Inflammation is an integral component of the normal immune response that occurs when cells encounter harmful stimuli, such as invading pathogens, damaged cells, or irritants. During inflammation, cells activate inflammatory processes and complexes that increase the production of cytokines—proteins that recruit and activate immune cells.
Inflammation and mitochondrial metabolism are closely associated. The mitochondria are often called the “powerhouses” of the cell as they produce the energy that the cell needs to function. This energy is produced by converting fatty acids and glucose into adenosine triphosphate (ATP) by a process called oxidative phosphorylation. During inflammation, mitochondrial metabolism is temporarily reprogrammed to suppress oxidative phosphorylation.1,2 Instead of making ATP, fatty acids and glucose are diverted to increase the production of proinflammatory mediators.3 Because oxidative phosphorylation is suppressed, the mitochondria release chemically-reactive molecules called “reactive oxygen species,” or ROS, which can directly attack harmful stimuli and amplify the production of cytokines.4
In the normal immune response, the resolution phase of inflammation begins after the harmful stimuli have been eliminated. During this phase, cytokine production is turned off, ROS are neutralized, and mitochondrial metabolism returns to its normal state.
However, in many chronic and genetic diseases, the resolution phase of inflammation fails to occur or is inadequate, leading to the persistent production of cytokines, ROS, and mitochondrial dysfunction. These processes cause chronic inflammation, which can ultimately lead to tissue damage and loss of organ function.5
Nrf2 is a protein that plays a key role in the resolution phase of inflammation by regulating the expression of specific genes that are involved in mitochondrial metabolism, redox balance, and cytokine production.6 In chronic disease, the activity of Nrf2 is often inadequate, which renders the cell unable to turn off the processes that lead to chronic inflammation.7-9
Our two lead product candidates, bardoxolone methyl and omaveloxolone, are Nrf2 activators that promote the resolution of inflammation. Bardoxolone methyl and omaveloxolone selectively bind to Keap1, a protein that governs the activity of Nrf2 in response to cellular stress. By binding to Keap1, bardoxolone methyl and omaveloxolone stabilize Nrf2 and increase its activity.
When activated, Nrf2 promotes the resolution of inflammation by:
Mitochondria can reprogram their metabolism according to the energetic demands placed on the cell. Once the demand is met, metabolism shifts back to its normal state. Mitochondrial dysfunction, a key feature of a variety of diseases, occurs when metabolism does not return to its normal state and leads to the persistent production of ROS and other inflammatory mediators. Nrf2 activation can potentially normalize mitochondrial function in several ways:
Nrf2 restores redox balance and lowers ROS levels by increasing the transcription of many genes, including those that encode components of the glutathione and thioredoxin systems, antioxidant enzymes, and proteins that regulate iron metabolism.15,16
Bardoxolone methyl and omaveloxolone have been extensively studied by many investigators. Their cytoprotective and therapeutic effects have been observed in many preclinical models and associated with meaningful improvements in disease symptoms, such as inflammation, tissue remodeling, and fibrosis.