Vigil Neuroscience (VIGL) Stifel 2025 Virtual CNS Forum summary

Company overview and program focus

• Focused on neurodegeneration by harnessing the brain's immune system, particularly microglia, to develop new treatment options.

• Lead program targets ALSP, a rare monogenic microgliopathy, using a TREM2 antibody (iluzanebart), with a phase II readout expected in Q2.

• Additional small molecule TREM2 agonist program for Alzheimer's disease completed phase I and will enter phase II in Q3.

• Both antibody and small molecule programs are designed to modulate TREM2 but differ significantly in mechanism and target engagement.

Insights from industry developments and scientific rationale

• Recent failure of a competitor's TREM2 antibody in Alzheimer's was attributed to insufficient target engagement, not the mechanism itself.

• ARIA safety signals can occur independently of amyloid plaque clearance, suggesting antibody-related mechanisms rather than target engagement.

• Small molecule approach avoids Fc-mediated ARIA risk and offers better brain penetration and target access.

• Small molecule acts as a positive allosteric modulator, enhancing natural ligand activity and avoiding antibody 'sink' effects.

Small molecule program data and development

• Phase I included 14 cohorts and 89 participants, with robust safety and tolerability, especially in older adults.

• Demonstrated high brain penetration and strong dose-dependent reduction in soluble TREM2, supporting target engagement.

• Achieved about 50% greater reduction in soluble TREM2 at max dose compared to the antibody program.

• No need for genetic enrichment in phase II due to consistent biomarker response across genotypes.

• Actively seeking a partner for the Alzheimer's program, with Sanofi holding a right of first negotiation.