NT-0249

The drugs caused only minimal weight loss in lean mice, suggesting that their mechanism is specific to obesity. NodThera’s lead clinical-stage drug for Parkinson’s disease is almost as effective at inducing weight loss as Novo Nordisk’s blockbuster GLP-1 receptor agonist Wegovy, according to new data.  In an article (PDF) published Feb. 19 in the Journal of Pharmacology and Experimental Therapeutics, NodThera directly put its drugs NT-0796 and NT-0249 head-to-head with Wegovy and with calorie restriction in obese mice. NT-0796 caused weight loss at nearly the same rate as Wegovy, while NT-0249 reduced inflammatory biomarkers associated with heart disease. “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,” NodThera CEO Alan Watt said in a press release.  A three-times-daily, 100 mg/kg oral dose of NT-0796 reduced the body weight of mice with diet-induced obesity by 19% by day 28, according to the journal article. The same dosing regimen of 100 mg/kg of NT-0249 led to a roughly 6.8% decrease in body weight by the same point. In comparison, a once-daily 0.01 mg/kg dose of semaglutide, the active ingredient in Wegovy, reduced their weight by 21.5%; while obese mice on a calorie-restricted diet lost 16.9%.  Notably, lean mice given NT-0796 or NT-0249 lost minimal weight, suggesting that the drugs' mechanism is specific to obesity. While NT-0249 was unable to demonstrate significant weight loss, it did reduce circulating levels of several biomarkers associated with cardiovascular inflammation that were elevated in obese mice compared with controls, even at a lower dose. Levels of fibrinogen, sVCAM-1 and suPAR were all reduced in mouse models treated with the drug compared to those that received semaglutide or were on a calorie-restricted diet. Meanwhile, NT-0796 reduced levels of PCSK9—a liver enzyme associated with higher amounts of low-density cholesterol—while semaglutide and caloric restriction did not. NT-0796, semaglutide and caloric restriction reduced levels of total cholesterol by similar amounts, according to the study's findings.  The results demonstrated that NLRP3 inhibitors are “uniquely positioned” over GLP-1 receptor agonists to block the initiation of cellular inflammatory responses to obesity-related damage-associated molecular patterns, the researchers wrote in the paper. “In addition, when NLRP3 inhibitors are dosed to levels achieving brain exposure, we demonstrate for the first time their capacity to reverse pre-established obesity with similar efficacy to ... semaglutide,” they wrote.  NT-0796 and NT-0249 both act on a multi-protein complex, or inflammasome, associated with the gene NLRP3. The NLRP3 inflammasome helps regulate the immune system but can lead to too much inflammation if it’s dysregulated. Non-alcoholic hepatosteatosis, cardiovascular disease, diabetes and neurodegenerative conditions have all been linked to excessive NLRP3 activity, sparking interest from companies like Novo Nordisk in targeting it.  In the case of obesity, researchers have shown in mice that a high-fat diet raises levels of NLRP3 and that blocking it causes weight loss. One hypothesis for this phenomenon is that the presence of saturated fatty acids in the cerebrospinal fluid bump up NLRP3 inflammasome activity by activating a subset of cells called microglia in the brain’s hypothalamus—a process called gliosis, the NodThera researchers explained in their paper. Activity in the hypothalamus regulates the balance between food intake and calorie output, they said, noting that dysregulation there has been linked to obesity.  The results are a positive sign for the scientific validity of this idea and for NT-0796’s future in the obesity market. The drug is currently being tested in a phase 2a clinical trial, in which participants are receiving twice-daily doses of the drug—the thrice-daily dosing in the preclinical study was necessary due to the drug's short half-life in mice.) Once-daily doses are also being studied in a phase 1/2 study for Parkinson’s disease.  While NodThera noted in its release that NLRP3 inhibitors might be a solution for patients who can’t tolerate GLP-1 receptor agonists, the company claimed to have additional unpublished preclinical data suggesting that NLRP3 inhibitors could be combined with GLP-1 agonists for an additive weight loss effect. The data also hints at “stable weight maintenance following cessation” of GLP-1 receptor agonist drugs “by dosing of a … NLPR3 inhibitor, thereby preventing body mass regain,” the company added.