Background

VG-3927 is a brain-penetrant, small-molecule agonist of the TREM2 receptor on microglia. TREM2 activation stimulates proliferation and phagocytic function of microglia, which play a central role in Alzheimer's disease pathology. Genetic variation in TREM2 is linked to AD (see TREM2 Mutations), whereby reductions in receptor activity increase risk.

TREM2 agonist antibodies and small molecules are being tested for their ability to spur phagocytosis and clearance of Aβ and treat Alzheimer's disease. VG-3927 is taken by mouth.

Preclinical work has been presented at conferences. At AD/PD 2023, the company reported that its TREM2 agonist compounds bring together TREM2 receptors on the cell surface. In humanized TREM2 mice, and in nonhuman primates, the compounds entered the brain. There, they suppressed the levels of soluble TREM2, an extracellular domain receptor fragment. This suggests the compounds may slow processing and internalization of TREM2 (Apr 2023 conference news). At AD/PD 2024 in Lisbon, the company presented that 5XFAD mice fed VG-3927 for six weeks had about 40 percent less plaque and insoluble Aβ42. Microglia expressed a neuroprotective, disease-associated microglia (DAM)-like gene expression signature (Apr 2024 conference news).

Preclinical results presented at AAIC 2024 showed that VG-3927 preferentially binds to membrane TREM2 over soluble receptor fragments, suggesting that the compound’s activity may not be diminished by soluble TREM2 that accumulates around plaques in AD brain. In mice, the compound increased microglial amyloid phagocytosis comparably to an approved Aβ antibody. VG-3927-induced phagocytosis was not affected by Fc antibody receptor blockage, confirming that its mechanism differs from Aβ antibodies, and that the two could be used together without reducing efficacy.

Findings

In September 2023, VG-3927 became the first small-molecule TREM-2 agonist cleared to enter the clinic. In October 2023, the first volunteer was treated in a Phase 1, placebo-controlled, single- and multiple-ascending-dose safety study being conducted in Miami. The trial plans to enroll 90 healthy volunteers in seven single-dose and four multiple-dose cohorts. Endpoints are to be safety, pharmacokinetics, and CSF levels of drug and soluble TREM2. The FDA allowed the trial to begin under a partial clinical hold that limited the maximum drug exposure (press release). The agency subsequently requested additional preclinical toxicology data before it would lift the limit. The company claims that predicted efficacious doses fall below the exposure limit set by the FDA (press release).

At the July 2024 AAIC, Vigil presented single-dose results, reporting that VG-3927 thus far was safe. Adverse events were mild or moderate and resolved on their own; there were no serious adverse events. Pharmacokinetics were suitable for daily dosing. The drug caused significant reductions in soluble TREM2 at the three highest doses, demonstrating target engagement. In a press release, the company claimed safety and lower CSF soluble TREM2 in two completed multiple-dose cohorts, who received drug daily for two weeks. The company intends to add a cohort of AD patients to explore biomarker responses to VG-3927, and to report complete trial data in early 2025.

For details on VG-3927 trials, see clinicaltrials.gov.