In the wake of their seismic ascension over the lucrative weight loss market, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are facing scrutiny over side effects and post-treatment weight regain. As next generation weight loss alternatives emerge, one particular type—mitochondria-targeting drugs— are being positioned as safer and more sustainable options.
In a global obesity market estimated by GlobalData to reach $173.5bn by 2031, GLP-1RAs retain the lion’s share. In 2031, Novo Nordisk is projected to bring in $22.8bn and $21.7bn that year from sales of its semaglutide formulations Ozempic and Wegovy, respectively. Meanwhile, Eli Lilly is expected to outpace the Danish giant with its tirzepatide formulation projected to earn $36bn as Mounjaro and $28bn as Zepbound.
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Alongside their efficacy, side effects including nausea and loss of muscle or bone mass, have become increasingly apparent. This is a significant problem for GLP-1RAs, according to Dr. Antonio Vidal-Puig, professor of molecular nutrition and metabolism at Cambridge University, UK.
As GLP-1RAs decrease patient appetite, they also downregulate energy expenditure by lowering the resting metabolic rate. Vidal-Puig says this is a key factor behind the weight regain often experienced by patients after stopping GLP-1RAs.
Mitochondrial modulators propose a solution. Rather than limiting appetite, these drugs target the cell’s mitochondria to increase the resting rate of metabolism and raise energy expenditure to encourage weight loss. Developers say preclinical and early clinical data show these approaches offer weight loss comparable to GLP-1RAs, but with less lean mass loss and more sustainable results.
However, whether mitochondrial modulators can be controlled enough to remain safe at efficacious levels, or whether their impact can targeted away from certain mitochondria such as those in cardiac tissue, essential for heart function, is key to whether they can become viable weight loss therapies says Olivier Boss, CEO of Energesis Pharmaceuticals, based in Cambridge, Massachusetts. Energesis’s therapeutic approach does not modulate mitochondria directly but rather increases brown fat to enhance thermogenesis.
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By GlobalDataSince they take a distinct approach from GLP-1RAs, these drugs could be complementary. By combining GLP-1RAs with mitochondrial modulators, Vidal-Puig envisions a maintenance of a healthy metabolic rate while minimising the side effects of either therapy class through lowered doses. Boss adds that the next generation of obesity treatments must include agents that increase resting metabolic rates.
Mitochondrial modulators encompass a number of approaches taken by biotechs to target the mitochondria and energy expenditure. Here are some of the key ones:
Mitochondrial uncouplers
Mitochondria create a gradient by pumping protons into the intermembrane space. The gradient allows protons to re-enter the inner mitochondria through ATP-synthase channels, which generates ATP. Uncouplers, or protonophores, open channels across the mitochondrial membrane, forcing the mitochondria to expend energy, maintaining a proton gradient without commensurate ATP production.
Foremost in the class is HU-6, developed by Charlottesville, Virginia-based Rivus Pharmaceuticals. In a Phase IIa trial (NCT05284617) of 66 participants with obesity-related heart failure with preserved ejection fraction (HFpEF), patients lost a mean 6.8lbs in weight compared to 0.5lbs with placebo (p=0.0026), reducing body fat by a mean 4.8%, as per a 12 March 2025 press release. Notably, there were no significant changes to lean or skeletal muscle mass with HU-6 treatment.
Palo Alto, California-based OrsoBio is also studying a mitochondria uncoupler, TLC-6740, in a Phase I study (NCT05822544). Preclinical data with another of the company’s uncouplers, TLC-3595, showed that lowered blood sugar in mice by as much as 40%, on par with semaglutide, as per a poster at the American Diabetes Association 2024 meeting.
Creatine-dependent thermogenesis
Eolo Pharma is developing a small molecule called MVD-1, which activates creatine-dependent thermogenesis to raise energy expenditure by enhancing mitochondrial respiration.
As per results published in Nature, a 3% weight loss over two weeks with MVD-1 in a Phase I trial (ACTRN12622001519741) was observed, which the study’s authors said was similar to the efficacy of semaglutide. No serious adverse events were reported.
Sunchales, Argentina-based Eolo’s CEO María Pía Garat emphasises MVD-1 does not have the same impact on patients’ lifestyles as GLP-1RAs since it does not suppress appetite, potentially instilling longer-term weight management. With a Phase II trial planned to begin by the end of 2025, Garat says Eolo ultimately hopes to target patients dissatisfied with the side effects of GLP-1RAs.
Pyruvate carrier modulators
In preclinical development is azemiglitazone, a pyruvate carrier modulator being developed by Grand Rapids, Michigan-based Cirius Therapeutics. It targets the mitochondrial target of thiazolidinedione (mTOT) protein to inhibit the import of the metabolic product pyruvate into the mitochondria. This increases insulin sensitivity, encourages production of mitochondria, and favours the metabolism of fats.
Results from a study in mice presented at the 2024 European Association for the Study of the Liver (EASL) Congress showed azemiglitazone with liraglutide led to significant preservation of lean body mass over liraglutide alone. Liraglutide is sold by Novo Nordisk as Saxenda.
The therapy also increased brown adipose tissue, key to weight loss according to Boss. He notes brown adipose cells have a greater number of mitochondria than white cells, meaning this tissue is disproportionally responsible for energy expenditure.
Sulfide donors
Oxford, UK-based MitoRx Therapeutics is taking another approach involving the mitochondria. Myo-4 restores dysfunctional sulfide signaling in mitochondria to enhance metabolism, an approach stemming from the work of cofounder and CSO Matthew Whiteman, PhD, who found that fat loss correlates with systemic levels of sulfur-containing amino acids in patients.
As per data presented at the 2025 European Conference on Obesity in May, Myo-4 normalised blood sugar levels in mice while reducing the loss of muscle and bone mass in comparison to semaglutide. “We’ve got immense advantages over a GLP-1RA,” says Jon Rees, MitoRX CEO. The company plans to begin clinical study in 2027.
New approaches raise fresh concerns
Boss believes the next generation of obesity treatments must include agents like these that increase resting metabolic rates. His own company is developing therapeutics to enhance energy expenditure for weight loss by increasing patients’ brown fat mass. But he warns that in their effort to overcome the shortcomings of GLP-1RAs, mitochondrial modulators introduce their own risks.
According to Vidal-Puig, strategies like uncoupling may be effective in brown fat cells, but uncouplers need to be targeted to these tissues and away from other organs like the heart, liver, and kidneys where mitochondria support vital functions. Unless this is achieved, he suspects the window between minimum effective doses and maximum tolerated ones could prove too narrow.
Boss points out that as far back as 1938, the uncoupler dinitrophenol saw its US Food and Drug Administration (FDA) approval withdrawn over safety concerns. Beyond uncouplers, he says target selectivity is a key issue for other mechanisms such as creatine-dependent thermogenesis. Though effective in brown fat cells, he notes these are sparse among obese patients with greater numbers of white fat cells.
A synergistic solution
In terms of where these drugs might fit in the current landscape, Boss says “We’re not trying to replace GLP1-RAs, but to complement them.” Garat says Eolo is also considering a similar approach. In both cases, developers have found encouraging results in combination with GLP-1RAs.
Vidal-Puig suggests mitochondrial modulators could bolster GLP-1RAs by maintaining patients’ rate of energy expenditure to better sustain weight loss and retain bone and muscle. Combined treatments would likely also lower the doses of GLP-1RAs needed, which Boss believes could be key in limiting their associated side effects such as nausea.
In contrast, Rees envisions Myo-4 as a monotherapy. “In 10 years’ time, it won’t be acceptable to people who are living with obesity to risk loss of muscle mass and function”, he states. “This is the first flush of weight loss medicines. They’ve created a huge market and now it’s time for the next generation of molecules to come forward.”
