NodThera, a biotech company based in Cambridge, England, is developing a new class of medicines that inhibit the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome to treat diseases driven by chronic inflammation. Research in mice suggests that the company’s drug candidates, originally aimed at Parkinson’s disease, have promise as therapies for obesity and cardiovascular disease, challenging the efficacy of the popular drug semaglutide.
NLRP3 Inflammasome Inhibition
The NLRP3 inflammasome, a component of the innate immune system, plays a role in producing proinflammatory cytokines. Cardiovascular disease, diabetes, non-alcoholic hepatosteatosis, as well as neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, have been linked to NLRP3 inflammasome activation. In mice, a high-fat diet increases NLRP3, and a calorie-restricted diet has the opposite effect. Researchers have suggested that the presence of saturated fatty acids in the cerebrospinal fluid activates the NLRP3 inflammasome via cells in the hypothalamus. This brain region is involved in regulating calorie consumption and output. NodThera’s drug candidates, NT-0796 and NT-0249, work by inhibiting the NLRP3 inflammasome.
A Novel Approach to Combat Obesity and Heart Disease
In study results published in the Journal of Pharmacology and Experimental Therapeutics, NT-0796 and NT-0249 show potential beyond their initial target. Alan Watt, NodThera’s CEO, highlighted the significance of the findings in a press release, stating, “These remarkable findings … 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.”
The study results show that NT-0796 facilitated a 19% weight loss in obese mice over 28 days, closely approaching the 21.5% reduction observed in mice receiving the GLP-1 receptor agonist semaglutide. Meanwhile, NT-0249 significantly reduced markers of cardiovascular inflammation, though it was less effective in weight reduction (6.8% decrease in body weight). Non-obese mice that received either drug candidate lost minimal weight, pointing to the drug’s specificity.
Cardiovascular Inflammation and Weight: A Dual Focus
Beyond their effects on body weight, the NodThera drug candidates also affected cardiovascular markers. Mice that received NT-0249 had lower circulating levels of fibrinogen, vascular cellular adhesion molecule-1 (VCAM-1) and soluble urokinase plasminogen activator receptor (suPAR), biomarkers associated with cardiovascular inflammation.
In addition, compared to those treated with NT-0249 or semaglutide, mice that received NT-0796 had lower levels of proprotein convertase subtilisin kexin 9 (PCSK9), a liver enzyme associated with higher amounts of low-density cholesterol.
Next Steps
NT-0796 is moving into Phase Ib/IIa clinical trials to assess its effects on cardiometabolic biomarkers in obese participants with risk factors for cardiovascular disease. Participants will receive twice-daily oral doses. A separate Phase I/II study is evaluating daily doses of the drug for Parkinson’s disease.
NodThera suggested in their press release that NLRP3 inhibitors could be a viable option for patients who are unable to tolerate GLP-1 receptor agonists. Furthermore, the company mentioned as-yet unpublished preclinical data that “have demonstrated an additive weight loss effect when combining the brain-penetrant NLRP3 inhibitors with low dose GLP-1RAs, and stable weight maintenance following cessation of GLP-1RA therapy by dosing of a brain penetrant NLPR3 inhibitor, thereby preventing body mass regain.”
NodThera’s drug candidates join a growing list of potential new options for treating obesity and heart disease. By targeting inflammation, these drugs offer new possibilities for managing these two pressing health challenges, among others.
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