Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis
Xavier Montalban, Stephen L Hauser, Ludwig Kappos, Douglas L Arnold, Amit Bar-Or, Giancarlo Comi, Jérôme de Seze, Gavin Giovannoni, Hans-Peter Hartung, Bernhard Hemmer, Fred Lublin, Kottil W Rammohan, Krzysztof Selmaj, Anthony Traboulsee, Annette Sauter, Donna Masterman, Paulo Fontoura, Shibeshih Belachew, Hideki Garren, Nicole Mairon, Peter Chin, Jerry S Wolinsky, ORATORIO Clinical Investigators, Stephen C Reingold, Magnhild Sandberg-Wollheim, Frederik Barkhof, Thomas Dörner, Scott Evans, Henry F McFarland, Israel Steiner, Özgür Yaldizli, Marcus D’Souza, Michaela Andelova, Heiko Rust, Leslie Sedal, Bruce Taylor, Hamid Assar, Eduard Auff, Thomas Berger, Michael Guger, Georg Pilz, Peter Wipfler, Emmanuel Bartholomé, Danny Decoo, Jefferson Becker, Irenio da Silva Filho, Denise Diniz, Antônio Gomes Neto, Soniza Leon, Lyubomir Haralanov, Ivan Milanov, Amir Bar-Or, Mark Freedman, François Grand’Maison, James Marriott, Paul O’Connor, Daniel Selchen, Michael Yeung, Yvonne Benesova, Eva Krasulova, Marta Vachova, Laura Airas, Irina Elovaara, Markus Färkkilä, Jaana Korpela, Marja-Liisa Sumelahti, David Brassat, Bruno Brochet, William Camu, Giovanni Castelnovo, Michel Clanet, Pierre Clavelou, Marc Debouverie, Giles Defer, Olivier Gout, Olivier Heinzlef, David Laplaud, Christine Lebrun-Frenay, Caroline Papeix, Jean Pelletier, Ayman Tourbah, Patrick Vermersch, Sandra Vukusic, Klemens Angstwurm, Martin Berghoff, Christian Förch, Norbert Goebels, Judith Haas, Lutz Harms, Ingo Kleiter, Jürgen Koehler, Eckard Lensch, Volker Limmroth, Sven Meuth, Patrick Oschmann, Michael Platten, Florian Then Bergh, Hayrettin Tumani, Ulf Ziemann, Tjalf Ziemssen, Theodora Afradou, Nikolaos Fakas, Stefanos Tsounis, Nikolaos Vlaikidis, Gábor Jakab, Sámuel Komoly, Csilla Rózsa, Mária Sátori, Gyöngyi Szabó, László Vécsei, Anat Achiron, Mark Hellmann, Arnon Karni, Dimitrios Karussis, Ron Milo, Radi Shahien, Antonio Bertolotto, Maria Giovanna Marrosu, Antonio Uccelli, Lina Malciene, Daiva Rastenyte, Sigla Sceponaviciute, Freddy Castro Farfan, Eduardo Duriez Sotelo, Jose Flores-Rivera, Sarug Reyes Morales, Rogier Hintzen, Raymond Hupperts, Christopher Lynch, Stuart Mossman, Elisabeth Gulowsen Celius, Jorge Gavidia Chucan, Julio Perez Villegas, Edwin Pretell Alva, Dariusz Bielecki, Waldemar Brola, Jan Kochanowicz, Maciej Maciejowski, Zbigniew Stelmasiak, Janusz Zbrojkiewicz, Luis Cunha, José Gonçalves, Irene Mendes, João Sá, Vasco Salgado, Ana Silva, Rodica Balasa, Silviu Manescu, Cristina Aura Panea, Mihaela Adriana Simu, Eduard Yakupov, José Álvarez Cermeño, Carlos Álvarez Cermeño, Rafael Arroyo, Antonio Escartín Siquier, Oscar Fernández, Guillermo Izquierdo Ayuso, José Enrique Martinez Rodríguez, Victoria Fernandez Sanchez, Francisco Javier Olascoaga Urtaza, Virginia Meca, Javier Olascoaga, Celia Oreja-Guevara, Angel Perez Sempere, José María Prieto González, Lluis Ramió Torrentá, Alfredo Rodríguez-Antigüeda, Albert Saiz, Claudio Gobbi, Jens Kuhle, Anatoliy Galusha, Alla Goloborodko, Tetyana Litovchenko, Olena Moroz, Sergii Moskovko, Tetyana Nehrych, Valeriy Pashkovskyy, Valerii Shkolnyk, Olga Shulga, Larysa Sokolova, Nataliya Voloshyna, Peter Brex, Cris Constantinescu, Martin Duddy, Klaus Schmierer, Carolyn Young, Mark Agius, Paul Ash, Daniel Bandari, Martin Belkin, Evanthia Bernitsas, James Bowen, Jonathan Cahill, Adam Carpenter, Jonathan Carter, Mirela Cerghet, Jill Conway, Joanna Cooper, Patricia Coyle, Anne Cross, Corey Ford, Edward Fox, S Mitchell Freedman, Elliot Frohman, Jeffrey Gitt, Malcolm Gottesman, Mark Gudesblatt, Barry Hendin, George Hutton, Sylvia Klineova, Lauren Krupp, Sharon Lynch, Clyde Markowitz, David Mattson, Aaron Miller, Augusto Miravalle, Suraj Muley, Nancy Nealon, Gabriel Pardo, Mary Ann Picone, Michael Racke, Syed Rizvi, Howard Rossman, Vernon Rowe, Alan Schulman, Stuart Shafer, Sheremata William, Lee Stein, Emmanuelle Waubant, Xavier Montalban, Stephen L Hauser, Ludwig Kappos, Douglas L Arnold, Amit Bar-Or, Giancarlo Comi, Jérôme de Seze, Gavin Giovannoni, Hans-Peter Hartung, Bernhard Hemmer, Fred Lublin, Kottil W Rammohan, Krzysztof Selmaj, Anthony Traboulsee, Annette Sauter, Donna Masterman, Paulo Fontoura, Shibeshih Belachew, Hideki Garren, Nicole Mairon, Peter Chin, Jerry S Wolinsky, ORATORIO Clinical Investigators, Stephen C Reingold, Magnhild Sandberg-Wollheim, Frederik Barkhof, Thomas Dörner, Scott Evans, Henry F McFarland, Israel Steiner, Özgür Yaldizli, Marcus D’Souza, Michaela Andelova, Heiko Rust, Leslie Sedal, Bruce Taylor, Hamid Assar, Eduard Auff, Thomas Berger, Michael Guger, Georg Pilz, Peter Wipfler, Emmanuel Bartholomé, Danny Decoo, Jefferson Becker, Irenio da Silva Filho, Denise Diniz, Antônio Gomes Neto, Soniza Leon, Lyubomir Haralanov, Ivan Milanov, Amir Bar-Or, Mark Freedman, François Grand’Maison, James Marriott, Paul O’Connor, Daniel Selchen, Michael Yeung, Yvonne Benesova, Eva Krasulova, Marta Vachova, Laura Airas, Irina Elovaara, Markus Färkkilä, Jaana Korpela, Marja-Liisa Sumelahti, David Brassat, Bruno Brochet, William Camu, Giovanni Castelnovo, Michel Clanet, Pierre Clavelou, Marc Debouverie, Giles Defer, Olivier Gout, Olivier Heinzlef, David Laplaud, Christine Lebrun-Frenay, Caroline Papeix, Jean Pelletier, Ayman Tourbah, Patrick Vermersch, Sandra Vukusic, Klemens Angstwurm, Martin Berghoff, Christian Förch, Norbert Goebels, Judith Haas, Lutz Harms, Ingo Kleiter, Jürgen Koehler, Eckard Lensch, Volker Limmroth, Sven Meuth, Patrick Oschmann, Michael Platten, Florian Then Bergh, Hayrettin Tumani, Ulf Ziemann, Tjalf Ziemssen, Theodora Afradou, Nikolaos Fakas, Stefanos Tsounis, Nikolaos Vlaikidis, Gábor Jakab, Sámuel Komoly, Csilla Rózsa, Mária Sátori, Gyöngyi Szabó, László Vécsei, Anat Achiron, Mark Hellmann, Arnon Karni, Dimitrios Karussis, Ron Milo, Radi Shahien, Antonio Bertolotto, Maria Giovanna Marrosu, Antonio Uccelli, Lina Malciene, Daiva Rastenyte, Sigla Sceponaviciute, Freddy Castro Farfan, Eduardo Duriez Sotelo, Jose Flores-Rivera, Sarug Reyes Morales, Rogier Hintzen, Raymond Hupperts, Christopher Lynch, Stuart Mossman, Elisabeth Gulowsen Celius, Jorge Gavidia Chucan, Julio Perez Villegas, Edwin Pretell Alva, Dariusz Bielecki, Waldemar Brola, Jan Kochanowicz, Maciej Maciejowski, Zbigniew Stelmasiak, Janusz Zbrojkiewicz, Luis Cunha, José Gonçalves, Irene Mendes, João Sá, Vasco Salgado, Ana Silva, Rodica Balasa, Silviu Manescu, Cristina Aura Panea, Mihaela Adriana Simu, Eduard Yakupov, José Álvarez Cermeño, Carlos Álvarez Cermeño, Rafael Arroyo, Antonio Escartín Siquier, Oscar Fernández, Guillermo Izquierdo Ayuso, José Enrique Martinez Rodríguez, Victoria Fernandez Sanchez, Francisco Javier Olascoaga Urtaza, Virginia Meca, Javier Olascoaga, Celia Oreja-Guevara, Angel Perez Sempere, José María Prieto González, Lluis Ramió Torrentá, Alfredo Rodríguez-Antigüeda, Albert Saiz, Claudio Gobbi, Jens Kuhle, Anatoliy Galusha, Alla Goloborodko, Tetyana Litovchenko, Olena Moroz, Sergii Moskovko, Tetyana Nehrych, Valeriy Pashkovskyy, Valerii Shkolnyk, Olga Shulga, Larysa Sokolova, Nataliya Voloshyna, Peter Brex, Cris Constantinescu, Martin Duddy, Klaus Schmierer, Carolyn Young, Mark Agius, Paul Ash, Daniel Bandari, Martin Belkin, Evanthia Bernitsas, James Bowen, Jonathan Cahill, Adam Carpenter, Jonathan Carter, Mirela Cerghet, Jill Conway, Joanna Cooper, Patricia Coyle, Anne Cross, Corey Ford, Edward Fox, S Mitchell Freedman, Elliot Frohman, Jeffrey Gitt, Malcolm Gottesman, Mark Gudesblatt, Barry Hendin, George Hutton, Sylvia Klineova, Lauren Krupp, Sharon Lynch, Clyde Markowitz, David Mattson, Aaron Miller, Augusto Miravalle, Suraj Muley, Nancy Nealon, Gabriel Pardo, Mary Ann Picone, Michael Racke, Syed Rizvi, Howard Rossman, Vernon Rowe, Alan Schulman, Stuart Shafer, Sheremata William, Lee Stein, Emmanuelle Waubant
Abstract
Background: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease.
Methods: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis.
Results: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections.
Conclusions: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).
Source: PubMed