The Future Of Inflammation: The Inflammasome And Beyond

November 14, 2024

In this article, In Vivo, highlights companies that are transforming the landscape of chronic inflammatory disease treatment, including Utah-based Halia Therapeutics. Halia is in the race to treat neurological diseases, obesity, and more via the inflammasome. Halia Therapeutics has been working in the field since it was founded in 2017 by Brigham and Women’s researcher John Kauwe.

Anti-inflammatory drugs have come a long way since the advent of corticosteroids. While they marked a pivotal moment in the 20th century for managing devastating inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) and, more recently, targeted biologics have transformed the landscape of chronic inflammatory disease treatment.

Now, novel strategies that go beyond suppressing inflammatory symptoms or targeting specific cytokines are being developed. Researchers are targeting upstream pathways, such as the NLRP3 inflammasome. And the next frontier in anti-inflammatory treatment holds promise not only for conventionally considered inflammatory conditions but for everything from neurodegenerative diseases to cardiovascular health and metabolic disorders.

Targeting the NLRP3 Inflammasome

With locations in the US and UK, NodThera is one of several companies targeting the inflammasome, a complex of proteins within immune cells that detects harmful substances and initiates an inflammatory response. Backed by prominent investors like Sofinnova Partners and Novo Holdings, the company is focusing on the NLR family pyrin domain containing 3 (NLRP3) inflammasome specifically. Other well-studied inflammasomes include the NLRP1, NLRP4, AIM2 and pyrin inflammasomes.

The NLRP3 inflammasome is primarily expressed in macrophages and plays a key role in detecting cellular damage markers and triggering immune responses, notably by releasing cytokines like IL-1beta and IL-18. This inflammasome is increasingly being implicated in disorders like Parkinson’s disease and Alzheimer’s disease and brain-penetrant oral small molecule NLRP3 inhibitors are being tested for these indications, see below.

Champions of inflammasome-targeting therapeutics will note that current IL-targeting biologics leave room for improvement. Not only do they fail to treat some patients, but they also increase the risk of infection. NLRP3 inhibitors, in contrast, target sites of chronic inflammation while allowing acute inflammatory responses to infection.

Hard To Drug At First

NodThera president and chief scientific officer Alan Watt told In Vivo that he had tried and failed to develop NLRP3-inhibiting oral small molecules during his time at GSK in 2008. It was not until 2016 that a seminal publication identified a Pfizer compound called CP456773 (MCC950), which was designed to modulate IL-1beta, and subsequently found to be a selective NLRP3 inhibitor. Shortly after, several inflammasome-focused companies emerged from the academic group that published those findings.

“There is now enough evidence that these NLRP3 molecules are potent anti-inflammatories,” Watt said.

Targeting Obesity And Cardiovascular Disease

NodThera’s long-term aim is to treat neurodegenerative illnesses, such as Parkinson’s disease, but Watt said, “in the short term, we’re looking at obesity and cardiovascular disease, which is where we see the most prevalence of NLRP3 activation.”

“There is a switch in the thinking about obesity as being a peripheral disease of the adipose tissue to actually being a central disease of the brain,” he explained.

That school of thought postulates that excess caloric intake – in particular, foods high in saturated fatty acids –trigger the NLRP3 inflammasome and cause inflammation in the hypothalamus, consequently dysregulating hormonal signaling and leading to loss of appetite control.

“There is a switch in the thinking about obesity as being a peripheral disease of the adipose tissue to actually being a central disease of the brain”

Alan Watt, NodThera

The company has generated preclinical data supporting this anti-inflammatory approach in mice, showing its lead molecule, a brain penetrant NLPR3 inhibitor, NT-0796, can match the weight loss of semaglutide in obese mice.

The company is also studying whether the agent can reduce cardiovascular risk. There is a growing body of evidence pointing to an inflammatory etiology for cardiovascular disease, but one recent study in the New England Journal of Medicine showed that higher levels of high sensitivity C-reactive protein (HS-CRP) – a serum marker of inflammation – is more predictive of cardiovascular risk than low-density lipoprotein cholesterol levels and lipoprotein(a).

Data announced in June from Phase I/IIa findings from obese individuals with elevated CRP showed, along with a calorie-reduced diet, NT-0796 led to significant CRP reductions by four weeks in 75% of treatment recipients, compared to 25% of placebo recipients.

“If we can lower CRP, we’re lowering people’s cardiovascular risk moving forward,” said Watt.

In the first half of 2025, the company is planning a Phase II trial of NT-0796 in overweight and obese participants and will measure weight loss at three months, as well as cardiovascular-related secondary endpoints within six months.

Pending financing for this and other studies, there should be “definitive proof of concept by mid-2026,” Watt said.

Watt expects the company will garner funds for these studies, as “inflammation is increasingly seen as the next wave of therapeutics, and it’s going to be the best molecule that wins.”

Unlike GLP-1 agents, which have both an anti-obesity effect but come with treatment-limiting gastrointestinal side effects, the NLRP3 mechanism is “very benign, and unless the inflammasome is activated, the molecules essentially don’t do anything,” said Watt.

An oral NLRP3 inhibitor would cost less to produce and is more convenient than the currently injectable GLP-1 agonists.

“We see huge advantages,” he said.

A slew of other conditions not currently adequately treated or not viewed through the lens of inflammation could potentially be treatable by targeting the inflammasome.

Addressing Neuroinflammation

However, other companies are also in the race to treat inflammation via the inflammasome. Salt Lake City-based Halia Therapeutics has been working in the field since it was founded in 2017 by Brigham and Women’s researchers John Kauwe.

Kauwe had discovered a family, all of whom had the APOE4 genetic mutation, a known risk factor for Alzheimer’s, but none of which developed the illness. Kauwe ultimately found a protective gene mutation in RAB10, but Halia researchers could not drug this target.

“However, what we discovered was that when this RAB10 mutation is present, the phenotypic consequence was that the cell had a hard time organizing the NLRP3 inflammasome,” explained CEO Dave Bearss.

The Halia team turned to LRRK2, a well-known drug target that also activates RAB10 and successfully developed a brain-penetrant LRRK-2 inhibitor, HT-4253, that is now in Phase I research in healthy individuals, to validate target activation of both LRRK-2 and RAB10, and to measure the impact on inflammatory biomarkers.

“As soon as we’re done with that trial, which should be in the second quarter of 2025, we plan to roll into a clinical trial,” Bearss told In Vivo.

In the clinical study, older APOE4-positive patients at high risk of developing Alzheimer’s disease and early signs of Alzheimer’s disease will receive HT-4253.

“That will be a first-of-its-kind clinical trial to use a neuroinflammatory-targeted pathway to intercept early changes in patients with a high genetic risk for Alzheimer’s,” Bearss emphasized.

Like NodThera’s Watt, Bearss stressed the safety of NLRP3-targeting drugs. NLRP3 is “a major player” in chronic inflammatory signaling, but targeting this element of the inflammasome “just takes out a portion of the innate immune response,” Bearss emphasized.

“What’s interesting about NLRP3 is that it clearly has a role in the innate immune response, but it seems to have a larger role in chronic inflammation.”

Dave Bearss, Halia

“What’s interesting about NLRP3 is that it clearly has a role in the innate immune response, but it seems to have a larger role in chronic inflammation,” he said.

Whereas autoimmune diseases used to be understood as conditions where acute inflammatory responses “just never got turned off,” it is now understood that chronic inflammation can be activated independent of acute inflammatory response.

Like NodThera, Halia is studying its treatment in the context of obesity. Bearss explained that adipose tissue from obese individuals where the NLRP3 pathway is turned on is “wildly different” from adipose tissue from lean individuals, in terms of the infiltration of immune cells.

Preclinical data from Halia shows that blocking the NLRP3 inflammasome “can make obese fat look like lean fat in terms of the immune component, and it turns off chronic inflammatory signaling,” he said.

“And what we’ve shown definitively in multiple animal experiments is there are high amounts of synergy by combining an anti-NLRP3 targeted drug with a GLP-1 agonist,” he said.

That means using a normally subtherapeutic dose of semaglutide with Halia’s drug can achieve as much weight loss as using a high dose of semaglutide but avoid the toxicity of therapeutic doses, Bearss said. The company is planning a clinical trial to confirm that effect in humans within several months.

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