Pushing Boundaries to Revolutionize Chronic Inflammation Therapy

During BIO International Convention 2024, CEO Dave Bearss, PhD, of Halia Therapeutics, discussed the biopharmaceutical company’s progress in inflammation drug discovery. Founded in 2017, Halia Therapeutics supports the discovery and development of novel therapies to improve the lives of patients with inflammatory disorders and neurological diseases.

Bearss discussed the clinical pipeline, upcoming announcements, and study readouts that others in the industry should look forward to, and personal thoughts regarding the industry’s focus on caring for patients with, or at risk for, chronic inflammatory diseases and neurodegeneration.

PharmTech: What is the current state of myelodysplastic syndromes (MDS) and inflammatory pain? What are your expectations, looking into the future clinical pipeline?

Bearss: It's been a busy year and an even busier summer. We’ve got a ton of good things going on. We have fully enrolled our post-procedural information study, meaning the evaluation of inflammatory pain after surgery. We are going to report the results of that study very soon. This is a randomized, placebo-controlled, blinded study. It will be the very first NLRP3 targeted drug to have randomized Phase II data reported out, so we are excited about this. We're excited to see what that data looks like. We are optimistic that there’s a positive signal there.

We started with a focus on MDS because we know the NLRP3-related inflammatory pathway is the driver of that disease and here we can sample the affected tissue. It's hard to do that in the brain, lung, liver, or heart. You can't. However, we can take bone marrow pretty easily and watch what happens from baseline. The reason why we started here is because we can read out results quickly and show that the drug is affecting biology in the way we expect.

We provided an update at EHA, the European Hematology Congress (2024). We've treated 16 people so far in that study, and we have 26 people in screening right now. And so, the study has really picked up. There are 40 patients total, planned to be in the study. We hope to have them all enrolled this year (2024).

After four months of therapy, we want to look at hematologic improvement, marrow improvement, and quality of life. One of the challenges associated with MDS is that patients feel terrible all the time. In addition to being terribly anemic, they have active inflammation throughout their body, in their marrow. Because of this, they have cytokines constantly being pumped out.

Having the capabilities to lower these, we should be able to make people feel better. So, we're very encouraged. I’d like to add that this is an open label study, so we can watch what's happening. So far, the longest patient on the study has been on it for six months. We started the Phase 2 study in December, so we're just analyzing the marrow from the first few individuals right now. This summer, we’ll have several more. We are hoping to get good objective responses.

For this specific indication a few drugs have been approved more recently, but they haven't really made an impact on the disease. We hope that we will be able to share something with the potential to modify the history of the disease and put people in a different place. We continue to generate data in the lab ourselves, and with collaborators that suggest that this pathway is the driver for these bone marrow failure disorders and anemia, more broadly.

People don't realize how common anemia is. A lot of people walk around anemic and don’t realize that they are. In fact, most of anemia is not because they're iron deficient. Our body is efficient at absorbing and recycling iron. Most anemia is the result of inflammation.

Anemia of chronic disease, or anemia of chronic inflammation is a very common condition that is difficult to treat. Patients just learn to cope and live with the condition. The condition is associated with patient age, because we all have more chronic inflammation as we get older. In fact, the condition is very common. Almost one-quarter of the world's population has anemia. Some of that is transient, but a lot of it is chronic and impacts patients for a long time.

In addition, there’s a phenomenon called clonal hematopoiesis that no one ever speaks about and is not well understood. When we're young, our blood is produced by lots of different stem cells and clones in our body. As we age, a single clone actually starts to produce most of our blood. There are sensitive techniques available to help analyze this.

As we get older, our hematopoiesis shifts and that shift is driven by inflammation. Inflammation in the bone marrow can prevent the differentiation of normal hematopoietic stem cells. Those precursor cells there give rise to myeloid and erythroid cells, and platelets that come from a progenitor cell in the bone marrow. When you have inflammatory signaling in the marrow, it can block that differentiation.

I tell people the marrow is the hardest working tissue in our body. We have billions of blood cells. Our tissue is working like crazy. We have to have blood. Your body will find a way to fix whatever needs to be fixed. This is done by selecting mutations to overcome suppression.

Obviously, having mutant blood cells doesn't sound like a positive thing, and it's not. And as patients age, mutations can accumulate in your marrow. They don’t necessarily lead to cancer, although they can. But they can increase the risk for the development of other diseases. If there are mutations found in a person’s white blood cells that were derived or were selected to overcome inflammation, those white blood cells are not normal anymore.

PharmTech: What clinical data readouts can we expect over the course of the next 12 to 18 months?

Bearss: We’ll have the formal readout on the post-surgical information study by the end of this summer (2024). We’ll publish and present that data. That will be the first placebo-controlled randomized study for our program.

The MDS trial is actually a two-stage design. The initial stage will be analyzed this summer. The trigger to initiate an expansion study will be dependent upon seeing a certain level of responses in the first stage. We'll have that readout this summer as well.

We also have some other exciting data in other areas that we'll be releasing this summer. We have already publicly stated, but we'll announce the first patient treated on a new program that targets Alzheimer disease (AD). We're approaching AD very differently, and we are looking at high-risk populations—people who are APOE4 positive. APOE4 has been well established. It’s not a rare marker. In fact, 20-30% of the population has at least one APOE4 mutation or allele, and 2-3% of the population has two. Patients who are double positive have more than a 90% risk of developing AD.

And our entire company, Halia Therapeutics, was founded on a genetic observation. We discovered a way to protect people who have APOE4 from developing AD. Through a human genetics study, we found another mutation that protects against this risk. And so, we have a clinical program, following up on that observation, that we’ll announce results on next month.

We've got a rapid development strategy for that in APOE4-positive patients who are pre symptomatic, so we're going to try to prevent AD, which is cool. Waiting and then trying to treat late-stage AD is a bad idea, right? You can't unscramble scrambled eggs. Once you have too much neurodegeneration, it’s hard to come back from that. A lot of great work has been done getting imaging endpoints and biomarker strategies validated and even FDA approved, and we believe we can leverage those tools to look at high risk populations and show they have changes pre-symptomatically, before they have cognitive effects. We already know their brain chemistry is starting to change.

So, we're looking at people over age 50 who are double positive APOE4 and already shows signs of being on the on the path to AD, and are exploring the potential to take them off this path to AD. The human genetic experience says that we should be able to do this. There is another mutation that we found in a protein, RAB10. If we can inhibit RAB10 function, we can block the progression of AD down that pathway, specifically in people who are APOE4 positive. We’re very excited about this.

We are always looking for new, non-invasive ways to monitor symptoms of disease and to objectively track things. One of the big challenges in studying CNS disorders is a lot of the data is subjective. We’ve been looking to see if there are more objective ways to do this. In fact, we have a partner, Canary Speech, in Utah who has been developing specific vocal biomarkers, or speech biomarkers. It turns out that how we talk is indicative of a lot of things that are happening physiologically, especially things in our brain. We can measure things such as how much pain somebody's in. You can talk to physicians who, based on clinical experience, can pinpoint whether a patient is faking their symptoms based on certain cues.

With help from Canary Speech, we’ve been training algorithms using speech biomarkers. In a 30 second recording, we can pick up over 2500 biomarkers that are reproducible and can distinguish between different disorders. We can assess for cognitive decline, depression, anxiety, etcetera. Maybe we can apply these to pre symptomatic patients and identify issues earlier than normal cognitive tests would detect symptoms.

When we consider the future and shifts toward digital capabilities like telemedicine, it’s been challenging. Physicians haven’t had the tools to help manage patients appropriately via a virtual call. But if you could put patients into a virtual waiting room and have them speak to an algorithm and then look at the data to assess pain levels, anxiety levels, etcetera, now physicians have something they can work with. So, we think there’s a future there. We are trying to get better at giving people tools to be able to monitor this stuff. And especially for things related to the brain, I think this all makes perfect sense.

PharmTech: What about preventive interventions?

Bearss: Even though the field has had a couple of approvals in the AD space, I don’t believe anyone thinks those are game changers, in terms of altering cognitive decline. I think everybody accepts the notion that we must get out in front of these diseases and determine how to prevent them. I’ve been reading statistics and we’re an aging population. Our birth rate has been declining for decades but the population is living longer.

We have made some advances to help prolong life, but the problem with life prolongation is corresponding chronic conditions. I just read a statistic that if you add just one year of general health to the entire world's population, it is worth trillions of dollars to the economy. This is something we should all be thinking more about.

We all joke that nutrition and regular exercise is the answer to everything. In reality, there is a role, especially for patients with genetic predispositions or those who are predisposed to metabolic disorders or neurological disorders, to supplement healthy habits with interventions, and early. This has already been demonstrated. Statin therapy is probably one of the most successful examples.

In regards to statin therapy, we had a biomarker that we could measure early, we had a drug that we could tie to that, and we've made an impact. It’s one of the reasons why we're living longer, right? The drug can be taken at a pretty low dose and has very few adverse effects. Right now, GLP-1 inhibitors are a perfect example. Everyone is excited about the potential for weight loss, but the long-term effects are exciting. It's not just weight loss. You're restoring a metabolic defect. We spoke earlier about the immune system.

The immune system is actually very sensitive to the environment that those immune cells find themselves in and the nutrients they have available to them. The oncology world has been excited about taking the break off the immune system, but the gas of the immune system is the nutrients. If there are too many or too few, the way the immune system responds to certain signals is altered.

Metabolic syndrome certainly affects what our immune system does. We're starting to see, already, some of the long-term benefits of these GLP-1 drugs aren't necessarily tied directly to weight loss but, instead, are tied to the restoration of metabolic function and can normalize the immune system. Even for Parkinson disease, a recent readout highlighted that GLP-1 drugs have demonstrated alleviation of symptoms. That's a game changer. We’re looking forward to releasing some data on targeting inflammation and using GLP-1.

PharmTech: What does the future hold for Halia Therapeutics?

Bearss: It’s very interesting. Right now, pharma is changing. We, as a field, are considering swinging the pendulum back, the other direction, to focus on some of the big problems we are facing, instead of only focusing on niche issues. At the start of my career, when statin therapy first began making an impact, stakeholders in the industry were very excited about the “big problems.”

And then, the focus shifted to personalized medicine and isolation of small, more specific patient populations. Obviously, we've made progress and great advances, but I really like where we're headed. Let’s look at big stuff again and go after the big problems.