New Drug Targets Obesity Causes for Lasting Weight Loss

Details of a new drug that aims to treat the underlying causes of obesity were presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in Vienna, Austria (15–19 September).

The treatment of obesity has been transformed in recent years by glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide, which reduce appetite, slow the release of food from the stomach and increase feelings of fullness.

These drugs are highly effective for weight loss but many people regain weight after stopping treatment. That's because obesity is driven by more than appetite alone—it also involves disrupted lipid and glucose metabolism, changes in adipose tissue and mitochondrial dysfunction, leaving plenty of room for new approaches, explains Riccardo Panella, co-founder and CEO of Turin-based biotech Resalis Therapeutics.

The company's approach involves an antisense oligonucleotide—a small, lab-made fragment of genetic material designed to block a specific RNA in the body. The new drug, which is called RES-010, is designed to block an RNA molecule called miR-22.

miR22 is a "master controller" of many processes involved in obesity, including lipid metabolism (how the body breaks down and uses fats), the production and activity of mitochondria (the tiny structures that provide cells with energy) and adipose tissue remodeling (changes in how body fat is organized and how it functions), says Dr. Panella, who is one of the authors of the new research.

The hope is that by tackling all these factors simultaneously, RES-010, which is administered once a week as a subcutaneous injection, will reprogram the metabolism, producing long-lasting weight loss.

Pre-clinical studies show that the compound can induce significant weight loss—and that the lost weight isn't regained when treatment stops.

In tests on obese mice, mice given weekly injections of the drug lost about 12% more weight than untreated mice. The weight loss occurred gradually over the five months of treatment, leading to the animals returning to healthy weight.

"Importantly, the treated mice lost weight despite eating the same amount as the untreated mice, which suggests RES-010 isn't suppressing appetite but reprogramming the metabolism," says Dr. Panella.

Experiments also showed that mice that had been treated with RES-010 did not regain weight after the drug was stopped.

The team also explored giving RES-010 and semaglutide alone and together to mice and non-human primates (NHPs).

They found that RES-010 selectively targeted fat mass. This is important because rapid weight loss when on a diet or taking GLP-1 drugs can lead to lean mass, which includes muscle and bone, being lost too.

"Lean mass, especially skeletal muscle, is central to strength, stamina and blood sugar regulation, and so its loss is potentially harmful," says Dr. Panella.

NHPs given RES-010 lost 15% fat mass and 1% lean mass over 10 weeks. This compares with 16% fat mass and 8% lean mass for semaglutide alone.

The team also looked at whether the animals regained weight after treatment was stopped.

They observed that while the NHPs given semaglutide alone regained weight after semaglutide was discontinued, the animals receiving the combination treatment did not regain weight after semaglutide was stopped and they remained on RES-010 alone. Moreover, no rebound occurred when RES-010 was also stopped a few weeks later.

No significant side effects were seen in the mice or the NHPs at therapeutic doses, says Dr. Panella.

Tests on animals and non-human organoids have shown how the drug works.

Dr. Panella says, "RES-010 works by reprogramming how cells handle fat and energy. Rather than reducing appetite, it changes the way in which the body uses fats, boosts the production and activity of mitochondria, the 'batteries' that power cells, and helps convert white fat, which stores energy, into brown fat, which burns it.

"Because it acts on these fundamental pathways, weight regain is less likely.