Articles
`
`
`
`Ocrelizumab in relapsing-remitting multiple sclerosis:
`
`@‘3
`
`a phase 2, randomised, placebo-controlled, multicentre trial
`
`Ludwig Kappos, DavidLi, PeterA Coiabresi, Paul O’Connor, Amit Bar-Or, Frederik Barkhof, Ming Yin, DavidLeppert, Robert Glanzman,
`Jeroen Tinbergen, Stephen L Hauser
`
`Su m mary
`Background B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and
`safety oftwo dose regimens ofthe humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-
`remitting multiple sclerosis.
`
`Methods We did a multicentre, randomised, parallel, doubleblind, placebo-controlled study involving 79 centres in
`20 countries. Patients aged 18—55 years with relapsing-remitting multiple sclerosis were randomly assigned (l:l:l:1)
`via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg)
`ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-la (30 pg) once a week. The randomisation
`list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups
`were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24,
`patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the
`2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions
`(GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intenfion-to-treat basis. This trial
`is registered with Clinical'lrialsgov, number NCT00676715.
`
`Findings 218 (99%) of the 220 randomised patients received at least one dose of oaelizumab, 204 (93%) completed
`24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-tO-treat population of 218 patients, at
`week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68—97; p<0~0001) lower in the 600 mg
`ocrelizumab group than in the placebo group, and 96% (89-99; p<0 -0001) lower in the 2000 mg group. In exploratory
`analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We
`noted serious adverse events in two of 54 (4%; 95% CI 3 0-44) patients in the placebo group, one of 55 (2%; 13—2 - 3)
`in the 600 mg ocrelizumab group, three of55 (5%; 4—6-66) in the 2000 mg group, and two of54 (4%; 3-0—44) in the
`interferon beta-1a group.
`
`Law“ 2011; 378: 1779-87
`Published Online
`November 1, 2011
`DOI:10.1016/50140‘
`6736(11)61649~8
`See Commentpage 1759
`Univuity Hospital, Bull,
`Swill-land (ProfL KapposMD);
`Univuity of British (obmbiy
`Venoouvu, BC, 0.de
`(D Li MD);]ohns Hopkins
`Univusitx Baltimore, MD, USA
`(PA Czlabresi MD); University
`Mommenbn, 0N, (and:
`(P O’Connor MD); McGI
`Univuity, Montreal, QC,
`(1an BarOrMD);
`VU Url'vu'sity Medial (Ultra,
`Amstmfim, Netherhnds
`(ProfF BarkhofMD);
`Gmentech Inc, South
`San Francisco, CA, USA
`(MWn PhD);
`F Hofimlnn-LI Roche Ltd, Basel,
`Sarita-tend (D qupert MD,
`R Ghnzrmn MD, Jl'mbevgm MD),-
`
`$E:m;ff;'xg u.
`USA(ProfSLHauserMD)
`
`Interpretation The similarly pronounced efl'ects of B-cell depletion with both ocrelizumab doses on MRI and relapse Commandment
`related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-
`Prof LudwigKappos.
`term trials
`Departments of Neurologyand
`Biomedic'ne, Univers'ty Hospital,
`Petersgvaben 4, CH 403L Basel,
`“mum
`IhppOIOUPbs‘h
`
`Funding F Hoifmann-La Roche Ltd, Biogen Idec Inc.
`
`Therefore, targeting ofthese cells might disrupt processes
`Introduction
`in multiple sclerosis pathogenesis.
`Inflammation in multiple sclerosis was previously
`Studies of rituximab—a chimeric monoclonal antibody
`thought to be mainly mediated by proinflammatory CD4
`against CDZO—have shown that B-cell depletion is of
`T cells (Thl, ThIL-17).1 However, B cells might also con-
`clinical benefit as treatment for Some lymphoma types,
`tribute to multiple sclerosis through antibody-dependent
`chronic
`lymphocytic
`leukaemia,’
`and
`rheumatoid
`and antibody-independent mechanisms. B cells might
`arthritis‘°'“ and as a potential treatment for multiple
`differentiate into plasma cells and produce CNS-directed
`sclerosis.“ Ocrelizumab is a recombinant humanised
`autoantibodies,
`triggering cellular and complement-
`antibody designed to selectively target CD20 B cells.
`dependent cytotoxic effects} These cells can also function
`as antigen-presenting cells and thereby modulate priming Compared with rituximab, ocrelizumab is associated with
`of effector T cells.’ Secretion ofproinflammatory and anti-
`increased antibody-dependent cell-mediated cytotoxic
`inflammatory cytokines by B cells is a function that seems
`effects, and reduced complement-dependent cytotoxic
`to be abnormal in patients with multiple sclerosis.“
`effects in vitro.‘“5 By increasing antibody-dependent cell-
`Production of cytokines and chemolcines by B cells could mediated cytotoxic effects, ocrelizumab might modulate
`also contribute to formation of ectopic lymphoid-like
`tissue-dependent mechanisms of pathogenic response
`stIuctures, resulting in CNS-compartmentalised presen— more effectively than does rituximab. AS a humanised
`tation of autoantigens and further immune activation.” molemle,ocrelizumabisexpectedtobeless irnmunogenic
`B cells could also be the reservoir for Epstein-Barr virus, with repeated infusions and might thus have a more
`which has been associated with risk of multiple sclerosis.
`favourable benefit—risk profile than rituximab.
`Biogen Exhibit 2074
`Mylall V. Biogen
`IPR 2018-01403
`
`www.thelance1t).caogeVol3?8ngovember 19, 2011
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`1779
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`Articles
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`
`
`We did this phase-2, placebo-controlled trial to assess
`efiicacy and safety of two dose regimens of ocrelizumab
`in patients with relapsing-remitting multiple sclerosis.
`We also compared ocrelizumab with once a week
`interferon beta-1a (avonex) as open-label treatment.
`
`Methods
`Patients
`
`We recruited patients from 79 centres in 20 countries, and
`did an international multicentre, randomised, parallel,
`double-blind, placebo-controlled, dose-finding Study with
`ocrelizumab. 58 patients were from centres in North
`America, 120 from centres in east-central Europe and Asia,
`34 from centres in western Europe, and eight from centres
`in Latin America. Eligible patients were aged 18—55 years
`with a diagnosis of relapsing-remitting multiple sclerosis,“
`had had two or more documented relapses within 3 years
`before screening, at least one ofwhich occurred within the
`past year, had expanded disability status scale (EDSS)‘7
`score of 1—6 points at baseline, and evidence of previous
`multiple sclerosis inflammatory disease activity with six
`T2 lesions or more per MRI, or two relapses in the year
`before screening.
`Key exclusion u'iteria were secondary or primary
`progressive multiple sclerosis; diSeaSe duration more
`than 15 years in patients with an EDSS of2 or less; known
`history or presence of other neurological or systemic
`autoimmune disorders;
`treatment with rituximab or
`lymphocyte-depleting therapies; use of lymphocyte
`traflicking blockers within previous 24 weeks; use of
`B interferons, glatiramer acetate, intravenous immuno-
`http://wwwneurostatusmt globulin,
`plasmapheresis,
`and
`irnmunosuppresive
`
`For moreon n-Jrobgiul
`assessment criteria see
`
`Study design
`Treatment period (96 weeks)
`
`IIIIIII
`MRI
`-4024
`8
`1216201425
`Screen (4 weeks)
`
`
`
`Screening
`
`Tratment period
`
`Secondcycle
`
`treatnents within previous 12 weeks, use of systemic
`glucocorficoids within previous 4 weeks; or intolerance
`to interferon beta-1a. After a screening period of up to
`4 weeks, eligible patients began treatment consisting of
`four treatment cycles of 24 weeks. This period was
`followed by a treatrnent-free follow-up and observation
`period ofabout 172 weeks from randomisation, dependent
`on the time taken for B-cell repletion.
`Institutional Review Board approval was obtained at each
`trial site. We did the study in accordance with Intemational
`Conference on Harmonization Good Clinical Practice
`
`guidelines, and with the Declaration of Helsinki. Patients
`provided written informed consent before participation.
`
`Procedures
`
`Our primary objective was to investigate the effect of
`ocrelizumab on the total number of gadolinium-
`enhancing T1 lesions observed on brain MRI scans for
`weeks 12, 16, 20, and 24 versus placebo. A fourth study
`group with interferon beta-1a was included as an active,
`open label, rater-masked control (figure 1). Key secondary
`endpoints
`included the annualised protocol-defined
`relapse rate; proportion of relapse-free patients;
`total
`number of gadolinium-enhancing T1 lesions (all data-
`points from 4-24weeks) ; total number ofnew gadolinium-
`enhancing T1 lesions; change in total volume ofI'Z lesions
`from baseline to week 24; safety and tolerability of two
`dose regimens of ocrelizumab versus placebo and
`interferon beta-1a at week 24; and safety of ocrelizumab
`therapy up to 96 weeks. Here we present the results of
`the 24—week placebo and interferon beta-1a Controlled
`phase, and results of the second cycle for another
`24 weeks, in which patients in comparator groups were
`switched to ocrelizumab.
`
`Every study site had two investigators: the treating
`investigator and the examining investigator. The treating
`investigator had access to safety and eflicacy data, and
`made all treatment decisions on the basis of patients'
`clinical responses and laboratory findings. A trained and
`certified examining investigator, who had no access to
`other study or patient-related information, did a full
`neurological examination,
`including assessment of
`walking capacity, and assigned the functional systems
`and EDSS.
`
`We obtained brain M R] (proton density and T2-weighted
`images, T1-weighted images before and alter gadolinium
`enhancement) scans at baseline and thereafter at intervals
`of4weeks to week 24, and centrally reviewed and analysed
`the scans with no clinical information to ensure they were
`masked. Patients were assessed for relapse by the treating
`investigator at each visit throughout the study and, if
`necessary, at unscheduled visits. We designated protocol-
`defined relapses as the occurrence of new or worsening
`neurological symptoms attributable to multiple sclerosis,
`and immediately preceded by a stable or improving
`neurologin state of at least 30 days. Symptoms had to
`persist for more than 24 h and be accompanied by
`
`www.1helancet.com Vol 378 Novemberls, 2011
`
`
`
`
`
`Intravenous
`placebo
`
`Intravenous
`ocrelizumab
`300 mg
`Intravenous
`
`
`
`Intravenous
`ocrelizumab
`300 mg
`Intravenous
`Intravenous
`ocrelizumab
`ocrelizumab
`600 mg placebo
`600 mg
`Intravenous
`Intravenous
`ocrelizumab
`placebo
`Ocrelizumab
`2000 mg
`1000 mg
`Intravenous
`Intravenous
`ocrelizumab
`ocrelizumab
`300 mg
`300 mg
`
`Intramuscular avonex
`
`Interferon beta-1a
`
`30 P9 everyweek
`
`Figural: Study design and treat ment protocol
`Randomlsatlon stratlfied by geographiml reglon.
`
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`objective neurological worsening consistent with an
`increase of at least half a step on the EDSS, or two points
`on one, or one point on two or more of the functional
`systems scores. The examining investigator assessed
`disability progression (measured by EDS S) at screening
`and every 12 weeks throughout the study. We defined
`such progression as an increase of 1 point or more from
`baseline EDSS score confirmed at the next scheduled
`
`examination 3 months after initial screening. In addition
`to routine laboratory tests, we examined CD19 B-cell
`counts, irnmunoglobulin concentrations (total immuno-
`globulin, IgG, IgM, and IgA), ocrelizumab concentrations,
`and human antihuman antibodies against ocrelizumab.
`The 600 mg ocrelizumab group had a dual infusion of
`300 mg for the first treatment cycle (days 1 and 15), and
`then infusions of 600 mg for the subsequent trealInent
`cycles (weeks 24, 48, and 72). The 2000 mg group had a
`dual infusion of 1000 mg (days 1 and 15) for the first
`treatment cycle, and then an infusion of 1000 mg for the
`subsequent treatment cydes. Patients in the placebo
`group received placebo on days 1 and 15 of the first
`treatment cycle. The interferon beta-1a group received
`intramuscular interferon beta-1a once a week for the first
`
`24 weeks. The placebo and interferon beta-la groups were
`offered ocrelizumab 600 mg for the Second, third, and
`
`fourth treatment cycles (figure 1). Safety was assessed at
`weeks 2, 4, 8, 12, 16, 20, 24, and 48 with regular neurological
`and physical examinations, vital signs, electrocardiograph,
`and the occurrence of adverse events. By week 24,
`six patients withdrew for safety reasons. One patient in
`the 2000 mg ocrelizumab group died of systemic
`inflammatory response syndrome of undetermined
`origin. We did ]C virus testing for early detection and
`follow-up in case of suspected progressive multifocal
`leukoencephalopathy every 12 weeks. We assessed clinical
`relapses in the efficacy and safety analyses and recorded
`every relapse as an adverse event. Although defined
`retrospectively, we also recorded progression of relapsing-
`rernitting multiple sclerosis to secondary progressive
`multiple sclerosis as an adverse event. All study MRIs
`underwent safety review by the site radiologist to identify
`any new clinically relevant abnormal MRI findings that
`were not consistent with the diagnosis of multiple
`sclerosis, with particular attention to the possibility of
`progressive mullifocal
`leukoencephalopathy, and to
`provide a report ofthe MRI to the treating investigator.
`To reduce potential infusion-related reactions, 30 min
`before the start of each infusion, patienm in the
`ocrelizumab or placebo groups received intravenous
`methylprednisolone 100 mg. Patients in the interferon
`
`Age (years)
`Sat
`Female
`Race
`wh ite'
`
`Disease duration (years)
`Since onset ofMS symptoms
`Since MS diagnosis
`Relapsoslnpast3years
`
`Plxebo (n=54)
`38-0(8-8)
`
`Ocrel'uumab 600 mg (rI=5$)
`35-6 (8-5)
`
`Ocrelizumab 2000 mg (rI=5$)
`38-5 (8-7)
`
`Interferon beta-1:01:54)
`38-1 (9-3)
`
`36 (67%)
`
`52 (9636)
`
`4-8 (0-6—262)
`2.7 (01—192)
`
`35 (64%)
`
`51(93%)
`
`6-5 (05—205)
`3-6 (0-1—165)
`
`38 (69%)
`
`53 (9696)
`
`7-7 (0-25—28-0)
`4-4(o.1—19.2)
`
`32 (59%)
`
`53 (98%)
`
`5-3 (0.3—35-2)
`3-3 (01—202)
`
`4 (796)
`26 (48%)
`1'; (28%)
`9 (17%)
`3-2 (1-4); 30 (1-0-6-0)
`8951 (9776-3) 4765 (47—39 920)
`
`1 (2%)
`28 (51%)
`16 (29%)
`10 (18%)
`3-5 (1-5); 3-5 (1-0—6-0)
`13 973 (19 930-2); 6688 (11-93778)
`
`o<--)
`1 (2%)
`3O (56%)
`30 (55%)
`21 (39%)
`14(25%)
`3 (6%)
`10 (18%)
`3-1 (15); 2-8 (1-0—60)
`34(13): 3-5 (lo-60)
`13 178 (142714)- 7129 (203—59 432) 13209 (17 206-5); 8247 (24-102 912)
`
`3-9 (9-88);1(0—46);l0R(0-3)
`
`2-2 (6-33); 0 (0-37); IQR (0-1)
`
`2-3 (5-26),- 0 (0-24); IQR (0-1)
`
`25 (49%)
`6 (12%)
`6 (12%)
`6 (12%)
`8 (16%)
`26 (47%)
`
`29 (55%)
`12 (23%)
`4(8%)
`2 (4%)
`6 (11%)
`27 (49%)
`
`33 (66%)
`7 (14%)
`2 (4%)
`0 (..)
`8 (16%)
`37 (69%)
`
`
`
`Basellne EDSS
`Volume ofT2 lesions at
`baseline (mm')
`1-6 (4-05); 0 (0-25); IQR (0-1)
`Gadolln ium—enhandng T1 lsions
`Total gadolinium-enhandng T1 lesion count ('4)
`26 (55%)
`11 (23%)
`2 (456)
`2 (4%)
`6 (13%)
`38 (70%)
`
`No previous lmmunomomlatory
`treatment
`
`Data are mean (SD), "(1‘), ormedian (min-max), unlusoiherwise stated. MS-multifle sdmosis. EDSS-explmhd disability slams sale. 'The studywas done in mainlywllite individuals; odierswere mfiy
`black (six individmls) amt Gaines: (two).
`Table 1: Baseline charxneristia
`
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`beta-1a group received this concomitant treatment at the
`corresponding time at days 1 and 15 during the fi rst
`treatment cycle. We recommended preinfusion treatment
`with an oral analgesic or antipyretic (eg, acetaminophen),
`and an oral antihistaminine (eg, diphenhydramine).
`
`Randomisation and masking
`A randomisation list was generated by an independent
`group within Roche. This list was provided to an
`interactive voice response system, which then randomised
`patients (1:1:1:1) to one of the four treatment groups
`stratifi ed by geographical region (fi gure 1). The list was
`not disclosed to the study centres, monitors, project
`statisticians, or to the project team at Roche and
`Genentech. All individuals directly involved in this study
`remain blinded to the dose of ocrelizumab. Project
`statisticians remained blinded until data lock and
`statistical analysis at week 24. We masked treatment
`assignment for patients in the placebo and both
`ocrelizumab groups throughout the study. In the
`interferon beta-1a group, only the raters were masked to
`
`allocation; therefore comparisons of the other groups
`with this group on the primary and secondary outcomes
`were exploratory.
`
`Statistical analysis
`On the basis of results from the rituximab proof-of-
`concept study,13 we estimated a sample size of 35 patients
`per group was needed to provide 80% power with a two-
`sided signifi cance level of 0·05 to detect a diff erence in
`the total number of gadolinium-enhancing T1 lesions
`between each ocrelizumab group versus placebo with the
`Wilcoxon rank-sum test. To allow for drop-outs, we
`planned for up to 50 patients to be randomly assigned to
`each treatment group. Because screening was faster than
`expected, once all sites were started, we allowed a
`maximum of 220 patients to be randomly assigned to
`avoid exclusion of scheduled patients. We did no interim
`analysis. Analysis was by intention to treat. We applied
`the van Elteren test, stratifi ed by geographical region
`and presence of baseline gadolinium-enhancing lesions
`(absent or present), to compare each ocrelizumab group
`
`273 patients screened for eligbility
`
`53 patients excluded
`
`54 assigned to placebo
`
`56 assigned to ocrelizumab
`600 mg
`
`55 assigned to ocrelizumab
`2000 mg
`
`55 assigned to interferon
`beta-1a
`
`1 not treated
`
`1 not treated
`
`54 included in the ITT and
`safety populations
`
`55 included in the ITT and
`safety populations
`
`55 included in the ITT and
`safety populations
`
`54 included in the ITT and
`safety populations
`
`4 discontinued
`2 had an adverse event
`2 withdrew consent
`
`7 discontinued
`2 had an adverse event
`2 withdrew consent
`1 died
`1 violated selection
`criteria
`1 failure to return
`
`3 discontinued
`1 had an adverse event
`2 withdrew consent
`
`54 patients completed
`24 weeks
`
`51 patients completed
`24 weeks
`
`48 patients completed
`24 weeks
`
`51 patients completed
`24 weeks
`
`2 discontinued
`1 refused treatment
`1 insufficient response
`
`2 discontinued
`2 withdrew consent
`
`2 discontinued
`1 refused treatment
`1 withdrew consent
`
`2 discontinued
`1 had an adverse event
`1 withdrew consent
`
`52 patients completed
`48 weeks
`
`49 patients completed
`48 weeks
`
`46 patients completed
`48 weeks
`
`49 patients completed
`48 weeks
`
`Figure 2: Trial profi le
`ITT=intention-to-treat.
`
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`
`
`with placebo for the primary endpoint. We replaced
`missing values for gadolinium-enhancing T1 lesions
`with the average number of lesions on available scans
`from that patient obtained during the first 24 weeks of
`treatment, excluding MRIs that were done after early
`
`termination from the treatment period. We did similar
`analyses for other lesion-count endpoints.
`We analysed annualised relapse rates with Poisson
`regression, offsetting for exposure fime in years, and
`adjusfing for geographical region. No imputation was
`
`MRI
`
`Plxebo (n=54)
`
`Ocrel'uurnab Goo mg (n=55) Ocrel'uurrub 2000 mg (n=55)
`
`Interferon hen-1:01:54)
`
`Total number-of galodl nlumenhanclngn leslons overweeks 12, 16, 20, and 24'
`n (96)
`54 (100%)
`Mean (SD)
`5-5 (12-5)
`Medlan (mIn-max)
`1-6 (0-79)
`9596 Cl
`0-8—2-6
`p value (ocrellzumab vs placebofi
`--
`p value (ocrellzumab vs Interferon beta-1a)1’
`--
`Total numberof galodlnlum—enhandng T1leslors overweeks 12, 16, 20, and 24 by Gregory' (96)
`19 (3596)
`6 (11%)
`7 (B96)
`3 (6%)
`19 (3596)
`--
`p value vs placebo:
`Total numberof new galodlnIum-enhandng leslons overweeks 4, 8, 12, 16, 20, and 24'
`Man (SD)
`6-6 (14-2)
`Medlan (mln—max)
`2-2 (0-93)
`9596 CI
`10-40
`
`--
`
`51 (9396)
`0-6 (1-5)
`0-0 (0-7)
`--
`<0-0001
`<0-0001
`
`39 (77%)
`2 (496)
`6 (1296)
`0
`4(8%)
`<0-0001
`
`0-8 (2-0)
`0.0 (0-11)
`0-0-0-0
`
`<0-0001
`
`52 (9596)
`02 (07)
`00 (0-3)
`--
`(00001
`<00001
`
`43 (82-796)
`6 (ll-5%)
`1(1-996)
`2 (3-896)
`0
`(00001
`
`08 (2-2)
`no (0-14)
`0-0—0-0
`
`<00001
`
`52 (9696)
`6-9 (160)
`10 (0-78)
`0-0-2-0
`
`25 (48%)
`5 (1096)
`5 (1096)
`0
`17 (3396)
`04182
`
`7-2 (16-3)
`10 (0-95)
`00-2-0
`
`0-9
`
`p value vs placebo‘l
`Change In volume of'l'l lslon from basellne toweek 24
`n (96)
`Mean (SD)
`Medlan (mln—max)
`9596 Cl
`p value vs placebos
`Total numberof newor enlarging T2 Islons at week 24
`n (96)
`Mean (50)
`p value vs planebos
`Rehpss
`Total numberof patients with relapses by week 24 (96M
`Annuallsed relapse rate by week 24
`95% CI
`
`p value vs placebo"
`p value vs Interferon beta-1a"
`Proportlon relapse-free atweek 24 (96)
`9596 CI“
`Relatlve rlsk comparedwlth placebo (9596 G)
`Total numberof relapses between wedr 24 andweek 48 (96)1l
`Annualbed relapse rate between weeks 24 and 48 (9596 Cl)||
`Proportlon relwse-free from weeks 2410 48 (96)
`9596 Cl“
`
`
`
`47 (8796)
`—1.14-0 (1400-8)
`5-2 (-5689-2 to 25049)
`-42-1 to 179-2
`--
`
`47 (8596)
`—841-4 (2702-2)
`-65-8 (-16298-6to 1520-3)
`-179-1to —5-3
`0-2
`
`46 (8496)
`—578-1 (2109-2)
`-17-1 (7301-2 to 5212-5)
`—679~5 to —60-5
`02
`
`48 (89%)
`996-7 (4418-1)
`00 (-6713-8 to 254594)
`-121-2 to 292-4
`0-5
`
`51 (9496)
`0.0 (0.1)
`<0-0001
`
`3 (5%)
`013
`053-029
`0-0005
`0-03
`
`48 (8796)
`78-5—96-1
`0-53 (0.2}1-22)
`2 (3-996)
`009 (004—020)
`47 (9296)
`84-8—99-5
`
`52 (9696)
`00 (0.1)
`«mom
`
`40%)
`017
`005-035
`00014
`009
`
`45 (8296)
`71-6-92-0
`076 (036157)
`6 (10.696)
`028 (0.174147)
`42 (8996)
`80-5-98-2
`
`52 (9696)
`1-8 (5-2)
`0-3
`
`9 (1796)
`0-36
`022—060
`007
`
`42 (78%)
`66-7-88-9
`0-92 (0461-84)
`3 (5-996)
`044 (007—028)
`46 (9096)
`820-984
`
`16 (3096)
`0-64
`0-43-0-94
`0-07
`
`41 (7696)
`645—873
`
`4 (7-496)
`016 (009-030)
`49 (9196)
`830-985
`
`Dakar: mun (SD), n (96), Ild "Infill (IQR), uriessotherwise shted'M'ss'ng valueat afimqacintisimpmiedwiflrthe merge ofavailable afler basiine cinwafiars lrd before M246 Wm Bureaus!
`strafifiui by geogrqirkal region and [lemme ofbaseine garblinium—erirancing lesions (absent or punt). tfisfin’k Exacttest. SVan Eleven test stratified by geogrqahial reg'on. 1l0bservationll values. IIPo'ssorr
`rgreu‘on ofisetling for orposure lime inyelsand aijustingforgeogmhial reg’on “We minted palimtswho dsmntinued earlywifllom hiring "elm 3 having arelapse.
`
`Tablel- MRI and clinical outcomes
`
`
`Page 5 of 9
`www.melancetm Vol 378 November19, 2011
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`1783
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`Articles
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`
`
`
`7—
`+ Placebo (n-54)
`—I— Ocrelizumab 600 mg (n-Sl)
`+ Ocrelizumab 2000 rng(n-52)
`-O- Interferon beta-1a (n-52)
`
`
`
`
`
`MeanT1galodinium—enhancinglesions(95%Cl)
`
`6-
`
`
`20
`
`16
`24
`12
`8
`4
`0
`Weeks
`
`
`
`
`Figure} Gaiolinium enhancing lsions byweek in each study group
`
`(n=54)
`
`Ocrdizurmb Ocrelimmab
`2000 mg
`600 mg
`(n=SS)
`(n=55)
`
`Interferon
`beta-1:
`(n=54)
`
`Patienswith adverse events (56)
`Week 0-24
`Week 24—48
`
`Patiens with serious adverse events (96)
`Week 0—24
`Week 24-48
`
`38 (70%)
`36 (68%)
`
`34 (62%)
`26 (52%)
`
`36 (66%)
`22 (47%)
`
`30 (56%)
`30 (60%)
`
`2 (4%)
`1 (2%)
`
`1 (2%)
`1 (2%)
`
`3 (6%)'
`2 (4%)
`
`2 (4%)
`3 (6%)
`
`Adverse evens leading towithdnwd (96)
`Week 0-24
`Week 24-48
`Adverse evens rdated to study treatment,
`week 0—24 (‘36)
`Most common adverse events relatedto study treatment from week 0 to 24' (96)
`Influenza-like illness
`o (..)
`0(--)
`Headache
`1 (2%)
`3 (6%)
`5 (9%)
`3 (6%)
`2 (4%)
`4 (7%)
`2 (4%)
`1 (2%)
`o (..)
`1 (2%)
`3 (6%)
`1 (2%)
`3 (6%)
`1 (2%)
`13 (25%)
`7 (14%)
`
`o (..)
`o (..)
`25 (46%)
`
`2 (4%)
`0 (..)
`17 (31%)
`
`1 (2%)
`N")
`15 (27%)
`
`1 (2%)
`1 (2%)
`19 (35%)
`
`1o (19%)
`S (9%)
`1 (2%)
`o (..)
`3 (6%)
`3 (6%)
`0 (0)
`0 (0)
`7 (14%)
`
`0(~)
`2 (4%)
`2 (4%)
`1 (2%)
`1 (2%)
`
`06)
`3 (6%)
`2 (3-6)
`2 (3-6)
`0 (..)
`1 (1-8)
`1 (1-8)
`0 (..)
`s (17%)
`
`o (..)
`o (..)
`0 (..)
`o (..)
`1 (2%)
`
`used for the annualised relapse rate analysis. Exposure
`times were calculated up to either the week 24 Cutoff (for
`patients who completed week 24) , or up to early withdrawal.
`We analysed the proportion of patients who remained
`relapse-free between week 0 and week 24 with a Cochran-
`Mantel-Haenszel x2 test stratified by geographical region
`and baseline presence of gadolinium-enhancing lesions
`(present or absent) to compare each ocrelizumab group
`with placebo and interferon beta-1a. For proportion
`analyses, we counted patients who discontinued treatment
`early without a relapse as having a relapse (worse-case
`scenario). We did sensitivity analyses by classifying
`patients who discontinued treatment early without having
`a relapse as without a relapse (best-case scenario). We
`implemented no multiplicity adjustment for the sample-
`size calculation or for the statistical tests. This trial is
`
`registered with ClinicalTrials.gov, number NCT00676715.
`
`Role of the funding source
`The study was designed jointly by the sponsors and
`investigators. Data were collected by the investigators
`and held and analysed by the sponsor. All authors had
`full access to the data and approved its completeness and
`analysis. The corresponding author had final respon-
`sibility for the decision to submit for publication.
`
`Results
`Baseline characteristics were similar in all groups (table 1).
`Of the 220 randomly assigned patients, 204 (93%)
`completed the 24—week study period (figure 2). Completion
`rates for week 48 were similar to those for week 24. We
`
`noted highly significant differences in both ocrelizumab
`groups
`(p<0-0001)
`for
`total number of gadolinium-
`enhancing T1 lesions at weeks 12, 16, 20, and 24, versus
`placebo. Overall, the relative reductions were 89% (95% CI
`68—97) for the 600 mg ocrelizumab group, and 96% (89—99)
`for the 2000 mg group compared with placebo (table 2).
`More patients in both ocrelizumab groups remained free
`of gadolinium-enhancing T1 lesions (77%, 88%) than did
`so in the placebo and interferon beta-1a groups (table 2).
`Whereas mean lesion numbers remained at the same level
`
`in the placebo group, by week 4, both ocrelizumab groups
`had reduced mean numbers of gadolinium-enhancing
`T1 lesions, which lasted to week 24 (figure 3).
`Annualised relapse rates over 24 weeks were 80%
`(95% CI 45—99) lower in the 600 mg ocrelizumab group
`than in the placebo group, and 73% (29—97) lower in the
`2000 mg group (table 2). Compared with placebo, the total
`number of new and persisting gadolinium-enhancing
`lesions (all datapoints) was also lower for both ocrelizumab
`groups (p<0-0001). Change in total volume of T2 lesions
`did not differ significantly between groups at week 24.
`From week 24 to week 48, the level of dinical activity
`(relapses)
`in the ocrelizumab groups remained low
`(table 2). Patients in the placebo and interferon beta-1a
`groups reached a similar low disease activity after one
`treatment qrcle with ocrelizumab. We noted no clear dose
`
`
`
`Urinary tract Infection
`Upper respiratory tract Infection
`Nasopharyngitls
`Chills
`
`Multiple sderosis relapse
`Oral herpes
`Patienswith adverse evens rdatedto study
`treatment, week 24—48 (%)
`Most common adverse evens relatedto study treatment from week 24m 481‘
`Urinary tract Infection
`3 (6%)
`0 (..)
`Headache
`2 (4%)
`1 (2%)
`Nausea
`0 H
`0 l")
`Upper rupllatmy uact Infection
`2 (4’6)
`OH
`2 (4%)
`1 (2%)
`Respiratorytiact Infection
`Infusion— related reactions (96)
`Cyde one
`Day 1
`Day 15
`Cycle two
`Day 1
`Day 15
`
`S (9%)
`6 (11%)
`
`19 (35%)
`2 (4%)
`
`24 (44%)
`S (9%)
`
`15 (30%)
`8 (17%)
`1 (2%)
`3 (6%)
`(Continue on next page)
`
`
`22 (42%)
`2 (4%)
`
`8 (16%)
`1 (2%)
`
`1784
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`Page 6 of 9
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`www.fl1elancet.com Vol 378 Novemberls, 2011
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`

`

`
`
`Articles
`
`Ocrelizumab Ocrdizurmb Interferon
`600 rrg
`2000 mg
`beta-11
`(ness)
`(n=55)
`(n=54)
`
`(Continued from previous page)
`Infections
`
`22 (4196)
`16 (30%)
`
`Any event (30)
`Week 024
`Week 24—48
`Serious infections (96)
`10%)
`Week 0-24
`1(296)
`Week 2410 Week 48
`Patients positive for human amt human antibodies
`Baseline ('A)
`1/49 (2%)
`Week 12 (‘36)
`1/39 (3%)
`Week 24 (96)
`1/36 (3%)
`Week 48 (36)
`0/47 (--)
`
`23 (42%)
`17 (34%)
`
`18 (33%)
`9 (19%)
`
`0 (--)
`1 (2%)
`
`1151(256)
`0/44 H
`1137 (3%)
`0144 (~-)
`
`O (--)
`o (..)
`
`0149 (~-)
`0/39 (--)
`0137 (~-)
`0140 (--)
`
`ND
`ND
`7131 (7%)
`0145 (--)
`
`Datum n (it). ND-not done. 'includes one dnih. tlncidence 25% in my group; infusion-related reactions «druid.
`
`Tufle3: Safety outcome atweeks 24 and 48
`
`See Online forwebappendx
`
`
`
`
`
`
`
`
`
`
`
`separation in the intention-to-treat population, although
`the estimated mean annualised relapse rate from week 24
`to week 48 was lower in the 600 mg group (0-09, 95% CI
`0 .04—0-20) versus the 2000 mg group (0-28, 0-17—0-47).
`One patient had a serious adverse event in the 600 mg
`ocrelizumab group (2%, 95% CI 1-3—2~3) as did three
`(6%, 4- 6-63) in the 2000 mg group, and four (4%,
`3-0—4-4) in the placebo group, and two (4%, 3 -0—4-4) in
`the interferon beta-1a group. Serious infections occurred
`at similar rates in ocrelizumab and placebo patients
`(table 3). One patient in the 2000 mg group died in
`week 14. A 41-year-old woman with a 10-year history of
`multiple sclerosis, earlier treated with interferon, had an
`inconspicuous course in the trial until week 12. See
`webappendix p 1 for a detailed account of this notable
`adverse event in our study.
`Most infusion-related events during first infusion were
`mild to moderate (table 3). At first infiision, more patients
`given 6“) mg (35%, 95% CI 22—47) and 2000 mg (44%,
`31—57) ocrelizumab had infusion-related adverse events
`than did those in the placebo group (9%, 2—17). The
`number of events was much the same as for placebo in the
`second part of the dual infusion. We noted no differences
`in immunoglobulin concentrations over time. The number
`of patients with human antihuman antibodies was similar
`in all groups (table 3). In the 600 mg group, one patient
`had positive human antihuman antibody results at
`baseline, week 24, and on study day 91. CD19 peripheral
`B cells were rapidly and completely depleted in patients
`treated with ocrelizumab. By week 2 after injection, B-cell
`Counts were reduCed by 99 -0% and 99-296 for both
`ocrelizumab groups, which persisted until week 24.
`From 24—48 weeks we recorded no imbalance in adverse
`
`events for the treatment groups, and serious events were
`similar (one in the placebo group; one and two in the
`600 mg and 2(XX) mg ocrelizumab groups, respectively;
`and three in the interferon beta-1a group). Rates ofserious
`infection-related events were similar for patients receiving
`either 600 mg (3 .4 per 100 patient-years; 95% c1 1.3—9 - 0)
`or 2000 mg (3 ~ 5 per 100 patient-years; 0 - 9—14) ocrelizumab,
`or placebo (3 .8 per 100 patient-years; 0 5—27). We did not
`record any opportunistic infections and, overall, identified
`no clinically relevant abnormal laboratory changes In a
`pre-specified exploratory analysis, both ocrelizumab doses
`were better for the primary endpoint, (600 mg ocrelizumab
`91% reduction, 95% CI 73—98; 2000 mg ocrelizumab
`97% reduction, 90-99) versus interferon beta-1a (figure 4).
`
`Discussion
`
`The total number of gadolinium-enhancing MRI lesions
`at weeks 12, 16, 20, and 24 was lower in both ocrelizumab
`dose groups than in patients given placebo. Annualised
`relapse rates were also lower in the ocrelizumab treafinent
`groups than in the placebo group. Both ocrelizumab
`doses seemed to be equivalent because we recorded no
`clear dose separation in key endpoints for the intention-
`to-treat population. The low level of clinical disease
`
`Page 7 of 9
`www.thelancet.<o
`Vol 378 November19,2011
`
`Amualisedrehpserate(95%Cl)
`
`0-24 24-48
`(n-54)(n-54)
`Placebo
`
`0-24 24-48
`(n-SS) (n-51)
`600 mg OCR
`
`0-24 24-48
`0-24 24-48
`(n-S4)(n-51)
`(n-55)(n-S4)
`2000 mg OCR Interferon beta—la
`
`Figun4: 48-week relapse data
`0CR=oaelizumab. ‘One patient in the 2000 mg group had four relapses: two in
`weeks 0—24, and two lnweeks 24—48.
`
`activity in the original ocrelizumab groups at week 48
`indicates sustained efficacy.
`Although the comparison with interferon beta-1a was
`planned only as a tertiary analysis, and only rater masked
`with respect to the clinical assessments, the benefit in
`both ocrelizumab treatment groups was clearly better for
`the primary endpoint. Furthermore, the 600 mg dose had
`a significant effect on the relapse rate compared with
`interferon beta-1a. After only 6 months of treatJ'nent, and
`with a sample size planned to detect an increased effect
`size, we expected the difference between interferon beta-
`la and placebo to not reach statistical significance. A
`slight imbalance in baseline characteristits (10w ratio of
`
`1785
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`

`

`Articles
`
`men to women and somewhat diff erent proportion of
`patients with past experience of immuno modulatory
`treatment) might have masked a minor eff ect of
`interferon beta-1a. The clear reduction of disease activity
`in the placebo and interferon beta-1a groups after
`switching to ocrelizumab provides evidence against a
`major eff ect of baseline imbalances and further supports
`the advantage of ocrelizumab.
`The rapid reduction of disease activity with ocrelizumab
`reported here adds to the increased evidence that B