Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial

D. Cadavid, Michelle Mellion, Raymond Hupperts, Keith R. Edwards, Peter A. Calabresi, Jelena Drulović, G. Giovannoni, Hans Peter Hartung, Douglas L. Arnold, Elizabeth Fisher, Richard Rudick, Sha Mi, Yi Chai, Jie Li, Y. Zhang, Wenting Cheng, Lei Xu, Bing Zhu, Susan M. Green, Ih ChangA. Deykin, Sarah I. Sheikh, Eduardo Agüera Morales, Abdullatif Al Khedr, R. Ampapa, Rafael Arroyo, Martin Belkin, Robert Bonek, Alexey Boyko, Ruggero Capra, D. Centonze, Pierre Clavelou, Marc Debouverie, Jelena Drulovic, K. Edwards, N. Evangelou, Evgeniy Evdoshenko, O. Fernández, Victoria Fernández Sánchez, Mark Freedman, Steven Freedman, Waldemar Fryze, Antonio Garcia-Merino, Mira Gavric-Kezic, A. Ghezzi, Olivier Gout, L. Grimaldi, B. Hendin, H. Hertmanowska, Rogier Hintzen, P. Hradilek, Jan Ilkowski, Evelina Ivashinenkova, Guillermo Izquierdo, Francois Jacques, G. Jakab, F. Khabirov, Gabriela Klodowska-Duda, Samuel Komoly, Smiljana Kostic, I. Kovarova, Marcelo Kremenchuzky, Christopher Laganke, Yves LaPierre, Maciej Maciejowski, Francois Grand Maison, Girolama Alessandra Marfia, Sergio Martínez Yélamos, Eva Meluzinova, Xavier Montalban, Ronald Murray, Robert Naismith, S. Newsome, Viet Nguyen, D. Oreja, Gabriel Pardo, E. Pasechnik, Francesco Patti, Andrzej Potemkowski, S. Prokopenko, Peiqing Qian, Alfredo Rodríguez-Antigüedad, Howard Rossman, Csilla Rozsa, Fernando Sánchez López, Krzysztof Selmaj, Eli Silber, Adam Stepien, Anna Stepniewska, Maciej Swiat, Gordana Toncev, A. Tourbah, Tatyana Trushnikova, Antonio Uccelli, M. Vachova, Martin Valis, Laszlo Vecsei, Sandrine Wiertlewski, M. Zaffaroni, Tomasz Zielinski

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis. Methods: We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18–58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov, number NCT01864148. Findings: Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment. Interpretation: Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose. Funding: Biogen.

Original languageEnglish
Pages (from-to)845-856
Number of pages12
JournalThe Lancet Neurology
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

ASJC Scopus subject areas

  • Clinical Neurology

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