OPERA Ocrelizumab

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Ocrelizumab versus Interferon Beta-1a

in Relapsing Multiple Sclerosis
S.L. Hauser, A. Bar‑Or, G. Comi, G. Giovannoni, H.-P. Hartung, B. Hemmer,
F. Lublin, X. Montalban, K.W. Rammohan, K. Selmaj, A. Traboulsee,
J.S. Wolinsky, D.L. Arnold, G. Klingelschmitt, D. Masterman, P. Fontoura,
S. Belachew, P. Chin, N. Mairon, H. Garren, and L. Kappos,
for the OPERA I and OPERA II Clinical Investigators*
A BS T R AC T
BACKGROUND
B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a human- The authors’ full names, academic de-
ized monoclonal antibody that selectively depletes CD20+ B cells. grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
METHODS Hauser at the Weill Institute for Neuro-
In two identical phase 3 trials, we randomly assigned 821 and 835 patients with sciences, Department of Neurology, Uni-
versity of California, San Francisco, 675
relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg Nelson Rising Ln., San Francisco, CA
every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times 94158, or at stephen.hauser@ucsf.edu;
weekly for 96 weeks. The primary end point was the annualized relapse rate. or to Dr. Kappos at University Hospital
Basel, University of Basel, Petersgraben
RESULTS 4, CH-4301 Basel, Switzerland, or at
ludwig.kappos@usb.ch.
The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a
in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 * A complete list of investigators in the
OPERA I and OPERA II trials is provided
vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of in the Supplementary Appendix, available
patients with disability progression confirmed at 12 weeks was significantly lower at NEJM.org.
with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; Drs. Hauser and Kappos contributed
95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients equally to this article.
with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; This article was published on December 21,
95% CI, 0.43 to 0.84; P = 0.003). The mean number of gadolinium-enhancing le- 2016, at NEJM.org.
sions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus N Engl J Med 2017;376:221-34.
0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocreliz DOI: 10.1056/NEJMoa1601277
umab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, Copyright © 2016 Massachusetts Medical Society.
P<0.001). The change in the Multiple Sclerosis Functional Composite score (a com-
posite measure of walking speed, upper-limb movements, and cognition; for this
z score, negative values indicate worsening and positive values indicate improve-
ment) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs.
0.17, P = 0.004) but not in trial 1 (0.21 vs. 0.17, P = 0.33). Infusion-related reactions
occurred in 34.3% of the patients treated with ocrelizumab. Serious infection oc-
curred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those
treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients
treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.
CONCLUSIONS
Among patients with relapsing multiple sclerosis, ocrelizumab was associated with
lower rates of disease activity and progression than interferon beta-1a over a period
of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required.
(Funded by F. Hoffmann–La Roche; OPERA I and II ClinicalTrials.gov numbers,
NCT01247324 and NCT01412333, respectively.)
n engl j med 376;3 nejm.org January 19, 2017 221

The New England Journal of Medicine
Downloaded from nejm.org on December 5, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
D
espite the availability of several were analyzed by the sponsor; the aggregated and
disease-modifying treatments for relaps- individual results of the participants were reviewed
ing forms of multiple sclerosis, patients by the sponsor and steering committee. An inde-
often continue to have clinical and subclinical pendent data and safety monitoring committee
disease activity, and neurologic disability continues reviewed ongoing safety data and provided guid-
to accrue. Thus, there is a need for more effective ance on trial continuation, modification, or ter-
treatments with acceptable safety profiles.1-3 mination (see the Study Oversight section in the
B cells are thought to influence the underly- Supplementary Appendix).
ing pathogenesis of multiple sclerosis by means All the authors vouch for the accuracy and
of antigen presentation,4 autoantibody produc- completeness of the data and for the fidelity of
tion,5,6 cytokine regulation,4 and the formation the trial to the protocol. A subgroup of authors,
of ectopic lymphoid aggregates in the meninges, which included academic authors and authors who
which possibly contribute to cortical demyelin- are employees of the sponsor, drafted the manu-
ation and neurodegeneration.7,8 Ocrelizumab is a script, and all the authors approved the final
humanized monoclonal antibody that selectively version and made the decision to submit the
targets CD20, a cell-surface antigen that is expressed manuscript for publication. Medical-writing as-
on pre-B cells, mature B cells, and memory B cells sistance was funded by the sponsor. The trial
but not on lymphoid stem cells and plasma cells.9 was conducted in accordance with the Interna-
Humanized anti-CD20 antibody was designed to tional Conference on Harmonisation guidelines
reduce immunogenicity, which was shown in a for Good Clinical Practice17 and the Declaration
phase 2 study.10 Ocrelizumab binds to the large of Helsinki.18
extracellular loop of CD20 with high affinity,
selectively depleting CD20-expressing B cells11,12 Patients
while preserving the capacity for B-cell recon- Key eligibility criteria included an age of 18 to
stitution and preexisting humoral immunity.13,14 55 years; a diagnosis of multiple sclerosis (accord-
B-cell depletion is achieved by means of several ing to the 2010 revised McDonald criteria19); an
mechanisms, including antibody-dependent cell- Expanded Disability Status Scale (EDSS) score of
mediated phagocytosis, antibody-dependent cell- 0 to 5.5 at screening (scores range from 0 to 10.0,
mediated cytotoxicity, complement-dependent cy- with higher scores indicating a greater degree of
totoxicity, and induction of apoptosis.15 disability20); at least two documented clinical re-
On the basis of results from previous phase 2 lapses within the previous 2 years or one clinical
studies of the chimeric anti-CD20 antibody ritux- relapse within the year before screening; magnetic
imab16 and ocrelizumab,10 we undertook two resonance imaging (MRI) of the brain showing
phase 3, multicenter, randomized, double-blind, abnormalities consistent with multiple sclerosis;
double-dummy, active-controlled, parallel-group and no neurologic worsening for at least 30 days
trials (OPERA I and OPERA II) to investigate the before both screening and baseline (day 1 trial
efficacy and safety of ocrelizumab, as compared visit). The key exclusion criteria were a diagnosis
with subcutaneous interferon beta-1a, in patients of primary progressive multiple sclerosis, previ-
with relapsing multiple sclerosis. The two trials ous treatment with any B-cell–targeted therapy or
used identical protocols but were conducted in- other immunosuppressive medication as defined
dependently at nonoverlapping trial sites (see the in the protocol (available at NEJM.org; also see
Supplementary Appendix, available with the full the Additional Methodology Details section in
text of this article at NEJM.org). the Supplementary Appendix), and a disease dura-
tion of more than 10 years in combination with
an EDSS score of 2.0 or less at screening. All the
Me thods
patients provided written informed consent.
Trial Oversight
The sponsor, F. Hoffmann–La Roche, designed Trial Design
the trials in consultation with members of the In the OPERA I trial, patients from 141 trial sites
OPERA I and OPERA II steering committee. Data across 32 countries underwent randomization be-
were collected by the site investigators, queries tween August 31, 2011, and February 14, 2013.
were responded to by site personnel, and the data In the OPERA II trial, patients from 166 trial sites
222 n engl j med 376;3 nejm.org January 19, 2017

Ocrelizumab vs. Interferon Beta-1a in Relapsing MS
across 24 countries underwent randomization chically ordered secondary end points: the pro-
between September 20, 2011, and March 28, 2013. portion of patients with disability progression
Patients were randomly assigned, in a 1:1 ratio, confirmed at 12 weeks in a pooled time-to-event
to receive ocrelizumab at a dose of 600 mg by analysis of both trials through week 96, in which
means of intravenous infusion every 24 weeks, disability progression was defined as an increase
administered as two 300-mg infusions on days from the baseline EDSS score of at least 1.0 point
1 and 15 for the first dose and as a single 600-mg (or 0.5 points if the baseline EDSS score was >5.5)
infusion thereafter, or interferon beta-1a at a dose that was sustained for at least 12 weeks; the total
of 44 μg (Rebif, EMD Serono), administered sub- (cumulative) mean number of gadolinium-enhanc-
cutaneously three times weekly throughout the ing lesions identified on T1-weighted MRI of the
96-week treatment period (Fig. S1 in the Supple- brain at weeks 24, 48, and 96; the total number
mentary Appendix). Patients in each group re- of new or newly enlarged hyperintense lesions
ceived a matching subcutaneous or intravenous on T2-weighted MRI of the brain at weeks 24, 48,
placebo, as appropriate. All the patients received and 96; a pooled analysis of the proportion of
one 100-mg dose of intravenous methylpredniso- patients with disability improvement confirmed
lone before each infusion. Prophylaxis with anal- at 12 weeks through week 96, which was defined
gesic or antipyretic agents and an antihistamine as a reduction from the baseline EDSS score of at
was recommended, but the decision to use these least 1.0 point (or 0.5 points if the baseline EDSS
medications was left up to the infusion center. score was >5.5) that was sustained for at least
Adjustment of the infusion rate and treatment of 12 weeks in patients with a baseline EDSS score
symptoms during infusion were permitted in or- of at least 2.0; a pooled time-to-event analysis
der to manage infusion-related reactions. of the rate of disability progression confirmed at
Randomization was performed centrally with 24 weeks through week 96; the total number of
the use of an independent interactive Web-response new hypointense lesions on T1-weighted MRI
system. Each trial center had separate treating of the brain at weeks 24, 48, and 96; the change
and examining investigators, all of whom were in the Multiple Sclerosis Functional Composite
unaware of the treatment assignments through- score from baseline to week 96; the percentage
out the trial. The examining investigator conducted change in brain volume from week 24 to week 96;
the neurologic assessments, including the Mul- the change in the physical-component summary
tiple Sclerosis Functional Composite (a compos- score of the Medical Outcomes Study 36-Item
ite quantitative measure, expressed as a z score, Short-Form Health Survey (SF-36, on which scores
of walking speed, upper-limb coordinated move- range from 0 to 100, and higher scores indicate
ments, and cognition; for this z score, negative better physical health–related quality of life) from
values indicate worsening and positive values baseline to week 96; and the proportion of pa-
indicate improvement)21 and the EDSS. The EDSS tients with a baseline EDSS score of at least 2.0
assessment and data collection were captured who had no evidence of disease activity (defined
with the use of a real-time, electronic data-entry as no relapse, no disability progression con-
system in conjunction with an algorithm and firmed at 12 weeks or at 24 weeks, no new or
central consistency check and feedback on the newly enlarged lesions on T2-weighted MRI, and
basis of expert review. MRI scans were analyzed no gadolinium-enhancing lesions on T1-weighted
centrally at an MRI reading center by personnel MRI) by week 96. The analysis of percentage
who were unaware of the treatment assignments. change in brain volume was performed with the
Details are provided in the protocol, including use of SIENA/X software.22 Additional secondary
the statistical analysis plan, and in Table S9 in end points were the pharmacokinetics, pharmaco-
the Supplementary Appendix. dynamics, and immunogenicity of ocrelizumab;
and the safety profile of ocrelizumab.
Trial Procedures and End Points
The primary end point was the annualized relapse Statistical Analysis
rate by 96 weeks, which reflects the number of We performed efficacy analyses in the intention-
relapses meeting the prespecified criteria that were to-treat population (all the patients who under-
observed per person-year of follow-up (see the went randomization) or, for the end point of no
Supplementary Appendix). There were 10 hierar- evidence of disease activity, in a modified inten-

tion-to-treat population that excluded patients who R e sult s

were withdrawn from the trial for reasons other
than efficacy failure or death and who had no Patients
evidence of clinical disease activity at the time of Overall, 1656 patients underwent randomization
treatment discontinuation in the trial. The an- (intention-to-treat population), with 821 patients
nualized relapse rate was analyzed with the use in the OPERA I trial and 835 in the OPERA II
of a negative binomial model testing for treatment trial. The demographic and disease characteristics
differences between ocrelizumab and interferon at baseline were similar in the assigned groups in
beta-1a, with adjustment according to geograph- the two trials (Table 1). In the OPERA I trial, 366
ic region and baseline EDSS score. A significant of 410 patients (89.3%) in the ocrelizumab group
result at a two-sided alpha of 0.05 would show and 340 of 411 (82.7%) in the interferon beta-1a
the superiority of ocrelizumab with regard to a group completed the 96-week treatment; in the
lower annualized relapse rate than that observed OPERA II trial, 360 of 417 patients (86.3%) and
with interferon beta-1a. 320 of 418 (76.6%), respectively, completed the
The sample size for each trial was based on 96-week treatment (Fig. S2 in the Supplementary
an estimated annualized relapse rate of 0.165 in Appendix). There was no interaction between
the ocrelizumab group and 0.33 in the interfer- treatment group and trial, which allowed the
on beta-1a group. Using a two-sided t-test, we pooling of data for the prespecified planned hi-
calculated that a sample of 400 patients per erarchical analysis (Table S9 in the Supplemen-
group would provide the trials with 84% statisti- tary Appendix). In the pooled analysis, which
cal power to maintain a type I error rate of 0.05 included 827 patients treated with ocrelizumab
and to detect a 50% lower rate with ocrelizumab and 829 treated with interferon beta-1a, all the
than with interferon beta-1a (assuming a with- primary and secondary end points significantly
drawal rate of approximately 20%). favored the ocrelizumab group over the interferon
According to the statistical analysis plans of beta-1a group.
the individual trials, 10 secondary efficacy end
points were prespecified to be tested in a hierar- Efficacy
chical order at a two-sided alpha of 0.05 (see the Relapses
Supplementary Appendix). Seven end points of Clinical, MRI, and patient-reported outcomes are
this hierarchy were to be tested in each individ- summarized in Table 2. The primary end point,
ual trial, and three end points (disability pro- the annualized relapse rate at 96 weeks, in the
gression confirmed at 12 weeks and at 24 weeks OPERA I trial was 0.16 in the ocrelizumab group,
and disability improvement confirmed at 12 weeks) as compared with 0.29 in the interferon beta-1a
were to be assessed in the pooled data set. From group (difference, 0.14 annualized relapses [dif-
the first P value that was above 0.05, all subse- ferences are based on unrounded data]). In the
quent P values in the predetermined hierarchy OPERA II trial, the annualized relapse rate was
were considered to be nonconfirmatory (i.e., de- 0.16 in the ocrelizumab group, as compared with
scriptive only). (See the Statistical Analysis section 0.29 in the interferon beta-1a group (difference,
in the Supplementary Appendix.) 0.14 annualized relapses) (Table 2). These findings
All patients who received any study treatment indicate a 46% lower annualized relapse rate with
were included in the safety population. All data ocrelizumab in the OPERA I trial and a 47% lower
collected during the double-blind, double-dummy rate with ocrelizumab in the OPERA II trial
treatment period and the safety follow-up were (P<0.001 for both comparisons).
included in the main safety analyses. Data from
patients who entered the safety follow-up earlier Disability
than week 96 were included in this analysis In the prespecified pooled analysis, the percent-
from the time that they entered the safety fol- age of patients with disability progression con-
low-up until week 96. Safety outcomes are re- firmed at 12 weeks was 9.1% in the ocrelizumab
ported for the individual trials with the exception group, as compared with 13.6% in the interferon
of herpesvirus infections and neoplasms, for beta-1a group (40% lower risk with ocrelizumab;
which pooled data are presented because of low hazard ratio, 0.60; 95% confidence interval [CI],
incidences. 0.45 to 0.81; P<0.001) (Fig. 1A). Over the 96-week

Table 1. Demographic and Disease Characteristics of the Patients at Baseline (Intention-to-Treat Population).*
Characteristic OPERA I Trial OPERA II Trial
Ocrelizumab Interferon Beta-1a Ocrelizumab Interferon Beta-1a

(N = 410) (N = 411) (N = 417) (N = 418)
Age — yr 37.1±9.3 36.9±9.3 37.2±9.1 37.4±9.0
Female sex — no. (%) 270 (65.9) 272 (66.2) 271 (65.0) 280 (67.0)
Geographic region — no. (%)
United States 105 (25.6) 105 (25.5) 112 (26.9) 114 (27.3)
Rest of the world 305 (74.4) 306 (74.5) 305 (73.1) 304 (72.7)
Time since symptom onset — yr 6.74±6.37 6.25±5.98 6.72±6.10 6.68±6.13
Time since diagnosis — yr 3.82±4.80 3.71±4.63 4.15±4.95 4.13±5.07
No. of relapses in previous 12 mo 1.31±0.65 1.33±0.64 1.32±0.69 1.34±0.73
No previous disease-modifying therapy — 301/408 (73.8) 292/409 (71.4) 304/417 (72.9) 314/417 (75.3)
no./total no. (%)†
Previous disease-modifying therapy — 107/408 (26.2) 117/409 (28.6) 113/417 (27.1) 103/417 (24.7)
no./total no. (%)‡
Interferon 81/408 (19.9) 86/409 (21.0) 80/417 (19.2) 75/417 (18.0)
Glatiramer acetate 38/408 (9.3) 37/409 (9.0) 39/417 (9.4) 44/417 (10.6)
Natalizumab 0/408 1/409 (0.2) 1/417 (0.2) 0/417
Fingolimod 1/408 (0.2) 0/409 4/417 (1.0) 0/417
Dimethyl fumarate 1/408 (0.2) 0/409 0/417 0/417
Other 2/408 (0.5) 3/409 (0.7) 1/417 (0.2) 1/417 (0.2)
Mean EDSS score§ 2.86±1.24 2.75±1.29 2.78±1.30 2.84±1.38
No. of gadolinium-enhancing lesions on T1-weighted MRI
— no./total no. (%)
0 233/405 (57.5) 252/407 (61.9) 252/413 (61.0) 243/415 (58.6)
1 64/405 (15.8) 52/407 (12.8) 58/413 (14.0) 62/415 (14.9)
2 30/405 (7.4) 30/407 (7.4) 33/413 (8.0) 38/415 (9.2)
3 20/405 (4.9) 16/407 (3.9) 15/413 (3.6) 14/415 (3.4)
≥4 58/405 (14.3) 57/407 (14.0) 55/413 (13.3) 58/415 (14.0)
No. of lesions on T2-weighted MRI 51.04±39.00 51.06±39.90 49.26±38.59 51.01±35.69
Volume of lesions on T2-weighted MRI — cm3 10.84±13.90 9.74±11.28 10.73±14.28 10.61±12.30
3
Normalized brain volume — cm 1500.93±84.10 1499.18±87.68 1503.90±92.63 1501.12±90.98
* Plus–minus values are means ±SD. The intention-to-treat population included all the patients who underwent randomization. There were no
significant differences in the baseline characteristics between groups in each trial and between the two trials. A full listing of countries in-
volved in the trials is provided in the Supplementary Appendix. Data on the number of relapses within the previous 12 months were missing
for 1 patient in the interferon beta-1a group in the OPERA I trial and for 1 patient in each group in the OPERA II trial. Data on the number
and volume of lesions on T2-weighted MRI were missing for 2 patients in the ocrelizumab group and for 3 in the interferon beta-1a group in
the OPERA I trial and for 3 in the ocrelizumab group and 2 in the interferon beta-1a group in the OPERA II trial. Data on the normalized
brain volume were missing for 4 patients in the ocrelizumab group and for 7 in the interferon beta-1a group in the OPERA I trial and for 3 in
the ocrelizumab group and 4 in the interferon beta-1a group in the OPERA II trial.
† Data include patients who were untreated with any disease-modifying therapy in the 2 years before screening. The inclusion criteria did not
select for untreated patients.
‡ Data on previous treatment were collected only for the 2 years before screening. Patients could be counted in several categories. Treatment
with cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, or methotrexate within 2 years before screening was an exclu-
sion criterion. Patients treated with natalizumab were eligible for the trial only if the duration of treatment with natalizumab was less than
1 year. Other medications were intravenous immune globulin, mycophenolate mofetil, and azathioprine (protocol deviation if ≤24 months
before screening).
§ Scores on the Expanded Disability Status Scale (EDSS) range from 0 to 10.0, with higher scores indicating worse disability.20 Data were
missing for one patient in the interferon beta-1a group in the OPERA I trial.

226
Table 2. Clinical and MRI End Points during the 96-Week Trials.*
End Point OPERA I Trial OPERA II Trial Pooled Trials
Ocrelizumab Interferon P Interferon P Interferon P

(N = 410) Beta-1a Value Ocrelizumab Beta-1a Value Ocrelizumab Beta-1a Value
(N = 411) (N = 417) (N = 418) (N = 827) (N = 829)
Primary end point
Annualized relapse rate at 96 wk 0.16 0.29 0.16 0.29
(95% CI) (0.12 to 0.20) (0.24 to 0.36) (0.12 to 0.20) (0.23 to 0.36)
Rate ratio (95% CI) 0.54 (0.40 to 0.72) <0.001 0.53 (0.40 to 0.71) <0.001
Secondary clinical end points
Disability progression confirmed at 12 wk†‡
Patients with event — % 7.6 12.2 10.6 15.1 9.1 13.6
Hazard ratio (95% CI) 0.57 (0.37 to 0.90) 0.01 0.63 (0.42 to 0.92) 0.02 0.60 (0.45 to 0.81) <0.001
The
Disability improvement confirmed at 12 wk†‡

No. of patients evaluated 310 306 318 308 628 614
Difference — % 61 0.01 14 0.40 33 0.02
Disability progression confirmed at 24 wk†‡
n engl j med 376;3

Hazard ratio (95% CI) 0.57 (0.34 to 0.95) 0.03 0.63 (0.40 to 0.98) 0.04 0.60 (0.43 to 0.84) 0.003
MSFC score§
nejm.org
Adjusted mean score at wk 96 0.21 0.17 0.28 0.17
n e w e ng l a n d j o u r na l
(95% CI) (0.15 to 0.27) (0.11 to 0.24) (0.22 to 0.33) (0.11 to 0.23)

of
Difference (95% CI) 0.04 (−0.04 to 0.12) 0.33 0.11 (0.03 to 0.18) 0.004
Patient-reported outcome
Change in SF-36 physical-component summary score from baseline to wk 96¶
January 19, 2017

Adjusted mean score (95% CI) 0.04 −0.66 0.22‖ 0.33 −0.83 0.04‖

m e dic i n e
(−0.86 to 0.93) (−1.59 to 0.28) (−0.55 to 1.20) (−1.76 to 0.09)

Difference (95% CI) 0.69 (−0.41 to 1.80) 1.16 (0.05 to 2.27)
Exploratory end point
No evidence of disease activity by wk 96‡**
No. of patients evaluated 382 384 379 375
Patients with no evidence of disease activity 47.9 29.2 47.5 25.1
—%
Difference — % (95% CI) 64 (36 to 98) <0.001‖ 89 (54 to 132) <0.001‖
Secondary MRI end points
Cumulative no. of gadolinium-enhancing lesions on T1-weighted MRI by wk 96††
Any lesion — % of patients 8.3 30.2 9.8 36.1
Mean no. of lesions per scan (95% CI) 0.02 0.29 0.02 0.42
(0.01 to 0.03) (0.20 to 0.41) (0.01 to 0.04) (0.31 to 0.56)
Total no. of new or newly enlarged hyperintense lesions on T2-weighted MRI by wk 96††
Any lesion — % of patients 38.3 61.3 39.1 62.0
(0.26 to 0.41) (1.12 to 1.78) (0.26 to 0.41) (1.54 to 2.36)
New hypointense lesions on T1-weighted MRI by wk 96††
(0.34 to 0.52) (0.78 to 1.24) (0.36 to 0.56) (1.00 to 1.57)
n engl j med 376;3

Brain-volume change from wk 24 to 96
Mean percentage change (95% CI) −0.57 −0.74 −0.64 −0.75
nejm.org
(−0.66 to −0.49) (−0.83 to −0.65) (−0.73 to −0.54) (−0.85 to −0.65)
Difference in rate of brain-volume loss — % 22.8 0.004‖ 14.9 0.09‖
* All rate ratios, hazard ratios, and difference values are for the ocrelizumab group versus the interferon beta-1a group. The order of the secondary end points according to the hierarchi-
cal analysis plan is provided in the Statistical Analysis section in the Supplementary Appendix.
† Only the pooled analysis was prespecified. The individual-trial results are presented for additional context and transparency. Disability progression that was confirmed at 12 or 24 weeks
January 19, 2017

was defined as an increase from the baseline EDSS score of at least 1.0 point (or 0.5 points if the baseline EDSS score was >5.5) that was sustained for at least 12 or 24 weeks.
Disability improvement that was confirmed at 12 weeks was defined as a reduction from the baseline EDSS score of at least 1.0 point (or 0.5 points if the baseline EDSS score was
>5.5) that was sustained for at least 12 weeks in patients with a baseline EDSS score of at least 2.0
‡ For these end points, individual-trial-level P values were not part of the hierarchical statistical analysis testing procedure.
§ The Multiple Sclerosis Functional Composite (MSFC) consists of a composite quantitative measure of walking speed, upper-limb coordinated movements, and cognition; for this
z score (numerical value reflects the number of standard deviations from a reference population), negative values indicate worsening and positive values indicate improvement in

function.21 MSFC scores were adjusted according to baseline MSFC score, interaction between baseline MSFC score and visit, geographic region (United States vs. the rest of the
world), and baseline EDSS score (<4.0 vs. ≥4.0).23
¶ The physical-component summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) ranges from 0 to 100, with higher scores indicating better physical
health–related quality of life.
‖ Nominal P values are reported but are nonconfirmatory (i.e., descriptive only) as a consequence of the failure in the statistical hierarchical testing procedure.
** No evidence of disease activity was defined as no protocol-defined relapse, no events of disability progression confirmed at 12 weeks, no new or newly enlarged lesions on T2-
weighted MRI, and no gadolinium-enhancing lesions. As prespecified, the end point of no evidence of disease activity was assessed in a modified intention-to-treat population that
excluded patients who were withdrawn for reasons other than efficacy failure or death and who did not have clinical disease activity at the time of treatment discontinuation in the trial.
†† The total number of lesions was calculated as the sum of the individual number of lesions at weeks 24, 48, and 96, divided by the total number of MRI scans of the brain.
227
A Disability Progression Confirmed at 12 Wk

(Fig. 1B). The effect of ocrelizumab on the risk
100 Hazard ratio, 0.60 (95% CI, 0.45–0.81)
of confirmed disability progression in each of the
90 P<0.001 two trials was consistent with the prespecified
Patients with Confirmed Disability
80
pooled analysis (Table 2).
70
20
15.2
In a pooled analysis, the percentage of pa-
16
tients with disability improvement confirmed at
Progression (%)
Interferon beta-1a
60 12 9.8
50
8 12 weeks was 20.7% in the ocrelizumab group,
4 Ocrelizumab
40 0
as compared with 15.6% in the interferon beta-
30
0 12 24 36 48 60 72 84 96 1a group (33% higher rate of improvement with
20
ocrelizumab, P = 0.02) (Fig. S5 in the Supplemen-
10
tary Appendix). The effect of ocrelizumab on the
0
rate of confirmed disability improvement was sig-
0 12 24 36 48 60 72 84 96 nificant in the OPERA I trial but nonsignificant in
Week the OPERA II trial (Table 2).
No. at Risk
The difference in the adjusted mean change
Interferon beta-1a 829 784 741 696 665 632 608 583 449 in the Multiple Sclerosis Functional Composite
Ocrelizumab 827 795 765 737 716 702 688 672 526 score from baseline to week 96 between the
B Disability Progression Confirmed at 24 Wk
ocrelizumab group and the interferon beta-1a
100 group was 0.04 in the OPERA I trial (P = 0.33,
Hazard ratio, 0.60 (95% CI, 0.43–0.84)
90 P=0.003 which was the first nonsignificant P value in the
Patients with Confirmed Disability
80 hierarchical testing) and 0.11 in the OPERA II

70
20
12.0 trial (P = 0.004) (Table 2, and Fig. S6 in the Sup-
16
Progression (%)
60 12 Interferon beta-1a 7.6 plementary Appendix). As a result of the failure in

50
8 the statistical hierarchical testing, all the P values
4 Ocrelizumab
40 0
for the subsequent secondary efficacy end points,
30
0 12 24 36 48 60 72 84 96 including the change in the SF-36 quality-of-life
20
physical-component summary and the measure
10
of no evidence of disease activity, were considered
0
to be nonconfirmatory.
0 12 24 36 48 60 72 84 96 In the intention-to-treat population in the
Week OPERA I trial, 47.9% of the patients in the ocreliz
No. at Risk
umab group had no evidence of disease activity
Interferon beta-1a 829 785 747 705 677 644 622 600 466 by 96 weeks (exploratory end point), as compared
Ocrelizumab 827 797 772 748 731 717 704 688 540
with 29.2% of those in the interferon beta-1a
group. In the OPERA II trial, 47.5% of the patients
Figure 1. Key Secondary Clinical End Points.
in the ocrelizumab group had no evidence of dis-
Shown are the proportions of patients with disability progression con-
firmed at 12 weeks (first secondary end point; Panel A) and at 24 weeks
ease activity by 96 weeks, as compared with 25.1%
(fifth secondary end point; Panel B) in time-to-event analyses in the pooled of those in the interferon beta-1a group. These
trial populations. Disability progression that was confirmed at 12 or 24 findings were considered to be nonconfirmatory
weeks was defined as an increase from the baseline Expanded Disability as a result of failure of the hierarchical analysis
Status Scale (EDSS) score (on a scale from 0 to 10.0, with higher scores (Table 2, and Table S6 in the Supplementary Ap-
indicating worse disability) of at least 1.0 point (or 0.5 points if the baseline
EDSS score was >5.5) that was sustained for at least 12 or 24 weeks. The
pendix).
numbers shown on the curves represent Kaplan–Meier estimates of the
risk of the event at week 96. The insets show the same data on an expand- MRI-Related Secondary End Points
ed y axis. The total mean number of gadolinium-enhancing
lesions per T1-weighted MRI scan in the OPERA I
trial was 0.02 with ocrelizumab versus 0.29 with
trial period, the rate of disability progression con- interferon beta-1a (94% lower number of lesions
firmed at 24 weeks was 6.9% in the ocrelizumab with ocrelizumab, P<0.001). The values in the
group, as compared with 10.5% in the interferon OPERA II trial were 0.02 with ocrelizumab versus
beta-1a group (40% lower risk with ocrelizumab; 0.42 with interferon beta-1a (95% lower number
hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P = 0.003) of lesions with ocrelizumab, P<0.001) (Table 2

and Fig. 2, and Fig. S7 in the Supplementary Ap- infusion-related reaction, nasopharyngitis, upper
pendix). respiratory tract infection, headache, and urinary
The total mean numbers of new or newly en- tract infection in patients treated with ocreliz
larged hyperintense lesions per T2-weighted MRI umab and influenza-like illness, injection-site
scan in the OPERA I trial was 0.32 with ocreliz erythema, headache, urinary tract infection, and
umab versus 1.41 with interferon beta-1a (77% upper respiratory tract infection in patients treat-
lower number of lesions with ocrelizumab, ed with interferon beta-1a.
P<0.001). The values in the OPERA II trial were Serious adverse events were reported in 6.9%
0.33 with ocrelizumab versus 1.90 with inter- of the patients treated with ocrelizumab and in
feron beta-1a (83% lower number of lesions with 7.8% of those treated with interferon beta-1a in
ocrelizumab, P<0.001) (Table 2, and Figs. S8 and the OPERA I trial and in 7.0% of the patients
S13 in the Supplementary Appendix). Most of the treated with ocrelizumab and in 9.6% of those
new or newly enlarged lesion activity on T2-weight- treated with interferon beta-1a in the OPERA II
ed MRI in the ocrelizumab groups occurred be- trial (Table 3). Three deaths occurred, including
tween baseline and week 24 (Fig. S8 in the Sup- one death in the ocrelizumab group (suicide in
plementary Appendix). From week 24 to week 48, the OPERA II trial) and two in the interferon
the number of lesions was 94% lower in the beta-1a group (one suicide in the OPERA I trial,
ocrelizumab group than in the interferon beta- and one death due to mechanical ileus in the
1a group in the OPERA I trial and 96% lower in OPERA II trial).
the ocrelizumab group than in the interferon beta-
1a group in the OPERA II trial. From week 48 to Infections
week 96 the number of lesions was 98% lower Infection was reported in 232 patients (56.9%) in
and 97% lower in the ocrelizumab group than in the ocrelizumab group and in 222 (54.3%) in the
the interferon beta-1a group in the OPERA I interferon beta-1a group in the OPERA I trial;
trial and the OPERA II trial, respectively. the corresponding values in the OPERA II trial
The total mean number of new hypointense were 251 (60.2%) and 219 (52.5%) (Table 3). The
lesions on T1-weighted MRI in the OPERA I trial most common infections (reported in ≥10% of the
was 0.42 with ocrelizumab versus 0.98 with inter- patients in either group across both trials) were
feron beta-1a (57% lower number of lesions with upper respiratory tract infection, nasopharyngi-
ocrelizumab, P<0.001). The values in the OPERA II tis, and urinary tract infection. There were more
trial were 0.45 with ocrelizumab versus 1.26 with reports in the ocrelizumab group than in the
interferon beta-1a (64% lower number of lesions interferon beta-1a group of upper respiratory tract
with ocrelizumab, P<0.001) (Table 2, and Fig. S9 infection (15.2% vs. 10.5%) and nasopharyngitis
in the Supplementary Appendix). As a result of (14.8% vs. 10.2%), whereas urinary tract infec-
the failure in the statistical hierarchical testing, tion was more frequent in the interferon beta-1a
the differences in the percentage of brain-vol- group (11.6% vs. 12.1%). The overall percentage
ume loss from week 24 to week 96 between the of patients reporting a serious infection was 1.3%
ocrelizumab group and the interferon beta-1a in the ocrelizumab group and 2.9% in the inter-
group were nonconfirmatory in the OPERA I trial feron beta-1a group (Table S5 in the Supplemen-
(nominal P = 0.004) and nonsignificant in the tary Appendix). The same pattern was seen when
OPERA II trial (nominal P = 0.09) (Table 2, and we used a broader definition of serious infection,
Fig. S10 in the Supplementary Appendix). including nonserious infection treated with an
intravenous antiinfective treatment (1.8% in the
Safety ocrelizumab group vs. 3.8% in the interferon
Adverse Events beta-1a group). No opportunistic infections were
A total of 327 of 408 patients (80.1%) in the ocre reported in any group over the duration of ei-
lizumab group reported an adverse event in the ther trial.
OPERA I trial, as compared with 331 of 409 Across the two trials, the percentage of pa-
(80.9%) in the interferon beta-1a group; the cor- tients reporting herpesvirus-associated infection
responding values in the OPERA II trial were 360 was 5.9% in the ocrelizumab group and 3.4% in
of 417 patients (86.3%) and 357 of 417 (85.6%) the interferon beta-1a group (Tables S3 and S4
(Table 3). The most common adverse events were in the Supplementary Appendix). All these events

A OPERA I Trial B OPERA II Trial

Interferon beta-1a Ocrelizumab Interferon beta-1a Ocrelizumab
(N=411) (N=410) (N=418) (N=417)
Mean no.
0.6 0.6 through 96 wk, 0.42
Mean no.
Mean No. of Lesions per Patient
Mean No. of Lesions per Patient

0.5 0.5
through 96 wk, 0.29
0.4 0.4
per MRI Scan
per MRI Scan

0.3 0.3
P<0.001 P<0.001
0.2 0.2
Mean no. Mean no.

0.1 through 96 wk, 0.02 0.1 through 96 wk, 0.02
0.0 0.0
24 48 96 24 48 96 24 48 96 24 48 96
Week Week
No. of Patients 372 357 335 382 377 359 No. of Patients 372 334 311 385 373 359
Figure 2. MRI End Point.

Shown are the mean numbers of gadolinium-enhancing lesions per T1-weighted MRI scan by week 96 (second sec-
ondary end point). The number of lesions was divided by the total number of MRI scans of the brain by week 96.
In the OPERA I trial, the number of lesions on the MRI scan at 96 weeks was 94% lower in the ocrelizumab group
than in the interferon beta-1a group; in the OPERA II trial, the number of lesions was 95% lower in the ocrelizumab
group than in the interferon beta-1a group. Adjusted P values are shown.
were mild or moderate (Common Terminology first infusion of dose 1; the patient declined hos-
Criteria for Adverse Events grade 1 or 2, as defined pitalization, recovered with treatment, and was
in Supplementary Appendix), with one exception: withdrawn from the trial according to the proto-
in the OPERA I trial, a patient treated with ocreliz col. The most frequent symptoms of infusion-
umab for 1.6 years was hospitalized for a severe related reaction with ocrelizumab included pruri-
genital herpes simplex infection, which resolved tus, rash, throat irritation, and flushing.
with treatment.
Laboratory Assessments
Infusion-Related Reactions CD19+ cells represent a measure of B-cell counts
More patients in the ocrelizumab group (34.3%) in anti-CD20–treated patients. The level of CD19+
than in the interferon beta-1a group (9.7%) had cells decreased to negligible levels with ocreliz
at least one infusion-related reaction. Patients in umab treatment by week 2. (See the Additional
the interferon beta-1a group received placebo infu- Methodology Details section and Fig. S12 in the
sions. In the OPERA I trial, at least one infusion- Supplementary Appendix.)
related reaction occurred in 30.9% of the patients Antidrug-binding antibodies developed in 3 of
in the ocrelizumab group and in 7.3% of those in 825 patients (0.4%) who received ocrelizumab
the interferon beta-1a group; the corresponding across the two trials, with neutralizing antibod-
values in the OPERA II trial were 37.6% and ies developing in 1 patient in the OPERA II trial.
12.0%. Most infusion-related reactions were mild Across the two trials, neutralizing anti–interferon
to moderate, were reported at the first infusion of beta-1a antibodies were detected in 21.3% of the
dose 1 (Fig. S11 in the Supplementary Appendix), patients.
and were managed with infusion adjustments and
treatment of symptoms. One patient in the ocre Neoplasms
lizumab group in the OPERA I trial had a life- Across these two 96-week trials, four neoplasms
threatening episode of bronchospasm during the (in 0.5% of patients) occurred in the ocrelizu

Table 3. Adverse Events (Safety Population).*
Variable OPERA I Trial OPERA II Trial
Ocrelizumab Interferon Beta-1a Ocrelizumab Interferon Beta-1a

(N = 408) (N = 409) (N = 417) (N = 417)
no. of patients (%)

Any adverse event 327 (80.1) 331 (80.9) 360 (86.3) 357 (85.6)
Adverse event leading to treatment discontinuation 13 (3.2) 26 (6.4) 16 (3.8) 25 (6.0)
At least 1 infusion-related reaction 126 (30.9) 30 (7.3) 157 (37.6) 50 (12.0)
Infection† 232 (56.9) 222 (54.3) 251 (60.2) 219 (52.5)
System organ class infection or infestation 231 (56.6) 216 (52.8) 251 (60.2) 217 (52.0)
Herpes infection
Herpes zoster 9 (2.2) 4 (1.0) 8 (1.9) 4 (1.0)
Oral herpes 9 (2.2) 8 (2.0) 15 (3.6) 9 (2.2)
Neoplasm‡ 3 (0.7) 1 (0.2) 1 (0.2) 1 (0.2)
Death§ 0 1 (0.2) 1 (0.2) 1 (0.2)
Any serious adverse event 28 (6.9) 32 (7.8) 29 (7.0) 40 (9.6)
Serious infection or infestation¶ 5 (1.2) 12 (2.9) 6 (1.4) 12 (2.9)
* Shown are data collected during the double-blind, controlled treatment period. Table S5 in the Supplementary Appendix provides an up-to-
date list of adverse events (including serious adverse events) for the pooled trials, including data that were based on information available
as of January 20, 2016. The safety population included all the patients who received any study drug. Data for patients who underwent ran-
domization and received a therapy that was different from that intended are summarized according to the therapy actually received. Patients
who did not undergo randomization but who received a study drug were included in the safety population, and their data are summarized
according to the therapy actually received.
† Infections were identified either as adverse events as defined in the Medical Dictionary for Regulatory Activities infections system organ class
“infections and infestations” or as an adverse event with pathogen information provided.
‡ The neoplasms reported in the OPERA I trial were ductal breast carcinoma (in two patients) and renal cancer (in one) in the ocrelizumab
group and mantle-cell lymphoma (in one) in the interferon beta-1a group. The neoplasms reported in the OPERA II trial were malignant
melanoma (in one patient) in the ocrelizumab group and squamous-cell carcinoma (in one) in the interferon beta-1a group. For an up-to-
date list of all additional neoplasms recorded in the latest extended safety follow-up analysis of all exposure until June 30, 2016, (including
open-label extension data) across the OPERA I, OPERA II, ORATORIO, and phase 2 trials of ocrelizumab in patients with multiple sclerosis,
see the Supplementary Appendix of Montalban et al.24
§ Deaths occurring during the trials were due to suicide (one in the ocrelizumab group in the OPERA II trial and one in the interferon beta-1a
group in the OPERA I trial) and mechanical ileus (one in the interferon beta-1a group in the OPERA II trial).
¶ Serious infections and infestations reported in the ocrelizumab group were appendicitis (in three patients), cellulitis (in two), pyelonephritis
(in two), and biliary sepsis, device-related infection, herpes simplex infection, pneumonia, and upper respiratory tract infection (in one pa-
tient each). Serious infections and infestations reported in the interferon beta-1a group were appendicitis (in three patients), limb abscess
(in two), injection-site cellulitis (in two), pneumonia (in two), urinary tract infection (in two), and acute tonsillitis, anal abscess, infective
cholecystitis, cystitis, infectious enterocolitis, viral gastritis, gastroenteritis, perirectal abscess, staphylococcal septic arthritis, staphylococcal
sepsis, tooth infection, viral infection, and viral pericarditis (in one patient each).
mab group (two cases of invasive ductal breast were detected during the open-label extension
carcinoma, one case of renal-cell carcinoma, and study, during which all the patients received
one case of malignant melanoma), and two oc- ocrelizumab. As of June 30, 2016, the overall
curred (in 0.2%) in the interferon beta-1a group incidence rate of first neoplasm among patients
(one case of mantle-cell lymphoma and one case treated with ocrelizumab across all studies in-
of squamous-cell carcinoma in the chest) (Ta- volving patients with multiple sclerosis was 0.40
ble 3). Between the clinical cutoff dates of the per 100 patient-years of exposure to ocrelizumab
two trials (April 2, 2015, in the OPERA I trial and (6467 patient-years of exposure), as compared
May 12, 2015, in the OPERA II trial) and June 30, with 0.20 per 100 patient-years of exposure in the
2016, five additional cases of neoplasm (two cases pooled comparator groups (2053 patient-years of
of breast cancer, two cases of basal-cell skin carci- exposure in groups receiving interferon beta-1a
noma, and one case of malignant melanoma) or placebo). (See Table S6 in the Supplementary

Appendix for the ORATORIO trial, the results of ocrelizumab was shown by the low incidence of
which are now published in the Journal.24) antidrug antibodies among patients treated with
ocrelizumab; the incidence of neutralizing anti-
bodies with interferon beta-1a was consistent
Discussion
with historical data.26,27
In the OPERA I and OPERA II trials, ocrelizumab The traditional view of the pathophysiology
was associated with significantly lower annualized of multiple sclerosis is that it is predominantly a
relapse rates (the primary end point) than the ac- T-cell–mediated disease. The findings in our two
tive comparator, interferon beta-1a, during the trials are consistent with evidence that B cells
96-week treatment period. In addition, patients play a role in the pathogenesis of multiple scle-
receiving ocrelizumab had better outcomes, as rosis.28,29 The mechanism of action of ocrelizu
assessed in the first 6 of 10 secondary end points mab involves immunomodulation by means of the
in the hierarchical testing. Ocrelizumab was as- reduction in the number and function of CD20+
sociated with a lower rate of disability progression B cells.30,31 The trafficking of activated oligoclonal
confirmed at 12 weeks and at 24 weeks than in- populations of B cells between the central ner-
terferon beta-1a, both in the prespecified pooled vous system and peripheral circulation has been
analysis and in each of the two phase 3 trials observed in persons with relapsing multiple
separately. Ocrelizumab also was associated with sclerosis,32,33 and the disruption of this network
a higher rate of disability improvement confirmed may explain the effects of ocrelizumab in our
at 12 weeks (a secondary end point) than inter- trials. Lymphoid stem cells and plasma cells lack
feron beta-1a in the pooled analysis. CD20, and thus B-cell reconstitution and preex-
These findings were supported by a signifi- isting humoral immunity should be relatively
cantly greater suppression of development of new preserved with ocrelizumab treatment.26,27,34
areas of inflammation (as assessed by means of The numerical imbalance in the neoplasms ob-
MRI of the brain with the use of gadolinium en- served in the OPERA I trial and in the ORATORIO
hancement) and new or newly enlarged plaque trial,24 which involved patients with primary
formation (as measured by lesions on T2-weight- progressive multiple sclerosis, warrants ongoing
ed MRI) (Figs. S7 and S8 in Supplementary Ap- evaluation in the context of the epidemiology of
pendix). However, the change in Multiple Sclero- neoplasm in the population of patients with
sis Functional Composite score, whole brain-volume multiple sclerosis and long-term experience with
loss, and the change in the SF-36 physical-com- ocrelizumab and other anti-CD20 treatments.35-37
ponent summary score were significantly better No cases of progressive multifocal leukoencepha-
with ocrelizumab than with interferon beta-1a lopathy (PML) have been reported so far with
in one trial but not in the other. Although the ocrelizumab across all clinical studies (F. Hoff-
findings were nonconfirmatory as a result of man–La Roche data on file). Further long-term
failure of the hierarchical analysis, the percent- assessment of the safety profile of ocrelizumab
ages of patients who had no evidence of disease is required in order to fully characterize the risk
activity were higher with ocrelizumab than with of uncommon adverse events, including PML.
interferon beta-1a in the two trials. Inflammation and neurodegeneration are un-
Infusion-related reactions were more com- derstood to be two distinct but overlapping mecha-
mon in patients treated with ocrelizumab than nisms of the pathogenesis of multiple sclero-
in those treated with interferon beta-1a and in- sis,38,39 with inflammation dominating the early
cluded one life-threatening (grade 4) broncho- stages of disease.40 The use of current therapies
spasm. The most likely mechanism for an infu- in patients with relapsing multiple sclerosis has
sion-related reaction is a type 2 hypersensitivity been associated with an improved overall prog-
reaction, in which cytokines are released from nosis, as compared with the pretreatment era.
an effector cell after the ligation of low-affinity However, most treated patients still have wors-
Fc receptors by ocrelizumab-opsonized B cells.25 ening neurologic disability over time in this life-
The incidence and severity of infusion-related reac- long disease.3,41-43 Additional and extended studies
tions decreased over the administration of subse- will be required in order to determine whether
quent doses; however, such reactions could occur the outcomes observed in these 96-week trials,
at any infusion. The limited immunogenicity of including a near-complete cessation of new plaque

formation as assessed by MRI of the brain, trans- Wollheim, Scott Evans, Henry F. McFarland, Israel Steiner,
Thomas Dörner, and Frederik Barkhof for serving as members
late into enhanced protection against accrual of of the independent data and safety monitoring committee; Nata-
disability over the long term. lie Nkwor, of Articulate Science, for writing and editorial assis-
Supported by F. Hoffmann–La Roche. tance with earlier versions of the manuscript; Monika Garas for
Disclosure forms provided by the authors are available with scientific contribution to the trial; Alexander Kulla, Michele Li-
the full text of this article at NEJM.org. bonati, and Mercedes McClean for critical review and technical
We thank the patients and all the investigators for making advice; and Qing Wang for statistical support during the prepa-
these trials possible; Stephen C. Reingold, Magnhild Sandberg- ration of the manuscript.
Appendix
The authors’ full names and academic degrees are as follows: Stephen L. Hauser, M.D., Amit Bar‑Or, M.D., Giancarlo Comi, M.D.,
Gavin Giovannoni, M.D., Hans‑Peter Hartung, M.D., Bernhard Hemmer, M.D., Fred Lublin, M.D., Xavier Montalban, M.D., Kottil W.
Rammohan, M.D., Krzysztof Selmaj, M.D., Anthony Traboulsee, M.D., Jerry S. Wolinsky, M.D., Douglas L. Arnold, M.D., Gaelle Klin-
gelschmitt, Ph.D., Donna Masterman, M.D., Paulo Fontoura, M.D., Ph.D., Shibeshih Belachew, M.D., Ph.D., Peter Chin, M.D., Nicole
Mairon, M.D., Hideki Garren, M.D., Ph.D., and Ludwig Kappos, M.D.
The authors’ affiliations are as follows: the University of California, San Francisco (S.L.H.), and Genentech, South San Francisco
(D.M., P.C., H.G.) — both in California; McGill University (A.B.-O., D.L.A.) and NeuroRx Research (D.L.A.), Montreal, and University
of British Columbia, Vancouver, BC (A.T.) — both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); Barts and the London
School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and the
Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) — both in Germany; Icahn School of
Medicine at Mount Sinai, New York (F.L.); Hospital Vall d’Hebron University, Barcelona (X.M.); University of Miami, Miami (K.W.R.);
Medical University of Lodz and Center for Neurology, Lodz, Poland (K.S.); McGovern Medical School, University of Texas Health Sci-
ence Center at Houston, Houston (J.S.W.); and F. Hoffmann–La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, Univer-
sity of Basel (L.K.), Basel, Switzerland.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Ocrelizumab versus Interferon Beta-1a

n engl j med 376;3 nejm.org January 19, 2017 221

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tion-to-treat population that excluded patients who R e sult s

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Characteristic OPERA I Trial OPERA II Trial

Ocrelizumab Interferon Beta-1a Ocrelizumab Interferon Beta-1a

n engl j med 376;3 nejm.org January 19, 2017 225

End Point OPERA I Trial OPERA II Trial Pooled Trials

Ocrelizumab Interferon P Interferon P Interferon P

Disability improvement confirmed at 12 wk†‡

n engl j med 376;3

The New England Journal of Medicine

January 19, 2017

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

(−0.86 to 0.93) (−1.59 to 0.28) (−0.55 to 1.20) (−1.76 to 0.09)

n engl j med 376;3

January 19, 2017

The New England Journal of Medicine

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

A Disability Progression Confirmed at 12 Wk

80 hierarchical testing) and 0.11 in the OPERA II

60 12 Interferon beta-1a 7.6 plementary Appendix). As a result of the failure in

228 n engl j med 376;3 nejm.org January 19, 2017

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n engl j med 376;3 nejm.org January 19, 2017 229

A OPERA I Trial B OPERA II Trial

Mean No. of Lesions per Patient

per MRI Scan

Mean no. Mean no.

Figure 2. MRI End Point.

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Table 3. Adverse Events (Safety Population).*

Variable OPERA I Trial OPERA II Trial

Ocrelizumab Interferon Beta-1a Ocrelizumab Interferon Beta-1a

no. of patients (%)

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TRACK THIS ARTICLE’S IMPACT AND REACH

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