Many of the biggest public-health crises of our time, like obesity, diabetes, cardiovascular disease and neurodegenerative disorders, share a common pathology: abnormal activation of the immune system that leads to chronic low-grade inflammation.
NodThera, a US and UK-based biotech, is ushering in a paradigm shift in the treatment of these diseases by developing best-in-class inhibitors of a well-validated but underutilized target, the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome.
NodThera has led the field in building an advanced pipeline of multiple clinical-stage small-molecule NLRP3 inflammasome-inhibitor candidates. NodThera has generated compelling first-in-class clinical data in patients and is accelerating clinical development towards multiple approvals.
The inflammasome: master switch for chronic inflammation
Inflammasomes are innate immune sentries of the cell, keeping a lookout for signs of infection and damage. Discovered over two decades ago, inflammasomes are found in the cell as cytosolic, multiprotein sensor–adaptor–effector complexes that assemble in response to cues including pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs, e.g. cholesterol) and homeostasis-altering molecular processes (HAMPs, e.g. mitochondrial reactive oxygen species).
Canonical inflammasomes comprise three core components. The first is a pattern-recognition receptor (PRR) sensor protein around which the inflammasome nucleates. The second is an adaptor protein called PYCARD, or apoptosis-associated speck-like protein containing a CARD (ASC), which contains a caspase activation and recruitment (CARD) domain. The third is the effector protein pro-caspase-1 that is activated to mature caspase-1; this in turn cleaves precursors of pro-inflammatory cytokines, as well as the pore-forming molecule gasdermin D (GSDMD), which causes membrane depolarization and induces a pro-inflammatory form of cell death called pyroptosis.
Inflammasomes are differentiated from one another by their sensor proteins, the adaptors they recruit and downstream caspase effectors. One family of inflammasomes—from which NodThera takes its name—is defined by the presence of a NOD-like receptor (NLR) sensor component. Depending on which NLR is present, the inflammasomes can be classified as NLRP1, NLRP3 or NLRC4.
NLR inflammasomes nucleate in response to the detection of danger signals carried by PAMPs, DAMPs and HAMPs. The formation of NLR inflammasomes leads to activation of pro-caspase-1, which in turn leads to cleavage of pro-interleukin 1β (pro-IL-1β) and pro-IL-18 into their mature, pro-inflammatory forms.
The NLRP1 inflammasome was the first to be discovered, but NLRP3 is today the most intensively researched and the most validated as a therapeutic target. NodThera’s small-molecule therapeutics target the monomer proteins from which the NLRP3 inflammasome assembles, preventing its formation and thereby muting downstream inflammatory processes. Figure 1 illustrates the pharmacological potential of NLRP3 inhibition in the context of other approved and investigational approaches that modulate cytokine release, driving chronic inflammation.
Fig. 1 | Inhibiting the inflammasome to dampen chronic inflammation. NLRP3 inhibitors block the assembly of the NLRP3 inflammasome, and subsequent expression of proinflammatory cytokines such as interleukin-1β (IL-1β), IL-18 and IL-6. ASC, apoptosis-associated speck-like protein containing a CARD.
Targeted NLRP3 inhibition is not expected to increase the risk of infections. NLRP3 is only one of several inflammasome and non-inflammasome pathways that generate cytokine responses. Infections usually activate these redundant mechanisms, antimicrobial cytokine responses therefore remain intact even if NLRP3 is blocked. Moreover, NLRP3’s primary role is not in host defense, but rather in sensing sterile danger signals; this provides a strong physiological basis for NLRP3 inhibition to have clinical potential to demonstrate lower infection risks than blocking IL-1β or IL-6 directly.
Harnessing NLRP3: from science to best-in-class molecules
NLRP3 emerged as a pivotal therapeutic target from the discoveries that gain-of-function mutations in the protein cause human autoinflammatory diseases, and that danger signals underlying many common inflammatory conditions converge on its activation. Genetic ablation of NLRP3, on the other hand, leads to 30% longer lifespan in mice.
NodThera has spent close to a decade discovering and fine-tuning molecules that can target the right tissue for the right patient group. For example, NodThera has designed a potent and highly selective small-molecule brain-penetrant NLRP3 inhibitor, NT-0796, which can cross the blood–brain barrier (BBB) and become active specifically in immune cells in the central nervous system (CNS)1,2,3.
NodThera scientists have advanced the field of NLRP3 research, including pioneering work demonstrating the potential of NLRP3 inhibition in the treatment of obesity. NT-0796 monotherapy in mouse diet-induced obesity (DIO) models reduced body weight, inflammation and neuroinflammation, and reset multiple endocrine hormones4. In combination with the glucagon-like peptide-1 (GLP-1) receptor antagonist Wegovy (semaglutide), NT-0796 demonstrated additive weight loss, reversing the obese phenotype in mouse DIO models. Furthermore, switching the animals from combination therapy to NT-0796 monotherapy maintained the observed weight loss5.
Compelling clinical data
• Cardiovascular disease. Genetic, epidemiologic and clinical trial data show strong potential for anti-inflammatory mechanisms in preventing cardiovascular events such as myocardial infarction, stroke and cardiovascular death. In a recent clinical trial, NT-0796 showed a reduction of inflammation markers in people at high risk of cardiovascular disease, one of the leading causes of death globally. In this trial, hsCRP reduction with NodThera’s oral agent was comparable to injectable monoclonal antibodies, providing a convenient and rapidly reversible option for patients6.
• Parkinson’s disease. In a recent publication, the NodThera team showed for the first time in Parkinson’s disease patients that NLRP3 activity in the brain can be inhibited, thereby reducing markers of neuroinflammation that have long been associated with disease progression. The consistency and speed of biomarker modulation observed, much of it within seven days, is highly encouraging and opens the door to a fundamentally different, disease-modifying treatment strategy7.
Multiple paths to patients
Compelling preclinical and clinical data lay the foundation for NodThera’s accelerated path to patients. NodThera is pursuing multiple parallel paths to serving patients: people living with cardiovascular disease, obesity, pain and peripheral inflammation, and neurogenerative/neuro-inflammatory diseases (Fig. 2).
Fig. 2 | NodThera’s clinical progress and paths to patients. NodThera is pursuing multiple parallel paths to serving patients, informed by multiple clinical datasets. CNS, central nervous system; CV, cardiovascular; RCT, randomized controlled trial.
In obesity, NodThera’s therapeutic approach is grounded in the role of hypothalamus in regulating energy balance. Neuroinflammation is rapidly activated with nutrient excess leading to the development of neuronal insulin and leptin resistance. NodThera is targeting these inflammatory drivers of obesity in the brain to restore homeostasis, thereby addressing dysregulation of the hypothalamic setpoint, a fundamental pathological feature of people living with obesity. NodThera’s preclinical studies have demonstrated the need for brain exposure to address this central pathology4. NodThera’s small-molecule approach offers a number of advantages. As biologics are large macromolecules, they require administration by injection or infusion and do not cross the BBB. They instead access the brain through the circumventricular organs, leading to discrete activation of specific brain regions only.
NT-0796 is currently in two phase 2 clinical studies for obesity. In its RESolution Of infLammation to treat obesity and cardioVascular disEase (RESOLVE-1) trial, NT-0796 is being studied as a monotherapy, either once or twice daily, for 24 weeks in patients with or without type 2 diabetes who have a body-mass index (BMI) of 30–40 kg/m2. The primary endpoint for RESOLVE-1 is change in body weight. Secondary endpoints include a range of biomarkers of metabolic and inflammatory health.
RESOLVE-2 investigates NT-0796 as a twice-daily therapy in comparison to NT-0796 in combination with semaglutide in patients with obesity. Both studies are on track to deliver top line data in the second quarter (2Q) of 2026. These studies will not only inform clinical development in obesity, but together with recent cardiometabolic data they will also enable multiple paths towards treating patients with cardiovascular disease.
In neurological indications, NodThera has developed differentiated brain-penetrant small-molecule inhibitors. NT-0150, a novel chemotype built around a pyridazinone structure, has shown excellent preclinical efficacy across multiple animal models of inflammatory disease, rapidly and robustly reducing brain and peripheral pro-inflammatory cytokines, as well as other neurological markers. Phase 1 SAD/MAD studies of NT-0150 are in progress.
In pain and peripheral inflammation, NodThera’s final candidate molecule NT-0249 is an NLRP3 inhibitor well positioned based on its pharmacodynamic and pharmacokinetic properties. Preclinical studies have demonstrated excellent activity in inflammatory and neuropathic pain models, while human studies have shown favorable pharmaco-kinetics commensurate with once-daily dosing.
A potent portfolio
NodThera has demonstrated the preclinical and clinical efficacy of targeting the NLRP3 inflammasome as a master switch for quelling the fire of chronic inflammation. With NT-0796 positioned for cardiometabolic disease, NT-0150 for neuro-degeneration, and NT-0249 for inflammatory and neuropathic pain, NodThera stands on the verge of ushering in a new era in the treatment of inflammatory-driven disorders.