MitoRx Therapeutics Announces Publication Showing Mitochondrial Sulfide Donor AP39 Significantly Alleviates Obesity

Oxford, England, 10 October 2024 - MitoRx Therapeutics (MitoRx), a platform biotechnology company developing novel mitochondrial-targeted sulfide-donor therapeutics (mtH2SD) in obesity-related disorders and myopathies announces a publication in Elsevier’s prestigious biomedical sciences journal Pharmacological Research. The work led by collaborators at Jagiellonian University Medical College showed that in a preclinical mouse study involving high-fat diet (HFD)-induced obesity, the company’s mtH2SD compound AP39, significantly slowed the rate of gain in weight. This is the first comprehensive study designed to test whether mitochondrial sulfide donors could address weight gain and fatty liver (steatosis).

Mounting evidence suggests that hydrogen sulfide is an important signalling molecule in the liver, regulating lipid metabolism and mitochondrial function, but its direct delivery to mitochondria had not been investigated as a therapeutic strategy in obesity-related metabolic disorders. This is what the Pharmacological Research paper examined. MitoRx’s CSO, Prof Matt Whiteman, and their Senior Discovery Chemist, Dr. Roberta Torregrossa, with co-inventor Dr. Mark Wood at the University of Exeter are co-authors on the paper. It showed that treatment with AP39 reduced weight gain in animals fed HFD by 32% at the end of the research. (1)

AP39 is a versatile mtH2SD tool compound that mediates very large and statistically significant reductions in liver steatosis, large and significant reductions in triglycerides, reductions in de novo lipogenesis, reductions in inflammatory markers, and significant downregulation of known liver proteomic markers of weight gain and the development of obesity, indicating mtH2SD-mediated downregulation mTOR/SREBP-1/SCD1 pathway alleviates obesity. MitoRx is developing undisclosed next-generation mtH2SDs to take to the clinic.  Importantly, this modality is both muscle protective including in a severe fibrotic muscle atrophy model and is also anti-obesogenic.  With this double therapeutic benefit, MitoRx’s next-gen mtH2SDs could potentially address the loss of lean muscle mass which is a serious side effect of marketed GLP-1 receptor agonist drugs in general, especially with age. This approach could be applicable in sarcopenic (age-related muscle mass and strength loss) obesity while also addressing muscle wasting in obese patients in general.

Dr. Jon Rees, Chief Executive Officer of MitoRx, said: “MitoRx is advancing its first-in-class mitochondriotropic platform initially focused on myopathies and is now applying it to obesity offering a small molecule anti-obesogenic which is also muscle protective. This latest publication provides solid pre-clinical evidence that AP39 substantially suppressed the gain of weight in HFD-fed animals, suggesting a new pathway to alleviate obesity, whilst avoiding the muscle wasting side-effects that blight GLP-1 receptor agonist drugs. Powerful international research collaborations like this, with the talented team at Jagiellonian University’s Faculty of Medicine, help speed therapeutic advances to patients.”

Dr. Aneta Stachowicz, Department of Pharmacology at the Faculty of Medicine, Jagiellonian University Medical College, Poland, and lead author of the Pharmacological Research paper, said: “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.”

Matt Whiteman, Professor of Experimental Therapeutics at the University of Exeter Medical School, UK, and co-author of the study added: We discovered impaired sulfide metabolism in overweight patients with type 2 diabetes in 2010 (2) and we noticed that this impairment was driven by the amount of fat tissue these individuals were carrying; an observation since confirmed by many others. These findings suggested that treating this impairment with mtH2SD could potentially treat diabetes, obesity and complications arising from having too much fat in the body. It is gratifying to now translate those observations toward clinically viable drugs with MitoRx

References:

(1): Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and

obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and

inflammation via mTOR/SREBP-1 and NF-Kappa-B signaling pathways. Pharmacological Research 209 (2024):107428

https://doi.org/10.1016/j.phrs.2024.107428

(2): Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulphide. Diabetologia 53(8):1722-6 (2010). https://doi.org/10.1007/s00125-010-1761-5