预约演示

NodThera Parkinson's drug almost matches Wegovy for weight loss in mice, with bonus heart benefits

2024-02-21

临床结果临床2期

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 lobesityNovo Nordisk’s blockbuster GLP-1 receptor agonist Wegovy, according to new data.

NodTheraticle (PDF) published Feb. 19 inParkinson’s diseasermacology and Experimental Therapeutics, NodThera dNovo Nordiskits drugs NT-07GLP-1 receptor head-to-Wegovyith 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 NNodTheraibition and the resultinNT-0796inflaNT-0249 effect confers not only reversal of obesity but metabolic benefits thNT-0796nd well beyond this,” NodThera CEO Alan Watt saWegovya press NT-0249.heart disease

A three-times-daily, 100 mg/kg oral dose of NT-0796 reduced the body weight of mice with diet-inducNLRP3esity by 19% by day 28, according to the journal article. The same dosing regimen ofobesity/kg of NT-0249 led to a roughly 6.8% decrease in body wNodThera 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 NT-0796nimal weight, suggesting that the drugdiet-induced obesityific to obesity.NT-0249 semaglutide Wegovy

While NT-0249 was unable NT-0796nstrNT-0249nificant weight loss, it did reduce circulating levels of several biomarkeobesityciated 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.

MeanwhNT-0249-0796 reduced levels of PCSK9—a liver enzyme associated with higher amounts of low-density cholesterol—while semaglutide ancardiovascular inflammationot. NT-0796, semaglutide and caloric restriction reduced levels of total cholesterol by similar amounts, according to the study's findings.semaglutide

The resultsNT-0796trated that NLRP3 iPCSK9—ars are “uniquely positioned” over GLP-1 receptor agonists to block the initiatsemaglutideular inflammatory responses to obeNT-0796lasemaglutideassociated molecular patterns, the researchers wrote in the paper.

“In addition, when NLRP3 inhibNLRP3 inhibitors NLRP3 are dosed to levels achieving brain exposuGLP-1 receptorrate for the first time their capacity to reverse pre-established obesity with similar efficacy to ... semaglutide,” they wrote.

NT-0796 and NT-0249NLRP3 inhibitors NLRP3 act on a multi-protein complex, or inflammasome, associated with the gene NLRP3. The NLRP3 inflammasome helps regulate the immune sysobesity can lead to too much inflammasemaglutides 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.

NT-0796case NT-0249ity, researchers have shown in mice that a high-fat diet raises levels of NLRP3 NLRP3hat blNLRP3 inflammasomeeight loss. One hypothesis for this phenomenon is that the inflammationsaturated fatty acids iNon-alcoholic hepatosteatosisp cardiovascular diseaseacdiabetesy actneurodegenerative conditionslled microglia in the brain’s hypotNLRP3us—a process called gliosis, the NodThera researcNovo Nordisked in their paper.

Activity in theobesityalamus regulates the balance between food intake and calorie output, thNLRP3id, noting that dysregulation there has been linked to obesity.NLRP3 inflammasome

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 testobesity 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 forNT-0796ts who can’t toleobesityP-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.Parkinson’s disease

The daNodTherahints at “stable weight maiNLRP3 inhibitors NLRP3nce following cessation” of GLP-1 receptor agonist drugs “by dosGLP-1 receptorR3 inhibitor, thereby preventing body mass regain,” the company added.NLRP3 inhibitors NLRP3 GLP-1