One of the hallmarks of Alzheimer’s disease is the extracellular deposition of amyloid-β (Aβ) plaques. Current treatments for Alzheimer’s disease include anti-Aβ therapeutics that have demonstrated proof-of-concept disease modification; however they have yielded only modest clinical benefits. Because of this, researchers aim to identify other targets and have recently focused on microglia—the brain’s resident innate immune cells whose duties include maintaining neural networks and clearing cellular debris.
Now, a small molecule therapy for Alzheimer’s disease that targets the brain’s microglia cells protected neurons in a mouse model and was found to be safe in humans, according to new research that includes results from a Phase I trial involving 115 participants and patients. More specifically the new work reports on “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.”
This work is published in Science Translational Medicine in the paper, “Preclinical and first-in-human evaluation of VG-3927/SAR448851, an oral small-molecule TREM2 agonist for Alzheimer’s disease.” The therapy stands at the leading edge of a new class of experimental drugs that target microglia through small molecules rather than antibodies, the latter of which have faced various obstacles to translation.
Microglia contain the transmembrane receptor TREM2, which supports the cells’ ability to respond to signs of disease and to break down amyloid-beta. Genetic studies have identified multiple rare coding variants of TREM2—such as p.R47H (Arg47→His)—which impair TREM2 signaling and correlate with a higher risk of late-onset Alzheimer’s disease.
Here, a large collaboration across multiple research teams engineered two small molecules that activate human TREM2: VG-3927 and VG-3909. The compounds reduced markers of neuronal damage and inflammatory signaling when given to cultured neurons and microglia and boosted microglia’s ability to break down amyloid-beta in a mouse model.
More specifically, the authors note, “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.”
The team then tested ascending doses of the small molecules in a Phase I trial. In the first-in-human, randomized, double-blind, placebo-Phase I trial (NCT06343636), VG—3927 was well tolerated across single and multiple ascending doses of up to 140 milligrams and penetrated the central nervous system. It also reduced levels of a marker of TREM2 in the cerebrospinal fluid in patients with Alzheimer’s disease—a promising finding in the nascent field of TREM2-targeted therapies.