RARE Daily

Keeping the Sentinels of the Brain Vigilant

September 7, 2023

Microglia are specialized immune cells in the central nervous system that act as sentinels to maintain healthy brain function. They protect the brain against processes that can ultimately lead to neurodegeneration. Vigil Neuroscience is developing precision medicines designed to target microglia and restore and enhance the performance of these cells when they fail to act as they should due to disease. The company’s lead program is in development as a treatment for ALSP, a rare, genetic, neurodegenerative condition. We spoke to Ivana Magovčević-Liebisch, president and CEO of Vigil Neuroscience, about the role of microglia, what happens to these cells in ALSP, and why the company’s approach can have implications for a range of rare and common neurodegenerative conditions.

Daniel Levine: Thanks for joining us.

Ivana Magovcevic Liebisch: Thank you for having me.

Daniel Levine: We’re going to talk about the microglia, the rare neurological condition, ALSP, and Vigil Neurosciences’ efforts to develop a therapy to treat the condition. Perhaps we can start with microglia. What are microglia?

Ivana Magovcevic Liebisch: Microglia are the sentinel cells of the brain immune system. They maintain health and wellbeing in the brain, and they regulate a host of neurological functions to prevent neurodegeneration. So, you can think of microglia as cells that sense damage, and then they are the cleaning crew. They go out to the sides of that and remove that damage. And when they’re not properly functioning, that’s when we accumulate the debris in the brain, which leads to neurodegeneration.

Daniel Levine: And what is ALSP and what role does microglia play in that condition?

Ivana Magovcevic Liebisch: Sure. So, ALSP actually stands for adult onset leukoencephalopathy with axonal steroids and pigmented glia. It is a rare, inherited, autosomal dominant neurological disease. It is actually caused by a single mutation in a single gene called CSF1R, and it affects an estimated 10,000 people in the U.S. The disease generally presents in adults in their fourth decade of life, which is really devastating as many are in the prime of their lives, as you can imagine. They have responsibilities, aspirations, and often, dependents.

Daniel Levine: And how does the condition manifest itself in progress?

Ivana Magovcevic Liebisch: So, the symptoms typically exhibit rapid progression with the life expectancy of approximately six to seven years on average after diagnosis, which you can imagine causes very significant patient and caregiver burden. The symptoms tend to present like many other neurodegenerative diseases. This is why this disease tends to be misdiagnosed as well. So, a lot of cognitive issues, behavioral issues, as well as motor issues.

Daniel Levine: And how is the condition generally treated today and what’s the prognosis for someone with it?

Ivana Magovcevic Liebisch: So unfortunately, there are no treatments available today, the only treatment for potentially treating some of the symptoms. As I mentioned, the prognosis is devastating because from the onset of first symptoms until that is only six to seven years.

Daniel Levine: This, as you mentioned, is an adult onset condition. How do people with ALSP generally come to get a diagnosis, and once they seek medical help, how likely is it a doctor will perform the necessary test to provide a correct diagnosis?

Ivana Magovcevic Liebisch: Yeah, another challenge we have with the ALSP is that it’s a recently defined disease. The gene that causes the disease, the mutation, the CSFR gene, was only identified in 2012. So, when we actually started working in this disease, we knew that we needed to build this from the bottom up and we understood from the work that we were doing that, as I mentioned before, a lot of these patients tend to get misdiagnosed because it is a rare disease that the physicians are not familiar with. And so when people present with symptoms that could look like multiple sclerosis, or temporal dementia, or Alzheimer’s, they end up with the wrong diagnosis, which obviously creates tremendous amount of issues because they get treated for something that is not going to be helpful at all. And as I mentioned, there is no treatment at this point for the patients. So, what’s really important is to get properly diagnosed. And the best way to do that is with the genetic test. Because the genetic test is available, it is available globally and it’s a very straightforward diagnosis once you have the results of the test. What we are hearing from the community, because obviously we spend a lot of time out there in the community to try to make sure that we’re educating ourselves and others about this condition. So, what we hear, not only just from the physicians, but also from patients and their families, is that the cost and the access to the test make it very challenging to get a quick diagnosis. And this is why, after really speaking to the community and understanding what the main challenges around proper diagnosis, that is why we launched our ALSP Aware program.

Daniel Levine: Well, let’s talk about that program. In May the company announced ALSP Aware to provide no cost genetic testing and counseling services to people suspected of having ALSP. How does the program work?

Ivana Magovcevic Liebisch: So, the program is very straightforward. What we’re doing is we are providing free of charge not just genetic testing, but genetic counseling as well. Because as you can imagine, it’s one thing to get tested, but once you have the diagnosis, it’s really important to have the opportunity to talk to a professional who is familiar with the disease and can not only share what the disease is about, but also all the resources that can become available to a newly diagnosed patient. So, this is a program that we launched in the U.S. We launched actually two parts of the program. One is directed to patients and their families. We didn’t mention, but this is an autosomal dominant disease. What it means is that if you find a carrier, you usually have pretty large families because it gets passed from one generation to another. So, what we’re providing is free genetic testing and counseling to families that are affected by this disease. Anybody who is 18 years or older and has a family member or suspects that they have a disease are eligible to get tested. But we also want to deal with the misdiagnosis part of this issue. And so, we are also providing 24 gene panel testing that’s available to healthcare providers and this looks not just at ALSP, but a bunch of other leukodystrophies because we want to make sure that these patients are properly diagnosed as quickly as possible. So, that’s going to be available in, you know, we are focusing on clinics where we know these patients tend to end up as MS or FTD or Alzheimer’s disease. So, we want to make sure that we educate those physicians and make these tests available for them because we believe that getting a correct diagnosis is critically important, and not just getting the diagnosis, but then having access to all the resources that then can be available to patients suffering with this disease.

Daniel Levine: You alluded to discussions that you’ve had with healthcare providers and others that help shape the program. What did Vigil learn from those discussions?

Ivana Magovcevic Liebisch: What, what we learned and we learn every day, as I mentioned this is a disease that’s only been recently diagnosed, so we’re all still learning, is that one of the barriers is the cost and availability of the test, and also just the fact that physicians are not familiar with the disease. So, we spend a lot of time educating the physicians and to ensure that when they see these symptoms and they’re not sure about the diagnosis to be thinking about ALSP, and then obviously, also making sure that the resources are available for people once they are diagnosed so that they know that there are patient associations out there that can support them—that there are clinical activities that are happening in the space, that there are disease awareness websites, opportunities to really get educated and understand what it means to be living with this condition.

Daniel Levine: This is a relatively new condition that may be under the radar for a lot of physicians. How’s the programming helping the company identify potential participants for clinical trials or helping the company better understand the disease and the patient experience?

Ivana Magovcevic Liebisch: So, the main purpose of this is not really to find patients for clinical trials. The main purpose of this program is really to help families get the support and the information that they need once they have this diagnosis. And then the second purpose is really to reduce that misdiagnosis rate. Obviously, we want to make sure that the right education is also provided, but really it’s to make sure that the families have the opportunity to get tested and get that diagnosis early in the disease trajectory so that they can see what the options are for them. We are still learning about this disease. We are actually running the first natural history study ever in this indication called Illuminate. And the purpose of that study is to really learn about the disease, about the patient journey, really understand how the disease progresses so that we can ensure that in our clinical studies we are addressing and making sure that we’re impacting the most important symptoms of this disease, which are the most important in terms of patient wellbeing, but also helpful to the caregivers as well.

Daniel Levine: Vigil is developing VGL101 as a potential treatment for ALSP. What is VGL101?

Ivana Magovcevic Liebisch: VGL101 is a fully human monoclonal antibody that’s an agonist of a receptor on microglia called TREM2. And as I mentioned, microglia are the primary cells that sense damage in the brain. So TREM2 is actually the main damage sensor in the brain. And so, what we are doing is we are over activating that particular sensor in order to compensate for the mutation that’s happening in the CSF1R gene, which is another receptor of microglia. The reason we believe this is going to work is because these two receptors have signaling downstream that converges, and what that means is that they can compensate [for] each other. So, we believe that by over activating TREM2, we can actually compensate for the deficiency that results from the CSF1R mutation, which is really what happens is that the number of microglia are reduced and the number of active microglia are reduced as well in the disease. And what I mean by active is TREM2 activation, which is the receptor. So, the receptor on microglia needs to be activated in order for microglia to convert from there, we’re just in the brain watching over what’s happening, being vigilant. And this is why we named the company Vigil to say, oh, I need to get activated because there is damage here and now I need to be that cleanup crew that goes out there and cleans up the damage. That conversion only happens when TREM2 is activated and that’s what we’re trying to do with our antibody.

Daniel Levine: This is a fully human monoclonal antibody. Is it delivered systemically? Is there any issue getting it across the blood-brain barrier?

Ivana Magovcevic Liebisch: Yes, it is delivered systemically. It’s a monthly IV infusion. We are currently conducting a phase 2 study in in patients with ALSP, but prior to going into patients we conducted a phase 1 study in healthy volunteers where we actually showed that the drug is safe and tolerable, but in addition to that, have shown that it does cross the blood brain barrier and engages the target. So, we feel confident that we are getting the antibody to where we need to get it in the brain in order for it to activate the microglia.

Daniel Levine: And what’s the development path forward?

Ivana Magovcevic Liebisch: That will obviously depend on the results of the study, but we believe that if we can show efficacy and we’re looking at efficacy based on biomarkers. So, in this disease we know that there are very meaningful changes in the white matter lesions and ventricular volume in this patient population as well as changes in a biomarker called neurofilament light or NFL. You probably heard about it now that it’s just been approved for another indication as a surrogate endpoint, which is very, very exciting. It’s highly elevated in this patient population. So, what we’re looking for is to see if we can move these biomarkers. If we can move them, we believe that we have an opportunity to have early conversations with the agency and see how quickly can we get this drug approved based on our biomarker strategy. We’re obviously at clinical endpoints as well, but as you know, those take time. So, our study is 12 months in duration, but we’ll be taking early looks at six months in order to see whether we can move the biomarkers and then go talk to the agency about what is the right and the best pathway forward to get this to the patients as quickly as possible.

Daniel Levine: Vigil is looking at this as a potential therapy to treat other leukodystrophies. How broadly applicable do you think it might be beyond ALSP?

Ivana Magovcevic Liebisch: So, we believe that microglia are involved with a lot of different neurodegenerative diseases and are involved with other microglia. So some of the leukodystrophies are actually microglia, which means that there are issues with microglia and we think that in those specific indications there is an opportunity to explore beyond ALSP.

Daniel Levine: Ivana Magovcevic Liebisch, president and CEO of Vigil Neuroscience. Ivana, thanks so much for your time today.

Ivana Magovcevic Liebisch: Thank you. It was a real pleasure to talk to you.

This transcript has been edited for clarity and readability.



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