Exploratory MRI Biomarkers of Opicinumab (Anti-LINGO-1) Show Stabilization of Pre-existing T2 Lesions in Relapsing Multiple Sclerosis: Results from the Phase 2b SYNERGY Trial (P2.100)

Objective: To determine the effect of treatment on MRI measures/clinical response in SYNERGY. Background: SYNERGY (NCT01864148) evaluated opicinumab ( BIIB033) vs. placebo in participants with active relapsing multiple sclerosis. MRI markers of myelin integrity and/or repair are important to assess opicinumab treatment. Design/Methods: Participants received intravenous opicinumab 3, 10, 30 or 100 mg/kg or placebo every 4 weeks (19 doses) and intramuscular interferon beta-1a 30 mcg once weekly for 72–84 weeks. Brain MRI scans included conventional clinical sequences, magnetization transferratio (MTR) and diffusion tensor imaging (DTI), with derived measures of fractional anisotropy(FA) and radial diffusivity (RD). The putative myelin integrity markers examined were changes from baseline in mean MTR, DTI-RD and DTI–FA within pre-existing, non-enhancing T2 lesions, denoted as MTR T2-lesion , DTI-RD T2-lesion and DTI-FA T2-lesion , respectively. Results were analyzed by: treatment group (intention-to-treat; ITT population); baseline subgroups associated with treatment effect on the SYNERGY primary endpoint (clinical improvement); subgroups based on clinical response regardless of treatment. Results: 418 participants were randomized and dosed; 412 were analyzed. No clear treatment effect was seen on change from baseline in MTR T2-lesion , DTI-RD T2-lesion and DTI-FA T2-lesion in the ITT population. In participants with baseline whole brain DTI-RD −3 mm 2 /s), favorable DTI-RD T2-lesion and DTI-FA T2-lesion changes were observed in participants in the 10-mg/kg treatment arm. Furthermore, MTR T2-lesion , DTI-RD T2-lesion and DTI-FA T2-lesion showed more favorable changes in pure improvement responders (no worsening) vs. pure progressors (worsening; no improvement). Conclusions: SYNERGY demonstrated the feasibility of performing MTR and DTI imaging in global clinical trials. In participants with clinical improvement (vs. worsening), both MTR and DTI showed favorable changes in pre-existing T2 lesions. Potential biological efficacy was seen for the 10 mg/kg arm in participants with whole brain DTI values lower than the population median. The findings support further investigation of these candidate biomarkers. Study Supported by: Biogen Disclosure: Dr. Evans has received personal compensation for activities with Biogen Idec as an employee. Dr. Evans holds stock and/or stock options in Biogen Idec. Dr. Naismith has received personal compensation for activities with Acorda, Alkermes, Bayer, Biogen, EMD Serono, Genentech, Genyzme, Novartis, and Teva. Dr. Naismith has received research support from Alkermes. Dr. Arnold has received personal compensation for activities with Coronado Biosciences, Consortium of Multiple Sclerosis Centers, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MS Forum, NeuroRx Research, Novartis, Opexa Therapeutics, Roche, Merck Serono, S.A. Serono Symposia International Foundation, Teva, the Canadian Institutes of Health Research, and the Multiple Sclerosis Society of Canada. Dr. Arnold holds stock and/or stock options in NeuroRx Research. Dr. Boyko has received personal compensation for activities with Biogen Idec, Sanofi-Genzyme, Novartis, Teva, Merck-Serono, and Takeda as a consultant, advisor or speaker. Dr. Evangelou has received personal compensation for activities with Biogen Idec, merck & Co., Inc., Novartis and Roche. Dr. Valis has received personal compensation from Biogen, Krka, and Merck. Dr. Fisher has received personal compensation for activities with Biogen Idec as an employee. Dr. Fisher has received stock and/or stock options in Biogen Idec. Dr. Richert has received personal compensation for activities with Biogen as an employee. Dr. Richert holds stock and/or stock options in Biogen. Dr. Li has received personal compensation for activities with Biogen as an employee. Dr. Li holds stock and/or stock options in Biogen, which sponsored research in which Dr. Li was involved as an investigator. Dr. Xu has received personal compensation for activities with Biogen as an employee. Dr. Xu hold stock and/or stock options in Biogen. Dr. Cadavid has received personal compensation for activities with Biogen as a holder of stock and/or stock options and as an employee. Dr. Mellion has received personal compensation for activities with Biogen has an employee. Dr. Mellion holds stock and/or stock options with Biogen. Dr. Evans has received personal compensation for activities with Biogen Idec as an employee. Dr. Evans holds stock and/or stock options in Biogen Idec.