Preclinical and first-in-human evaluation of VG-3927/SAR448851, an oral small-molecule TREM2 agonist for Alzheimer's disease

Microglial dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with endogenous ligands including amyloid-β (Aβ), and restored signaling in disease-associated TREM2 variants. In human iPSC-derived neuron-microglia-astrocyte cultures, VG-3927 reduced inflammatory cytokines and markers of neuronal damage. In 5xFAD amyloidosis mice expressing the common variant of hTREM2 (5xFAD;hTREM2CV), VG-3909 induced neuroprotective transcriptional reprogramming of microglia, particularly in the plaque niche; enhanced Aβ phagocytosis; and boosted brain glucose metabolism. By contrast, a TREM2 agonist antibody, which may be sequestered by soluble TREM2 (sTREM2), failed to engage plaque microglia. In a first-in-human, randomized, double-blind, placebo-controlled phase 1 trial (NCT06343636, n = 115), VG-3927 was well tolerated across single and multiple ascending doses of up to 140 milligrams. Pharmacokinetics supported once-daily dosing with high CNS penetration (CSF-to-unbound plasma ratio of 0.91). VG-3927 induced dose-dependent reductions in CSF sTREM2, a biomarker of target engagement, consistent across healthy and elderly participants and participants with AD, supporting further clinical development in AD under the new designation SAR448851.