Given the importance of mitochondrial ROS in aging, researchers have long investigated the use of antioxidant compounds as a means to intervene in aging processes. These have uniformly failed, perhaps in part due to the fact that these molecules disperse throughout the entire body but fail to attain sufficient levels within the mitochondria.

Mitotech’s lead compound, SkQ1, is one of a family of molecules comprising an antioxidant plastoquinone moiety (a chloroplast electron carrier and antioxidant), a membrane-penetrating cation, and a decane or pentane linker. These molecules pass through phospholipid membranes and accumulate in mitochondria, driven by the mitochondrial membrane potential. Accordingly, it lowers mitochondrial lipid peroxides without impacting cytosolic ROS in models of oxidative stress.

Mitotech-affiliated researchers have reported that SkQ1 increased the lifespan of a short-lived colony of mice as well as mitochondrial mutator mice with a defective mitochondrial DNA polymerase, and ameliorated multiple models of age-related disease.

Dry Eye Disease
In late 202, the company completed a Phase IIb/III study, VISTA-2, of SkQ1 as a treatment for dry eye disease. The press release is silent on the co-primary endpoints (change of Ocular Discomfort Scale and Conjunctival Fluorescein Staining), but reference to the trial record indicates no effect on either outcome. SkQ1 did improve several secondary endpoints, including best corrected visual acuity (BVCA). The press release states, “Consistent signal in these secondary endpoints provides clear guidance for primary endpoint designation in Mitotech’s next pivotal study for the purpose of NDA submission, replacing VISTA-2 nominal co-primaries (conjunctival fluorescein staining and ocular discomfort at day 56) (emphasis added).”

There is not a clear Clinicaltrials.gov entry for a Phase III trial. Confusingly, a trial called VISTA-1, which is smaller than VISTA-2 and began before the release of its results, is listed as a Phase III trial. SkQ1 had no clear effects on the main outcomes in this trial.

In the same press release announcing the results of VISTA-2, Mitotech projected that Phase II studies of SkQ1 for dry age-related macular degeneration (ARMD) and for Leber’s Hereditary Optic Neuropathy (LHON) would start in 2021. No such trials are listed on Clinicaltrials.gov.

Neurodegenerative Disease
Mitotech highlights SkQ1’s potential for neurodegenerative and metabolic disorders. SkQ1 has been found beneficial in models of neurodegenerative disorders, including Friedreich’s Ataxia (FA) and Multiple Sclerosis (MS). Ferroptosis, a recently-discovered type of cell death caused by mitochondrial lipid peroxides generated by labile iron, has been implicated in Alzheimer’s, Parkinson’s, and ALS, and SkQ1 blocks ferroptotic cell death in FA patient fibroblasts by quenching the requisit lipid peroxides. Previously, unaffiliated researchers reported that SkQ1 SKQ1 treatment protected against ischemic or nephrotoxic mouse models of acute kidney injury by inhibiting ferroptosis.

Metabolic Disease
Although metabolic diseases are being revolutionized by the advent of incretin agonist drugs such as semaglutide and terzepitide, Mitotech emphasizes the potential of SkQ1 to improve SkQ1 metabolic disorders such as obesity and metabolic-associated steatohepatitis (MASH — previously nonalcoholic steatohepatitis (NASH)) by increasing mitochondrial efficiency and energy expenditure, as well as interrupting ferroptosis, which Mitotech believes contributes to inflammation in MASLD. SkQ1 preserves mitochondrial ultrastructure in the livers and hearts of mitochondrial mutator mice and increases the energy-generating capacity of their skeletal muscle mitochondria and brown adipose tissue.

According to the company, SkQ1 increased weight loss to 27% in a large non-rodent high-fat diet-fed animal model after two months of treatment with no impact on muscle mass and “Significant synergetic weight loss efficacy in a combination with GLP-1 agonist treatment vs both monotherapies” and enabled “Weight loss maintenance after discontinuation of optimal doses of GLP-1 agonists (for both semaglutide and tirzepatide).” They also state that they reported at the 75th AASLD Liver Meeting that SkQ1 ameliorated two different models of MASLD. In the obesity-driven DIO mouse model, “SkQ1 treatment led to significant improvements in liver triglyceride levels (p<0.001 vs. vehicle), plasma cholesterol levels (p<0.001) and liver histology, including significant improvements in steatosis (p< 0.001)” and a reduction in the “composite overall NAFLD score (p<0.001).” In a separate experiment, lean STAM mouse model demonstrated significant decrease in steatosis, ballooning, composite NAFLD score and fibrosis (p<0.05 for all).”