NodThera has published preclinical data in the journal Obesity demonstrating that its oral NLRP3 inflammasome inhibitor NT-0796 significantly enhances weight loss when combined with semaglutide and prevents weight regain following GLP-1 therapy discontinuation. The findings position NT-0796 as a potential solution to key limitations of current obesity treatments.
Combination Therapy Delivers Superior Weight Loss
In a high-fat diet murine obesity model, the combination of NT-0796 and semaglutide achieved weight loss of 23% over 28 days, nearly two-fold higher than semaglutide monotherapy. When animals were switched to a polyunsaturated fatty acid diet intended to reflect typical human dietary patterns, the combination therapy drove continued weight loss exceeding 30%, completely reversing the obese state to weights comparable to control animals fed a standard diet.
The brain-penetrating NLRP3 inflammasome inhibitor also reversed hypothalamic inflammation in animals maintained on combination therapy, supporting the role of central inflammation in obesity pathogenesis.
Sustained Weight Management Post-GLP-1 Treatment
A critical finding was NT-0796's ability to prevent weight regain following semaglutide cessation. Animals switched to NT-0796 monotherapy after treatment with either semaglutide alone or the combination therapy showed highly reduced weight regain compared to animals who stopped all treatment.
DEXA scan analysis revealed that combination therapy increased fat mass loss while preserving lean mass. Although calorie intake was further reduced in combination therapy animals, the degree of fat mass loss observed suggests additional mechanisms such as enhanced energy expenditure may contribute to the therapeutic effect.
Addressing Current Treatment Limitations
Daniel Swisher, Chief Executive Officer of NodThera, stated: "These data further reinforce our belief in the potential of our brain-targeting NLRP3 inflammasome inhibitor to deliver a step change in the management of obesity. While the efficacy of existing treatments is not in doubt, there are many limitations and challenges to their real-world use by patients."
The company positions NT-0796 as addressing key challenges with current GLP-1 receptor agonist therapies, including tolerability issues and weight regain following treatment discontinuation. The oral formulation offers potential advantages over injectable GLP-1 therapies by eliminating titration complexities.
Mechanism of Action and Clinical Development
Alan Watt, President and Chief Scientific Officer of NodThera, explained: "By harnessing both peripheral and central NLRP3 inhibition to correct multiple dysregulated pathways in the brain and throughout the body we have the potential to bring profound cardiometabolic benefits to patients, establishing an enhanced treatment approach to weight management that would enable sustained and healthier weight loss."
The research supports NodThera's approach of targeting chronic inflammation's role in weight regulation through selective NLRP3 inflammasome modulation. The fully brain-penetrating inhibitor reduced multiple cardiovascular, inflammatory and metabolic biomarkers in the preclinical studies.
NodThera is preparing to initiate a Phase 2 obesity study of NT-0796 in the second quarter of 2025, with trial design details to be communicated upon dosing initiation. The clinical-stage biotech company develops brain-penetrant NLRP3 inflammasome inhibitors for chronic inflammatory diseases and is backed by investors including 5AM Ventures, Blue Owl Capital, Novo Holdings, and Sanofi Ventures.
