The Use of MRI to Monitor the Safety of Anti-LINGO-1: Findings from Phase I Studies in Healthy Volunteers and Subjects with MS (P2.222)

OBJECTIVE: To assess the safety of BIIB033 vs placebo in a single-ascending-dose (SAD) study in healthy volunteers and multiple-ascending-dose (MAD) study in subjects with MS using MRI. BACKGROUND: LINGO-1, a CNS-specific, leucine-rich glycoprotein, suppresses axonal repair/remyelination by arresting oligodendrocyte maturation. BIIB033 is a humanized monoclonal antibody that blocks LINGO-1 and promotes remyelination in rodents after chemically-induced or inflammatory demyelination. In humans, no existing therapies have been shown to stimulate remyelination. DESIGN/METHODS: SAD subjects were randomized to 1 of 8 intravenous (IV) doses (0.1-100mg/kg) or one 3.0mg/kg subcutaneous dose of BIIB033. MAD subjects were randomized to 1 of 7 IV doses (0.3-100mg/kg) of BIIB033. Concomitant disease-modifying therapy was allowed if initiated 蠅3 months before enrollment. Conventional and non-conventional MRIs were performed at baseline and at Weeks 4, 8 in SAD and at Weeks 8, 16 in MAD. Magnetization transfer ratio (MTR) measured myelin integrity of 6 regions in normal-appearing white matter (NAWM) in SAD. Potential short-term efficacy on pre-existing lesions was explored using MTR and diffusion-tensor imaging (DTI) of pre-existing lesions in MAD. RESULTS: Conventional MRI showed no structural abnormalities, vasogenic edema, hemorrhage or infarction in SAD (N=72) or MAD (N=47). Incidental findings of mucosal thickening in the maxillary sinuses (n=2) and small venous angioma (n=1) were noted in 3 BIIB033 subjects in SAD. In MAD, there was no increase in new/enlarging T2 lesions or gadolinium-enhancing lesions with BIIB033 versus placebo. Compared with baseline, there was no change in NAWM MTR in either study during treatment. In MAD, an exploratory short-term efficacy analysis showed no difference in the net- or fold-change vs baseline (BIIB033 vs placebo) in MTR and DTI measurements in pre-existing T1 or T2 lesions or in whole brain volume or ventricular volume. CONCLUSIONS: BIIB033 was well-tolerated in both studies. MRI showed no evidence that BIIB033 negatively affected brain parenchyma tissue including myelin content. Continued evaluation of BIIB033 in Phase II studies is warranted. Study Supported by: Biogen Idec. Disclosure: Dr. Richert has received personal compensation for activities with Biogen Idec. Dr. Richert holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Richert was involved as an investigator. Dr. Melamed has received personal compensation for activities with IMMUNOe as an employee. Dr. Gevorkyan has received personal compensation for activities with the California Clinical Trials Medical Group as an employee. Dr. Xu has received personal compensation for activities with Biogen Idec. 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.