Competition for GLP-1s: Novel Compound Demonstrates 62% Fat-Selective Weight Loss

To my principal investigator’s chagrin, I started my first company about a year into my postdoc, while researching plant metabolism. I learned that I gain tremendous enjoyment from starting and building businesses. This is now my fourth or fifth business, depending on how you count…

In the case of MitoRx, I had been evaluating hundreds of technologies as a consultant for several clients. I kept coming back to only a couple of technologies, a little like an earworm.

One technology had a profound pharmacological effect across many models within multiple medical schools internationally. Critically, it had all the characteristics of what might be an important drug.

This was the technology around a tool compound licensed to MitoRx in 2021 that eventually led us to drug-like compounds such as MTRX31.

Our original focus of the invention was on muscle preservation in rare muscle degeneration diseases such as muscular dystrophy.  The underlying technology had demonstrated muscle protection properties in Duchenne and Huntington models, which we were really drawn to. Pharma interactions led us to consider muscle preservation in weight loss for obesity.

It became clear in a timely academic collaboration that early tool compounds could prevent weight gain, but even better, after optimization, it was very satisfying to see lead compounds drive fat-selective weight loss. 

My educational piece for the general public is that being overweight or obese isn't a result of massive excess calorie intake. It’s a surprisingly small difference between the energy we expend and the energy we take in.

When people eat less, their basal metabolic rate drops further, and unfortunately, they maintain this difference—they struggle to lose weight or continue to gain weight. The body has become wired to overcompensate for reduced calorie intake.

For those purposes, a therapy like ours is important. It generates that difference, which is enough to drop fat, maintain weight and prevent regression back to overweight and obesity.  We do this by preserving lean mass and boosting mitochondrial health, while shedding only fat.

The removal of ectopic fat, which is stored fat from metabolically active organs such as the pancreas and the liver, is one of the most important effects of metabolic modulation. This is what we observe in models of obesity.

Research has shown that if you clear fat from the pancreas through dieting and controlled food intake, you can drive diabetes regression. If you can take a pill to do that, you can prevent progression from a metabolically unhealthy obese state into the more serious diseases: type two diabetes, metabolic dysfunction-associated liver disease, cardiovascular disease, and so on. Our purpose is to reverse people’s trajectory away from those more serious illnesses.

The elephant in the room… why is a GLP-1 therapy not well-suited for this? Most patients cease this therapy in the first two years, so it's more like a sticking plaster.

Patients may benefit from weight loss, but when they stop the medication, they will re-continue that trajectory towards a more serious disease. MTRX31 does not modulate the gastrointestinal tract, so we don't expect the side effects that lead to the cessation you see with GLP-1s.

In the data we presented at the American Diabetes Association (ADA) conference, we showed that pancreas fat clearance with MTRX31 outperformed a dual GIP/GLP-1 receptor agonist in a head-to-head comparison*. Additionally, mice treated with MTRX31 achieved ~62% selective fat loss compared to the vehicle group.

MTRX31 is a subcutaneous injectable, and we are actively hunting for an oral. I think the commodification of weight loss means there are many, many more people willing to take injectables, and that market will continue to expand.

If you're talking to a patient who has been properly briefed by physicians and knows that, if they don't do something about the trajectory of high-risk metabolic disease toward more serious disease, they are less likely to turn down a treatment based on route of administration. One of the main reasons for the development of oral options is that they can reach an additional patient population, to grow the market for industry, rather than as a direct alternative to injectables.

For us, we're very interested in reaching the population of people living with high-risk obesity in which we can provide body weight loss “plus.” For MitoRx that means weight loss, clearance of fat from organs, muscle functional benefit, reversal of cardiometabolic markers, addressing the root cause of the disease, and so on. 

We need to treat patients with hypertriglyceridemia and expanded waist size (HTGW) and usually insulin resistance before they develop more serious diseases like type 2 diabetes, metabolic dysfunction-associated fatty liver disease, and metabolic dysfunction-associated steatohepatitis. In most patients who discontinue GLP-1 treatment, the wider cardiovascular benefits are reversed alongside weight bounce-back. The greatest opportunity is to address progression in these high-risk patients.

We're also interested in exploring to what extent, where patients may have already developed those serious complications of metabolically unhealthy obesity, we could regress those. We have seen very nice clearance of fat from liver and pancreas in obesity models, suggesting that this is possible.

Ultimately, for greatest impact as medicines developers we must focus metabolic health over cosmetic weight loss.

*This article is based on research findings that are yet to be peer-reviewed. Results are therefore regarded as preliminary and should be interpreted as such. Find out about the role of the peer review process in research here. For further information, please contact the cited source.