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

VG-3927, an oral TREM2 agonist, shows high CNS penetration and reduces CSF sTREM2 in humans, supporting further development for Alzheimer's disease.

• Why it matters: Microglial dysfunction and TREM2 variants are major risk factors for late-onset AD, highlighting the need for therapies that modulate microglial activity to potentially alter disease progression.
• What they did: The study evaluated VG-3927's potency, its effects in cell cultures and mouse models, and conducted a phase 1 trial with 115 participants, assessing safety, pharmacokinetics, and target engagement.
• The result: VG-3927 was well tolerated, demonstrated dose-dependent target engagement by lowering CSF sTREM2, and showed promising pharmacokinetics, enabling further clinical development in AD.