VX15/2503-N-131 (SIGNAL-HD) is a Phase 2, multi-center, randomized, double-blind, placebo controlled study of VX15/2503 (pepinemab) in subjects with late prodromal and early manifest Huntington's disease. The primary objective is to evaluate the safety and tolerability of monthly IV administration of a single dosage of pepinemab (or placebo). Efficacy endpoints include determining the effect of pepinemab on brain volumes (MRI), FDG-PET imaging, 11C-PBR28 (TSPO) PET imaging (subset of Cohort B only) and clinical features of HD including cognition, motor function, behavior, functional abilities, global function and global measurement of change. Additional endpoints include PK / PD, immunogenicity, and exploratory biomarkers. Subjects in Cohort B that have received 12 months of pepinemab who volunteer will undergo a lumbar puncture at V13 to collect cerebral spinal fluid (CSF) to evaluate pepinemab mAb concentrations, total sSEMA4D levels, and other biomarkers in their CSF. Enrollment will involve approximately 276 individuals who are 21 years of age or older with late prodromal (CAG-age product score (CAP score) of greater than 200 and Diagnostic Confidence Level (DCL) of 2 or 3) or early manifest HD (Total Functional Capacity (TFC) greater than or equal to 11). The study will be divided into Cohort A and Cohort B. Cohort A is now complete and an unblinded analysis has been performed. Cohort A subjects were treated for 6 months with either drug or placebo (1:1) and then all subjects were treated with drug for 6 months, followed by 3 months of follow up. Treatment duration for each subject in Cohort A was 12 months. Participation in Cohort A included a Screening visit, a Baseline visit within 30 days of screening; 12 monthly treatment visits beginning at baseline and continuing through Month 12; follow-up safety phone call at one month and a follow-up safety visit three months after the final infusion. Cohort A subjects participated in the study for approximately 16 months. Based on the analysis of Cohort A, it was decided to extend the duration of treatment for a subset of subjects in Cohort B to evaluate the clinical response to pepinemab after 36 months. Additional enrolled subjects in Cohort B will be treated with drug or placebo (1:1). Participation in Cohort B will include a Screening visit, a Baseline visit within 30 days of screening; 18 or 36 monthly visits beginning at baseline and continuing through Month 18 or Month 36; follow-up safety phone call or visit, and for a subset of subjects, a follow-up safety visit three and six months after the final infusion. Cohort B subjects will participate in the study for approximately 19 and up to 37 months.
The purpose of this study is to evaluate the safety, tolerability, PK, and efficacy of Pepinemab in subjects with late prodromal and early manifest Huntington's disease.