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N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

Collaborators (317)

Reingold SC, Sandberg-Wollheim M, Barkhof F, Dörmer T, Evans S, McFarland HF, Steiner I, Yaldizli Ö, D’Souza M, Andelova M, Rust H, Ballario C, Giannaula R, Reich EG, Parratt J, Eggers C, Buyle M, Van Pesch V, Vanopdenbosch L, Carneiro D, Friedrich M, Longo AL, Genov K, Ivanova S, Maslarov D, Lilovski H, Staikov I, Cueto G, Dufek M, Havrdova E, Novotna A, Skoda O, Talabova M, Vachova M, Gross-Paju K, Haldre S, Elovaara I, Brochet B, Castelnovo G, Clavelou P, De Seze J, Debouverie M, Braune S, Haas J, Heidenreich F, Schwarz W, Siever A, Urban PP, Zettl U, Ziemann U, Ziemssen T, Zipp F, Debreczeni R, Rozsa C, Satori M, Chapman J, Ghezzi A, Perini P, Pozzilli C, Kalnina J, Millers A, Budrys V, Kizlaitiene R, Malciene L, Vaitkus A, Castro Farfan G, Gongora Rivera JF, Frequin STFM, Gavidia Chucan JM, Perez Villegas J, Pretell EJ, Rodriguez Kadota LE, Fryze W, Hertmanowska H, Maciejowski M, Opala G, Cerqueira J, Arefieva E, Maslova N, Odinak M, Pankratov E, Perfiliev S, Poverennova I, Sazonov D, Shirshova E, Sivertseva S, Volkova L, Vorobyova O, Knezevic Z, Raicevic R, Vojinovic S, Hancinova V, Saffova P, Turcani P, Vyletelka J, Coetzee CC, Garcia-Merino A, Hernandez MA, Izquierdo Ayuso G, Rodriguez Antigüedad A, Gobbi C, Belal S, Frih-Ayed M, Gouider R, Mrissa R, Moskovko S, Sanotskyy Y, Sokolova L, Statinova O, Voloshyna N, Turner B, Wilson M, Applebee A, Bandari D, Belkin M, Birnbaum G, Borresen T, Boyd J, Cascione M, Cohan S, Cohen B, Conway J, Cree B, Dihenia B, Dissin J, Flitman S, Ford C, Giancarlo T, Gold S, Green B, Gwynn M, Honeycutt D, Huddlestone J, Klawiter E, Kohrman B, Langer-Gould A, Lava N, Lindsey W, Mitchell G, Naismith R, Nicolas J, Pardo G, Patel M, Porter JAH, Racke M, Robertson D, Rossman H, Schafer J, Shubin R, Singer B, Smith C, Suski V, Thrower B, Wilson C, Wynn D, Zabad R, Estol CJ, Scarlatti A, Alekseenko Y, Fedulau A, Kulesh S, Navumava H, Willekens B, Alajbegovic A, Sinanovic O, Christo P, Papais Alvarenga RM, Pereira Damasceno B, Baldaranov D, Grigorova O, Haralanov L, Milanova M, Ayotte C, Blevins G, Freedman M, Grand'Maison F, Jacques F, Yeung M, Basic S, Hajnsek S, Janko-Labinac D, Kidjemet Piskac S, Benesova Y, Hradilek P, Brassat D, Edan G, Hautecoeur P, Moreau T, Papeix C, Tourbah A, Vukusic S, Aktas O, Berthele A, Bodenschatz R, Foerch C, Hohlfeld R, Landefeld H, Lang M, Platten M, Puzich R, Schmidt S, Tubridy N, Ardito B, Capra R, Centonze D, Crociani P, Danni M, Grimaldi L, Gusmaroli G, Mantegazza R, Mirabella M, Uccelli A, Carbajal Ramirez A, Lopez Meza EG, Lopez Prieto JJ, Oropeza de Alba JL, Reyes-Morales S, San Juan Orta D, Myhr KM, Binek M, Czarnecki M, Klodowska-Duda G, Stelmasiak Z, Szczudlik A, Tutaj A, Belova A, Dorogov N, Fedyanin A, Khasanova D, Makarov N, Mishin G, Sherman M, Skoromets A, Trushnikova T, Donath V, Dupejova B, Gurcik L, Arroyo R, de Andres C, Fernandez Fernandez O, Lainez Andrep JM, Martinez Gines ML, Martinez Rodriguez JE, Martinez Yelamos S, Oreja Guevara C, Perez Sempere A, Ramio L, Ramo Tello C, Lycke J, Olsson T, Roshanisefat H, Sundström P, Svenningsson A, Akman Demir G, Petek Balci B, Boz C, Efendi H, Karabudak R, Siva A, Terzi M, Yuceyar AN, Chmyr G, Goncharova Y, Kareta S, Lutskiy I, Harrower T, Hawkins C, Pearson O, Silber E, Absher J, Arnold T, Bass A, Bernitsas E, Braley T, Calkwood J, Carnes K, Coyle P, Dunn J, Edwards K, English J, Ferencz G, Fox E, Frohman E, Gazda S, Gitt J, Goodman A, Gross J, Hendin B, Herrman C, Hillen M, Huang D, Hunter S, Hutton G, Jacobs D, Keller B, Khan O, Kister I, Krupp L, Lathi E, Lynch S, Miller T, Miravalle A, Omidvar O, Perumal J, Picone M, Rao TH, Repovic P, Riskind P, Rowe V, Sheremata W, Steingo B, Twyman C, Weisman D, Wendt J, Wray S, Yapundich R, Zarif M.

Author information

1
From 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 Science Center at Houston, Houston (J.S.W.); and F. Hoffmann-La Roche (G.K., P.F., S.B., N.M.) and University Hospital Basel, University of Basel (L.K.), Basel, Switzerland.

Abstract

BACKGROUND:

B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.

METHODS:

In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.

RESULTS:

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 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) 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 occurred 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.).

PMID:
28002679
DOI:
10.1056/NEJMoa1601277
[Indexed for MEDLINE]
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