Objective: Evaluation of VX15/2503, a first-in-class antibody to Semaphorin 4D (SEMA4D), in a randomized double-blind, placebo-controlled phase 2 clinical trial (SIGNAL) enrolling late prodromal and early manifest HD subjects. Background: SEMA4D signaling through its receptor triggers activation of inflammatory glial cells, inhibits migration and differentiation of oligodendrocyte precursor cells, and disrupts endothelial tight junctions that maintain the blood-brain barrier (BBB). Chronic inflammation, neuronal degeneration, and disruption of the BBB are believed to play important roles in neuroinflammatory and neurodegenerative diseases. Antibody neutralization of SEMA4D ameliorates neurodegenerative processes in several preclinical models, including HD transgenic mice. Design/Methods: The SIGNAL trial evaluates the safety, tolerability and efficacy of VX15/2503. Endpoints include clinical features of HD and imaging, including volumetric MRI, considered an early biomarker with prognostic significance for HD, and FDG-PET measures of glucose metabolism in prospectively defined brain regions of interest (ROI). Results: The recently completed first cohort in this first study of a biologic administered to HD subjects (n=36) demonstrated that rapid recruitment is feasible. No concerning safety signals were identified following up to 12 monthly IV administrations and a three-month safety follow-up. VX15/2503 treatment trended toward stabilization of disease-related reduction in MRI volume and favored VX15 over placebo in 24/31 ROI, especially among frontal and adjacent parietal lobes. FDG-PET imaging also favored VX15 in all ROI, with median increase in FDG uptake from baseline of 8.6% (range: 0.5-20.4%) compared to placebo control and p-value <0.1 in 19/31 ROI, including 12/14 ROI within the frontal and parietal regions. Conclusions: Data from Cohort A suggests that treatment with VX15/2503 was well tolerated and appeared to prevent loss of brain volume and restore metabolic activity. These results informed the design of a larger cohort of subjects in this continuing study, in which additional clinical features of HD, including cognition and motor assessments, will be evaluated.