CEMCAT), Vall d’Hebron University Hospital, Barcelona, Spain; F. Hoffmann-La Roche Ltd. (L.C., C.C., R.H., H.K., N.P.), Basel, Switzerland; Genentech, Inc. (A.P.), South San Francisco, CA; IQVIA Solutions Inc. (K.P.), Amsterdam, The Netherlands; and Department of Neurology (J.S.W.), McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. R. Hughes and H. Koendgen were employees of F. Hoffmann-La Roche Ltd. during completion of the work related to this manuscript. The Article Processing Charge was funded by F. Hoffmann-La Roche Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. e1546 Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Glossary AE = adverse event; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; BL = baseline; CI = confidence interval; CTP = controlled treatment period; DMT = disease-modifying treatment; ER = estrogen receptor; IFN = interferon; Ig = immunoglobulin; IRR = infusion-related reaction; LLN = lower limit of normal; MS = multiple sclerosis; NK = natural killer; NMSC = nonmelanoma skin cancer; OCR = ocrelizumab; OLE = open-label extension; PML = progressive multifocal leukoencephalopathy; PPMS = primary progressive multiple sclerosis; PR = progesterone receptor; PwMS = patients with multiple sclerosis; PY = patient-years; RMS = relapsing multiple sclerosis; SAE = serious adverse event; SEER = Surveillance, Epidemiology, and End Results; SI = serious infection; SIR = standardized incidence ratio; UTI = urinary tract infection; W12 = week 12. Ocrelizumab (OCR) is a recombinant humanized monoclonal time on OCR treatment and subsequent off-treatment (safety antibody that selectively depletes CD20-expressing B cells, while follow-up) up to January 3, 2020. The term “OCR all-exposure” preserving the capacity for B-cell reconstitution and preexisting describes the overall clinical trial patient population, whereas humoral immunity.1,2 The safety and efficacy of OCR were “phase 3 CTP+OLE” refers to the patient population from the characterized in phase 2 and 3 studies, leading to the approval of pivotal phase 3 trials (OPERA 1, OPERA 2, and ORATORIO) OCR for the treatment of patients with relapsing multiple scle- and respective OLEs (Figure 1). The cutoff date for post- rosis (RMS) and primary progressive multiple sclerosis marketing data was July 31, 2020 (fatalities, progressive mul- (PPMS).3-5 Results from these trials showed that OCR was as- tifocal leukoencephalopathy [PML], and female breast cancer). sociated with near-complete suppression of new brain MRI ac- tivity, significant reduction in disability progression compared Clinical and Laboratory Safety Assessments with interferon (IFN)-β-1a or placebo, and significantly lower and Statistical Analysis relapse activity compared with IFN-β-1a.3-5 The clinical benefits Safety outcomes including AEs, serious AEs (SAEs), and AEs of OCR were shown to be sustained over a follow-up period of up leading to treatment discontinuation were monitored and coded to 7 years, with more favorable disability outcomes in patients as per Medical Dictionary for Regulatory Activities (versions initiating OCR treatment earlier.6,7 18.0 to 22.1). Standard criteria for determining seriousness and severity were used. To account for different exposure lengths, In controlled treatment periods (CTPs) of the pivotal phase 3 rates of AEs per 100 patient-years (PY) are presented. Multiple trials, infusion-related reactions (IRRs), respiratory tract infec- occurrences of the same AE in 1 patient were counted multiple tions, and urinary tract infections (UTIs) were the most common times, except for malignancies. Calculation of 95% confidence adverse events (AEs) associated with OCR.4,5,8 A numerical intervals (CIs) used an exact method based on the Poisson imbalance of malignancies was observed in patients treated with distribution. For further details on clinical and laboratory safety OCR relative to its comparators, mostly driven by a higher rate of assessments, see the Supplemental Material (available from breast cancer; overall, these events were uncommon.4,5 Safety Dryad, doi.org/10.5061/dryad.w3r2280qn). surveillance to understand the long-term benefit–risk profile of OCR in patients with MS (PwMS) is therefore warranted. Standard Protocol Approvals, Registrations, and Patient Consents Here we provide an integrated safety analysis of PwMS trea- The protocols (ClinicalTrials.gov identifier numbers ted with OCR in 11 clinical trials as of January 2020, over a NCT00676715, NCT01247324, NCT01412333, NCT01194570, period of up to 7 years, and report assessments of special NCT02545868, NCT02637856, NCT02861014, NCT02688985, interest from global postmarketing surveillance. NCT03085810, NCT03523858, and NCT03599245) were ap- proved by relevant institutional review boards/ethics committees. All patients provided written informed consent. Methods Classification of Evidence Trial Design, OCR Exposure, and Data Cutoff This analysis provides Class III evidence that long-term, Safety analyses are based on integrated data from all PwMS continuous treatment with OCR has a consistent and favor- who received OCR during the controlled treatment and as- able safety profile in patients with RMS and PPMS. This study sociated open-label extension (OLE) periods of the phase 2 is rated Class III because of the use of OLE data and historical and 3 clinical trials, plus 7 phase 3b trials (Figure 1). Details controls. on study methodologies and designs are presented in the Supplemental Material and eTable 1 (available from Dryad, Data Availability doi.org/10.5061/dryad.w3r2280qn). Individual patient-level data are available to qualified re- searchers. For full details on governing policies and proce- Clinical trial exposure was determined for patients who re- dures to request access, see the Supplemental Material ceived at least one dose of OCR. Exposure time included both (available from Dryad, doi.org/10.5061/dryad.w3r2280qn). Neurology.org/N Neurology | Volume 97, Number 16 | October 19, 2021 e1547 Results with RMS or PPMS (N = 5,680) exposed to OCR over a period of up to 7 years remained consistent with the rates Patient Population and Treatment Exposure observed during the CTPs of the phase 3 trials (Table 1). As of January 2020, 5,680 PwMS (RMS 4,376; PPMS 1,304), with a median (range) age of 38.0 (18–66) years at start of Treatment Discontinuation Due to AEs treatment, had received OCR across multiple clinical trials, The proportion of patients discontinuing treatment due to resulting in 18,218 PY of exposure (Figure 1). Of these, 2,092 AEs over a period of up to 7 years was 3.19% (n = 181/5,680 PwMS had received OCR in the pivotal phase 3 trials (median patients). For patients treated with either placebo or IFN- [range] age at start of treatment: RMS 38.0 [18–58] years; β-1a, rates were 3.35% and 6.17%, respectively, over a period PPMS 47.0 [20–59] years), accounting for 11,424 PY of expo- of up to 3 years during the CTP. Malignancies (n = 40, sure over a period of up to 7 years. In the all-exposure pop- mandatory discontinuation), IRRs (n = 33) mostly occurring ulation, >50% of patients had received ≥5 doses of OCR and at the first infusion, and infections (n = 27, majority non- 28% of patients had received ≥10 doses of OCR. The total serious) were the most common AEs leading to discontinu- patient exposure in PY for each trial is presented in Figure 1. As ation in the OCR all-exposure population (available from of July 31, 2020, an estimated 174,508 PwMS have started OCR Dryad, eTable 2, doi.org/10.5061/dryad.w3r2280qn). globally, of which 167,684 initiated OCR in the postmarketing experience, amounting to an estimated exposure of 249,971 PY. Fatal Outcomes As of January 2020, 26 fatal outcomes (RMS 11/4,376; PPMS 15/1,304) had been reported in the OCR all-exposure pop- Overview of AEs ulation in clinical trials, a rate of 0.14 per 100 PY (95% CI All AEs and SAEs 0.09–0.21) (Table 1). This is consistent with the rate observed Cumulative rates of AEs (248 per 100 PY; 95% CI 246–251) at the end of the CTP and similar to rates observed for com- and SAEs (7.3 per 100 PY; 95% CI 7.0–7.7) in all patients parators (Table 1). The most frequent causes of fatal outcomes Figure 1 Safety Analyses Populations: Clinical Trials Overview and Patient Exposure as of January 2020 (A) Clinical trials overview and patient exposure. (B) Populations used in the analysis to report different clinical and laboratory safety assessments. Data cutoff: January 2020. Patients received ocrelizumab (OCR) 600 mg by IV infusion every 24 weeks, with the first dose split into two 300 mg infusions given 14 days apart. The exceptions were the controlled treatment period (CTP) of ORATORIO, where all doses were given as split 300 mg infusions, and the phase 2 trial, where in 1 treatment arm the first dose was split into two 1,000 mg infusions administered 14 days apart followed by another 1,000 mg dose at week 24. Prior to each infusion, patients were pretreated with IV 100 mg methylprednisolone (or equivalent), an IV or oral antihistamine, and an optional analgesic/antipyretic. The term “OCR all- exposure” is used to describe the overall clinical trial patient population, whereas the term “phase 3 CTP + open-label extension (OLE)” refers to the patient population from the pivotal phase 3 trials (OPERA 1, OPERA 2, and ORATORIO) and respective OLEs. Boxes are color-coded according to the populations used for respective safety measures, laboratory measures, and immunoglobulin, T cell, and antidrug antibody level measures. aPhase 2.3 bOPERA 1 and OPERA 2.4 c ORATORIO.5 dLIBERTO is the long-term extension study to CASTING, ENSEMBLE, and CONSONANCE. As of January 2020, only patients from CASTING were included in LIBERTO (n = 439; patient-years [PY] = 1,155). ALC = absolute lymphocyte count; CTP = controlled treatment period; NK = natural killer; PMS = progressive multiple sclerosis; PPMS = primary progressive multiple sclerosis; RMS = relapsing multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis. e1548 Neurology | Volume 97, Number 16 | October 19, 2021 Neurology.org/N Neurology.org/N Table 1 Rates per 100 Patient-Years (PY) of Adverse Events (AEs) in the Pivotal Phase 3 Controlled Treatment Period (CTP) + Open-Label Extension (OLE) and All-Exposure Populations OPERA ORATORIO CTPa CTP+OLEb CTPa CTP+OLEb IFN-β-1a OCR OCR Placebo OCR OCR OCR all-exposurec AE, rate per 100 PY (95% CI) (n = 826; 1,399 PY) (n = 825; 1,448 PY) (N = 1,448; 7,862 PY) (n = 239; 729 PY) (n = 486; 1,606 PY) (N = 644; 3,562 PY) (N = 5,680; 18,218 PY) Any AEs 296 (287–305) 290 (281–299) 206 (203–209) 259 (247–271) 252 (244–260) 237 (232–242) 248 (246–251) AEs leading to discontinuation 3.93 (2.96–5.12) 2.35 (1.63–3.28) 1.25 (1.01–1.52) 1.10 (0.47–2.16) 1.25 (0.76–1.92) 1.07 (0.76–1.46) 1.06 (0.92–1.22) Infusion-related reaction NA 0.76 (0.38–1.36) 0.27 (0.17–0.41) 0.14 (0.00–0.76) 0.13 (0.02–0.45) 0.06 (0.00–0.21) 0.19 (0.13–0.26) Malignancies 0.07 (0.00–0.40) 0.07 (0.00–0.39) 0.19 (0.11–0.32) 0.14 (0.00–0.76) 0.44 (0.18–0.90) 0.42 (0.24–0.70) 0.22 (0.16–0.30) Infections and infestations NA 0.14 (0.02–0.50) 0.20 (0.12–0.33) 0.41 (0.09–1.20) 0.25 (0.07–0.64) 0.20 (0.08–0.41) 0.16 (0.11–0.23) Serious AEs 6.3 (5.1–7.8) 5.4 (4.3–6.7) 5.9 (5.4–6.5) 12.1 (9.7–14.9) 10.2 (8.7–11.8) 12.9 (11.8–14.2) 7.3 (7.0–7.7) d,e Malignancies 0.14 (0.02–0.52) 0.28 (0.08–0.71) 0.36 (0.24–0.52) 0.27 (0.03–0.99) 0.93 (0.52–1.54) 1.00 (0.70–1.39) 0.46 (0.37–0.57) Fatal outcomes 0.14 (0.02–0.52) 0.07 (0.00–0.38) 0.05 (0.01–0.13) 0.41 (0.08–1.20) 0.25 (0.07–0.64) 0.39 (0.22–0.66) 0.14 (0.09–0.21) Infections and infestations 67.8 (63.5–72.2) 84.5 (79.9–89.4) 72.2 (70.3–74.1) 72.5 (66.5–79.0) 70.8 (66.8–75.0) 74.2 (71.4–77.1) 76.2 (74.9–77.4) Urinary tract infection 9.7 (8.1–11.4) 11.6 (9.9–13.5) 11.5 (10.7–12.2) 17.8 (14.9–21.2) 15.1 (13.2–17.1) 19.0 (17.6–20.5) 12.4 (11.9–13.0) Nasopharyngitis 8.3 (6.9–9.9) 13.0 (11.2–15.0) 10.3 (9.6–11.1) 17.7 (14.8–21.0) 12.8 (11.1–14.6) 12.4 (11.3–13.6) 13.4 (12.8–13.9) Upper respiratory tract infection 9.4 (7.8–11.1) 13.3 (11.5–15.3) 12.2 (11.4–13.0) 2.9 (1.8–4.4) 5.2 (4.2–6.5) 5.1 (4.4–5.9) 9.7 (9.3–10.2) Bronchitis 2.2 (1.5–3.1) 3.5 (2.6–4.6) 3.7 (3.3–4.1) 2.9 (1.8–4.4) 2.6 (1.9–3.5) 2.8 (2.2–3.4) 3.2 (2.9–3.4) Neurology | Volume 97, Number 16 | October 19, 2021 Influenza 3.3 (2.4–4.4) 3.1 (2.3–4.2) 2.5 (2.2–2.9) 3.4 (2.2–5.1) 4.6 (3.6–5.7) 4.0 (3.4–4.7) 3.7 (3.5–4.0) f Serious infections 1.79 (1.16–2.64) 0.83 (0.43–1.45) 1.32 (1.08–1.60) 3.02 (1.89–4.57) 2.74 (1.99–3.68) 4.41 (3.75–5.15) 2.01 (1.81–2.23) Pneumonia 0.14 (0.02–0.52) 0.07 (0.00–0.39) 0.25 (0.16–0.39) 0.41 (0.09–1.20) 0.50 (0.22–0.98) 0.59 (0.37–0.90) 0.30 (0.22–0.39) Urinary tract infection 0.14 (0.02–0.52) NA 0.10 (0.04–0.20) 0.69 (0.22–1.60) 0.25 (0.07–0.64) 0.90 (0.61–1.27) 0.30 (0.23–0.39) Cellulitis 0.07 (0.00–0.40) 0.14 (0.02–0.50) 0.05 (0.01–0.13) NA 0.19 (0.04–0.55) 0.45 (0.26–0.73) 0.14 (0.09–0.21) Injury, poisoning, and procedural complications 17.1 (15.0–19.4) 45.9 (42.4–49.5) 24.1 (23.1–25.3) 36.3 (32.1–41.0) 43.5 (40.3–46.8) 33.7 (31.8–35.7) 37.0 (36.1–37.9) Infusion-related reaction 7.9 (6.5–9.5) 34.9 (31.9–38.1) 14.3 (13.5–15.1) 20.3 (17.2–23.8) 31.0 (28.3–33.9) 20.3 (18.9–21.9) 25.9 (25.1–26.6) Abbreviations: CI = confidence interval; IFN = interferon; NA = not available; OCR = ocrelizumab. AEs were classified according to Medical Dictionary for Regulatory Activities (MedDRA) versions 18.0, 18.1, and 22.1. Multiple occurrences of the same AE in 1 patient are counted multiple times, except for malignancies and fatalities. a Data as of April–July 2015. b Includes patients who received any dose of OCR during the CTP and associated OLE periods of the phase 3 studies, including patients originally randomized to comparator (IFN-β-1a or placebo) who switched to open-label OCR treatment (data as of January 2020). c Includes patients who received any dose of OCR during the CTP and associated OLE periods of the phase 2 and phase 3 studies, including patients originally randomized to comparator (IFN-β-1a or placebo) who switched to open-label OCR treatment, plus VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO (data as of January 2020). d Malignancies are identified using AEs falling into the standard MedDRA query “Malignant tumors (narrow).” e For malignancies, incidence rates are reported and exposure in PY was calculated from first treatment to onset of first malignancy. f Serious infections are defined using AEs falling into the MedDRA system organ class “Infections and infestations” and using “Is the event nonserious or serious?” from the AE case report form. e1549 were suicides (n = 7), infections (n = 4), malignancies (n = 4), contrast, IFN-β-1a treatment resulted in decreases in NK cell and cardiac events (n = 3). No specific temporal patterns of counts up to week 96. exposure from first or last dose of OCR were identified. Absolute Neutrophil Count As of July 31, 2020, the fatality rate (0.28 per 100 PY; 95% CI Throughout the CTP of the pivotal phase 3 trials, mean 0.26–0.31) from postmarketing sources was slightly higher neutrophil levels remained above lower limit of normal than that observed in the clinical trial setting. (LLN) and stable. The proportion of patients with marked neutropenia, defined as absolute neutrophil count (ANC) Infusion-Related Reactions <1.5 × 109/L, was 4.4% (OCR) vs 18.2% (IFN-β-1a) in IRRs were among the most common AEs reported with OCR OPERA and 4.6% (OCR) vs 1.7% (placebo) in ORATORIO. in the CTPs of the phase 3 trials.4,5 Detailed analyses on IRRs Most marked neutropenia episodes in OCR arms were single during the CTP were reported previously.9 The rate of IRRs occurrences (OPERA: 68.3%; ORATORIO: 73.1%) that in the OCR all-exposure population decreased with sub- were not sustained or replicated. sequent infusions (Table 1). As of January 2020, 9 serious neutropenia cases were reported Laboratory Measurements in the OCR all-exposure population (n = 5,680 patients; Biochemistry 18,218 PY). Seven patients were symptomatic with signs No drug-induced hepatotoxicity was observed (hepatotox- suggestive of infection (most commonly pharyngitis), 2 pa- icity and other abnormalities data are available from Dryad, tients were asymptomatic. In 4 cases, neutropenia required eTable 3, doi.org/10.5061/dryad.w3r2280qn). specific treatment with a granulocyte-colony stimulating fac- tor (filgrastim). All 9 cases resolved (median [range] 10 Absolute Lymphocyte Count (T Cells, B Cells, and [3–61] days) and all patients remained on OCR. Natural Killer Cells) In patients treated with OCR, the mean absolute lymphocyte Immunoglobulins count (ALC) decreased by approximately 15% between Over a period of up to 7 years of OCR treatment, there was a mean baseline (BL) and week 12 (W12) in OPERA 1 (1.86 [BL] to absolute reduction in serum immunoglobulin M levels of −0.78 g/ 1.57 [W12] × 109/L), OPERA 2 (1.85 [BL] to 1.54 [W12] × L (mean relative reduction of 55.8%) in the OPERA population, 109/L), and ORATORIO (1.88 [BL] to 1.55 [W12] × 109/L) characterized by a faster drop in the first year followed by a trials. This was likely driven by pharmacodynamic effects of slower decline (available from Dryad, eFigure 2, doi.org/10.5061/ B-cell depletion, as mean/median ALC remained stable dryad.w3r2280qn). Serum immunoglobulin G (IgG) levels de- thereafter until the end of the CTP (data not shown). creased at an average rate of −0.33 g/L per year (−2.99% per year) (Figure 2A). A similar trajectory was observed for immunoglobulin The proportion of patients with episodes of marked lymphopenia A (IgA) levels (available from Dryad, eFigure 2, doi.org/10.5061/ (ALC <0.7 × 109/L) was 5.3% (OCR) vs 12.8% (IFN-β-1a) in dryad.w3r2280qn). The temporal evolution for serum immuno- OPERA, and 6.8% (OCR) vs 5.0% (placebo) in ORATORIO, globulin (Ig) in the ORATORIO population was comparable to but no episodes of ALC <0.2 × 109/L (grade 4) were reported in trajectories observed in OPERA (Figure 2B; eFigure 2 [available patients treated with OCR. Most marked lymphopenia episodes from Dryad, doi.org/10.5061/dryad.w3r2280qn]). were single occurrences (OPERA: 76.4%; ORATORIO: 71.1%) that were not sustained or replicated. Infections T Lymphocytes All Infections Flow cytometry analyses showed decreases of ≤6% in CD3+ The overall rate of infections (76.2 per 100 PY; 95% CI T-cell populations by week 2 in OCR-treated patients in the 74.9–77.4) in the OCR all-exposure population, over a period pivotal phase 3 trials. These were likely driven by the re- of up to 7 years, remained consistent with rates observed during duction in CD8+ T-cell levels, because only minimal changes the phase 3 CTPs. During this period, infections were fre- in the CD4+ T-cell levels were observed throughout the quently reported in both OCR and comparator groups, with an CTPs. During the OLEs of the phase 3 trials, CD3+CD4+ and increased risk of nonserious upper respiratory tract infections CD3+CD8+ T-cell counts gradually recovered to baseline (predominantly nasopharyngitis) and UTIs (Table 1). These levels (Figure 2, C and D; eFigure 1 [available from Dryad, remained the most common types of infections in the OCR all- doi.org/10.5061/dryad.w3r2280qn]). exposure population over a period of up to 7 years (Table 1). Natural Killer Cells Serious Infections During the CTP of the pivotal phase 3 trials, treatment with Over a period of up to 7 years, the rates of serious infections (SIs) OCR had no impact on natural killer (NK; CD16+CD56+) in the RMS all-exposure and PPMS all-exposure populations cell counts, remaining generally similar to levels observed for fluctuated over time but showed no meaningful year-on-year var- patients with PPMS in the placebo group (available from iation. Among patients with PPMS, the rate of SIs remained higher Dryad, eTable 4, doi.org/10.5061/dryad.w3r2280qn). In than in RMS (Figure 3A). The incidence of SIs in the OCR all- e1550 Neurology | Volume 97, Number 16 | October 19, 2021 Neurology.org/N exposure population over a period of up to 7 years was infrequent, As of July 31, 2020, no cases of PML were reported in the at a rate of 2.01 per 100 PY (95% CI 1.81–2.23) (Table 1). context of clinical trials. Nine confirmed (definite diagnosis)11 cases of PML were reported outside of clinical trials, of which The most common SIs in the OCR all-exposure population 8 were reported as carryover cases. Additional details have were UTIs (0.30; 95% CI 0.23–0.39), pneumonia (0.30; 95% been presented previously12 and can be found in eTable 5 CI 0.22–0.39), and cellulitis (0.14; 95% CI 0.09–0.21). Serious (available from Dryad, doi.org/10.5061/dryad.w3r2280qn). herpes virus-associated infections were uncommon (multi- dermatomal herpes zoster, n = 2; genital herpes, n = 2; herpes Most SIs resolved without sequelae (93.2%; 342/367 SIs) simplex, n = 1; herpes keratitis, n = 1; 0.03 per 100 PY [95% CI within the expected clinical course (57.7% lasted ≤14 days 0.01–0.07]; their incidence stable up to 7 years). These patients [206/357 resolved SIs]; 79.6% lasted ≤28 days [284/357 were hospitalized, no cases were life-threatening, and all re- resolved SIs]). Discontinuation of OCR due to SIs was un- solved within the expected clinical course (12–22 days). common (14/5,680 [0.25%] patients). No cases of hepatitis B virus infection reactivation, fever of Association Between SIs and Lymphocyte or unknown origin, cryptococcosis, aspergillosis, listeriosis, Neutrophil Levels toxoplasmosis, or cytomegalovirus infection were reported in In the phase 3 CTP+OLE population (n = 2,092, exposure up the OCR all-exposure population. to 7 years), no association between low lymphocyte levels Figure 2 Change in Serum Immunoglobulin G (IgG) Levels and CD3+ T-Cell Levels Through Controlled Treatment Period (CTP) and Open-Label Extension (OLE) Period of the Phase 3 Studies Data cutoff: January 2020. Change in serum levels of IgG from baseline (BL) through the CTP and OLE periods of the pooled OPERA studies (A) and the ORATORIO study (B). Change in CD3+ T-cell levels from BL through the CTP and OLE periods of the pooled OPERA studies (C) and the ORATORIO study (D). Data on proportion of patients with immunoglobulin (Ig) levels < lower limit of normal (LLN) shown only until week 312, as data at week 336 are not mature. Data at week 336 on change in T-cell levels are not shown as data are not mature. The proportion of patients randomized to ocrelizumab (OCR) in the OPERA population with IgG levels < LLN was 1.5% at week 96% and 7.7% at week 312 (OCR/OCR data). Similarly, the proportion of patients randomized to OCR in the ORATORIO population with IgG levels < LLN was 1.1% at week 120 and 5.1% at week 312 (OCR/OCR data). aIn patients treated with interferon (IFN), an increase in serum IgG levels was observed over a 2-year period. This is consistent with previous findings from other groups.10 CD = cluster of differentiation; CI = confidence interval; PBO = placebo; RMS = relapsing multiple sclerosis. Neurology.org/N Neurology | Volume 97, Number 16 | October 19, 2021 e1551 Figure 3 Rate of Serious Infections Over 7 years and Association With Immunoglobulin Levels Data cutoff: January 2020. (A) Yearly rates of serious infections (SIs) in patients with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS) treated with ocrelizumab (OCR) for a period of up to 7 years, during the controlled treatment period (CTP) and associated open-label extension (OLE) periods of the phase 2 and phase 3 studies, including patients originally randomized to comparator (interferon [IFN]-β-1a or placebo [PBO]) who switched to open-label OCR treatment, plus VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE (PPMS all-exposure only), and LIBERTO (n = 5,680; 18,218 patient-years [PY]). Yearly rates of SIs of patients who received PBO (gray) or IFN-β-1a (purple) during the CTPs are displayed. Due to the event-driven design of ORATORIO, some patients remained on PBO for up to 4 years. (B) Rates of SIs associated with immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) values above or below the respective lower limit of normal (LLN) in patients who received any dose of OCR during the CTP and associated OLE periods of the phase 3 trials (OPERA 1, OPERA 2, and ORATORIO). CI = confidence interval. (ALC <0.91 × 109/L) and rates of SIs was observed (3.17 per levels (ANC <1.96 × 109/L) and rates of SIs (2.02 per 100 PY 100 PY [95% CI 1.96–4.84] during episodes of ALC < LLN vs [95% CI 0.74–4.39] during episodes of ANC < LLN vs 2.29 2.23 per 100 PY [95% CI 1.95–2.53] during episodes of ALC ≥ per 100 PY [95% CI 2.02–2.59] during episodes of ANC LLN). No association was observed between low neutrophil ≥ LLN). e1552 Neurology | Volume 97, Number 16 | October 19, 2021 Neurology.org/N Association Between SIs and Ig Levels Outside the clinical trial setting, the age-standardized in- In the phase 3 CTP+OLE population, an association be- cidence rate of female breast cancer was 0.07 per 100 PY (95% tween decreased IgG levels (IgG <5.65 g/L) and increased CI 0.06–0.09) in the US postmarketing experience (total rates of SIs was observed (Figure 3B). Among 2,092 patients exposure over 99,200 PY), as of July 31, 2020. There is no continuously treated with OCR up to 7 years, 15 (0.7%) indication of an excess in the incidence rate of female breast patients experienced an SI while IgG < LLN. The type, se- cancer in women treated with OCR in the US real-world verity, duration, and outcome of SIs observed during epi- setting compared with the US (SEER) general population sodes of IgG < LLN (n = 20, in 15 patients) were consistent (SIR 0.45 [95% CI 0.38–0.54]). with the overall SIs observed in OCR-treated patients. All events resolved and all patients continued OCR (data Humoral Immunity available from Dryad, eTable 6, doi.org/10.5061/dryad. The effect of OCR on preexisting humoral immunity to w3r2280qn). bacterial and viral antigens was assessed during the CTP of the phase 3 trials by measuring changes in specific antibody titers Malignancies and Female Breast Cancer to common viral and bacterial antigens. At the end of the Over a period of up to 7 years, the crude incidence rate of all CTP, the proportion of patients with protective titers against malignancies (including nonmelanoma skin cancer [NMSC]) in mumps, rubella, and varicella zoster viruses was overall un- the OCR all-exposure population was 0.46 per 100 PY (95% CI changed from baseline in both the OPERA and ORATORIO 0.37–0.57) (Table 1). Yearly crude incidence rates of all malig- trials (Table 2). Changes from baseline in the antibody titers nancies and female breast cancer fluctuate and do not suggest a against Streptococcus pneumoniae were small and consistent causal or time-dependent/cumulative dose-dependent exposure with those in comparator groups in both OPERA and ORA- effect (Figure 4, A and B). TORIO (Table 2). Standardization of incidence rates of all malignancies and Antidrug Antibodies female breast cancer was also performed (see Supplemental Minimal immunogenicity was observed over a period of 6.5 Material, available from Dryad, doi.org/10.5061/dryad. years, with a total of 24 patients testing positive for treatment- w3r2280qn). Cases of NMSC were excluded from the OCR emergent antidrug antibodies (RMS: 1.0% [14/1,427]; PPMS all-exposure population and the Danish MS registry for 1.6% [10/635]; for more details, see Supplemental Material, comparison with the general US population (Surveillance, available from Dryad, doi.org/10.5061/dryad.w3r2280qn). Epidemiology, and End Results [SEER] database). Stan- dardized rates of NMSC (0.20 per 100 PY [95% CI 0.11–0.38]) remained stable and consistent with epidemio- logic references (0.19 per 100 PY [95% CI 0.15–0.24]).13 Discussion The present analysis provides a comprehensive assessment on Over a period of up to 7 years, age- and sex-standardized the long-term safety of PwMS treated continuously with OCR in incidence rate of all malignancies (excluding NMSC) was 0.23 clinical trials, as well as the broader population treated in the per 100 PY (95% CI 0.15–0.39) and age-standardized in- postmarketing setting. The overall rates of AEs and SAEs cidence rate of female breast cancer was 0.13 per 100 PY (95% reported with OCR in the CTP of the phase 3 trials were CI 0.08–0.32) in the OCR all-exposure population (Figure 5, comparable to those reported for placebo or IFN-β-1a. The A and B). Calculated standardized incidence ratios (SIRs) OCR safety profile remained stable throughout the OLE of the indicate no significant excess in the incidence of all malig- phase 2/3 trials, and with the use of OCR in a more heteroge- nancies in the OCR all-exposure population compared with a neous MS population across 7 additional studies, as well as real- typical MS population or the general population (Figure 5A). world settings. The low rates of patients discontinuing OCR due The SIR for breast cancer indicates no increased risk in to AEs suggest favorable long-term tolerability, which together women treated with OCR compared with a typical MS pop- with its sustained efficacy, contributes to the high persistence ulation (Danish) and a nonsignificant excess compared with observed in real-world cohorts.15-18 Fatality rates in the clinical the general population (SEER) (Figure 5B). trials remained below those observed in postmarketing settings, as well as the expected fatality rates (0.37–0.90 per 100 PY) In the OCR all-exposure population, the median age at onset observed in real-world MS cohorts.18,19 It should be noted that of the 21 patients diagnosed with breast cancer was 49 years. postmarketing patients tend to have older age, longer disease Most had a personal or family history of cancer (n = 13/21) duration, higher proportion of progressive MS, and a greater and current or previous smoking history (n = 8/21). Invasive number of previous disease-modifying treatments (DMTs) and ductal carcinoma was the most common histologic pre- comorbidities.15 sentation and most breast cancers were positive for estrogen receptor (ER) and/or progesterone receptor (PR) (ER+ 15/21 Whereas IRRs were among the most frequently reported AEs patients; ER+ PR+ 13/21 patients), consistent with the known with OCR, most patients did not experience IRRs, and epidemiology of breast cancers14 (available from Dryad, eTa- the majority were mild to moderate, decreased with the ble 7, doi.org/10.5061/dryad.w3r2280qn). number of infusions, and were effectively managed through Neurology.org/N Neurology | Volume 97, Number 16 | October 19, 2021 e1553 Figure 4 Yearly Crude Incidence Rates of all Malignancies and Female Breast Cancer in Ocrelizumab (OCR) All-Exposure Population Data cutoff: January 2020. Includes patients who received any dose of OCR during the controlled treatment period (CTP) and associated open-label extension (OLE) periods of the phase 2 and phase 3 studies, including patients originally randomized to comparator (interferon [IFN]-β-1a or placebo) who switched to open-label OCR treatment, plus VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. (A) Crude incidence rates of all malignancies from years 1–7, including nonmelanoma skin cancer (NMSC). Crude incidence rate of all malignancies (including NMSC) in the OCR all-exposure population, as of January 2020: 0.46 (0.37–0.57). (B) Crude incidence rates of female breast cancer from years 1–7. Data on yearly crude incidence rates of all malignancies and female breast cancer shown until year 7. Year 7 data are not mature due to limited exposure (543 patient-years [PY] for female breast cancer). AE = adverse event; CI = confidence interval. administering premedication, adjustment to infusion rates, frequently reported AEs in patients treated with OCR. and symptomatic treatment. An appropriate premedication However, the rates of SIs were numerically lower in OCR- protocol with mandatory methylprednisolone and antihista- treated patients compared with controls. Moreover, these mines, as well as an optional analgesic, was followed. Results rates remained stable with only minimal fluctuation over time from studies investigating a shorter infusion protocol also in patients with PPMS, and consistent with rates of infection- indicate that reducing infusion duration does not increase the related hospitalizations reported in well-characterized MS incidence, patterns, or severity of IRRs.20-22 This may allow registries.26,27 UTIs, pneumonia, and cellulitis accounted for improvements in the overall patient experience and optimi- the most common SIs, a pattern also observed in real-world zation of resources at infusion clinics.23 MS cohorts,24 suggesting that the most common types of SIs in OCR-treated patients do not differ from those expected in Real-world studies show an increased risk of infection in PwMS. Herpes was the unique cluster of serious potentially PwMS relative to non-MS controls, both in treated and un- opportunistic infections, but the rates remained infrequent treated cohorts.24,25 Infections were among the most and causal association with OCR was not established. Most e1554 Neurology | Volume 97, Number 16 | October 19, 2021 Neurology.org/N Figure 5 Cumulative Standardized Incidence Rates of Malignancies and Comparison With Danish Multiple Sclerosis (MS) Registry and Surveillance, Epidemiology, and End Result (SEER) Database a Standardized incidence rates per 100 patient-years (PY) (95% confidence interval [CI]) were derived using a direct standardization method that applies age–sex specific rates to the US population (2010 census), with restriction to the age range of the MS clinical trials (15–59 years). For all malignancies, cases of nonmelanoma skin cancer (NMSC) were excluded from the ocrelizumab (OCR) all-exposure population and from the Danish MS registry to allow a com- parison with the SEER database. bThe standardized incidence ratio (SIR) (95% CI for Poisson distribution) was calculated as observed number of events/ expected number of events. For “OCR-comparison” SIR, SEER database and the Danish MS registry were used as reference populations. For “Danish- comparison” SIR, SEER database was used as reference population. cOCR all-exposure population: data represent the follow-up of 5,680 patients covering a period of approximately 7 years (up to January 2020). dDanish MS registry: data represent the follow-up of approximately 10,000 patients from 1995 to 2015.44 e SEER database: data cover approximately 27.8% of the US population (based on 2010 census) from 2000 to 2016 (available at: seer.cancer.gov). confirmed cases of PML observed in OCR-treated patients the preserved counts of NK cells, suggest that OCR has limited were classified as carryover cases28 from natalizumab or fin- effect on the innate immune system. golimod, except one case in a 78-year-old man with prior intermittent mild lymphopenia of unknown etiology, not Regarding the adaptive immune system, a small initial decrease previously treated with any other DMTs.29 Whereas PML in median circulating lymphocyte counts was observed, but develops almost exclusively in patients with a severely com- remained stable with continued treatment. This was likely driven promised immune system,30 anecdotal PML cases have been by the rapid and sustained depletion of CD20+ B cells, the most reported in individuals with minimal or nonapparent immu- relevant pharmacodynamic effect of OCR, but could in part nosuppression, including older patients, in whom age- occur by depletion of CD3+CD20+ cells, which represents associated immunosenescence is identified as a risk factor.31,32 3%–5% of circulating T cells,33 and are susceptible to depletion by OCR.34 Alternatively, B-cell depletion from lymphoid tissue The selective effects of OCR on the immune system may pro- might drive homeostatic changes in T-cell distribution between vide an explanation as to why the rates of SIs remained low and blood and lymph nodes. However, a highly diverse T-cell rep- stable over a period of up to 7 years. OCR showed a differential ertoire persists, suggesting that antigen presentation by B cells, effect on innate and adaptive immune system components. The which is essential for maintenance of T-cell-mediated adaptive changes observed in neutrophil levels were mostly transient and immunity, is preserved.35 Moreover, by the end of the 7-year appear to be within the range of biologic variability, with similar observation period, T-cell levels had returned to normal. proportions of patients with neutropenia in the OCR (OPERA: 14.7%, ORATORIO: 12.9%) and the placebo arms (ORATO- The reduction in serum Ig levels may be explained by the RIO: 10.0%). Cases of serious neutropenia remained infrequent, mechanism of action of OCR. However, at the dosing regimen were not treatment-limiting, and importantly, were not associ- of 600 mg every 6 months, Ig levels remained within normal ated with an increased risk of SIs. These findings, together with ranges for most patients even after 7 years of continued Neurology.org/N Neurology | Volume 97, Number 16 | October 19, 2021 e1555 Table 2 Preexisting Humoral Immunity in the Phase 3 Studies OPERA (pooled) ORATORIO IFN-β-1a OCR Placebo OCR (n = 826) (n = 825) (n = 239) (n = 486) Week Week Week Week BL 96 BL 96 BL 120 BL 120 Patients with positive antibody titer at baseline and end of CTP, % Mumps virus 94.1 92.7 93.6 91.8 92.8 92.7 92.9 92.7 Rubella virus 87.9 90.8 89.0 88.7 90.7 92.3 93.1 92.5 Varicella-zoster virus 95.5 97.2 95.5 95.0 96.4 99.3 96.1 95.3 Change in absolute S. pneumoniae capsular polysaccharide titers from 53.67 51.74 55.35 54.06 73.96 68.85 68.11 60.76 baseline to end of CTP, mean (SD) antibody levels, mg/L (54.13) (42.50) (67.00) (80.98) (84.64) (80.15) (67.53) (63.30) Abbreviations: BL = baseline; CTP = controlled treatment period; IFN = interferon; OCR = ocrelizumab. BL is the patient’s last observation prior to the initiation of the study drug. For OPERA 1 and OPERA 2, antibody titers were collected at weeks 12, 24, 48, 72, and 96 postbaseline. Antibody titers were collected at week 120 only postbaseline in ORATORIO. treatment. Most patients reaching IgG levels below the LLN Vaccination is one important way of reducing the risk of some were found to be in the lowest baseline IgG quartile, al- infectious diseases. Recommendations may vary across coun- though the relative reduction observed over time was similar tries, but in line with the latest American Academy of Neurology across quartiles.36 Baseline age, body mass index, Expanded guidance,42 patients who require vaccination should complete Disability Status Scale score, disease duration, and treatment their immunization with live or nonlive vaccines at least 4 and 2 with previous DMTs were, overall, similar across quartiles, weeks prior to initiation of OCR, respectively.8 Such time frames whereas higher IgG levels were observed in women,36 con- allow for the humoral response to occur, while observing safety sistent with well-known biological sex differences.37 An ap- considerations related to live vaccines. Nonlive vaccines (e.g., parent association between decreased levels of IgG and rates annual seasonal influenza) are also recommended in patients of SIs was observed, but the types, severity, duration, and while on treatment with OCR, and ideally should be adminis- outcomes of these infections were similar to the overall tered 4 weeks prior to the next scheduled dose, similar to rec- population treated with OCR, and to the general MS pop- ommendations available for other B-cell-depleting therapies.43 ulation. It should be noted that other risk factors, such as age, For nonlive vaccines that require 2 doses, such as the coronavirus body mass index, comorbidities, disability level, and previous disease 2019 (COVID-19) vaccine, the first dose should be treatment with other DMTs24,25,38 may influence the risk of administered around 12 weeks following the prior OCR infusion SIs; the relative importance of these factors in the OCR- and the second dose given 4 weeks (latest) prior to the next treated population will be reported elsewhere (manuscript scheduled OCR infusion, as per the VELOCE study.39 under preparation). Analyses of malignancy and female breast cancer rates in the Despite observed reductions in serum IgG levels, preexisting overall clinical program and additional postmarketing data do not specific humoral immunity to certain common viral (mumps, indicate an increased risk compared with matched reference MS rubella, varicella zoster viruses) and bacterial (S. pneumoniae) and general populations44,45 or a time-dependent exposure effect. antigens was preserved over a period of approximately 2 years. These results are consistent with findings from other anti-CD20 The effects of OCR on humoral responses against clinically therapies such as rituximab, which show no predisposition to relevant vaccines were also assessed in the VELOCE study, second primary malignancies.46 Considering the inherent limi- showing that patients treated with OCR mounted a humoral tations of a clinical trial population in identifying rare events, and response, although attenuated, to clinically relevant vaccines the potential underreporting in the postmarketing setting, more and a neoantigen, despite peripheral B-cell depletion.39 This data are required. Postapproval safety studies (CONFIDENCE, may be explained in part by the fact that tissue-resident MANUSCRIPT, VERISMO) that will follow approximately memory B cells, which are abundant in the spleen and other 9,000 newly OCR-treated patients are ongoing to inform long- tissues, may not be fully depleted.40 A recent analysis of B term safety and, specifically, the potential risk of malignancies.47 lineage cells in tissues of healthy organ donors revealed tissue- specific differences and discordance between blood and tis- Finally, in contrast to other humanized monoclonal anti- sues; blood levels did not appear to predict memory B-cell bodies used in the treatment of MS48,49 and similar to fully compartments in terms of frequency and Ig isotype in any of human monoclonal antibodies,50 immunogenicity observed the tissues and that blood was not in equilibrium with the with OCR was infrequent and mostly transient, thereby spleen.41 supporting its long-term use. e1556 Neurology | Volume 97, Number 16 | October 19, 2021 Neurology.org/N This integrated general safety analysis has some limitations. and writing assistance from F. Hoffmann-La Roche Ltd and The nature of the OLEs and phase 3b studies limits conclu- Novartis for CD20-related meetings and presentations. L. sions due to the absence of control groups. Whereas the Kappos’ institution (University Hospital Basel) received in the stability of the overall rates and patterns of AEs in the OLE last 3 years and used exclusively for research support at the period relative to the CTP provides a comparative reference, Department steering committee, advisory board, consultancy response bias due to underreporting cannot be excluded. For fees, and support of educational activities from Actelion, AEs such as malignancies, fatal outcomes, and SIs, the use of Allergan, Almirall, Baxalta, Bayer, Biogen, Celgene/Receptos, data from MS registries and postmarketing sources allows CSL-Behring, Desitin, Excemed, Eisai, Genzyme, Japan To- further contextualization of the incidence rates, although se- bacco, Merck, Minoryx, Novartis, Pfizer, F. Hoffmann-La lection bias may be present given possible differences in Roche Ltd, Sanofi Aventis, Santhera, and Teva, and license fees populations. Moreover, potential underreporting in the for Neurostatus-UHB products; the Research of MS Center in postmarketing setting could lead to further bias; however, the Basel has been supported by grants from Bayer, Biogen, more severe cases of AEs are often reported. In studies with a Novartis, the Swiss MS Society, the Swiss National Research long follow-up period, attrition bias is also a recognized lim- Foundation, Innosuisse, the European Union, and Roche Re- itation, but rates of discontinuation remain infrequent and search Foundations. X. Montalban received speaking honoraria over 90% of patients who completed the CTPs entered the and travel expenses for scientific meetings and has been a long-term extensions.6,7 steering committee member of clinical trials or participated in advisory boards of clinical trials in the past 3 years with In conclusion, these results suggest that continuous ad- Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, ministration of OCR for up to 7 years is associated with a EXCEMED, Genzyme, MedDay, Merck, MSIF, Nervgen, favorable and manageable safety profile. No new safety NMSS, Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceuti- concerns have emerged in a heterogeneous MS population cal, and TG Therapeutics. L. Craveiro is an employee and (in more recent clinical trials and real-world settings) that shareholder of F. Hoffmann-La Roche Ltd. C. Chognot is an includes early treatment-naive patients with relapsing- employee of F. Hoffmann-La Roche Ltd. R. Hughes was an remitting multiple sclerosis, patients with RMS previously employee of F. Hoffmann-La Roche Ltd during completion of treated with other DMTs, and patients with active secondary the work related to this manuscript. H. Koendgen was an em- progressive multiple sclerosis or PPMS who are older, are ployee and shareholder of F. Hoffmann-La Roche Ltd during more disabled, and have a longer DMT history and higher completion of the work related to this manuscript. N. Pas- number of comorbidities. Long-term follow-up and post- quarelli is an employee and shareholder of F. Hoffmann-La marketing studies will continue to monitor the safety of Roche Ltd. A. Pradhan is an employee of Genentech, Inc. K. long-term treatment with OCR in increasing numbers of Prajapati has received consulting fees from F. Hoffmann-La patients. Roche Ltd for statistical assistance and is an employee of IQVIA Solutions Inc. J.S. Wolinsky has received personal compensa- Acknowledgment tion for consulting, serving on a scientific advisory board, The authors thank Erwan Muros-Le Rouzic, MPH; Annette speaking, or other activities with Avotres, Brainstorm Cell Sauter, PhD; Kocho Fitovski, MD; Steve Matsuoka, PharmD; Therapeutics, Cleveland Clinic Foundation, EMD Serono, Christian Mueller, PhD; and David Wormser, PhD, for their MedDay Pharmaceuticals, NervGen Pharma Corp., Novartis, contributions to this work; and the patients, their families, and Roche/Genentech, Sanofi Genzyme, and University of Ala- the investigators who participated in this trial. This research bama; royalties are received for outlicensed monoclonal anti- was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. bodies through UTHealth from Millipore Corporation. Go to Heather Latimer of Articulate Science, UK, wrote the first Neurology.org/N for full disclosures. draft of the manuscript based on input from the authors, which was funded by F. Hoffmann-La Roche Ltd. The authors Publication History had full editorial control of the manuscript and provided their Received by Neurology January 15, 2021. Accepted in final form final approval of all content. Statistical Analysis performed by: July 29, 2021. Kalpesh Prajapati, MSc, MPhil, IQVIA Solutions Inc., Amsterdam, the Netherlands. Appendix Authors Study Funding Name Location Contribution This work was supported by financial support from F. Hoffmann-La Roche Ltd, Basel, Switzerland, for the study and Stephen L. University of California, Designed and conceptualized Hauser, MD San Francisco studies; reviewed the data; publication of the manuscript. drafted and revised the manuscript content Disclosure Ludwig University Hospital Designed and conceptualized S.L. Hauser serves on the board of directors for Neurona and Kappos, MD Basel, University of studies; reviewed the data; on scientific advisory boards for Alector, Annexon, Accure, and Basel, Switzerland drafted and revised the manuscript content Molecular Stethoscope, and has received travel reimbursement Continued Neurology.org/N Neurology | Volume 97, Number 16 | October 19, 2021 e1557 at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 2019. Appendix (continued) 13. Kingwell E, Bajdik C, Phillips N, et al. Cancer risk in multiple sclerosis: findings from British Columbia, Canada. Brain. 2012;135(pt 10):2973–2979. Name Location Contribution 14. Yang XR, Chang-Claude J, Goode EL, et al. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Con- Xavier Vall d’Hebron University Designed and conceptualized sortium studies. J Natl Cancer Inst. 2011;103(13):250–263. Montalban, Hospital, Barcelona, studies; reviewed the data; 15. Butzkueven H, Spelman T, Ozakbas S, et al. Real-world experience with ocrelizumab MD, PhD, MBA Spain drafted and revised the in the MSBase Registry. Presented at the 8th Joint ACTRIMS-ECTRIMS Meeting; manuscript content 2020; MSVirtual2020. 16. Engmann N, Sheinson D, Ng C, Julian L, Pardo G. Persistence and adherence to Licinio F. Hoffmann-La Roche Designed and conceptualized ocrelizumab compared with other disease-modifying therapies for multiple sclerosis Craveiro, MD, Ltd, Basel, Switzerland CONSONANCE study; reviewed for up to 18 months in the US. Presented at the 8th Joint ACTRIMS-ECTRIMS PhD the data; drafted and revised Meeting; 2020; MSVirtual2020. the manuscript content 17. Meuth S, Buttmann M, Weber M, et al. Treatment persistence and adherence to ocrelizumab in the real-world setting: an ad-hoc analysis of the CONFIDENCE study. Cathy F. Hoffmann-La Roche Designed and conceptualized Presented at the 8th Joint ACTRIMS-ECTRIMS Meeting; 2020; MSVirtual2020. Chognot, PhD Ltd, Basel, Switzerland VELOCE study; reviewed the 18. Leray E, Vukusic S, Debouverie M, et al. Excess mortality in patients with multiple data; drafted and revised the sclerosis starts at 20 years from clinical onset: data from a large-scale French obser- manuscript content vational study. PLoS One. 2015;10(:e0132033. 19. Goodin DS, Corwin M, Kaufman D, et al. Causes of death among commercially Richard F. Hoffmann-La Roche Reviewed the data; drafted and insured multiple sclerosis patients in the United States. PLoS One. 2014;9(18): Hughes, MD Ltd, Basel, Switzerland revised the manuscript content e105207. 20. Vollmer T, Cohen J, Alverez E, et al. Safety results of administering ocrelizumab per a Harold F. Hoffmann-La Roche Reviewed the data; drafted and shorter infusion protocol in patients with primary progressive and relapsing multiple Koendgen, Ltd, Basel, Switzerland revised the manuscript content sclerosis. Mult Scler Relat Disord. 2020;46(1):102454. MD, PhD 21. Bermel R, Waubant E, Pardo G, et al. Evaluation of shorter infusion times for ocre- lizumab treatment in an extension substudy of the phase IIIb CHORDS trial. Pre- Noemi F. Hoffmann-La Roche Reviewed the data; drafted and sented at the 35th Congress of the European Committee for Treatment and Research Pasquarelli, Ltd, Basel, Switzerland revised the manuscript content in Multiple Sclerosis (ECTRIMS); 2019; Stockholm, Sweden. PhD, MSc 22. Hartung HP, Berger T, Bermel RA, et al. Shorter infusion time of ocrelizumab: results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with Ashish Genentech, Inc., South Designed and conceptualized relapsing-remitting multiple sclerosis. 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