Background

VGL101 is a humanized monoclonal antibody that acts as an agonist for TREM2. This receptor is expressed on microglia and macrophages, and mediates their proliferation and function. VGL101 is claimed to activate TREM2 signaling with sub-nanomolar potency and selectivity. While other TREM2 agonist antibodies are in trials for Alzheimer’s disease, Vigil is developing VGL101 for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). A rare and fatal neurodegenerative disease, ALSP is caused by mutations in the gene for the glial protein Colony Stimulating Factor 1 Receptor (CSF1R), which shares a common downstream signaling pathway with TREM2. The rationale for VGL101 is that TREM2 activation should compensate for loss of CSFR1 function and rescue glia function.

Vigil licensed this antibody from Amgen, which had published preclinical work on TREM2 antibodies that activated signaling and abrogated defects in microglia carrying the rare R47H TREM2 gene variant, a risk factor for AD (Cheng et al., 2018). Amgen’s monoclonal antibody hT2AB activated microglia in 5XFAD mice with R47H TREM2, but had limited efficacy in mice with the more common TREM2 variant (Ellwanger et al., 2021).

Vigil presented preclinical work on VGL101 in ALSP cell models at the August 2022 AAIC (abstract; poster). In human iPSC-derived microglia depleted of CSF1 or treated with a CSF1R kinase inhibitor, VGL101 stimulated TREM2 signaling, rescued cell viability, and promoted morphological changes consistent with microglia activation.

Findings

According to Vigil’s Securities and Exchange Commission filing, the FDA approved an Investigational New Drug application for VGL101 in November 2021, at doses up to 20 mg/kg. VGL101 subsequently entered Phase 1 in the U.S. with a single- and multiple-ascending-dose trial that does not appear in any of the common trial registries. In June 2022, the company announced it had expanded the trial to Australia, where it was allowed to test doses above the FDA limit (press release; trial details).

In November 2022, Virgil released interim data for Phase 1 (press release; slides). At the time of the report, the trial had enrolled 82 healthy volunteers who received single intravenous infusions of 1, 3, 10, 20, 30, or 40 mg/kg or placebo, or three 20 mg/kg infusions at monthly intervals. The antibody reportedly showed acceptable safety and tolerability at the highest doses tested. Pharmacokinetics were dose-proportional, with an antibody half-life of 27 days, and CSF concentrations reaching 0.1-0.2 percent of serum. Repeat administration led to dose-dependent decreases in CSF soluble TREM2 and increases in soluble CSF1R, indicating target engagement and pharmacodynamic effects.

Complete Phase 1 results of single and multiple dosing up to 60 mg/kg were presented at the September 2023 American Neurology Association meeting (press release). In 136 healthy volunteers, single or multiple doses up to 60 mg/kg were safe and tolerable, with pharmacokinetics sufficient for monthly dosing, the company said.

Phase 2 began in December 2022, with an open-label study in 20 people with ALSP and CSF1R mutations. Participants receive infusions of 20 or 40 mg/kg VGL101 every four weeks for one year. The primary outcome is adverse events; secondaries are brain volume on MRI, ALSP symptom severity scores, and the CSF biomarkers neurofilament light and CSF1R. The study is running at three sites in the U.S., and additional sites in France, Germany, Netherlands, and the U.K. . An optional long-term extension offers treatment for up to an additional two years.

The company is also conducting a two-year observational MRI study in 36 CSF1R mutation carriers, with and without symptoms. Completion of this natural history study is expected in November 2024.

In March 2023, Vigil announced that the FDA had removed the Phase 1 dose cap, after more preclinical and clinical data became available (press release).

In April 2024, Vigil presented interim Phase 2 results at the American Academy of Neurology annual meeting (slides). In six patients treated with 20 mg/kg for six months, soluble CSF1R and osteopontin biomarkers of microglial activity were increased, while the neurodegeneration biomarker NfL trended down. No treatment-related serious adverse events or discontinuations were noted.

The FDA has granted Orphan Drug and Fast Track designation to VGL101 for ALSP.

For details on the phase 2 VGL101 study, see clinicaltrials.gov.