Energesis’ Energy Expenditure Approach to Obesity: Brown Fat, GLP-1s, and the Competitive Landscape

GLP-1 drugs such as semaglutide and tirzepatide have changed the obesity treatment landscape. They have helped many people lose meaningful weight and have made obesity one of the most important areas in medicine today.

But we do not believe they are the end of the story.

The GLP-1 therapies work by reducing appetite and food intake. This can be effective, but it addresses only one side of the body-weight equation. The other side is energy expenditure - how much energy the body burns.

At Energesis, we are focused on that second side of the equation.

Why Energy Expenditure Matters

Body weight is influenced by both the calories we take in and the energy we burn. When a person loses weight by eating less, the body responds by slowing its metabolic rate. This is the body’s way of conserving energy.

That response can make additional weight loss harder. It also contributes to weight regain when dieting stops or when an appetite-focused therapy is discontinued.

This is one reason we believe increasing energy expenditure is such an important area of obesity drug development.

Energesis is developing drug candidates designed to increase energy expenditure by restoring a healthy level of brown fat. Brown fat is sometimes called “good fat” because it burns energy rather than storing it. Our approach is intended to increase the amount of brown fat, with the goal of helping the body burn more energy in a healthier and more sustainable way.

Why We Believe This Could Complement GLP-1 Drugs

We do not view the GLP-1 drugs as competitors. GLP-1s reduce energy intake. Energesis is focused on increasing energy expenditure. These are different mechanisms that can potentially work well together.

In our preclinical studies, we observed greater weight-loss effects when our lead candidate, EGS-2632, was combined with a GLP-1 therapy. In fact, the weight loss effects were greater than the sum of the two therapies. We believe this supports the idea that an energy-expenditure drug could potentially complement appetite-focused treatments in humans.

Energesis is still preclinical. FDA-approved human studies will be needed to formally develop this approach in patients.

The Deeper Competitive Landscape

The obesity market is currently dominated by GLP-1 agonists, including semaglutide and tirzepatide. These drugs have been transformative, but several unmet needs remain.

Some patients do not tolerate GLP-1 therapies well. Most lose significant amounts of lean mass along with fat mass. Patients also regain a large fraction of lost weight after discontinuing treatment.

This is why energy expenditure has become an important area of interest.

Reducing food intake can drive weight loss, but the body responds by lowering its metabolic rate. This compensatory reduction in metabolism is one reason weight loss can plateau. It is also a major reason why the body tends to return to a prior higher weight after treatment stops. This is often described as part of the body’s “weight set point.”

An approach that increases energy expenditure could potentially address this issue from the other side of the body weight equation. Instead of only reducing calories in, it seeks to increase calories burned.

In our preclinical studies, EGS-2632 increased energy expenditure without reducing food intake. We have also observed that combining EGS-2632 with GLP-1 therapies produced greater-than-additive weight-loss effects. If these findings translate to humans, we believe our approach could potentially support better combination therapy, improved weight-loss maintenance, or both.

Other Approaches Being Studied

Several different strategies are being investigated to increase energy expenditure.

One category is known as mitochondrial protonophores. These compounds increase energy burning by uncoupling the breakdown of high-energy substrates from the production of ATP, the useful energy currency of the cell. The excess energy is released as heat.

However, this category has a complicated safety history. The prototype protonophore, DNP, was used for weight loss in the 1930s but was withdrawn after serious adverse events, including deaths. Modern protonophore programs are attempting to improve safety, often through lower dosing or targeted approaches, but safely achieving adequate weight loss remains an open question.

Another group of programs focuses on targets known as ALK7 and Inhibin E. These are molecular pathways that have shown potential in animal models of obesity. ALK7 in particular appears to be associated with “browning” of white fat - a process in which ordinary white fat begins to behave somewhat like brown fat and burn more energy. Early clinical data suggest that these approaches may be more useful in combination with GLP-1 therapies than as standalone treatments, but the field is still developing.

A separate approach involves reducing miR-22, a transcriptional regulator linked to brown fat biology and energy expenditure. This strategy has shown anti-obesity effects in non-human primates and is now being tested in early human studies.

How Energesis Is Different

We believe Energesis has several potential advantages compared with other energy-expenditure and fat-browning strategies.

First, our lead candidate, EGS-2632, is oral, while the competing browning approaches are all injectable.

Second, EGS-2632 is based on a combination of previously approved drugs with established human safety. This does not eliminate development risk entirely, and the specific combination must still be studied for obesity. However, we believe the safety risk - a critical aspect of drug development in obesity, is very low and will provide a different development profile than entirely new molecular entities or first-in-human targets.

Finally, based on our review of available preclinical data, our approach seems to produce the most meaningful increase in energy expenditure and weight loss, including in combination with GLP-1 therapies. These findings remain preclinical at this time and must be confirmed in human studies.

Why We Believe This Opportunity Is Interesting

The obesity market is moving quickly. GLP-1 therapies have opened the door, but there is still a need for additional approaches that may improve tolerability, preserve lean mass, support long-term maintenance, and work alongside existing therapies.

At Energesis, we are pursuing one of the most important unsolved questions in obesity treatment: can a therapy that safely increases energy expenditure help patients achieve higher quality and more sustainable weight loss?

We believe our oral, brown-fat-focused approach could become part of the next generation of obesity treatment, potentially as a complement to GLP-1 therapies and other appetite-focused drugs.

Energesis is still in development, and there is no guarantee that our preclinical results will translate to humans. But in a field dominated by drugs that reduce food intake, we are taking a differentiated approach: helping the body burn more energy by restoring healthy brown fat biology.