Overview

  • Chronic inflammation and altered mitochondrial metabolism contribute to abnormal cellular proliferation, tissue remodeling, fibrosis, and organ damage and are associated with many diseases1-3
  • The Keap1/Nrf2 pathway plays a key role in the resolution of inflammation by normalizing mitochondrial function, restoring redox balance, and suppressing cytokine production4-6
  • Reata is developing a series of small molecules that facilitate the resolution of inflammation by binding to Keap1 and increasing Nrf2 activity. Our two lead Nrf2 activators—bardoxolone methyl and omaveloxolone—exhibit broad anti-inflammatory, antifibrotic, and promitochondrial activity in vitro and in preclinical disease models
  • Bardoxolone methyl and omaveloxolone are being evaluated in phase 2 and/or phase 3 clinical trials for the treatment of several chronic diseases in which mitochondrial dysfunction and inflammation are implicated. Bardoxolone methyl is being evaluated in several forms of chronic kidney disease including Alport syndrome, autosomal dominant polycystic kidney disease, IgA nephropathy, type 1 diabetic CKD, and focal segmental glomerulosclerosis as well as a severe from of pulmonary arterial hypertension associated with connective tissue disease. Omaveloxolone is being evaluated in a severe neurologic disease called Friedreich’s ataxia.

Nrf2 Activators Details

References
  1. Noone D, Licht C. An update on the pathomechanisms and future therapies of Alport syndrome. Pediatr Nephrol. 2013;28(7):1025-1036.
  2. Savige J. Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment. J Physiol. 2014;592(18):4013-4023.
  3. Gilroy D, De Maeyer R. New insights into the resolution of inflammation. Semin Immunol. 2015;27(3):161-168.
  4. Ma Q. Role of Nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401-426.
  5. Uruno A, Furusawa Y, Yagishita Y, et al. The Keap1- Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol. 2013;33(15):2996-3010.
  6. Kobayashi EH, Suzuki T, Funayama R, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624.