Vigil Neuroscience, a clinical-stage biotechnology company, announced positive results from its Phase 1 clinical trial of VG-3927, a novel, orally available small molecule TREM2 agonist for the potential treatment of Alzheimer's disease (AD). The trial, which included both healthy volunteers and individuals with AD, demonstrated a favorable safety and tolerability profile, robust target engagement, and supported the advancement of VG-3927 into a Phase 2 clinical trial. The company plans to initiate the Phase 2 trial in the third quarter of 2025, using a 25mg once-daily oral dose.
The Phase 1 trial enrolled 115 participants across multiple cohorts to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VG-3927. The study included single and multiple ascending dose (SAD/MAD) evaluations in healthy volunteers, an elderly cohort, and a single-dose cohort of AD patients, some with genetic risk factors for AD. Key findings revealed that VG-3927 was well-tolerated across all cohorts, with all adverse events reported as mild or moderate. Notably, the trial demonstrated a significant reduction of soluble TREM2 (sTREM2) levels, reaching up to approximately 50% in the cerebrospinal fluid (CSF). This reduction indicated a strong PK/PD relationship and sustained target engagement.
Targeting TREM2 for Alzheimer's Therapy
VG-3927 is designed to enhance the protective responses of microglia, the brain's immune cells, without exacerbating inflammation. Mutations and loss of function in TREM2, a receptor expressed on microglia, have been linked to an increased risk of late-onset Alzheimer's disease. Vigil's approach with VG-3927 aims to stimulate TREM2, promoting the clearance of amyloid and tau aggregates and reducing neuroinflammation.
Differentiated Mechanism of Action
Unlike antibody TREM2 agonists, VG-3927, as a small molecule, does not bind to sTREM2, potentially increasing its access to the therapeutic site in the brain. Additionally, VG-3927 lacks an Fc domain, which can engage elements of the immune system associated with amyloid-related imaging abnormalities (ARIA), a potential safety concern with some Alzheimer's therapies.
Management Commentary
"We are very excited by these positive Phase 1 data, which further support continued development of VG-3927 as a potential next-generation therapy for AD," said Ivana Magovčević-Liebisch, Ph.D., J.D., President and Chief Executive Officer of Vigil Neuroscience. Petra Kaufmann, M.D., F.A.A.N., Chief Medical Officer of Vigil, added, "Based on our comprehensive dataset, we are confident that VG-3927 is a well-characterized molecule that is highly brain penetrant and engages TREM2 to harness the neuroprotective potential of microglia."
Next Steps
Vigil Neuroscience plans to present additional data from the Phase 1 trial at the AD/PD™ 2025 International Conference on Alzheimer’s and Parkinson’s Disease in Vienna, Austria. The company is strategically positioned to advance VG-3927 into a Phase 2 trial in Q3 2025, further evaluating its potential as a disease-modifying therapy for Alzheimer's disease.
