We are developing a pipeline of innovative microglial therapeutics across modalities of biologics and small molecules, which can be developed for multiple neurodegenerative diseases, some of which have very large patient populations
Iluzanebart (VGL101) – Our lead clinical candidate, iluzanebart, is a highly-targeted fully human monoclonal antibody directed against human TREM2 for the treatment of rare genetically defined microgliopathies
In multiple preclinical in vitro (cell-based) and in vivo (animal model) studies, iluzanebart has demonstrated sub-nanomolar potency and selective target engagement with TREM2 that activates the cascade of downstream signals to mediate neuroprotective and homeostatic functions of microglia. We are initially developing iluzanebart for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, genetically defined, and fatal neurodegenerative disease caused by microglial dysfunction. We have also identified other rare neurodegenerative diseases, such cALD, Krabbe, and MLD as potential indications for future iluzanebart development.
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 that affects an estimated 10,000 people in the US, with about 1,000 – 2,000 new cases annually. Similar epidemiology exists for Europe and Asia.The disease generally presents itself in adults in their forties, is diagnosed through genetic testing and established clinical/radiologic criteria 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.
Small Molecule Program – We are advancing our novel, oral TREM2 agonist program for the treatment of more common neurodegenerative diseases
An orally available and highly CNS penetrant small molecule has many potential clinical and commercial advantages in large chronic indications such as AD, including ease of administration and use in outpatient settings.
Compounds in our lead series have been observed to be highly CNS penetrant after oral dosing, and similar to iluzanebart, are highly targeted and selective activators of TREM2. However, they function via a mechanism of action that is differentiated from iluzanebart, which potentially broadens our optionality in activating TREM2 as a therapeutic approach for neurodegenerative diseases.
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
The role of microglial dysfunction in plaque development in AD is based on the observation that normally functioning microglia reduce levels of toxic amyloid plaques in the brain, while increasing the number of inert, dense core plaques. In addition, normal TREM2 function is required to prevent AD-associated tau protein aggregates from forming. Loss-of-function TREM2 variants occur in 7-8% of the AD population and are linked to both disease progression and worsened patient outcomes. For example, the R47H variant, which represents 2-3% of the AD population, has been reported to triple AD risk in genome-wide association studies and is associated with a 23% faster rate of dementia compared with non-variant carriers.
Our strategy in AD is to follow a precision medicine approach that first establishes the role of TREM2-mediated microglial dysregulation in the pathogenesis of AD within certain genetically defined patient subpopulations, which includes TREM2 and other variants.
Novel Targets and New Indications
We plan to expand our pipeline, either through internal discovery and development, or through strategic collaborations or alliances with academic organizations or pharmaceutical or biotechnology companies.
