Omaveloxolone (RTA 408) is an agent for Friedreich’s Ataxia. And it acts through a combination of activation of the antioxidative transcription factor Nrf2 and inhibition of the pro-inflammatory transcription factor NF-κB. Nrf2 is an emerging regulator of cellular resistance to oxidants. Nrf2 transcriptionally regulates multiple genes that play both direct and indirect roles in producing antioxidative potential and the production of cellular energy within the mitochondria. Consequently, unlike exogenously administered antioxidants, 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 and bioenergetics.
On the other hand, NF-κB is a protein complex that controls transcription of DNA, cytokine production and cell survival. Meanwhile, the transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation, and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases.
Omaveloxolone is an investigational and orally active activator of Nrf2.
Omaveloxolone can slow and prevent the progression of Friedreich’s Ataxia. Friedreich’s Ataxia is a slowly progressive neurodegenerative disorder leading to ataxia, dyscoordination, dysarthria, and in many individuals vision and hearing loss. Genetic mutations that lead to low levels of frataxin cause Friedreich’s Ataxia. What’s more, frataxin is a protein that’s necessary for the functioning of mitochondria, which serve as the energy production centers of cells. Besides, in Friedreich’s Ataxia, mitochondrial dysfunction and impairments in cellular energy production drive chronic inflammation and vulnerability to oxidative stress. Therefore, Omaveloxolone has the potential for the research of Friedreich’s Ataxia.
All in all, Omaveloxolone is a potent and orally active Nrf2 activator and an NF-κB inhibitor.