Immunomodulation/ImmunosuppressionThursday, October 03, 2013, 15:45 - 17:00
The use of magnetic resonance imaging to monitor the safety of anti-LINGO-1: findings from phase 1 studies in healthy volunteers and subjects with multiple sclerosisD. Cadavid, I. Melamed, H. Gevorkyan, L. Xu, N. Richert (Cambridge, Centennial, Glendale, US)
Background: In patients with multiple sclerosis (MS), immunomodulatory therapies can reduce inflammation but do not promote remyelination, a process suppressed by myelin-associated inhibitors, such as leucine-rich repeat and immunoglobulin domain-containing neurite outgrowth inhibitor receptor-interacting protein-1 (LINGO-1). LINGO-1 is a component of the Nogo receptor 1 (NgR1)/p75/LINGO-1 and NgR1/tumor necrosis factor receptor/LINGO-1 signaling complexes. BIIB033, a human monoclonal antibody (aglycosyl immunoglobulin gamma 1) against LINGO-1, promotes remyelination in rodent models.
Objective: To assess the safety of BIIB033 vs placebo in a single ascending-dose (SAD) study in healthy volunteers and a multiple ascending-dose (MAD) study in stable subjects with MS using magnetic resonance imaging (MRI).
Methods: SAD subjects were randomized to 1 of 8 intravenous (IV) doses (0.1-100 mg/kg) or one 3.0 mg/kg subcutaneous (SC) dose. MAD subjects were randomized to the same regimen except that 2 IV doses were given 14 days apart. Conventional MRI verified the absence of structural change, hemorrhage, infarction and inflammation. Non-conventional MRI was done at Weeks 4 and 8 in SAD and at Weeks 8 and 16 in MAD. Magnetization transfer ratio (MTR) measured myelin integrity of 6 regions in normal-appearing white matter (NAWM) in SAD. Short-term safety and efficacy was explored using MTR and diffusion tensor imaging (DTI) of pre-existing lesions and non-lesional NAWM in MAD.
Results: There were no structural abnormalities, 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, MRI showed no increase with drug versus placebo in new/enlarging T2 lesions or Gadolinium-enhancing lesions. No change in NAWM MTR was observed in either study vs baseline. In MAD, an exploratory efficacy analysis showed no difference in the net change or fold change vs baseline in MTR and DTI measurements in pre-existing white matter lesions. No significant change in whole brain volume or ventricular volume was observed with treatment at Weeks 8 or 16 in MAD.
Conclusions: BIIB033 was well-tolerated in both studies. MRIs showed no evidence that BIIB033 negatively affected brain parenchyma tissue including myelin content. Continued evaluation of BIIB033 in Phase II studies is warranted.
Nancy Richert and Diego Cadavid are full-time employees of Biogen Idec. Isaac Melamed and Hakop Gevorkyan have no conflict of interest to disclose. This study was funded by Biogen Idec. Linda Goldstein of UBC Scientific Solutions provided medical writing and editorial support to the authors in the development of this abstract, which was funded by Biogen Idec.