Better obesity medicine may be coming

Therapy Breakthroughs 15. dec 2024 4 min Associate Professor Zachary Gerhart-Hines, Postdoctoral Fellow Frederike Sass Written by Kristian Sjøgren

Semaglutide and tirzepatide have revolutionised the treatment of people with obesity by reducing how much they eat. The next generation will need to target different mechanisms and lead to healthier and greater weight loss for more people. Researchers have found an interesting drug target that may address such needs by increasing people’s ability to burn calories.

In recent years, there has been a surge in drugs to treat people with obesity and associated conditions such as type 2 diabetes, cardiovascular disease and kidney disease.

Semaglutide started this pharmaceutical adventure in obesity, and tirzepatide has followed closely behind. Both drugs have revealed the enormous potential of targeting the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), with tirzepatide also activating the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR). GLP-1R and GIPR are both part of a class of receptors (called G protein–coupled receptors (GPCRs)) that is renowned for being excellent drug targets.

Another GPCR, called neurokinin receptor 2 (NK2R), has now been identified to have the potential to provide the next big leap in the treatment of people with metabolic diseases.

A new study shows that drugs targeting NK2R can lead to healthier weight loss in a way that current obesity drugs cannot. Drugs targeting NK2R may also lead to significant weight loss for people who do not achieve satisfactory weight loss with existing treatments.

“Our research focuses on developing treatments to help people living with both obesity and type 2 diabetes – a population numbering about 380 to 400 million globally. The current treatments are significantly less effective at lowering body weight for these individuals compared with people living with obesity and not diabetes. We are seeking other mechanisms to improve treatment,” explains a researcher behind the study, Zachary Gerhart-Hines, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark.

The research has been published in Nature.

Lighting our inner fire

Weight can be lowered in several ways. Semaglutide and tirzepatide, for example, reduce appetite. The control of food intake achieved by these drugs is also linked to nausea and contributes to stopping treatment prematurely.

Another possibility would be to increase the body’s capacity to burn calories, but so far no one has found an optimal way to increase energy expenditure. Gerhart-Hines’ group focuses on this unmet need.

“We specifically looked for GPCRs that could increase energy expenditure. To increase the translational potential of our work, we further examined whether human genetic mutations in these receptors were linked to metabolic dysfunction (such as insulin resistance and obesity). Despite NK2R being known for more than 30 years, we were fortunate that it had been previously overlooked because of negative effects of other closely related receptor family members,” says Zachary Gerhart-Hines.

Two previous attempts

The researchers developed very specific molecules that only activate NK2R and not the other neurokinin receptors. Starting from the natural ligand that normally binds to NK2R and only works for a few minutes, they developed molecules that became more and more specific and had long-lasting effectiveness.

Zachary Gerhart-Hines suspects that the molecule the researchers developed and are continuing to study (neurokinin A (4–10)-S5K/F6Y/L9mL/M10Mox (EB1002)) has the potential to be administered once weekly – just like semaglutide.

They found that specific NK2R activation was able to safely increase energy expenditure in obese rodents. Importantly, the mechanism did not go through the adrenergic (also known as fight or flight) pathway or uncoupling of mitochondria, two of the major previous attempts at leveraging energy expenditure that have proved to be unsafe for humans.

More than calorie-burning

The most ideal obesity therapeutic would likely be one that both reduces food intake and increases energy expenditure. Current attempts to achieve this involve combining multiple molecules that activate different receptors.

However, while characterising how NK2R affects energy expenditure, the researchers made another startling discovery. Activating NK2R not only increased energy expenditure but also reduced appetite. Even more notably, the reduced appetite was not accompanied by nausea as is observed with the GLP-1-based drugs, such as semaglutide and tirzepatide.

The obese and diabetic mice in the experiments also lost weight and had a considerably improved metabolic profile, with better insulin response, lower blood glucose, lower levels of triglycerides and lower cholesterol.

“We are very excited about the results, since the weight loss is achieved by combining appetite reduction without nausea or vomiting and increases in energy expenditure without adverse effects on the cardiovascular system. This has the potential to result in better-quality weight loss and patient compliance,” explains another researcher behind the study, Frederike Sass, Postdoctoral Fellow, Novo Nordisk Foundation Center for Basic Metabolic Research.

Preserves muscle mass

In the next part of the study, the researchers performed a similar experiment in obese and diabetic primates and achieved metabolic improvements equivalent to or better than the corresponding results from the first liraglutide primate trials. This was particularly evident with the NK2R-treated primates, which were severely diabetic and would not have responded as well to a GLP-1 receptor agonist. Even before significant weight loss, NK2R agonism corrected their insulin resistance to the levels of the nondiabetic animals.

The researchers further discovered another appealing property of NK2R agonism.

“There has been a great deal of discussion that GLP-1 receptor agonists not only lead to a loss of fat mass but also muscle mass. This is especially problematic if people stop treatment and gain weight again, since the weight is regained in the form of fat, potentially leaving the person with a larger proportion of body fat than before treatment. Preserving muscle mass is clearly advantageous, and EB1002 appears to only lead to loss of fat mass while maintaining muscle mass,” says Zachary Gerhart-Hines.

The only one of its type

Zachary Gerhart-Hines says that the results have led to the researchers moving towards human clinical trials.

The researchers cannot disclose much yet because of patent regulations and copyrights, but Zachary Gerhart-Hines expects to be able to announce something within the next few years.

There are virtually hundreds of molecules currently being developed as obesity therapeutics, but the researchers believe that the unique properties of EB1002 make it stand out.

“NK2R agonists would represent a completely new class of drugs. If these can be successfully brought to market, they could help people living with obesity and diabetes achieve sustained weight loss and prevent cardiometabolic diseases. Whether NK2R-based drugs can be stand-alone treatments or will be even more effective in combination with current weight-loss treatments has not yet been investigated,” concludes Zachary Gerhart-Hines.

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