Waging war on chronic inflammation

Halia Therapeutics CEO on moving into multiple Phase 2 trials for chronic inflammation and whether the company may have created a ‘longevity drug.’

Fresh from announcing positive Phase 1 trial results for its inflammation-targeting drug candidate, Utah-based biotech Halia Therapeutics is now pursuing Phase 2 studies in a range of indications. The Salt Lake City company’s lead compound is an inhibitor of the NLRP3 inflammasome, a known driver of systemic chronic inflammation, which is linked to conditions including fibrotic disease, Alzheimer’s, Parkinson’s and many others.

Halia is taking a unique approach to the NLRP3 inflammasome by targeting the protein NEK7, which plays a key role in gene’s activity. In preclinical models, the company has shown its approach disrupts the formation of the NLRP3 inflammasome and promotes its disassembly once activated, reducing the overall inflammatory response. In its recent Phase 1 trial, in addition to showing positive safety and tolerability data, Halia’s drug demonstrated positive effects in blood samples taken from healthy volunteers, showing “over 90% suppression of multiple NLRP3-mediated cytokines and chemokines.”

Waging war on chronic inflammation
Halia’s lead drug candidate, HT-6184, is a highly selective and orally bioavailable NLRP3 inhibitor.

Longevity.Technology: Chronic inflammation is a frequent topic of discussion in longevity circles. The term “inflammaging” refers to the increase of inflammatory cytokines in our bodies as we age, which is linked to chronic morbidity, disability, frailty and premature death. While there is no doubt that Halia believes that its approach can potentially impact many diseases, does the company have aging itself in its sights? We caught up with CEO Dr David Bearss to find out.

Interestingly, the core scientific breakthrough on which Halia was founded is very much rooted in longevity science. Earlier in his career, the company’s scientific co-founder, renowned geneticist Dr John “Keoni” Kauwe, was involved in research at Washington University linking the APOE4 gene with increased risk of Alzheimer’s disease. APOE4 hit the headlines in 2022 when the actor Chris Hemsworth learned he had two copies of the gene.

“Keoni moved from WashU back to Utah, which is a great place to study human genetics, because public health records are merged with the genealogical records of the LDS Church,” says Bearss. “We can ask questions here that you can’t do in other places, like finding families that have Alzheimer’s in every generation, for example.”

Protection against inflammation

While looking for data on families at high risk for Alzheimer’s, Kauwe was surprised to find a family that had the APOE4 gene, but no one in that family appeared to get the disease. This led him to explore if there was something else in their genetics that was protecting them from developing Alzheimer’s and he discovered that they all had a polymorphism in a gene called RAB10.

“We started the company to see if we could somehow target that pathway to treat Alzheimer’s,” says Bearss. “We initially thought we might be targeting the mechanism of depositing beta-amyloid in the brain as we age, but our big discovery was that stem cells created from people with this polymorphism were resistant to inflammation, thanks to its effect on this big protein complex called the NRLP3 inflammasome.”

Waging war on chronic inflammation
Halia is headquartered in Salt Lake City, Utah.

Excited by this discovery, Halia refocused its efforts on therapeutics designed to target the assembly and activation of the inflammasome.

“As we get older, we have more and more propensity to develop chronic inflammatory diseases and disorders, and NLRP3 plays an important role in chronic inflammation,” says Bearss. “So that’s really been the focus of the company – we have gone on to develop a drug that works through a unique mechanism of action to block the assembly and promote the disassembly of the inflammasome.”

“We’ve tested it in every model of inflammation that we could think of – it works in the brain, it works in the heart, it works in the lungs, the liver, and the gut. It seems to be a general mechanism that is a driver in many chronic inflammatory disorders.”

Multiple shots on goal

This broad applicability is why Halia isn’t putting all its eggs in one, or even two, baskets when it comes to the next phase of clinical development. The company has already dosed first patients in a Phase 2 trial for treatment of myelodysplastic syndromes, with subsequent trials expected to begin imminently in arthritis and chronic inflammatory pain.

“We feel confident that we have solid data that tells us the drug does what we think it does in terms of targeting the NRLP3 pathway, so now we’re excited to see what it does in patients with real diseases,” says Bearss.

The company’s trial in myelodysplastic syndrome is interesting from a longevity standpoint. The condition is essentially a disruption of normal bone marrow function, typically affecting people aged 65 and older.

“What we can see is that that the NRLP3 pathway is very active in the bone marrow from those individuals,” says Bearss. “If we look at young, healthy donors, their bone marrow doesn’t have those pathways activated, so we think this is an interesting place for us to show the mechanism of our drug and that we can target this pathway.”

Implications for aging

While relatively rare, myelodysplastic syndrome is linked to clonal hematopoiesis, a common age-related condition, which can lead to increased risk of certain blood-related disorders, such as leukemia or cardiovascular diseases.

“With this study, we hope to show we can target inflammation in the bone marrow of individuals that have myelodysplastic syndrome and relieve the inflammatory signalling and restore the normal function of differentiation of these stem cells,” says Bearss. “If we can do that, then potentially we can break clonal hematopoiesis, and the implications of that could be huge.”

A positive result in the myelodysplastic syndrome could ultimately lead to an opportunity to have a real impact on aging and what happens to our bone marrow as we age.

“If we can reverse it, what impact does that have on keeping our marrow younger and healthier, and can that extend the healthspan of individuals?” asks Bearss. “This is first step on the way down that path, so we’re excited to see what happens. The cool thing is, we can measure most of the effects in the blood, so we should have a signal pretty fast. We hope that, in the first 20 patients treated, we can say that it seems to be working.”

A potential longevity drug?

With so many potential indications and positive preclinical results in inflammation across multiple biological systems, does Bearss feel that Halia may actually have a “longevity drug” under development? 

“It’s been interesting to watch the explosion in GLP-1 agonists and how that impacts all kinds of things,” he says. “It’s always been fascinating to me that things like periodontal disease, chronic inflammation in your mouth, can actually affect your health across your whole body. It’s interesting how one thing being wrong can have this this wide-ranging systemic effect, so we’re excited to try and pull out all that information and then try to connect the dots.”

Bearss thinks it’s “possible” that Halia’s approach could one day be used to reset the NRLP3 pathway on a on a regular basis as we age.

“There are markers that we’re starting to develop that you can measure in the blood, so you can start to envision the kind of stuff could happen,” he says. “Let’s say you get a physical, you get your blood drawn with a few more markers in that blood panel and you see your inflammation seems to be going up. Well, let’s put you on a course of this for a little while and see if we can move that down… I’d sign up for that!”