Interim Results on VGL101 from IGNITE: First Interventional Phase 2 Study in Patients with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)
David Lynch1, Jeffrey Gelfand2, Rajeev Kumar3, Donald McLaren4, Andreas Meier4, Rajasimhan Rajagovindan4, Zbigniew Wszolek5
1National Hospital for Neurology & Neurosurgery; UCL Institute of Neurology, 2University of California, San Francisco, 3HCA Healthcare, 4Vigil Neuroscience, Inc., 5Mayo Clinic, Jacksonville
Objective:
To report interim results of a TREM2 (triggering receptor expressed on myeloid cells 2) agonist from the first interventional study in ALSP.
Background:
ALSP is a rare, fatal, inherited, autosomal-dominant, rapidly progressing neurodegenerative disorder caused by a loss-of-function mutation in the colony-stimulating factor-1 receptor gene (CSF1R), resulting in microglial dysfunction. ALSP is characterized by progressive cognitive, psychological, and motor dysfunction. Average survival is 6-8 years from diagnosis. VGL101 is a fully human IgG1 monoclonal antibody TREM2 receptor agonist. Preclinical evidence indicates VGL101-induced TREM2 activation enhances the neuroprotective function of microglia, supporting a disease-modifying therapeutic potential in ALSP. VGL101 was well tolerated and demonstrated durable target engagement and pharmacological activity following multiple dosing in a phase 1 healthy volunteer study at all administered doses.
Design/Methods:
IGNITE is a phase 2, proof-of-concept, multicenter, open-label study evaluating safety, tolerability, and clinical effects of VGL101 on MRI and disease progression biomarkers in ALSP (NCT05677659). Eligible patients are ≥18 years old with a documented CSF1R gene mutation and clinical and MRI findings consistent with ALSP. Intravenous VGL101 is administered every 28±7 days for a total of 13 doses. Primary endpoint is safety and tolerability assessed by adverse events. Week 24 change from baseline in MRI brain volume, MRI ALSP severity score, NfL (neurofilament light chain), and additional biomarkers are secondary endpoints. Exploratory clinical endpoints associated with ALSP are assessed. Enrollment is ongoing (target 15 patients).
Results:
Detailed study design plus safety, tolerability, longitudinal MRI findings, disease-related biomarkers, and/or clinical measures from the interim analysis of 6 patients after the 24-week treatment period from IGNITE will be presented.
Conclusions:
No therapies are currently approved for ALSP, and disease-modifying therapies are a critical unmet need. These are the first clinical trial results of a potential disease-modifying therapy for ALSP and of TREM2 agonism as a therapeutic approach in a neurodegenerative disorder.