We are developing a pipeline of innovative microglial therapeutics across modalities of biologics and small molecules, which can be developed for multiple neurodegenerative diseases
Iluzanebart (VGL101) – a fully human monoclonal antibody TREM2 agonist
Iluzanebart is currently being studied in a Phase 2 proof-of-concept (PoC) trial in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare and fatal neurodegenerative disease
Expected Mechanism of Action of Iluzanebart
About adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
ALSP is a rare, inherited, autosomal dominant neurological disease with high penetrance. ALSP is caused by a loss-of-function mutation in the colony stimulating factor 1 receptor (CSF1R), a receptor that shares a common downstream signaling pathway with TREM2 and affects an estimated 19,000 people in the U.S., and an estimated 29,000 in Europe and Japan.The disease generally presents itself in adults, with symptoms most commonly first presenting in their forties, is diagnosed through genetic testing, and is characterized by cognitive dysfunction, neuropsychiatric symptoms, and motor impairment. These symptoms typically exhibit rapid progression with a life expectancy of approximately six to seven years on average after diagnosis, causing significant patient and caregiver burden. There are currently no approved products for the treatment of ALSP, underlining the high unmet need in this rare indication.
Therapeutic Rationale for ALSP
ALSP is caused by loss-of-function mutations in the CSF1R gene, which lead to microglial dysfunction. Both TREM2 and CSF1R transduce their biological effects, including cell survival and proliferation signals, through the same signaling partner, DAP12/SYK. Iluzanebart is designed to increase signaling through DAP12/SYK to compensate for CSF1R loss-of-function by mitigating microglial dysfunction. Vigil has generated robust evidence that TREM2 agonism can rescue CSF1R loss of signaling in preclinical models. We believe iluzanebart represents a compelling therapeutic approach for ALSP through TREM2 agonism to compensate for CSF1R’s decreased signaling and correct microglia dysfunction.
VG-3927 – an orally-available, small molecule TREM2 agonist
VG-3927 is currently being evaluated in a Phase 1 clinical trial
About Alzheimer’s disease (AD)
AD is the most common cause of dementia, a general term for the loss of memory and other cognitive abilities severe enough to interfere with daily life. AD accounts for 60-80% of dementia cases, and the majority of people with AD are aged 65 and older. A progressive disease, AD usually presents with mild memory loss and progresses to include disorientation, loss of initiative or judgment, difficulty with self-care, behavioral problems, and general mental decline. AD affects an estimated 6.2 million patients in the U.S.
Therapeutic Rationale for AD
We believe that the next Alzheimer’s disease-modifying treatments will go beyond targeting single toxic species and boost the brain’s immune system to broadly and effectively counter multiple processes that contribute to AD.
Strong genetic and functional data have established a causal link between TREM2 and AD in humans. Genome wide association studies (GWAS) have shown that a specific mutation in a TREM2 variant (R47H) is one of the strongest genetic risk factors for AD, second in magnitude only to that associated with the apolipoprotein E4 (ApoE4) genotype. Beyond the evidence demonstrating that TREM2 mutations are associated with increased AD risk, recent studies further strengthen its role by showing that increased TREM2 expression is protective against AD.
TREM2 is the key receptor that senses the presence of multiple ligands that indicate trouble – including Aβ and ApoE. When these ligands are elevated, they bind to TREM2, triggering changes in microglia so they can remove the damage or pathologic aggregates and debris. By activating TREM2 with an agonist, we aim to enhance the natural neuroprotective function of microglia in AD, boosting their ability to neutralize multiple causes of AD pathology
Novel Targets and New Indications
We plan to expand our pipeline through internal discovery and development as well as strategic collaborations or alliances with academic organizations or pharmaceutical or biotechnology companies.
