Clinical Trials in Neurology
Vaccinex is studying pepinemab in clinical trials of patients with Alzheimer’s & Huntington's Disease
Semaphorin 4D (SEMA4D) has been found to contribute to driving the neuroinflammation implicated in progression of these disorders, suggesting that blocking SEMA4D has promising potential as a new therapy with broad applications for neurodegenerative diseases.
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Linked to a pathway that drives underlying disease progression, pepinemab has the potential to be a disease modifying therapy for Alzheimer's Disease that is different from approaches targeting amyloid plaques or tau tangles.Â
"[L]ecanemab and donanemab, both approved by the FDA in 2023 and 2024 respectively — work by clearing amyloid deposits from the brain. Pepinemab does something structurally different: it targets an upstream inflammatory signal from stressed neurons that triggers reactive astrocytes to abandon their normal support functions and accelerate neurodegeneration." - Mike Gonzales
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Alzheimer’s Drug Targets Astrocytes, Not Amyloid: Pepinemab Advances to Phase 2b.
Vaccinex SEMA4D antibody blocks reactive astrocyte cascade, avoids ARIA risk of approved amyloid drugs.
TechTimes, July 13, 2026
Data from a randomized Phase 2 study in Huntington’s disease as well as the completed SIGNAL-AD phase 1/2a study in Mild Cognitive Impairment and mild Alzheimer’s Disease suggest that pepinemab was well-tolerated and that treatment early in disease has favorable effects on biomarkers related to disease progression and appears to slow cognitive decline.
Neurology Trials
Note:Â Pepinemab (VX15/2503) is an investigational drug currently in clinical studies. There is no guarantee that pepinemab (VX15/2503) will be approved for the treatment of any disease by the U.S. Food and Drug Administration or by any other health authority worldwide.
About the Trial
SIGNAL-AD was a randomized double-blind, placebo-controlled, parallel-group study of pepinemab in early AD dementia defined as MCI and mild Alzheimer’s dementia. The study was 48 weeks in duration.
Pepinemab is well-tolerated by patients with AD. No Serious Treatment Emergent Adverse Events (TEAE) Related to Treatment were reported [in the
SIGNAL-AD trial].
Emerging evidence shows benefits in biomarker changes and clinical cognitive and functional assessments
Clinical Trial Evaluating the Safety and Efficacy of Pepinemab in Patients with Alzheimer’s Disease
In collaboration with the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation
Key Eligibility Criteria    MMSE 17-26
                       CDR-GS 0.5-1
                       Confirmed Amyloid positivity
Secondary Outcome Measures
Clinical Dementia Rating (CDR-SB)
Alzheimer's Disease Assessment Scale (ADAS-Cog13)
AD Cooperative Study Activities of Daily Living (ADCS-ADL)
Mini Mental State Examination (MMSE)
Biomarkers of brain metabolism (FDG-PET)
Fluid biomarker assessments
Primary Outcome
Measures
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Safety & Tolerability:
Treatment EmergentÂ
Adverse Events (TEAE)
A Study in Subjects with Late Prodromal and Early Manifest Huntington’s Disease to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Pepinemab
About the Trial
The purpose of this Phase 2 study was to evaluate the safety, tolerability, PK, and efficacy with respect to HD cognitive assessments and Clinical Global Impression of Change of pepinemab (VX15/2503) in participants with late prodromal and early manifest Huntington’s disease. A comprehensive analysis of results was published in Nature Medicine in 2022:
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The SIGNAL [HD] clinical study (Feigin et al, Nature) established the safety and tolerability of pepinemab immunotherapy in individuals with Huntington’s Disease. No concerning clinically relevant safety issues were identified, concordant with other completed clinical studies of pepinemab in individuals with multiple sclerosis (LaGanke et al)  and advanced solid tumors (Patnaik et al, Shafique et al).
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Findings from the SIGNAL trial suggested meaningful treatment effects in cognitive and biomarker assessments.
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The SIGNAL trial was a Phase 2 study comparing pepinemab or placebo in Huntington's Disease patients. Throughout the study, participants were assessed for clinical features of Huntington’s disease, as well as brain imaging and PK/PD assessments.Â