Omaveloxolone

Omaveloxolone (RTA 408) is a second generation member of the synthetic oleanane triterpenoid compounds and currently in clinical development by Reata Pharmaceuticals. Preclinical studies have demonstrated that omaveloxolone possesses antioxidative and anti-inflammatory activities and the ability to improve mitochondrial bioenergetics. Omaveloxolone is currently under clinical investigation for a variety of indications, including Friedreich’s ataxia, mitochondrial myopathies, immunooncology, and prevention of corneal endothelial cell loss following cataract surgery. Omaveloxolone (RTA 408) is a second generation member of the synthetic oleanane triterpenoid compounds and currently in clinical development by Reata Pharmaceuticals. Preclinical studies have demonstrated that omaveloxolone possesses antioxidative and anti-inflammatory activities and the ability to improve mitochondrial bioenergetics. Omaveloxolone is currently under clinical investigation for a variety of indications, including Friedreich’s ataxia, mitochondrial myopathies, immunooncology, and prevention of corneal endothelial cell loss following cataract surgery. The effects of omaveloxolone and related synthetic triterpenoid compounds have been documented in over 200 peer-reviewed scientific manuscripts. The mechanism of action of omaveloxolone and its related compounds has been demonstrated to be through a combination of activation of the antioxidative transcription factor Nrf2 and inhibition of the pro-inflammatory transcription factor NF-κB. Nrf2 transcriptionally regulates multiple genes that play both direct and indirect roles in producing antioxidative potential and the production of cellular energy (i.e., adenosine triphosphate or ATP) within the mitochondria. Consequently, unlike exogenously administered antioxidants (e.g., vitamin E or Coenzyme Q10), which provide a specific and finite antioxidative potential, omaveloxolone, through Nrf2, broadly activates intracellular and mitochondrial antioxidative pathways, in addition to pathways that may directly increase mitochondrial biogenesis (such as PGC1α) and bioenergetics. There appears to be dose-dependent induction of Nrf2 target genes, along with induction of biomarkers of mitochondrial function in one early clinical trial. Time- and dose-dependent neurological improvements were observed. A phase 1 with patients was completed in 2017 and a phase 2 study should be completed in 2020.