Efficacy and Safety of Anti LINGO-1 for the Treatment of Relapsing Forms of Multiple Sclerosis: Design of the Phase 2 SYNERGY Trial (P3.154)

OBJECTIVE: To present the design of a Phase 2, dose-ranging study of the efficacy, safety, tolerability and pharmacokinetics of the anti-LINGO-1 monoclonal antibody, BIIB033 in subjects with active RRMS and SPMS. BACKGROUND: Available immunomodulatory treatments can reduce clinical disease activity in subjects with relapsing MS, but they do not affect the repair of axons and myelin in MS lesions. It is hypothesized that axonal remyelination is suppressed by inhibitors, such as LINGO-1 (leucine-rich repeats and immunoglobulin domain-containing neurite outgrowth inhibitor receptor-interacting protein-1). LINGO-1 in axons is a component of the neuroaxonal Nogo receptor 1 (NgR1)/p75/LINGO-1 and NgR1/tumor necrosis factor receptor/LINGO-1 signaling complexes whose expression is restricted to oligodendrocytes and neurons in the CNS. Blocking LINGO-1 with systemic BIIB033 promoted CNS remyelination in rodent models. Phase 1 studies of BIIB033 in healthy volunteers and MS patients supported advancing its development into Phase 2. DESIGN/METHODS: 396 subjects with active RRMS and SPMS are being randomized to intravenous infusions of BIIB033 (3, 10, 30, 100 mg/kg) or placebo for 72 weeks. All subjects are also receiving once-weekly intramuscular interferon beta-1a (IFNβ-1a). BIIB033 doses were selected to characterize the exposure-response relationship, considering the potential minimum efficacious dose and maximum tolerated dose. The primary efficacy endpoint is sustained improvement in neurophysical and/or cognitive function for 蠅3 months; sustained worsening in function for 蠅3 months is the key secondary endpoint. Exploratory efficacy imaging endpoints include conventional and nonconventional MRI. The safety, tolerability, immunogenicity and pharmacokinetics of BIIB033, including a CSF sub-study, will be assessed. Patient-reported outcomes will also be evaluated using electronic collection devices. RESULTS: The Phase 2 SYNERGY study design will be presented. CONCLUSIONS: Results of the SYNERGY study should establish whether blocking LINGO-1 can facilitate CNS repair in patients with active MS undergoing treatment with IFNβ-1a, and they will inform decisions on further clinical development of BIIB033 for CNS remyelination and/or neuroaxonal protection. Study Supported by: Biogen Idec. Disclosure: Dr. Cadavid has received personal compensation for activities with Biogen Idec. Dr. Cadavid holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Cadavid was involved as an investigator. Dr. Cadavid hodls stock and/or stock options in Biogen Idec. Dr. Phillips has received personal compensation for activities with Biogen Idec as an employee. Dr. Phillips holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Phillips was involved as an investigator. Dr. Dong-Si has received personal compensation for activities with Biogen Idec as an employee. Dr. Tran has received personal compensation for activities with Biogen Idec as an employee. Dr. Tran holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Tran was involved as an investigator. Dr. Xu has received personal compensation for activities with Biogen Idec.