Axial S-1 Club — Vigil Neuroscience

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Vigil Neuroscience is a drug development company focusing on microglia, the immune cells of the brain, to treat neurodegeneration. Started by Atlas Venture and in-licensing a program from Amgen to start, Vigil began with the biological hypothesis that microglial dysfunction plays a large role in diseases like Alzheimer’s and adrenoleukodystrophy. With this premise, the company is focused on genetically defined patient populations as a way to increase their chances for success and design more efficient clinical trials. Founded in 2020 and going public in early 2022, filing a corresponding S-1, Vigil is an interesting case study for the potential of neuroimmunology.

Who leads Vigil Neuroscience?

Ivana Magovčević-Liebisch is the company’s President and CEO. Before Vigil, she was CBO at Ipsen and also spent time at Axcella Health, Teva, and Dyax. At the latter, she helped drive the launch of Kalbitor, an antibody mimic, to treat hereditary angioedema. Beyond her work, Ivana has had a fascinating career starting at immigrating from Serbia to the US in the 1980s with 2 suitcases to attend Wheaton College on a full scholarship. She is a master at operating outside a comfort zone — she is trained as a geneticist and on top of that went to law school with a career spanning everything from operations to strategy and science.

Beyond the CEO, Vigil’s CMO is Spyros Papapetropoulos who used to work at Teva, Allergen, Biogen, among others. However, the initial conditions of Vigil were really set by Atlas Venture who helped build out the executive team, enter into a licensing agreement with Amgen for TREM2 agonists (an antibody candidate and small molecule), and establish the initial strategy.

What does Vigil do?

Vigil’s biological hypothesis is that microglia cells in disease-associated states could actually increase the clearance of amyloid-β deposits in Alzheimer’s (AD) patients. With this premise, Vigil in-licensed an antibody to agonize TREM2 and activate microglia to convert to an inflammatory state. This is a pretty controversial stance — for AD and neurodegeneration in general do you want to increase TREM2 activity or decrease it? Human genetic studies have pointed to loss-of-function (LoF) variants of TREM2 are associated with Alzheimer’s while in vivo studies have produced somewhat opposing results. For example, work out of the Holtzman Lab in 2017 suggests that TREM2 is protective early on in AD but then becomes detrimental once tau pathology of the disease develops later in the disease. As a result, Vigil’s TREM2 pipeline might only be really useful for early-stage AD patients. This unveils the massive need for early-stage detection tests in neuro. The success of drug candidates in neurodegeneration will not only be successful for the underlying biology but knowing when to intervene.

Microglia were discovered in 1919 by Pío del Río-Hortega. The phrase glia had been used throughout the 1800s to describe the glue that holds the brain together. Once cell biology developed far enough to determine that the brain was composed of individual cells, Santiago Ramón y Cajal classified the brain into 3 main cell types: neurons, glial cells, and astrocytes (they are now considered the largest subset of glial cells). Río-Hortega trained with Cajal and did the work to establish the distinguishing features between oligodendrocytes (a type of glia cell that help form myelin sheaths around axons) and astrocytes (involved in BBB integrity) mainly by their shape. Only around the 2000s have different subpopulations of microglia been established. This has only accelerated with the advent of single-cell transcriptomics over the last 7 years.

Despite this work, microglia biology is still a black box. This comes from the historical difficulties of disentangling microglia from macrophages. For decades, the origins of microglia were still a hotly debated scientific topic. Two 2007 papers in Nature Neuroscience offered clues to an answer and set the field for rapid progress over the subsequent years:

• The Rossi Lab at the University of British Columbia used parabiosis to establish the microglia were not derived from blood monocytes under physiological conditions suggesting they were locally maintained and expanded — https://pubmed.ncbi.nlm.nih.gov/18026097/
• Then Marco Prinz’s group established that irradiated mice, likely with disrupted blood-brain barriers (BBB), recruit microglial progenitors from blood circulation to the CNS — https://pubmed.ncbi.nlm.nih.gov/18026096/
• This research from the Prinz Lab was later found to be an artifact of the experimental design: transplantation of bone marrow cells in mice created “synthetic” monocyte-to-microglia conversion. The Rossi group’s use of parabiosis avoids this problem by decoupling transplantation from irradiation and later work from the Rossi Lab established that blood monocytes cannot persist in the CNS — https://pubmed.ncbi.nlm.nih.gov/21804537/
• This work in the 2000s and early 2010s was a major breakthrough in the microglia field. These elegant experiments showed that microglia self-renew and do not depend on circulating cells. Microglia actually arise from macrophage progenitors that settle into the early brain during embryonic development (i.e. showing the power of fate mapping) — https://pubmed.ncbi.nlm.nih.gov/20966214/ On a side note, there are countless opportunities to build fate mapping platforms for everything from HSCs to neurons/microglia.

Despite this progress there is still so much work left to do to characterize microglia biology. They have two main states — M1 = pro-inflammatory, M2 = anti-inflammatory — but they come in so many different variants that are dependent on the disease context. The M1 state has a high degree of variation on what is cleared — plaques? Other cells? For neuroimmunology, and CNS in general, there is a need for better translational models that more accurately represent the neuroimmune system.

In this backdrop, Vigil got started to drug this rapidly changing field. There is a biological risk of knowing when/where TREM2 activation is positive in AD. Then there’s so many more opportunities to map out the neuroimmune system. Vigil’s lead asset, VGL101, is a monoclonal antibody (mAb) that activates TREM2. The phase 1 clinical trial began in late 2021 at doses up to 20 mg/kg with an initial focus on adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP affects around 10K patients in the US), a rare disease caused by dysfunctional microglia. Executing a rare-to-common drug development strategy, the plan is to expand to larger diseases like genetically-defined AD populations and cerebral adrenoleukodystrophy (cALD). Really excited to see the results from this trial. TREM2’s role is still not fully characterized but genetic studies and in vivo work hints at a protective role early-on in neurodegeneration.

Vigil among others are focused on pipelines leaving a window for a new company to build a platform to map out and index this new biology. The first step is a better atlas of the brain that will probably reclassify immune cells in the CNS. With a higher-resolution map, the downstream tools become a lot more valuable:

• You put a lot more biological context behind the genetics of neurodegeneration (i.e. APOE4, TREM2). Most neurodegeneration, especially AD, is somatic so finding new ways to find genes similar across individuals but key drivers of disease could unlock new starting points for drug developers.
• Immune signaling, especially cytokines in the CNS, becomes much more clearer
• Then new methods like PET imaging can be overlaid on this atlas to measure neuroinflammation. In particular, there is a need for a non-invasive imaging agent for microglia activity. For example, florbetapir acquired by Eli Lilly in 2010, transformed AD diagnoses by allowing PET scans to measure amyloid-β levels in patients.
• Combinatorial therapeutics in neuro might become easier to design. Specific cell types in the brain, especially microglia, often coordinate with other brain cell types. So drugging one specific cell type might not work — you have to pursue a collection.
• Animal models can be designed more accurately. A lot of our knowledge about microglia might not fully translate to humans. The transcriptional profiles of microglia from mice and humans are pretty different. On top of this, behavioral tests in mice are not truly correlated to humans. New platforms are needed to merge neurodegeneration with neuropsychiatry.
• Genetic-dose response curves in neuro would lead to a massive acceleration to go from hypothesis to human testing

Neurodegeneration is the largest opportunity in medicine. Within this category, AD has the largest need. We can’t wait decades when a disease like Alzheimer’s will affect 10Ms of patients by then. If amyloid-β is the spark for AD and tau is the fire, microglia have a more complex role, they can either help grow the fire or dampen it. Plus, their activity can be location-specific. For companies like Vigil, you’re either preventing the fire or trying to put the fire out. Many more companies will emerge with their own take here.

Denali Therapeutics is another company working on neuroimmunology that is worth touching upon. Versus Vigil, Denali is focused on diversification across pathways and targets. Microglia is part of their pipeline in combination with lysosomal biology and pathways involved in cell homeostasis. Denali’s RIPK1 inhibitor is developed with the premise of restoring microglia to a normal, non-inflammatory state. They announced a recent deal with Sanofi for a phase 2 trial of the drug candidate in ALS. And Denali’s diversified approach has allowed the company to execute a partnership with Takeda and with Biogen focused on LRRK2 in Parkinson’s. In combination with a broad purview, Denali’s platform is also centered around delivery across the BBB and focus on target engagement. The latter is a very important concept for neuro drug development.

In CNS drug development, dose selection is notoriously difficult due to inaccurate translational animal models. Instead of relying on complex animal models, Denali wants to safely get into the clinic and dose specific patient populations. Their premise relies on comprehensively mapping target engagement for a drug candidate. Everything from mass spec, immunoprecipitation, chemical probes, BRET, and more. The entire kitchen sink. Then doing the same in phase 1 trials, measuring similar metrics in both patient plasma and CSF. This type of work has allowed Denali to pick doses more systematically. Excited to see data from late-stage trials for their RIPK1 and LRRK2 programs. If animal models can’t improve fast enough, then more neuro companies might need to rely on getting to first-in-human trials as safely and quickly as possible. However, the safety bar in neuro, say versus cancer, is a lot higher. Vigil as well as other companies can take a piece from the Denali playbook. More diversification across pathways and targets enables a few more shots-on-goal. One view is that drug development is a top of a funnel problem. It’s too hard to substantially improve success rates. So it’s easier to generate high quality leads and put more of them through the clinic.

What makes Vigil unique?

Vigil’s pure focus on neuroimmunology in a backdrop where others are either pursuing Aβ/Tau or diversified puts the company in a interesting position — if their TREM2 hypothesis translates in the clinic, Vigil is the market leader and if not, the entire field has to go back to the drawing board and figure out ways to know when to activate/inhibit microglia and where. Whatever happens, the neurodegeneration field will make progress. In short, given the patient need, we need to iterate across new targets as quickly as possible.

Vigil’s focus on TREM2 comes from their overall approach of linking microglia to rare-and-common CNS diseases. Everything from AD to leukoencephalopathies and leukodystrophies, ALS, epilepsies, and more. Genomics has shown genetic mutations affecting microglia function are connected to neuronal function and neurodegeneration. This makes sense at a biological level where microglia are essential to maintain CNS homeostasis. In their normal state, microglia monitor for damage from infections to myelin (i.e. axon insulation) damage. In a disease-associated state (DAM), they move towards phagocytosis of cellular debris (would be plaques in AD) to axon pruning. Vigil’s hypothesis is that DAM has neuroprotective functions so the company’s 2 lead assets are centered around pushing microglia to a DAM state.

TREM2 is a receptor specifically expressed by microglia that senses cellular damage and is essential to activate the DAM state. It triggers a signaling cascade that promotes microglia migration/proliferation and activates phagocytosis. And GWAS studies confirm that TREM2, specifically the R47H variant, deficiency plays a role in neurodegeneration. Vigil is also relying on clinical data in Nasu-Hakola disease (NHD), a rare autosomal recessive disorder, where TREM2 is inactivated due to mutations in either TREM2 itself or DAP12 (interacts with the TREM2 complex. Beyond TREM2 agonism, there are so many opportunities to map out this pathway and uncover new target/disease relationships. Similar to drugging the RAS pathway in cancer. For example, from the Gan Lab at Cornell, they put out recent work to uncover a new TREM2-related target, in AKT signaling, for AD. The group designed a tauopathy mouse model that mimics the TREM2 (R47H) variant. More work like this is likely to come out given the increasing amount of genetic data in neuro that needs to be validated in new translational models.

Why I like what Vigil is doing?

The company has a high conviction on their TREM2 program. Historically, drugging inflammation in neurodegeneration has not worked out in the clinic. Everything from COX inhibitors for AD in the 1990s/2000s to anti-TNF programs and RAGE inhibitors. Dosing, target selection, and trial design all probably led to these outcomes. Say Denali is focused on being best-in-class for dosing. Vigil is taking the position that TREM2 agonism is key for AD and other CNS diseases. This is mainly from past genetic studies linking TREM2 LoF gene expression to increases in risk of developing AD. Overall, neuro trials need to move faster and become more efficient. Companies like Unlearn are building the toolkit to solve this problem. Vigil, Denali, and other companies of this era, all show that the earlier we can intervene in neurodegeneration, the better chances we can change its trajectory.

Mention highlights in the S-1

• TREM2: 272
• VGL101: 188
• Preclinical: 125
• Microglia: 84
• Genetic: 34
• CSF1R: 33
• Neuroscience: 21
• Breakthrough: 17

You can find Vigil Neuroscience here.