For episode 37, we connect with David Bearss, President and CEO of Halia Therapeutics. Learn more about the connection between chronic inflammation and disease, and how Halia is using their novel therapies to treat both inflammatory disorders and neurological diseases. First In Human is a biotech-focused podcast that interviews industry leaders and investors to learn about their journey to in-human clinical trials. Presented by Vial, a tech-enabled CRO, hosted by Simon Burns, CEO & Co-Founder. Episodes launch weekly on Tuesdays.

Todd Kays: [00:00:00] Hi, I’m Todd Kays, Vice President of dermatology at Vial Health Technologies. I’m speaking today with Dave Bearss co-founder, CEO, and President of Halia Therapeutics. Welcome, David.

David Bearss: Thank you. It’s great to be here, Todd. I’m looking forward to having a chat with you, today.

Todd Kays: What you’re doing at Halia is great. I have a few questions we can go through. You previously founded companies like Tetragene LLC, Wasatch Scientific, and Tolero Pharmaceuticals. How do you think those experiences prepared you for launching Halia in 2020?

David Bearss: I’ve done this a few times now. I’ve learned through the school of hard knocks. I don’t have any business background or business degree, but I’m a scientist by heart. I’ve learned a lot about the process of translating science and turning that into things that can actually really benefit people. 

That’s what drives me every day and the things that I’ve learned. I try to mostly learn from my mistakes, and not to replicate those. But, I’ve had some good successes. I’ve been able to see a lot of things that we’ve worked on over my career move into clinical development and to drugs that you discovered being used by real patients. To me, there’s no greater feeling, and success I’ve enjoyed than having stuff that I’ve worked on benefit real people. 

The biggest lesson I’ve learned is good science is good medicine and good medicine is good business. So, if you get the science right, that’s where it all starts. Where I come from as a scientist in the business arena is trying to focus on doing the best science that we can and translating that into making good medicines. If we make good medicines, I’m sure that we can make a business out of that.

Todd Kays: How do you think Halia sets itself apart from other biopharma companies in approaching drug discovery for inflammation? How do you decide which inflammatory mediated diseases to prioritize when you’re developing new therapies?

David Bearss: We follow the science. We started the company with an interesting genetic discovery that one of our co-founders made. We had found a population of people that had a genetic high risk predisposition for developing neuroinflammatory diseases like Alzheimer’s disease. We found this population, a family here in Utah, has this genetic polymorphism that puts them at risk for developing early onset Alzheimer’s.

We made the discovery they had a second polymorphism or mutation in their family that protected them from Alzheimer’s. The result is they had less Alzheimer’s in the family than you would expect. We started the whole company based off of trying to figure out what exactly is driving that? How are these people protected from a strong genetic predisposition that they inherited?

They had this other genetic predisposition that protected them from the other one. What we discovered is the key to that whole protection had to do with suppression of chronic inflammation. We found a novel mechanism that we decided looked like something we could develop a drug against.

We were the first group to try to target this specific pathway, or at least the specific mechanism within the pathway of targeting inflammation. We started in the brain and then we discovered the same thing actually is present in basically every chronic inflammatory disease that we’ve looked at.

We’ve systematically, in the lab, examined the same pathway in inflammation in the skin, heart, eyes, lungs, liver, and the kidneys. We’ve just gone through the whole body and said, “Does it work everywhere?” It looks to be a very common mechanism that gets activated in chronic inflammatory diseases.

The end part of your question is how do you figure out what to do? Well, that’s a challenge. When you have something that potentially works for so many different things. It’s been an interesting process to try to figure out, well, if I can choose from a hundred different diseases, how do we focus on the right one?

The answer has been, once again, we try to follow the science. Every drug is unique in its properties so we look for clues to tell us this is an oral pill that we’ve discovered. Where does it go in the body once it gets ingested? That gives us some clues that if we get really good penetration into the liver and the intestines, but we don’t get as good penetration into the brain, then that helps direct things.

Those are the things that we’re exploring right now as we’ve entered early clinical trials trying to find what the pharmacology of our drug looks like and how we match that with the potential indications that we can go after clinically.

Todd Kays: With the explosion of research into the inflammatory mediated processes in so many diseases, what are some of the biggest challenges you faced in developing therapies for these?

David Bearss: It’s been an interesting process to watch over my career. When I was a graduate student, I took an immunology class and we were taught chronic inflammation was just the failed resolution of acute inflammation. You have an acute inflammatory response that just never got turned off. We thought that way about chronic inflammation for a long time. What we know now is that these diseases actually activate inflammation in a different way. That’s fairly recent discoveries of how that all happens. 

We found a big protein complex that can get activated in chronic inflammatory diseases that we [00:05:00] call the inflammasome. There’s actually multiple of these. The one that we study is called the NLRP3 inflammasome. Just in the past five years, we’ve put the pieces together of how this thing gets activated, how it gets assembled, what it does when it’s activated, and potentially ways to turn it off.

One of the challenges we face is what’s the best targeting strategy? The inflammasome is like a machine inside the cell that’s just putting out signals. One of the approaches people have tried to take is blocking the signals that come out of that machine. Trying to soak up the messages the machine is creating. Others have tried to compete with the enzymatic activity, that big molecular complex. 

What we’ve done differently is targeting the assembly and promoting the disassembly of this machine. Instead of trying to block its output or to compete for its function, we try to break the whole thing apart. That’s been trying to figure out the targeting strategy. Matching that with the right models, and the right disease situations to try to test this. 

One of the big things we face is how do you measure chronic inflammation as opposed to acute inflammation? In medical school, they teach the doctors inflammation associated with swelling, redness, heat, and pain. So, Chronic inflammation really is not exactly the same. You don’t get as much redness and heat. You get pain, and some swelling associated with it, but it’s more of a low grade, constant inflammation. Measuring that and trying to get a sense of it is your drug doing what you think it’s doing. That’s been more challenging than a lot of people can imagine.

We tried to come up with different ways to measure that once we got into the clinic. We can’t always go in, and take biopsies and sample things that we want to sample from different tissues. We have to look at surrogates in the blood or in different accessible tissues or fluids from the body to try to get a sense of what’s going on. Those things make clinical development challenging.

Todd Kays: Do you have biomarkers that you’re using, and the diagnostics that go along with it, that help with that?

David Bearss: One thing I’ve learned over the years is having a good biomarker and a companion diagnostic that you can link your drug to is critically important for making the right decisions early on. A lot of bigger companies try to run a lot of studies to just try to sort out what’s going on. As a smaller company, we can’t run ten different studies. We have to be as smart as we can at trying to get as much information out of a single clinical trial. A larger company might run four or five clinical trials to get the right answer. We rely a lot on biomarkers. 

One thing that’s been a challenge in targeting inflammatory diseases is we know that we can measure inflammatory markers in the blood, these are things that we call cytokines or chemokines. Chemical messengers produced by immune cells that talk to the immune system to say, “Hey, there’s a problem over here. Recruit these types of cells. Come help fix this.” The problem with that is those markers tend to go up and down a lot. If I measured you in the morning and looked at your cytokines and chemokines in your blood, and then measured you in the afternoon, and in the evening, every one of those measurements would be different without any intervention.

 The big challenge has been, how can we find a stable biomarker that is consistently present at a level we feel confident that we see it go up or down, but, something clinically meaningful. One of the things that we’ve moved towards is, instead of looking at soluble circulating biomarkers, is isolating cells from the blood, and profiling those cells directly. We use a lot of what’s called single cell proteomic analysis where we can draw blood and isolate what we call peripheral blood mononuclear cells, so white blood cells in the blood. We can separate those cells into different types of cells. Neutrophils, monocytes, and macrophages, different cell populations. We can isolate those out and interrogate what are the messages each one of these populations are actually producing? We look at that at baseline, and after treatment and say, “Okay, how does our treatment change what the signals that those individual cell populations are communicating?”

We find that to be far more impactful in terms of our ability to understand what’s happening to the whole process of inflammation as opposed to focusing on a single circulating biomarker. When you have something like that, you potentially could come up with a score to say, “If this one goes up and this one goes down in this population,” then you have a scale that you can compare it to and say, “We want to move people from here to here.” That’s helpful in designing and developing a novel therapeutic.

Todd Kays: It’s great with the development of those tools. Let’s talk about your lead compound here, HT-6184. I’ve got a familial history of both early onset Alzheimer’s and Parkinson’s. So I’m particularly interested in your HT-4253, which I see you’re filing an IND for. I think it’s planned for Q4 2023. Can you give us a little bit more on the role of the LRRK2 inhibitors, like H2 in these diseases? 

David Bearss: We’ve known for years that there’s a gene called, LRRK2. If you have a specific polymorphism, this was discovered using genome-wide population studies, looking at [00:10:00] people that have specific early onset Parkinson’s or Alzheimer’s, and then looking at their genetics to see if they have different flavors of genes that might be associated with early onset of these conditions.

So LRRK2 was discovered years ago. This particular polymorphism was associated with early onset Parkinson’s disease. People have been studying it for a long time. It happens to be a very druggable target. It’s a class of proteins that are kinases (enzymes that phosphorylate other proteins). We’ve been successful at developing kinase inhibitors. The reason why we’re interested in this, by the way, is it’s tied back to the story that I told you earlier with this population of people that are resistant to this other genetic risk factor for Alzheimer’s. What we discovered is LRRK2 is in the pathway we found this second mutation in. We’ve developed a drug that’s slightly different than other LRRK2 inhibitors that have been out there. 

What we are trying to do is to affect the protein trafficking inside the cell. One of the things a cell has to do when it’s responding to a signal, and in our case, responding to inflammatory signals, is they move a lot of proteins around inside the cell. There’s a machinery inside the cell that says we need to put these proteins over here on this side of the cell so they can get together and form this inflammatory complex.

We’ve discovered that LRRK2 plays an important role in that process. Instead of just targeting its enzymatic activity, it participates in a lot of interactions with other proteins. The target of our drug is trying to inhibit not only the enzymatic function of LRRK2, but also the way it interacts with other proteins. 

We think we’ve got something that’s differentiated that gets into the brain very well. That’s a challenge for developing drugs that target things in the brain. The brain has a very good barrier for keeping cells and molecules out that shouldn’t be there. We call it the blood-brain barrier. Getting things through the blood-brain barrier is actually a bit of a challenge. When we develop a drug to target a neurological disease, we want to make sure that drug can get to the right place and stay in the right place in the brain for a while.

Our drug has those characteristics. We’re excited to see what happens in early clinical studies. We’ve designed those studies and we’re just wrapping up the regulatory preparation studies that we need to file with the FDA to get the drug into the clinic.

Todd Kays: That’s great news because both of those conditions have absolutely nothing that’s particularly effective. I’ve seen the debilitating effects of both. We always have to keep our finger on the pulse of what’s going on outside the pharmaceutical world. Particularly, what kind of research is going on in academia. Are there any new developments or breakthroughs in the field of inflammation, drug discovery that you’re excited about?

David Bearss: It’s been fascinating to watch, just over the last five years, how much we’ve learned about the role of inflammation in many different diseases. The thing I’m most excited about is what’s happening in the brain. Neurological diseases, as you just mentioned, they’ve been very challenging to develop drugs for.

 Just this year there’s been three drugs approved for Alzheimer’s. Before that we’ve really had nothing. Some of the older drugs we use to treat Alzheimer’s, were not much better than a placebo, to be honest, when we look at the data. It’s been a real challenge to develop effective drugs and what we’ve discovered is the importance of inflammation in the brain. Not just neurodegenerative diseases like Alzheimer’s and Parkinson’s, but even other diseases in the brain where we’re just scratching the surface in our knowledge of what drives things like bipolar depression, autism, things causing severe mental health problems in the country and around the world. We’re starting to realize that there’s an inflammatory component to these diseases.

When we look at people with severe depression and we measure inflammation in their brain, it’s much higher than it is in people that don’t have depression. A potential strategy to try to treat depression in a different way than we’ve ever tried before is to target the inflammatory component. Some of those things are new discoveries. No one has even attempted to try this in the clinic. But, we’re going to see some new drugs into the clinic in the next few years that have the potential to address some of the big challenges that we face right now in the central nervous system and neurological diseases where we’ve had really no good answers before this.

If you ask me what I’m looking for in the future, those are things all of us are concerned about. There’s not a person in the country who hasn’t had a connection to one of those types of disorders and diseases. Making breakthrough medicines is something I’m very excited about.

Todd Kays: Hearing about all your developments and looking into it, you’re offering a lot of hope for patients. What do you hope to achieve with Halia Therapeutics in the future? How do you see the company’s role in improving patient outcomes for inflammatory disorders and neurological diseases?

David Bearss: This new mechanism we’ve discovered, at least in the laboratory, seems to have application in many different diseases. What we’re trying to do as a company is come up with strategies that allow us to deliver drugs in different ways [00:15:00] to address these disorders all over the body. For example, we’ve discovered we can deliver a drug topically with eyedrops in the eye to target ocular inflammation. We have a program to look at inflammatory diseases in the eye. We have a transdermal patch that we’ve developed, where we can deliver locally through the skin in a way to target things like inflammatory pain.

It’s something we all experience. Certainly, people with disorders like osteoarthritis. Even after recovery from surgical pain. Most of that pain we’ve experienced is associated with inflammation. If we can direct that locally to the place where we’re having the problem, that’s pretty exciting.

What we’re trying to do is to see the discovery that we’ve made, the mechanism that we’re trying to target, the way that we target the NLRP3 inflammasome as a platform as opposed to a single opportunity. If we can target this mechanism in the skin, how would we do it? How would we do it in the eye? In the brain? In the joints? 

We’re trying to come up with different ways to target different locations in the body. Obviously, our lead program is an oral pill that systemically goes a lot of places. That’s going to be an important part of Halia moving forward. We’ve got a platform we can build off of and target this mechanism using different delivery approaches and be able to come up with not just a single medicine, but many medicines that can target a lot of different human diseases. 

As a company, we’ve been trying to figure out strategically, what’s the best first thing to do? What do we do after that? How do we build out that platform? We’re building the foundation, how do we build the pieces after that, and put those together? That’s been my job. How do we put all that together? How do we time it in the right way? I don’t know if I have all the answers, but we’re very excited about the opportunities that we have in front of us.

Todd Kays: David, it’s been a pleasure speaking with you. Everybody should be excited about the research and development that’s going on at Halia. There’s a lot of promise for a lot of disorders potentially impacting a lot of patients. As I said, particularly my family, as I get old, I can definitely identify with the inflammatory diseases of the joints, and all of that. I appreciate your time with us and, look forward to following Halia as you move forward.

David Bearss: Thank you so much, Todd. It was great talking to you.