Don Tracy, Associate Editor

Early-stage trial results indicate that NLRP3 inflammasome inhibitors were able to achieve nearly the same weight loss as Wegovy while also reducing inflammatory biomarkers linked to heart disease.

Results from an early-stage study found that a novel therapy for Parkinson disease produced nearly the same weight loss effect as the blockbuster GLP-1 receptor agonist Wegovy (semaglutide), while also lowering inflammatory biomarkers associated with heart disease.

In a study published by The Journal of Pharmacology and Experimental Therapeutics, researchers for NodThera, a clinical-stage biotech developing brain-penetrant NLRP3 inhibitors to treat chronic inflammatory diseases, aimed to discover the efficacy of the investigational NLRP3 inflammasome inhibitors NT-0249 and NT-0796 in reversing obesity-related complications. They focused on systemic inflammation and astrogliosis in the hypothalamus. To find a sufficient answer, the study relied on diet-induced obesity (DIO) mouse models treated with NT-0249 and NT-0796 to assess their impact on obesity reversal.

“The NLRP3 inflammasome is a highly validated anti-inflammatory drug target, and these findings demonstrate that NLRP3 plays a key role in controlling obesity and obesity-associated inflammation through the modulation of hypothalamic gliosis,” NodThera stated in a company press release. “Both NT-0796 and NT-0249, two structurally distinct NLRP3 inhibitors in clinical development by NodThera, have generated a wealth of preclinical and clinical data demonstrating brain-penetration and broad anti-inflammatory effects, with NT-0796 being the first NLRP3 inhibitor to show reduced neuroinflammation in the clinic.”

According to the study, both NT-0249 and NT-0796 demonstrated efficacy in reducing FAP immunoreactivity in the arcuate (ARC) and dorsomedial (DMH) hypothalamic regions, representing a reduction in astrogliosis associated with obesity. Additionally, NT-0796 exhibited higher tissue penetration compared to NT-0249, which the authors said could contribute to its superior efficacy. Furthermore, the compounds reportedly free fraction concentrations above their respective IC50 values in plasma and brain tissue, supporting their target engagement as a result.

Further, the study demonstrated significant ability with NT-0796 and NT-0249 in reversing DIO in a murine model, allowing for a comparison with the effects of Wegovy plus calorie restriction. Researchers noted that the three therapeutic approaches produced statistically significant body fat drops in DIO mice; however, the NLRP3 inhibitors lowered disease-relevant cardiovascular inflammatory biomarkers, which indicates the potential to reduce the risk of cardiovascular disease in those with obesity.

Further, NLRP3 inhibitors may help protect against weight regain associated with some GLP-1s after patients stop taking the drugs. NodThera stated that unpublished preclinical data show an additive weight loss effect with NLRP3 inhibitors combined with low-dose GLP-1 receptor agonists, along with a more durable response after stopping GLP-1 therapy via dosing of the NLPR3 inhibitor, which prevented body mass regain.

“These remarkable findings—the first in the field of NLRP3 inflammasome research—suggest that in obese mice consuming a high-fat diet, brain-penetrant NLRP3 inhibition and the resulting anti-inflammatory effect confers not only reversal of obesity but metabolic benefits that extend well beyond this,” said Alan Watt, CEO, NodThera, in the press release. “While GLP-1 receptor agonists have undoubtedly delivered significant achievements in the management of obesity, their adverse event profile is well established, presenting difficulties for some patients. Our brain penetrant NLRP3 inhibitors deliver robust weight loss and broad cardiometabolic benefits by targeting a novel molecular mechanism with the convenience of oral dosing and an exceptional safety profile. Our ongoing Phase IIa study in obese individuals at cardiovascular risk will further validate these pre-clinical findings.”

The researchers stated that the findings provide an encouraging pathway for developing novel therapeutic strategies targeting the NLRP3 inflammasome to address obesity and related metabolic disorders. They further suggest that understanding the role of NLRP3 in obesity-related astrogliosis has the potential to enhance the development of targeted interventions aimed at modifying neuroinflammation and metabolic dysfunction. They also stressed the importance of continued investigation of the central nervous system's involvement in obesity pathophysiology and the potential of NLRP3 inhibitors in reversing obesity-related complications.

“Obesity is a major public health issue, having tripled worldwide since 1975 and with the World Health Organization now declaring that at least 60% of Europeans are either obese or overweight,” the authors wrote. “Recent success in the field of obesity treatment has come with incretin mimetic drugs, although their adverse event profile is now established. Consequently, alternative or complimentary therapeutic strategies may be required.”