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Nrf2 Activators

©Reata Pharmaceuticals, Inc.
Proprietary Reata Nrf2 activator bound to Keap1
PDB Code 5DAF

Bard and Omav
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We are developing Nrf2 activators to treat chronic diseases characterized by mitochondrial dysfunction, oxidative stress, and chronic inflammation.

Bardoxolone methyl and omaveloxolone are investigational Nrf2 activators that selectively bind to Keap1 (1, 2), 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 in the nucleus (3, 4), where it controls the expression of a network of genes that coordinate many processes that help mitigate inflammation, reduce oxidative stress, and restore mitochondrial function (5-8).

Mitochondria are often called the "powerhouses" of the cell because of their ability to efficiently generate the energy cells need in the form of adenosine triphosphate (ATP). However, mitochondria also play an important role in inflammation. As part of the inflammatory response, cells undergo a "metabolic shift" that reduces ATP production by the mitochondria (9). Instead, mitochondria produce reactive oxygen species (ROS) and other byproducts that amplify inflammation (10-12). This metabolic shift is meant to be a temporary response to infection or injury. Once resolved, it is critical that mitochondrial metabolism returns to its normal state, ROS are neutralized, and inflammatory processes are turned off (13).

In many chronic, autoimmune, and genetic diseases, the resolution of inflammation fails to occur and ultimately leads to persistent mitochondrial dysfunction and excessive production of ROS and pro-inflammatory signaling molecules (13, 14). Chronic inflammation and altered mitochondrial metabolism contribute to abnormal cellular proliferation, tissue remodeling, fibrosis, and loss of organ function (15-18).

Nrf2 is a key player in the resolution of inflammation (19), and its activity is often suppressed in chronic disease (20-26). Several molecules that are naturally produced during the resolution of inflammation are activators of Nrf2, underscoring the importance of a well-timed Nrf2 response in this restorative process (27-30). Our Nrf2 activators have been shown to suppress inflammation, reduce oxidative stress, and restore mitochondrial function, resulting in broad anti-inflammatory and antifibrotic activity in nonclinical disease models (31-42).

Since mitochondrial dysfunction, oxidative stress, and chronic inflammation are features of many diseases, Nrf2 activators may have many potential clinical applications. Both bardoxolone methyl and omaveloxolone are in late-stage development for chronic kidney disease and Friedreich's ataxia, respectively.

Nrf2 Activator MOA
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nrf2 triangle indications
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kidney

Bardoxolone Methyl in Chronic Kidney Disease (CKD)

Bardoxolone methyl is an Nrf2 activator currently being investigated in clinical trials for the treatment of patients with different forms of chronic kidney disease.

Inflammation—initiated by a variety of pathogenic processes, including diabetes, systemic hypertension, IgA deposition, and genetic mutations—drives kidney function decline (43). At the molecular level, these pathogenic processes induce mitochondrial dysfunction, decrease ATP production, and promote production of ROS and pro-inflammatory signaling mediators that initiate and amplify inflammatory pathways in glomerular endothelial cells, mesangial cells, and podocytes, while also recruiting activated macrophages and other inflammatory effector cells to the renal interstitium. At the physiological level, chronic activation of pro-inflammatory pathways in these kidney cells leads to a reduction in the glomerular filtration rate (GFR) (44-46).

Bard in CKD
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In preclinical models, bardoxolone methyl suppresses inflammatory pathways that contribute to kidney function loss by increasing Nrf2 activity (4, 32-36). The beneficial activity of bardoxolone methyl and analogs has been observed in several nonclinical models of CKD, including CKD caused by diabetes, hypertension, autoimmune disease, nephron loss, and nephrosis (32, 34-36, 47, 48). In these models, bardoxolone methyl and analogs suppress inflammation and fibrosis (32, 34-36), reduce glomerulosclerosis (35, 36, 48), prevent tubulointerstitial damage (32, 34-36), and improve kidney function (32, 35, 47, 48).

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Omaveloxolone in Neurological Diseases

Omaveloxolone is an Nrf2 activator currently being investigated in clinical trials for the treatment of patients with Friedreich’s ataxia (FA). FA is a neurodegenerative disease characterized by mitochondrial dysfunction, increased sensitivity to oxidative stress, and impaired mitochondrial ATP production (49). Omaveloxolone has been shown activate Nrf2 and improve several disease parameters in nonclinical models of FA (37) (and Reata unpublished data).

Mitochondrial dysfunction and neuroinflammation are common features of many neurological diseases (17). Omaveloxolone and analogs have shown activity in numerous nonclinical models (31, 37-42, 50, 51), as well as patient biopsy samples (37. 50), and we believe the pharmacology is applicable to a broad set of neurological diseases, including other movements disorders, such as progressive supranuclear palsy (PSP), Parkinson’s disease, and Huntington’s disease, as well as diseases that affect neuromuscular function and memory.

Omav in Neuro
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In nonclinical studies, our Nrf2 activators reduced seizure frequency in refractory, progressive epilepsy models and restored mitochondrial function in models of FA (37), ALS (40), familial (51) and sporadic Parkinson’s disease (Reata unpublished data), and frontotemporal dementia (50). We believe that omaveloxolone has the potential to treat a number of neurological and neuromuscular diseases that currently have few or no effective therapies.

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References

References

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