Results of SIGNAL‐AD, a randomized, phase 1b/2 trial to evaluate safety and efficacy of targeting reactive astrocytes with pepinemab, SEMA4D blocking antibody, in people with mild Alzheimer’s dementia
Authors: Siemers Eric R , Evans Elizabeth E , Fisher Terrence L , Boise Megan , Foster Amber , Leonard John E , Mishra Vikas , Mallow Crystal L , Porsteinsson Anton P. , Turner Raymond Scott , Bond Wendy , Huffaker John , Farlow Martin R. , Honig Lawrence S. , Sheldon Elizabeth , Townley Ryan A , Winner Paul , Norton Jeffrey , Holub Richard , Patel Paayal , Geldmacher David S. , Capote Horatio , Thein Stephen , Zauderer Maurice 
Published: January 2025

Background

The earliest recognized biomarker of AD is deposition of Aβ amyloid that leads to formation of plaques and may, over time, trigger or at least be followed by gliosis/neuroinflammation and neurofibrillary tangles, accompanied by neurodegenerative changes including neuronal and synaptic loss. We have previously reported that semaphorin 4D (SEMA4D), the major ligand of plexin B receptors expressed on astrocytes, is upregulated in diseased neurons during progression of AD and Huntington’s disease (HD). Binding of SEMA4D to PLXNB receptors triggers astrocyte reactivity, leading to loss of neuroprotective homeostatic functions, including downregulation of glutamate and glucose transporters (doi:10.1186/s12974‐022‐02509‐8), and gain of neurotoxic processes, including release of inflammatory mediators and further activation of phagocytic glia.

Pepinemab, a high affinity, SEMA4D blocking antibody, demonstrated clinical benefit and was well tolerated in a completed Phase 2 study in early manifest HD (doi:10.1038/s41591‐022‐01919‐8). Pepinemab prevented disease‐associated metabolic decline in glucose uptake (FDG‐PET) and significantly reduced levels of plasma GFAP, biomarkers of astrocyte reactivity. Importantly, pepinemab appeared to slow cognitive decline in HD by 36% (p=0.007), as determined by the HD Cognitive Assessment Battery composite score (2).

Methods

The double‐blind, placebo‐controlled SIGNAL‐AD (NCT04381468) study enrolled 50 individuals with MCI or mild AD dementia (MMSE 17‐26) and amyloid positive status. Treatment was randomized 1:1 to pepinemab (40 mg/kg) or placebo (Q4W, IV infusion) for 12 months. The primary objective of the study is safety and tolerability, and key efficacy objective is evaluation of a biomarker for brain metabolic activity, FDG‐PET imaging. Additional secondary and exploratory assessments include fluid biomarkers, plasma GFAP and pTau‐217, and several validated, clinically meaningful cognitive scales (including CDR‐SB, iADRS, ADAS‐Cog13), as well as multiplex proteomics to evaluate neuroinflammatory activity.

Results

Topline data, including safety, brain metabolism (FDG‐PET), fluid biomarkers of reactive astrocytes (GFAP), tau phosphorylation (p‐tau 217), and inflammation, and potential treatment effects on cognitive decline will be presented.

Conclusions

Given the many physiological parallels between glial activation and inflammatory processes in HD and AD, prior results from the SIGNAL‐HD trial suggest that preventing astrocyte activation and reducing brain inflammation with pepinemab treatment could be an attractive alternative or complement to anti‐Aβ antibodies.