Pepinemab Produces Positive Effects on Plasma Biomarkers and Cognitive Measures in Phase 1b/2 SIGNAL-AD Trial

Elizabeth Evans, PhD, MS

New findings from the phase 1b/2 SIGNAL-AD trial (NCT04381468) of pepinemab (Vaccinex), an investigational semaphorin 4D (SEMA4D) blocking antibody, showed that treatment with the agent resulted in positive trends for plasma biomarkers and cognitive measures in patients with mild cognitive impairment (MCI). The study, although small in scale, also revealed a statistically significant increase in metabolic activity in medial temporal cortex, further supporting pepinemab as a potential treatment for MCI due to Alzheimer disease (AD).^1,2

Presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, the study featured 50 individuals with amyloid positive status, determined by PET scan and cerebrospinal fluid (CSF) markers, who were randomly assigned 1:1 to either pepinemab 40 mg/kg or placebo, every 4 weeks, for 12 months. Coming into the study, these patients had Mini-Mental State Exam scores between 17-26 and Clinical Dementia Rating-Global Score (CDR-GS) scores of 0.5-1.

Led by Elizabeth Evans, PhD, MS, chief operating officer, Vaccinex, pepinemab-treated patients demonstrated a statistically significant change in FDG-PET standard uptake value ration (SUVR) in medial temporal cortex, a brain region previously reported to undergo early changes in metabolic activity and atrophy in patients with MCI. The medial temporal cortex, which includes critical structures like the hippocampus and entorhinal cortex, plays a central role in memory and learning. In Alzheimer disease and MCI, it is one of the earliest brain regions to show signs of neurodegeneration.

In the study, a proteomic analysis of CSF from patients treated with pepinemab or placebo identified proteins typically increased in AD, but inhibited by pepinemab treatment. These constituted additional disease-associated biomarkers whose inhibition, the company believes, further supports the benefit of pepinemab treatment. Of note, similar treatment effects observed on plasma biomarkers and cognitive measures were not observed in patients with mild dementia.

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Pepinemab, a novel monoclonal antibody that blocks the activity of SEMA4D, did not demonstrated any concerning effects to vascular integrity of brain issue or risk of inflammation and hemorrhage. Using a human Brain-Chip model, investigators showed that damage caused by toxic aggregates of alpha-synuclein can be inhibited or reversed by treatment with pepinemab. Vaccinex plans on reporting the results of a similar analysis of damage caused by amyloid-ß in the presence or absence of anti-amyloid antibody.

Additional findings revealed that treatment with alpha-synuclein fibrils disrupted vascular integrity of brain chip compared with untreated controls. Concurrent pepinemab treatment significantly inhibited effects of alpha-synuclein while delayed pepinemab treatment significantly reversed the effects of alpha-synuclein.

The rationale for SIGNAL-AD came after pepinemab demonstrated positive effects in a subgroup of patients with Huntington disease (HD) in the previously completed phase 2 SIGNAL-HD study (NCT02481674). Over an 18-month period, treatment with the agent resulted in cognitive benefits among individuals with Montreal Cognitive Assessment (MoCA) scores less than 26. Additionally, pepinemab-treated patients with baseline total functional capacity (TFC) scores of 11 had reduced disease progression on Clinical Global Impression-Change (CGI-C) relative to placebo (P = .041); however, this was not the case for those with less advanced forms of the disease, indicated by TFC scores of 12-13.³

In the original SIGNAL-HD study, reported in September 2020, the therapy did not meet its prespecified coprimary end points; however, it did have a direct impact on cognitive assessments that reflect changes in planning ability and memory associated with disease progression.⁴ In the subgroup analysis, investigators identified a significant reduction in apathy severity that was related to treatment with pepinemab (P = .0291). Metabolic activity, assessed using FDG-PET, was slowed or reversed in all 26 brain regions examined, with significant benefit in 15 of the 26 (57%; P ≤.05). Treatment with pepinemab also resulted in reduced caudate atrophy (P = .017) and a trend of reduced ventricular expansion (P = .06) on MRI imaging analysis.³

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REFERENCES
1. Vaccinex Reports New Findings for SIGNAL-AD Phase 1b/2 Trial of Pepinemab at Clinical Trials on Alzheimer’s Disease (CTAD) Conference in Madrid, Spain. Vaccinex. October 31, 2024. Accessed November 4, 2024. https://www.globenewswire.com/news-release/2024/10/31/2972757/0/en/Vaccinex-Reports-New-Findings-for-SIGNAL-AD-Phase-1b-2-Trial-of-Pepinemab-at-Clinical-Trials-on-Alzheimer-s-Disease-CTAD-Conference-in-Madrid-Spain.html
2. Evans E, Porsteinsson A, Fisher T, et al. RESULTS OF SIGNAL-AD, A RANDOMIZED, PHASE 1B/2 TRIAL TO EVALUATE SAFETY AND EFFICACY OF PEPINEMAB, ANTI-SEMA4D ANTIBODY BELIEVED TO BLOCK REACTIVE ASTROGLIOSIS, IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT (MCI) DUE TO AD. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) conference; October 29-November 1, 2024; Madrid, Spain. ABSTRACT OC27
3. Evans E, Fisher T, Mishra V, et al. Clinical evidence that treatment with pepinemab, a novel regulatory of neuroinflammation, provides cognitive benefit to patients with Huntington’s and potentially other neurodegenerative diseases. Presented at: 2022 AAN Annual Meeting; April 2-7; Seattle, Washington. Abstract 2646
4. Top-line results of the phase 2 SIGNAL study in Huntington’s disease support potential for cognitive benefit of pepinemab. News release. Vaccinex. September 22, 2020. Accessed November 4, 2024. https://www.biospace.com/article/releases/top-line-results-of-phase-2-signal-study-in-huntington-s-disease-support-potential-for-cognitive-benefit-of-pepinemab/