by Angus Liu
Microbes that live in the gut are believed to play an important role in human metabolism. Now one company is one step closer to testing a drug based on that theory in humans.
Flagship Pioneering portfolio company Kintai Therapeutics said it is moving its anti-obesity drug candidate KTX-0200 into IND-enabling studies after rodent studies returned positive results. In diet-induced obesity rodent models, KTX-0200 induced sustained weight loss of 14%. What’s more, treatment with the drug led to improved blood sugar tolerance as shown in a 12% improvement in glucose clearance. It also increased insulin sensitivity with a 14.5% improvement based on a glucose clearance test, Kintai said.
The Cambridge, Massachusetts-based startup is keeping mum about the drug’s exact mechanism of action. But the company is developing small-molecule therapies that leverage the enteric signaling network, which includes the gut’s nervous system, immune cells and microbiome.
Rather than directly killing or delivering bacteria within the gut, “KTX-0200 has dual actions regulating carbohydrate absorption while increasing the colonic exposure of key microbial metabolites that act on human cells directly,” Kintai CEO Paul-Peter Tak told FierceBiotech via email. Early data also suggest that KTX-0200 may promote the induction of regulatory T cells, which is important because obesity is associated with inflammation, he added.
In the most recent study, animals treated with KTX-0200 also showed signs of improved liver health. In a model of nonalcoholic steatohepatitis (NASH), researchers observed a 30% reduction of liver fat after KTX-0200 dosing, a 19% decrease in total liver weight and a 38% lowering of liver enzymes, which is a common indicator of liver damage.
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Previous studies have linked the gut microbiome to obesity. In a 2018 paper, a research team at the University of Pennsylvania described microorganisms in the digestive tract that have a biological clock, the disruption of which can increase the risk of obesity.
Other methods for fighting obesity are making headway, too. Scientists at Yale University recently discovered that an enzyme called O-GlcNAc transferase (OGT) can be targeted to help control obesity, as mouse cells lacking the enzyme burn off lipids rapidly. Researchers at Hanyang University in Seoul used CRISPR interference to silence the FABP4 gene in unhealthy white fat and observed a reduction in lipid storage.
Kintai said all the preclinical data it’s seen so far suggests KTX-0200 is a promising obesity drug. So it’s moving the agent into studies that could lead to in-human clinical trials.
“In addition to stand-alone efficacy, KTX-0200 may potentially be an attractive medicine for combination therapy with current anti-satiety drugs, which we plan to evaluate,” Tak said in a statement.