Mitochondrial-targeted sulfide donor therapy shows metabolic disease promise, reducing weight gain and protecting against muscle loss in mice.
British mitochondrial therapeutics developer MitoRx has published the results of a study that demonstrates the potential of its approach to address obesity. The study showed that one of the company’s mitochondrial-targeted sulfide donor (mtH2SD) drugs significantly slowed the rate of gain in weight of mice on a high-fat diet while also protecting against muscle loss.
Published today in Pharmacological Research, the study involved preclinical trials in mice with high-fat diet (HFD)-induced obesity, in what MitoRx claims is the first comprehensive research of its kind to explore mitochondrial sulfide donors as a therapeutic strategy for obesity and its related conditions. Results revealed that treatment with the company’s AP39 compound slowed the rate of weight gain by 32% compared to controls.
“Having comprehensively demonstrated that mitochondrial-targeted sulfide donors alleviate weight gain and significantly reduce multiple markers of obesity, we mark the beginning of a new era in the development of an innovative therapeutic approach for metabolic disease through the modulation of mitochondrial sulfide-signalling,” said the paper’s lead author, Dr Aneta Stachowicz, from Jagiellonian University Medical College in Poland.
MitoRx, which had been primarily focused on mitochondrial treatments for myopathies, led by Duchene Muscular Dystrophy (DMD), is now also applying its platform to obesity. The company is developing next generation mtH2SD treatments that offer anti-obesity effects without the detrimental side effects of muscle loss, with plans to enter clinical trials in around two years’ time.
Longevity.Technology: We’ve been following progress at MitoRx closely since it first emerged in 2022. Licensing IP developed by University of Exeter Professor Matt Whiteman, the company is developing a pipeline of mitochondrial-protective therapeutics with potential in multiple age-related diseases, but its work in obesity is something new.
Hydrogen sulfide is known to play a crucial role in liver function, particularly in regulating lipid metabolism and mitochondrial processes. However, until this study, MitoRx says its direct delivery to mitochondria as a possible treatment for metabolic disorders had not been fully explored. We caught up with CEO Dr Jon Rees to find out more.
The recent study showed that AP39 not only reduced weight gain but also mediated substantial reductions in liver steatosis, triglycerides, de novo lipogenesis and inflammatory markers. Moreover, it downregulated key liver proteomic markers associated with weight gain and obesity development, particularly through pathways implicated in lipid synthesis and storage.
“In obesity, the hormonal response to mealtimes is blunted,” says Rees. “It’s been demonstrated independently of us that restoring sulfide signaling restores glucose-responsive GLP-1 release. So, it appears the hormonal response to mealtimes in general requires functional sulfide signaling, which we restore. Effectively, we’re putting the pathway back into order.”
Protection against loss of muscle mass
In addition to its anti-obesogenic properties, mtH2SDs also appeared to offer a dual therapeutic benefit by being muscle protective. Next-generation leads were tested in a severe fibrotic muscle atrophy model and were found to protect against muscle fibroses. This is potentially significant given the muscle wasting that often accompanies existing obesity treatments, such as GLP-1 receptor agonist drugs like Wegovy and Ozempic.
“Whereas GLP-1 receptor agonists like Wegovy agonise the GLP-1 receptor 24/7, which causes 70% of patients to cease therapy within two years due to gastrointestinal side-effects, our approach restores endogenous GLP-1 release at mealtimes which we think will have a cleaner side effect profile,” says Rees, who says MitoRx is investigating both combination and monotherapy approaches in its obesity program.
“In a single molecule, we believe we can combine muscle preservation with an anti-obesogenic activity, addressing the worst side-effect of the world’s largest-selling medicines, the GLP-1 receptor agonists.”
Combination and monotherapy potential
While Rees believes that potential pharma partners see MitoRx’s approach as a potential add-on to GLP-1 agonists to address lean muscle mass loss, he also feels it has significant potential as a standalone therapy.
“As a monotherapy, we may well have a cleaner side-effect profile, because we merely restore mealtime responsive GLP-1 release, which is what a normal person experiences,” he explains. “We’re not agonizing the GLP-1 receptor 24/7, which is what leads to the poor side effect profile and leads to patients ceasing therapy. We believe our approach could lead to a sustained quality weight loss without the side effects, and that would lead to better compliance, and the health economics would stack up better.”
From a healthy aging perspective, MitoRx’s next generation mtH2SDs, currently under development, also aim to address the muscle mass loss often seen in sarcopenic obesity and in obese patients more generally, offering hope for older individuals in addition to those at risk of muscle wasting while combating obesity.
“The muscle wasting side effects of GLP-1s are worse in older people, and there is also a subset of older people with sarcopenic obesity, where muscle wasting drives obesity, and obesity drives muscle wasting,” says Rees. “These people are currently completely unserved, so I think we’ve got a great opportunity to do something to help those patients.”
Human trials by 2027
Rees explains that the company’s decision to focus on obesity was solidified at this year’s JP Morgan Healthcare Conference.
“The pharma companies that had asked to meet with us there, all saw us as a metabolic disease company, largely as a result of the unique metabolic effects we had first seen in our preclinical Duchenne program, and later as a result of data we could see emerging from our collaboration with Jagiellonian University on this study,” he says. “We remain committed to our DMD program, but we’re also prioritizing obesity-related indications as a result of the evidence and also the significant pharma interest.”
To support its new efforts in obesity, MitoRx, which last year announced it had raised $5 million in seed funding, also announced two new appointments. Experienced pharma executive Dr David Holbrook becomes an independent Non-Executive Director, and world-renowned diabetologist, Professor Rury Holman, joins the company’s Scientific Advisory Board.
“David’s deep strategic healthcare knowledge and board experience, coupled with Rury’s unparalleled expertise in metabolic diseases, will be invaluable as we initiate our obesity program,” said Rees. “We’re expecting to be in our first in human trials for obesity related indications by January 2027.”
