3.22.2005 - Synthetic Triterpenoids are Extremely Potent Inducers of Phase 2 Response

Antiinflammatory Activity Functionally Related to Antioxidant Activity

DALLAS, TX -- March 22, 2005 -- Reata Pharmaceuticals, Inc. today announced the publication of a new paper demonstrating that the antiinflammatory properties of its synthetic triterpenoids are functionally related to the phase 2 enzyme induction activity of the compounds. The compounds were shown to be extremely potent inducers of phase 2 enzymes through activation of the ARE-Nrf2-Keap1 signaling pathway.

In an important paper recently published in the Proceedings of the National Academy of Sciences (PNAS), researchers from Johns Hopkins University and Dartmouth College demonstrated that a class of synthetic triterpenoids being developed by Reata Pharmaceuticals are extremely potent inducers of the phase 2 response (which is critical in protecting cells against oxidative and electrophile stress) through activation of the ARE-Nrf2-Keap1 signaling pathway. The investigators demonstrated an unexpected, close correlation between the compounds' phase 2 enzyme induction potency and the compounds' antiinflammatory potency (measured by inhibition of inflammatory responses in activated macrophages, a key cell type involved in inflammation).  This correlation held across six orders of magnitude of concentration in multiple cell lines. Further, by examining the activity of a variety of triterpenoid analogues with different potencies, they demonstrated that transcription factor Nrf2 was essential for this activity and that the triterpenoids react with redox-sensitive cysteine residues of Keap-1, a key regulator of the transcriptional activity of Nrf2.  One prominent finding of the study was the triterpenoids' potent induction of heme oxygenase 1 (HO-1) expresion.  Induction of HO-1, a phase 2 enzyme, has been suggested as a potential therapeutic strategy in a wide variety of important diseases, including atherosclerosis and Alzheimer's disease.

The relationship between phase 2 enzyme induction and antiinflammatory activity provides strong evidence that these processes are functionally related. Reata's synthetic triterpenoids have been studied extensively and, in other published studies, investigators have demonstrated that the compounds (a) inhibit induction of inflammatory cytokines such as iNOS and COX2 in activated macrophages, (b) induce apoptosis in a variety of cancer cell types by suppressing anti-apoptotic proteins such as cFLIP, IAP2, and BCL-2, (c) suppress angiogenesis promoting proteins VEGF and MMP-9, and (d) inhibit pro-proliferation proteins cyclin D1 and c-myc in cancer cells. Since these are all target genes of transcription factor NF-kB, the authors of the PNAS study hypothesize that the triterpenoids' phase 2 enzyme activity may dampen NF-kB by increasing the cells' capacity to process reactive oxygen species. They point out that Nrf2-dependent phase 2 enzyme induction has also been demonstrated for the endogenous regulator of acute inflammation, 15-deoxy-delta12,14-prostaglandin J2, which has been shown to inhibit the transcriptional activity of NF-kB. Additional research is underway to further clarify the pathways involved.

Attenuating inflammation through phase 2 gene activation could be a major breakthrough in treating a number of diseases. Reata Pharmaceuticals will begin clinical testing of triterpenoid analogue CDDO (designated RTA 401) for cancer applications in mid-2005. RTA 401 is pro-apoptotic and anti-proliferative in cancer cells and suppresses angiogenesis and pro-growth cytokine production in tumor stromal tissues. Reata is also developing a second triterpenoid analogue (designated RTA 402) that has good oral bioavailability. Reata and its collaborators are investigating the use of RTA 402 for a variety of inflammation-related diseases including inflammatory bowel disease, hepatitis, rheumatoid arthritis, ischemia/reperfusion disease, and atherosclerosis. RTA 402 is scheduled for IND filing in early 2006.

About Reata Pharmaceuticals
Reata Pharmaceuticals, Inc. is a development-stage biopharmaceutical company focused on the development of novel treatments for cancer, inflammation, and neurodegenerative diseases. Founded in 2002, Reata is developing five distinct classes of cancer drugs licensed from UT Southwestern, The University of Texas M. D. Anderson Cancer Center, Dartmouth College, Victoria University of Wellington, New Zealand, and the National Cancer Institute. The company's most advanced products, RTA 744 for primary brain cancer and RTA 401 for hematological cancers and solid tumors, are expected to enter clinical trials in mid-2005. Clinical testing of additional products is expected to begin in late 2005 or early 2006. Reata is also using a proprietary drug screening platform to identify potential breakthrough treatments for cancer and neurodegenerative diseases such as ALS (Lou Gehrig's disease) and Alzheimer's disease.

For further information, please Click Here to view an abstract of the article referenced above.

#########

For more information, press only: Warren Huff
(214) 800-8701
warren.huff@reatapharma.com