Vigil Neuroscience, Inc.

Microglial-focused therapeutic pipeline

Microglia sense brain signals, maintain homeostasis, and play a critical role in coordinating the clearance of pathogens and unwanted cellular debris that promote the formation of disease. Properly functioning microglia transition into a neuroprotective disease-associated microglia form known as the DAM phenotype when an issue is identified. DAM maintains the central nervous system by preventing harmful inflammation and removing protein clumps and other cellular debris that accumulate in the brain during the normal aging process and in patients with neurodegenerative diseases. Failing to transition into DAM and other incidences of microglia malfunction are linked to a range of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), leukoencephalopathies, leukodystrophies, Parkinson’s disease (PD) and multiple sclerosis (MS). 

TREM2 is a receptor that is expressed specifically on microglia. It is essential for the proper functioning of the microglia and is responsible for detecting and coordinating the removal of harmful substances to prevent damage. Most notably, observations during preclinical trials have shown that activation of the TREM2 receptor is essential for microglia to transition between its standard homeostatic form and the DAM phenotype. Equipped with this knowledge, Vigil Neuroscience focuses its therapeutic programs on developing activators of the TREM2 receptor.

Although TREM2 activation therapies have the potential to treat a broad range of neurodegenerative diseases, Vigil is taking a unique approach to therapeutic development by starting with rare diseases where microglial dysfunction has been established as a key driver. The company believes this will allow them to generate clinical proof-of-concept and sufficient data to enable them to efficiently move into broader indications of neurodegenerative diseases with large patient populations. 

VGL101

Vigil Neuroscience’s lead product candidate, VGL101, is currently undergoing clinical trials to treat adult-onset leukoencephalopathy (ALSP). ALSP is an inherited neurological disease that affects around 10,000 people in the United States. ALSP patients exhibit cognitive dysfunction and motor impairment, with the disease usually presenting in mid-adulthood. Rapid progression limits patients to an average lifespan of just six to seven years after symptoms show and there are currently no approved therapeutic products to treat ALSP. 

The cause of ALSP is a mutation in the CSF1R gene, which leads to microglial dysfunction. VGL101 is believed to be a potentially viable treatment for ALSP because CSF1R and TREM2 share a similar signaling pathway. Both CSF1R and TREM2 receptors transmit signals like cell survival or proliferation through the same signaling partner, DAP12/SYK. Designed to increase signaling through DAP12/SYK, VGL101 aims to mitigate microglial dysfunction by compensating for the mutation in CSF1R. 

Beyond ALSP, Vigil Neuroscience is planning to target other rare leukoencephalopathies and leukodystrophies, like cerebral adrenoleukodystrophy (CALD), metachromatic leukodystrophy (MLD), and Krabbe. 

Small molecule TREM2 agonist program

Currently in preclinical exploratory testing, Vigil has in-licensed over 1,000 small molecule TREM2 agonist compounds within its small molecule TREM2 agonist program. The program seeks to develop an orally available therapy to treat common neurodegenerative diseases. An orally available small molecule therapy that is highly penetrant of the central nervous system has many potential clinical and commercial advantages, like treatment in an outpatient setting. The program’s first target is Alzheimer’s disease in patients with TREM2 gene variants, and Vigil has plans to expand testing to the general population of AD patients if clinical data supports this approach.

Operational overview

Having recently begun operations in 2020, Vigil Neuroscience does not yet have any product candidates approved for commercial sale and therefore has generated no revenue from product sales. Since inception, Vigil has funded operations through common stock and preferred stock proceeds, as well as a Simple Agreement for Future Equity (SAFE) with Atlas Venture Fund XII, L.P.

Conclusion

Vigil Neuroscience’s product pipeline has the potential to enhance treatment across neurodegenerative disease, especially the rare indications it’s targeting early on. However, the company faces stiff competition from other major biopharmaceutical companies who are also pursuing microglia-targeted drug therapies, like Denali Therapeutics. Vigil will need to establish a patent portfolio to protect its therapeutic assets. If Vigil Neuroscience can obtain the necessary patents and show proof of concept for its product candidates during these early trial days, the company has a good chance of expanding its therapeutic pipeline into more common neurodegenerative diseases with more commercial opportunity and promote greater longevity for humanity by extending the lifespan and life outcomes for the many patients suffering from neurodegenerative disease.