Vaccinex to Present Novel Glial Biomarker Data for Pepinemab at AAIC 2026, Outlining Path to Phase 2b in Alzheimer's Disease

Vaccinex, Inc. announced today that it will present new biomarker findings from the Phase 1b/2 SIGNAL-AD clinical trial of pepinemab at the Alzheimer's Association International Conference (AAIC 2026), to be held July 12–15 in London.¹ Elizabeth Evans, PhD, chief operating officer and senior VP of Discovery and Translational Medicine, will chair a Featured Research Session on July 13 and present novel results demonstrating that SEMA4D-blocking antibody pepinemab regulates glial biomarkers associated with disease progression in patients with early-stage Alzheimer's disease (AD) — while outlining plans for SIGNAL-AD2, an enlarged Phase 2b randomized controlled study.¹ The presentation arrives as AAIC 2026 convenes what is shaping up to be one of the most data-rich Alzheimer's conferences in recent years, with pepinemab representing a mechanistically distinct approach to disease modification — one that targets neuroinflammation and reactive astrocytes rather than amyloid or tau directly.

What is the SEMA4D pathway and what is its significance in Alzheimer's disease?

Semaphorin 4D (SEMA4D, also known as CD100) is a signaling protein that binds to plexin-B1 receptors expressed on astrocytes in the brain.¹ Vaccinex scientists have established that SEMA4D is highly upregulated on stressed or damaged neurons during AD progression, and that its binding to astrocytes drives reactive astrogliosis — a pathological activation state in which astrocytes shift from their normal supportive roles to a pro-inflammatory, neurotoxic phenotype that contributes to synaptic loss, metabolic dysfunction, and accelerated neurodegeneration.²

This neuroinflammatory pathway is gaining recognition as a critical and early contributor to AD pathogenesis, operating alongside and interacting with the amyloid and tau cascades that have dominated drug development for the past two decades.³ Plasma glial fibrillary acidic protein (GFAP), a well-characterized marker of increasing astrocyte reactivity, and phosphorylated tau 217 (p-tau 217), a peptide fragment of toxic tau tangles accumulating in neurons, have emerged as key blood-based biomarkers of this process — both measurable non-invasively and increasingly incorporated into clinical trial endpoints and diagnostic frameworks.⁴

What will the AAIC presentation show?

The Featured Research Session presentation — titled Glial Biomarkers Associated With Disease Progression Are Regulated By SEMA4D Blocking Antibody Pepinemab in Patients with Early-stage AD — will present novel data demonstrating that pepinemab treatment modulates plasma GFAP and p-tau 217 biomarker expression in patients with early-stage AD enrolled in the Phase 1b/2 SIGNAL-AD trial (NCT04381468).¹

Prior data from SIGNAL-AD, presented at AAIC 2024 in Philadelphia and at the Clinical Trials on Alzheimer's Disease (CTAD) conference in Madrid in October 2024, established that: pepinemab met its primary safety endpoint with no serious treatment-emergent adverse events related to treatment across all 16 participating clinical sites; pepinemab treatment produced a statistically significant increase in FDG-PET signal in the medial temporal cortex of patients with MCI due to AD, indicating preservation of brain metabolic activity; plasma GFAP and p-tau 217 appeared to increase predominantly during MCI and that this increase was inhibited by pepinemab treatment; and cognitive effects were detectable in early-stage MCI patients who had not yet progressed to mild dementia.⁵

The new AAIC 2026 data extend these findings with additional biomarker analyses designed to characterize the relationship between SEMA4D pathway blockade and glial activation across the disease continuum — providing mechanistic support for the hypothesis that early SEMA4D inhibition can modulate the neuroinflammatory cascade upstream of neurodegeneration.¹

The session is entitled Alzheimer's therapy: mechanisms beyond amyloid, reflecting the growing scientific and regulatory appetite for disease-modifying approaches that complement rather than replicate anti-amyloid therapy.¹

What is pepinemab and what is the evidence behind it?

Pepinemab is a humanized IgG4 monoclonal antibody that inhibits SEMA4D, blocking its interaction with plexin-B1 receptors on astrocytes and thereby preventing downstream activation of reactive astrogliosis and neuroinflammation.¹ It is administered intravenously once every four weeks and was well tolerated across the SIGNAL-AD Phase 1b/2 trial population, which enrolled 50 patients with mild AD dementia across 16 US sites.⁵

Pepinemab's clinical development in neurodegeneration was preceded by a Phase 2 randomized, placebo-controlled trial in Huntington's disease (SIGNAL-HD; NCT02481674), which demonstrated that SEMA4D blockade prevented metabolic decline in glucose uptake as measured by FDG-PET, reduced plasma GFAP biomarkers of astrogliosis, and slowed cognitive decline across multiple cognitive scales in HD — a disease with overlapping neuroinflammatory pathology to AD.⁶ That proof-of-concept underpins the mechanistic rationale for the AD program and the hypothesis that SEMA4D inhibition represents a pathway common to multiple slowly progressive neurodegenerative diseases.

What are the plans for phase 2b?

Evans will outline plans for SIGNAL-AD2, an enlarged phase 2b randomized, placebo-controlled study of pepinemab in early AD.¹ The phase 2b design is expected to build on the biomarker and cognitive signal generated in SIGNAL-AD, enrolling a larger patient population with a longer treatment duration to evaluate whether SEMA4D blockade can produce a statistically meaningful and clinically relevant slowing of cognitive and functional decline. Vaccinex is actively exploring partnership opportunities with major pharmaceutical companies to support late-stage development.⁵

The phase 2b announcement at AAIC arrives alongside Eisai's own AD data package of more than 50 abstracts at the same conference — including presentations on the lecanemab subcutaneous formulation and etalanetug anti-tau antibody — reinforcing AAIC 2026 as a major inflection point for the field and underscoring the growing consensus that multi-target approaches addressing amyloid, tau, and neuroinflammation simultaneously may ultimately be required for meaningful disease modification.

References

1. Vaccinex to Report New Biomarker Data and Plans for Phase 2B Clinical Trial of Pepinemab in AD at the Alzheimer's Association International Conference in London on July 13, 2026. (2026 Jul 8). GlobeNewswire. https://www.globenewswire.com/news-release/2026/07/08/3324070/34858/en/vaccinex-to-report-new-biomarker-data-and-plans-for-phase-2b-clinical-trial-of-pepinemab-in-ad-at-the-alzheimer-s-association-international-conference-in-london-on-july-13-2026.html?_gl=1*mgflcl*_up*MQ..*_ga*MTU5NDk4NDYyMS4xNzgzNTMyMjQ1*_ga_ERWPGTJ5X8*czE3ODM1MzIyNDQkbzEkZzAkdDE3ODM1MzIyNDQkajYwJGwwJGgw*_ga_B6167QB2TF*czE3ODM1MzIyNDQkbzEkZzAkdDE3ODM1MzIyNDQkajYwJGwwJGgxNzQ2OTQyMDY2
2. Evans EE, Fisher TL, Mishra V, et al. (2025 Dec 25). Targeting SEMA4D/PLXN signaling through reactive glia as a common pathology for the treatment of neurodegenerative disorders. Alzheimers Dement. https://pmc.ncbi.nlm.nih.gov/articles/PMC12741495/
3. Holper S, Loveland P, Churilov L, et al. (2024 Aug 13). Blood astrocyte biomarkers in Alzheimer disease: a systematic review and meta-analysis. Neurology. https://pubmed.ncbi.nlm.nih.gov/38986050/
4. Lista S, Imbimbo BP, Grasso M, et al. (2024 Jul 30). Tracking neuroinflammatory biomarkers in Alzheimer's disease: a strategy for individualized therapeutic approaches? J Neuroinflammation. https://pubmed.ncbi.nlm.nih.gov/39080712/
5. Siemers ER, Evans EE, Fisher TL, et al. (2025 Jan). 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. Alzheimers Dement. https://www.researchgate.net/publication/387862389_Results_of_SIGNAL-AD_a_randomized_phase_1b2_trial_to_evaluate_safety_and_efficacy_of_targeting_reactive_astrocytes_with_pepinemab_SEMA4D_blocking_antibody_in_people_with_mild_Alzheimer's_dementia
6. Zauderer M, Evans EE. (2023 Jan 29). Conclusions of the SIGNAL study in Huntington and implications for treatment of other slowly progressive neurodegenerative diseases. Clin Transl Med. https://pmc.ncbi.nlm.nih.gov/articles/PMC9885077/
7. SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (SIGNAL-AD). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04381468https://clinicaltrials.gov/study/NCT04381468