SEMA4D BLOCKING ANTIBODY, PEPINEMAB, IS A NOVEL POTENTIAL TREATMENT FOR NEURODEGENERATIVE DISEASE: CLINICAL PROOF OF CONCEPT IN HD SUPPORTS CLINICAL DEVELOPMENT IN AD

BACKGROUND: Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons in response to stress and triggers activation of plexin-positive astrocytes with concomitant loss of normal astrocyte functions. Drivers of glial cell activation may represent important targets to preserve normal homeostatic maintenance and modify progression of neurodegenerative pathology. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington’s disease (HD) and Alzheimer’s disease (AD). SIGNAL-HD (NCT02481674) is a completed double-blind, randomized, placebo-controlled study of pepinemab in HD. SIGNAL-AD (NCT04381468) is an ongoing trial of pepinemab in AD that opened for enrollment in June 2021. OBJECTIVES: Present the updated safety, clinical, and biomarker data from the completed SIGNAL-HD trial. In addition, describe how neuroimaging and subgroup analysis of the clinical HD results provide further rationale for investigation in AD, and present the trial design and enrollment status for the Phase 1b/2a double-blind, randomized, placebo-controlled SIGNAL-AD trial. METHODS: The SIGNAL-HD study included 301 subjects with late prodromal (LP) and early manifest (EM) HD at 30 sites in the US and Canada. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD-CAB) and Clinical Global Impression of Change (CGIC). Imaging endpoints included structural MRI to assess brain atrophy and FDG-PET to assess brain metabolism. Clinical parameters and imaging biomarker analysis was stratified by disease severity, comparing pre-symptomatic LP subjects with early symptomatic EM subjects and, in a post-hoc analysis, according to Total Functional Capacity (TFC) in EM subjects. RESULTS: Pepinemab was well-tolerated and was shown to cross the BBB at the anticipated level of 0.1% or greater of circulating antibody. Co-primary efficacy outcome measures consisted of a two-item HD cognitive assessment family including One Touch Stockings of Cambridge (OTS) and Paced Tapping (PTAP) components of the HD-Cognitive Assessment Battery (HD-CAB), and CGIC, a global measure of clinical meaningfulness. The primary endpoints did not achieve statistical significance in this study, however, positive trends in the direction of pepinemab benefit were observed and analysis of secondary and exploratory endpoints including post-hoc subgroup analysis was, therefore, pursued. Treatment benefits reflected in clinical and imaging endpoints appeared to be restricted to the EM subjects. A treatment benefit was observed in 6/6 components of the HD-CAB cognitive assessment battery, with a significant HD-CAB composite score (p=0.007). In a posthoc subgroup analysis of EM subjects with somewhat more advanced disease progression (TFC 11 vs TFC 12 and 13), treatment appeared to reduce deteriorating CGIC status (p=0.04). Effects on cognition are further supported by prespecified exploratory imaging endpoints, demonstrating that pepinemab treatment reduced brain atrophy (volumetric MRI) and slowed or reversed decline in metabolic activity in 26/26 brain regions, with 15/26 regions showing a significant positive treatment effect (p≤0.05) in FDG-PET imaging. CONCLUSIONS: Pepinemab did not achieve primary efficacy outcome measures in the SIGNAL study, but favorable safety profile and positive trends in cognition and imaging endpoints encourage continued development in both HD and AD. A Phase 1b/2a study in AD (SIGNAL-AD), has been initiated with partial support from the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation.