The first human-tested weight-loss drug that burns calories through creatine-based heat generation, without reducing appetite, has successfully completed its Phase I trial.
Scientists from the Institut Pasteur de Montevideo (IP Montevideo) and the University of the Republic (Udelar) have built on their promising preclinical mouse study to demonstrate that SANA, a small molecule drug that harnesses an unexplored fat-burning pathway, is not only safe for human use but effective.
SANA is a world first several times over, with it being the first small molecule drug produced by a South American biotechnology startup Eolo Pharma – which was founded by its creators – and the first to be developed entirely within Uruguay.
“This result opens a completely new therapeutic pathway for obesity and metabolic disorders – one that complements GLP-1 therapies but focuses on enhancing the body’s energy-burning capacity rather than just suppressing appetite,” said Carlos Escande, researcher at IP Montevideo and a member of Eolo Pharma.
The compound was shown to be safe and well-tolerated in humans, and while it wasn't the focus of the Phase I trial it also reduced both body mass index and blood glucose levels in the 44 participants. A high-dose group in the trial lost an average of around 3% of body weight in just two weeks – and none of it through muscle wastage – compared to a placebo. What's more, it didn't affect appetite, and it improved fasting glucose and insulin resistance without any other interventions. And, unlike GLP-1 therapeutics, lean mass was preserved (it even increased in the preclinical study on mice).
Additionally, no serious side-effects were reported during the two weeks even at the highest dose (800 mg). More long-term impacts will be assessed as it moves into the next phase of human testing.
“This work has been a constant challenge, and it’s incredibly rewarding to see that the human trial results follow the same trend we observed in our lab models,” said Karina Cal, lead author of the study, researcher at IP Montevideo, and member of Eolo Pharma.
While the development and proliferation of the GLP-1 receptor agonist class of drugs has dominated headlines for several years, SANA is nothing like Ozempic. In fact, it works in a very different way, through a very different mechanism.
SANA triggers a unique form of internal thermogenesis – basically turning up the heat on fat cells to make them burn more energy even while at rest. It makes your fat cells work harder, without you lifting even a finger, let alone a dumbbell.
The synthetic molecule, a nitroalkene derivative of salicylate, activates a system based on creatine metabolism, turning the body's fat into a more active furnace – particularly in white fat tissue that usually just sits around storing calories.
In the comprehensive preclinical mice study, SANA boosted thermogenic energy expenditure via a pathway involving creatine metabolism, not the usual UCP1 (uncoupling protein 1) route that scientists have so far been investigating in this sort of "fat-burning pill" research. This alternative pathway is significant; UCP1-based thermogenesis is limited to brown fat, which we don't have a lot of as adults and is mainly involved in temperature regulation. SANA also sets fire to white adipose (fat) tissue, which accounts for the majority of our fat and drives obesity.
Integral in this process is L-arginine:glycine amidinotransferase (AGAT), a key enzyme in creatine biosynthesis. SANA binds to AGAT, turning the dial up on phosphocreatine cycling and heat production. This is a fancy way of saying that when the compound locks onto the AGAT protein, it speeds up the creatine-driven energy cycle in fat cells, shrinking fat stores much more rapidly than diet and exercise can. This could be particularly impactful for anyone with a sluggish metabolism.
Because SANA forms a covalent bond with its protein target AGAT, it is locked on permanently, which means it also permanently changes how that protein behaves (in this case, it revs up energy cycling in fat cells). In fact, the only way to break it would be by destroying and replacing the entire protein. Most drugs form reversible bonds with targets, which means the body can remove or outcompete them in time, but covalent bonds last until the cell recycles them. This means that a single pill could have a long-lasting fat-burn effect, bypassing the need for a daily or even weekly doses.
And unlike GLP-1 drugs, it doesn't impact hormones but targets the metabolism engine room to hardwire a change in fat cell activity. In mice, the drug increased energy expenditure, reduced fat mass, improved glucose tolerance and had no impact on appetite. Mice on high-fat diets continued to lose weight without having their diet or behavior altered. It also preserved muscle mass in the rodents.
However, this permanent metabolic programming also comes with significant risks. If SANA was to attach itself to non-target proteins, it could trigger unintended biological changes or adverse immune responses, with the immune system seeing the new compound as foreign.
These issues have not been tested for, but will come under scrutiny in longer studies going forward. Phase II human trials, which will enlist a larger cohort of participants – including adults with type 2 diabetes – are due to start in late 2025. SANA is the result of more than a decade's work by the team, which formed Eolo Pharma on the back of this discovery.
“We’re proud to be the first biotech company in South America to take a small molecule all the way from design and synthesis to clinical testing," said Pía Garat, CEO of Eolo Pharma. "We hope to advance this pioneering therapy for patients around the world who need safe and effective options for treating obesity."
The study was published in Nature Metabolism.
Source: Institut Pasteur de Montevideo
