Optimised drugs may revolutionise the fight against obesity

Obesity is a rapidly increasing global health challenge estimated to affect more than 1 billion individuals worldwide, and the World Health Organization predicts that the number of people living with obesity will increase significantly in the coming decades, leading to more people developing cardiometabolic diseases.

Although the current anti-obesity drugs are promising, even more effective and long-lasting agents are needed. Researchers are therefore working hard to improve the therapies by combining various pharmacological strategies that target specific receptors in the brain.

“Combining the well-known weight-loss hormone GLP-1 with a new substance targeting neuroplasticity can achieve significantly greater weight loss. You could say that we exploit GLP-1 as a particularly effective Trojan horse, since it is effective in its own right and brings another effective substance to exactly the right place in the brain, optimising the effectiveness without compromising safety. In some experiments, mice getting the conjugated therapy lost twice as much weight as the mice given only the GLP-1 drug,” explains lead author Christoffer Clemmensen, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark.

Chemical synthesis

The new strategy has shown promising results in animal experiments: significant weight loss without increased side-effects compared with, for example, semaglutide. They are now working to bring these results to clinical studies and hope that this method can revolutionise treatment for people with obesity and neurodegenerative disorders. The idea for these treatments was first conceived many years ago.

“In 2013, I travelled to Germany to work as a postdoc with Matthias Tschöp, Timo Müller and their team in Munich. They collaborated with a chemist from the United States, Richard DiMarchi, and together pioneered this new generation of multi-agonist drugs in the field of metabolism. Their collaboration laid the foundation for the successful weight-loss and diabetes drugs that have emerged in recent years, such as tirzepatide,” recalls Christoffer Clemmensen.

Creating conjugated drugs requires combining or connecting several active substances chemically in one molecule, typically a small molecule with a peptide. This enables drugs to be precisely delivered to specific targets in the body, improving efficacy and reducing side-effects by preventing one drug from exerting a non-specific effect.

“The researchers’ original concept involved linking hormones targeting steroid hormone receptors to the GLP-1 hormone. This enables non-specific hormones such as estrogen to be precisely delivered to the defined regions of the brain that have GLP-1 receptors, which minimises side-effects since the substances act very specifically in the whole brain or in other places in the body where estrogen has side-effects,” says Christoffer Clemmensen.

The brain restructures itself

When Christoffer Clemmensen started his research group at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen in 2017, he chose to further develop that strategy targeting novel compounds to specifically modulate ion channels in the brain. A key part of his research focuses on neuroplasticity – the brain’s ability to change and adapt throughout life.

“The brain can restructure itself by forming new neural pathways. This enables the brain to adapt to new experiences and learn new information and skills. We hope that, by modulating neuroplasticity in the appetite-regulating regions of the brain, we can potentially improve the effect and duration of existing anti-obesity drugs,” explains Christoffer Clemmensen.

The research team discovered that targeting the N-methyl-d-aspartate (NMDA) receptor with drugs can strengthen the brain’s synapses, which can potentially improve neuroplasticity and thus aid in reducing body weight.

“Our idea was to modulate neuroplasticity in the appetite-regulating regions to enhance the effect of existing medications. In 2019, we began to focus on the NMDA receptor, which is key to neuroplasticity but also a potential target for treatment-resistant depression and Alzheimer’s. Our ambition is to create drugs with a lasting effect, even after the treatment ends, making it easier to maintain weight loss,” adds Christoffer Clemmensen.

Promotes hyperthermia and hyperlocomotion

The NMDA receptor has an important role in brain function, including appetite regulation and metabolism. However, drugs that inhibit the NMDA receptor often have unwanted effects because these receptors are found throughout the brain. Therefore, the substances have non-specific effects that are undesirable from an anti-obesity perspective.

“We wanted to exploit the potential of the NMDA receptor and minimise side-effects by combining them with GLP-1. NMDA receptors are widely present in the brain, but GLP-1 receptors are more limited, which enables targeted delivery without widespread side-effects,” explains Christoffer Clemmensen.

GLP-1 affects the brain by binding to GLP-1 receptors, primarily in regions such as the hypothalamus and brainstem that regulate appetite and energy balance. This leads to increased satiety, reduced food intake and weight loss. The researchers linked GLP-1 to the NMDA receptor antagonist MK-801.

“MK-801 has been tested experimentally only with moderate weight loss as a result, but because there are receptors throughout the brain, it has serious side-effects. Chronic treatment with MK-801 promotes hyperthermia and hyperlocomotion, and our studies showed that even doses without weight loss significantly induce hyperthermia, so the drug is unsuitable as monotherapy against obesity,” says Christoffer Clemmensen.

Next step: human trials

Hyperthermia means that the body produces or absorbs more heat than it can give off, causing abnormally high body temperature. This can lead to hot flushes, dizziness, convulsions and, in severe cases, life-threatening heatstroke.

“When linked to GLP-1, MK-801 only works in the GLP-1 receptor-expressing regions of the brain, which avoids the serious side-effects. The combination instead resulted in more weight loss and improved metabolic parameters. The results therefore suggest that an equally safe and more effective treatment for people with obesity can be created,” explains Christoffer Clemmensen.

The trials with the new type of weight-loss medication are in the preclinical phase, which involves experiments in cells and animal models. The next step is clinical trials involving people.

“I consider the medicine we have today to be the first generation of effective drugs against obesity. The researchers are working intensively to develop the next generation of weight-loss drugs, which could potentially mean that people can take less medicine but achieve the same weight loss,” says Christoffer Clemmensen.

Brain leaky in some regions

This new type of drug could also be an alternative for people for whom the existing weight-loss drugs are not effective. To focus on developing new innovative drugs for treatment for metabolic disorders, Christoffer Clemmensen and colleagues Anders Klein and Jonas Petersen founded Ousia Pharma, which is associated with a start-up programme of the BioInnovation Institute.

“Compared with established weight-loss drugs, we initially aim to improve effectiveness by 5 percentage points. Current agents provide weight loss of about 15–20%, and those in the pipeline seem to achieve about 25%, so achieving another 5 percentage points will be an important achievement. Weight-loss models in experimental animals look promising, but understanding how these results translate to humans and ensuring efficacy and safety are important,” explains Christoffer Clemmensen.

The researchers are fundraising for their clinical programme and hope to start human trials within a year. The new concept of combining small molecules such as MK-801 with peptide hormones such as GLP-1 as Trojan horses is very exciting. By using GLP-1, researchers can smuggle substances into specific neurons important for appetite regulation. Without GLP-1, the molecules would affect the whole brain and thus be very non-specific.

“The blood–brain barrier protects the brain but is leaky in certain regions. This enables regions such as the hypothalamus to sense what is happening in the blood circulation, which is important for hormone regulation. The GLP-1 receptors in these regions enable specific drug delivery,” adds Christoffer Clemmensen.

Small molecules deep in the brain

Researchers are therefore now working to link specific hormones and peptides, thereby targeting treatments more precisely and reducing side-effects. This principle is being applied to various systems in the body to improve the efficacy and safety of new drugs.

“We have focused on obesity in this study, but the method can potentially be used to deliver drugs to specific regions of the brain for other diseases, such as neurodegenerative and mental disorders,” explains Christoffer Clemmensen.

Many brain diseases are difficult to treat because drugs have to cross the blood–brain barrier. Larger molecules such as peptides and proteins typically have difficulty obtaining access to the brain, whereas many smaller molecules can freely penetrate the entire brain.

“We can use peptides such as GLP-1 to limit access to specifically deliver one of the otherwise non-specific substances. They typically have major side-effects, as previous examples of drugs for neurobiological disorders have shown. Targeting specific regions in the brain could be one strategy to minimise side-effects,” says Christoffer Clemmensen.

The researchers are especially inspired by the fact that several pharmaceutical companies are currently testing weight-loss drugs against neurodegenerative disorders such as Alzheimer’s and Parkinson’s.

“Getting GLP-1 with small-molecule NMDA receptor antagonists deep into the brain could revolutionise Alzheimer’s treatment. GLP-1 receptors are present in the hippocampus and frontal lobes, but GLP-1 drugs rarely reach these regions. I hope that our work contributes to opening up a new class of drugs for neurodegenerative and mental disorders,” concludes Christoffer Clemmensen.