NT-0796 / NodThera - LARVOL DELTA

Evaluate the Efficacy and Safety of NT-0796 in Participants With Obesity With or Without Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=162 | Active, not recruiting | Sponsor: NodThera Limited | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

NLRP3 Inhibitor, NT-0796 Reduces MASH in Preclinical Models (OBESITY WEEK 2025) - "Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796...The Farnesoid X receptor agonist, Tropifexor, (0.5 mg, p.o. q.d.) was evaluated alongside... These findings indicate that NLRP3 inhibition with NT-0796 reduces key MASH-associated pathologies, including hepatic steatosis and fibrosis. Targeting hepatic NLRP3 may offer added therapeutic benefit for individuals at risk of MASH. Further translational studies are needed to explore the extent to which these mechanisms(s) may contribute to liver disease in patient cohorts."

Preclinical • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • NLRP3

NodThera Announces First Patients Dosed in RESOLVE-2 Clinical Trial Evaluating Oral NT-0796 in Combination with a GLP-1 Receptor Agonist (The Manila Times) - "Expects to complete the ongoing NT-0796 monotherapy trial (RESOLVE-1) and NT-0796 combination trial with GLP-1 receptor agonist (RESOLVE-2) by 3Q 2026....The trial is expected to enroll approximately 60 people living with obesity, all of whom will receive GLP-1RA, with one half randomized to NT-0796 and the other half to placebo (ClinicalTrials.gov NCT07220629)."

Trial status • Obesity • Type 2 Diabetes Mellitus

Study to Explore the Safety and Efficacy of NT-0796 as an Adjunct to Semaglutide in Participants With Obesity (RESOLVE-2) (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: NodThera Limited

New P2 trial • Genetic Disorders • Obesity

Anti-Neuroinflammatory and Anti-Inflammatory Effects of the NLRP3 Inhibitor NT-0796 in Subjects with Parkinson's Disease. (PubMed, Mov Disord) - "CNS inhibition of NLRP3 with NT-0796 reduced neuroinflammation over a sustained 28-day dosing period and demonstrates the potential for long-term dosing of NT-0796 in future studies of patients with neurodegeneration."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CRP • IL18 • IL1B • IL6 • NLRP3

NodThera Demonstrates Reversal of Neuroinflammation and Inflammation in Parkinson’s Disease with Oral NLRP3 Inhibitor (GlobeNewswire) - "NLRP3 inhibition demonstrated a clear anti-neuroinflammatory effect through reductions of neuroinflammatory biomarkers. In cerebrospinal fluid (CSF), the NLRP3-relevant cytokine IL-1β was reduced along with relevant downstream markers including CSF CCL2, IL-6, IL-8 and CXCL1....Additionally, in subjects with evidence of systemic inflammation at baseline, NT-0796 drove reductions in systemic inflammatory markers including high-sensitivity C-reactive protein, fibrinogen, IL-6 and IL-18....NT-0150, which is optimized for brain penetration and exceptional central nervous system (CNS) exposure, has been prioritized for further development in Parkinson’s disease, with Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies expected to commence in H2 2025, ahead of a planned Phase 2 trial."

New P2 trial • P1 data • Inflammation • Parkinson's Disease

Evaluate the Efficacy and Safety of NT-0796 in Participants With Obesity With or Without Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=162 | Recruiting | Sponsor: NodThera Limited

New P2 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

NodThera Charts Obesity Future with First Patients Dosed in Phase 2 RESOLVE-1 Trial of Oral NLRP3 Inflammasome Inhibitor NT-0796 (GlobeNewswire) - "NodThera...today announces that the first patients have been dosed in its Phase 2 RESOLVE-1 (RESolution Of infLammation to treat obesity and cardioVascular disEase) clinical trial investigating the potential of its lead candidate, oral NLRP3 inflammasome inhibitor NT-0796, in patients with obesity....Headline data from the study are anticipated in Q2 2026....The potential of NT-0796 to improve the efficacy and tolerability of existing GLP-1RA obesity therapies will be further investigated in NodThera’s upcoming Phase 2 combination trial, RESOLVE-2, expected to commence in H2 2025."

New P2 trial • P2 data • Trial status • Obesity

The NLRP3 inhibitor NT-0796 enhances and sustains GLP-1R agonist-mediated weight loss in a murine diet-induced obesity model. (PubMed, Obesity (Silver Spring)) - "Alleviation of obesity-associated inflammation via NLRP3 inhibition 1) constitutes an effective weight-loss strategy as monotherapy in mice with DIO, 2) augments the weight-loss efficacy of a subtherapeutic dose of semaglutide, and 3) blocks recovery of lost weight following cessation of semaglutide."

Journal • Preclinical • Genetic Disorders • Inflammation • Obesity • GFAP • NLRP3

NodThera’s Oral NLRP3 Inhibitor NT-0796 Enhances and Sustains Weight Loss in Combination with GLP-1 (GlobeNewswire) - "These data, published in the research journal Obesity, show that combined dosing of NodThera’s NT-0796 with semaglutide (Wegovy) drove greater weight loss than either monotherapy in an animal model of obesity. Treatment with the fully brain-penetrating NLRP3 inflammasome inhibitor also sharply limited weight regain following the cessation of semaglutide therapy and reduced multiple cardiovascular, inflammatory and metabolic biomarkers....NodThera is currently preparing to initiate a robust Phase 2 obesity study of NT-0796, expected in 2Q 2025."

New P2 trial • Preclinical • Obesity

[WITHDRAWN] A RANDOMIZED, DOUBLE-BLIND (SPONSOR-OPEN), PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFECT OF NT-0796 ON INFLAMMATION IN OBESE PARTICIPANTS AT RISK OF CARDIOVASCULAR DISEASE - Nicholas Clarke (ACC 2025) - No abstract available

Clinical • Cardiovascular • Inflammation • Obesity

Effects of NT-0796 in Obese Participants at Risk of Cardiovascular Disease (clinicaltrials.gov) - P1 | N=67 | Completed | Sponsor: NodThera Limited | Phase classification: P1/2 ➔ P1

Phase classification • Cardiovascular • Inflammation • Obesity • CRP

The ester-containing prodrug NT-0796 enhances delivery of the NLRP3 inflammasome inhibitor NDT-19795 to monocytic cells expressing carboxylesterase-1. (PubMed, Biochem Pharmacol) - "In contrast, when NDT-19795 is applied directly to cells observed cell-associated levels are below those present in the medium and remain stable over time. Dynamics observed within the context of a closed tissue culture system highlight the utility of NT-0796 as a vehicle for delivering the NDT-19795 acid payload to CES1 expressing cells."

Journal • Inflammation • CES1 • NLRP3

Effects of NT-0796 in Obese Participants at Risk of Cardiovascular Disease (clinicaltrials.gov) - P1/2 | N=67 | Completed | Sponsor: NodThera Limited | Recruiting ➔ Completed

Trial completion • Trial completion date • Trial primary completion date • Cardiovascular • Inflammation • Obesity • CRP

NodThera’s NLRP3 Inhibitor NT-0796 Reverses Neuroinflammation in Parkinson’s Disease Phase Ib/IIa Trial (GlobeNewswire) - P1b/2a | N=NA | "NodThera...today announces positive data from its Phase Ib/IIa study in Parkinson’s disease patients....NodThera’s study demonstrated mean reductions of key pro-inflammatory biomarkers in CSF...over 28 days compared to baseline to levels approximating those of healthy elderly controls, demonstrating reversal of NLRP3-mediated neuroinflammation. In addition, reductions in neurodegenerative markers were also observed following oral dosing of NT-0796, including NfL and soluble TREM (sTREM2). In subjects with elevated acute phase biomarkers CRP and fibrinogen, levels were reduced significantly, consistent with the peripheral anti-inflammatory effects of NT-0796 seen in elderly healthy volunteers studied in an earlier stage of the trial."

Biomarker • P1/2 data • CNS Disorders • Parkinson's Disease

NodThera Publishes Preclinical Data Demonstrating Reversal of Obesity and Inflammation with Clinical-stage Brain-penetrant NLRP3 Inflammasome Inhibitors (GlobeNewswire) - "NodThera...today announces the publication of preclinical data demonstrating its clinical-stage investigational compounds reversed diet-induced obesity (DIO) and inflammation in an animal model of disease....In this latest publication, NodThera’s researchers show for the first time the ability of NT-0796 and NT-0249 to reverse DIO in a murine model, providing comparisons against the effects of the GLP-1 receptor agonist (GLP-1RA) semaglutide (Wegovy) and calorie restriction. While all three therapeutic approaches led to statistically significant reductions in body fat in DIO mice, only the NLRP3 inhibitors reduced disease-relevant cardiovascular inflammatory biomarkers such as fibrinogen, sVCAM-1, suPAR, and PCSK9, suggesting their potential to further reduce cardiovascular risk in obese populations."

Preclinical • Metabolic Disorders • Obesity

AN INTERIM ANALYSIS OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF NLRP3 INHIBITOR, NT-0796, IN HEALTHY VOLUNTEERS AND PATIENTS WITH PARKINSON'S DISEASE (ADPD 2024) - "NT-0796's favourable PK, tolerability, and capacity to reduce peripheral cytokines and CSF neuroinflammatory markers, highlights its potential for the treatment of neuroinflammatory diseases."

Clinical • PK/PD data • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CRP • CXCL1 • IL18 • IL1B • NLRP3 • S100B

Reversal of high fat diet-induced obesity, systemic inflammation and astrogliosis by the NLRP3 inflammasome inhibitors NT-0249 and NT-0796. (PubMed, J Pharmacol Exp Ther) - "In addition, a direct comparison of an NLRP3 inhibitor to a GLP-1 receptor agonist, semaglutide (Wegovy®), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response and cerebral gliosis. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator, NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the GLP-1 agonist semaglutide or calorie restriction alone."

Journal • Cardiovascular • Diabetes • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Obesity • Systemic Inflammatory Response Syndrome • FAP • GFAP • NLRP3

Target cell activation of a structurally novel NLRP3 inhibitor NT-0796 enhances potency. (PubMed, J Pharmacol Exp Ther) - "To study pharmacodynamics of NT-0796 in vivo, a mouse line was engineered possessing more human-like traits with respect to carboxylesterase biology. In the context of these hCES-1 mice, NT-0796 serves as a more effective inhibitor of NLRP3 activation than the corresponding acid, highlighting the full translational potential of the ester strategy."

Journal • Inflammation • CES1 • IL1B • NLRP3

Effects of NT-0796 in Obese Participants at Risk of Cardiovascular Disease (clinicaltrials.gov) - P1/2 | N=69 | Recruiting | Sponsor: NodThera Limited

New P1/2 trial • Cardiovascular • Inflammation • Obesity • CRP

Discovery of Clinical Candidate NT-0796, a Brain-Penetrant and Highly Potent NLRP3 Inflammasome Inhibitor for Neuroinflammatory Disorders. (PubMed, J Med Chem) - "We designed a series of ester-substituted carbamate compounds as selective NLRP3 inflammasome inhibitors, leading to NT-0796, an isopropyl ester that undergoes intracellular conversion to NDT-19795, the carboxylic acid active species. NT-0796 was shown to be a potent and selective NLRP3 inflammasome inhibitor with demonstrated in vivo brain penetration."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Movement Disorders • Multiple Sclerosis • Parkinson's Disease • NLRP3

NodThera announces positive first-in-human data for two brain penetrant NLRP3 inflammasome inhibitors (GlobeNewswire) - P1 | N=NA | "NodThera...today announces positive data from first-in-human studies of its lead therapeutic candidates, NT-0249 and NT-0796, and provides an update on the Company’s priority clinical development programme. In the studies, both candidates were shown to clearly inhibit the NLRP3 inflammasome, a highly validated drug target that plays a pivotal role in controlling inflammatory diseases. The differentiated design characteristics of each candidate enabled them to penetrate different areas of the brain for optimal drug distribution in a range of NLRP3-driven diseases....Data from the recently completed multiple-ascending dose (MAD) cohorts of NT-0249’s first-in-human study confirm a potentially best-in-class pharmacokinetic/ pharmacodynamic (PK/PD) profile, suitable for once-daily dosing. NT-0249 demonstrated significant anti-inflammatory effects in healthy volunteers, with reductions in key inflammatory biomarkers, C-reactive protein (CRP) and fibrinogen..."

P1 data • CNS Disorders • Immunology • Inflammation • Parkinson's Disease