The article, "Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer," by researchers and Reata scientific collaborators from the Dartmouth Medical School Karen T. Liby, Mark M. Yore and Michael B. Sporn, focuses on two new classes of multifunctional drugs that it reports can prevent and treat cancer in experimental animals. One of Reata's lead clinical candidates, from one of the classes the article describes, the Synthetic Triterpenoids, is entering advanced clinical trials for deadly, late-stage cancers.
The article describes the Synthetic Triterpenoids as a new class of non-toxic and highly multifunctional drugs that have applications for the prevention and treatment of not only cancer, but also of many other diseases with an inflammatory component.
"An outstanding body of work is emerging on the Synthetic Triterpenoids from many top academic collaborators," commented Warren Huff, Reata's CEO. "Dr. Sporn and his team have provided an excellent summary of the broad research currently underway on these compounds and the underlying biological pathways they modulate. Reata is delighted to have the opportunity to collaborate with these researchers in taking take these important new drugs forward to provide a clinical benefit for patients with cancer and other diseases."
Reata in-licensed the complete series of Synthetic Triterpenoids from Dartmouth and the University of Texas M.D. Anderson Cancer Center in 2004. RTA 402, the lead agent from this series, has recently begun Phase 2 clinical studies for cancer and anti-inflammatory diseases. An ongoing Phase 1 study in cancer patients has demonstrated that RTA 402 has potent single-agent anti-cancer activity in patients with several different types of tumors, is exceptionally well tolerated with only mild, transient side effects, inhibits the activity of NF-kB and STAT3 (the drug's targets) in human tumors, and is able to suppress levels of tumor promoting cytokines and growth factors (for example, TNF and VEGF) at very low doses. Reata is also advancing a second Synthetic Triterpenoid capable of crossing the blood-brain barrier for neurological indications including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. This agent is in advanced preclinical development.
In the "Nature Reviews Cancer" article, the researchers provide a comprehensive overview of the discovery and activity of these agents. The authors note that Reata's Synthetic Triterpenoids have profound effects on inflammation and the redox state of cells and tissues, as well as being potent anti-proliferative and pro-apoptotic agents. Because of their unique pharmacology, these agents are being studied at leading research institutions and are the subject of more than 50 publications in peer reviewed journals. The article summarizes the current state of this literature. Some highlights of this comprehensive body of research reviewed in the article include the following:
-- How the drugs were optimized to inhibit the de novo synthesis of iNOS and COX2 in normal mouse macrophages. iNOS and COX2 have essential roles in the initiation of inflammation.
-- An explanation of the drugs' molecular targets and mechanism of action. The synthetic triterpenoids are potent inhibitors of transcription factors such as NF-kB and the STATs that are normally activated by reactive oxygen and nitrogen species. Inhibition is achieved by activation of the antioxidant transcription factor Nrf2, which activates the phase 2 genes and reduces cellular levels of reactive oxygen and nitrogen species. In addition, the triterpenoids directly re gulate activation of NF-kB by binding to IKKB, the kinase that inhibits NF-kB activation. The triterpenoids block the activation of STAT3 and STAT5 in cancer cells by upregulating negative regulators of the STATs. These transcription factors are the target of major drug development programs at multiple companies with applications in treating both inflammation and cancer.
-- A description of the anti-inflammatory and anti-carcinogenic activity of the compounds. Reata's triterpenoids suppress production of pro-inflammatory cytokines and reduce mortality in animal models of LPS-induced inflammation. Synthetic triterpenoids are highly effective in preventing the development of both lung cancer and liver cancer in animals exposed to known carcinogens.
-- Multi-functional anti-cancer activity of these drugs, which includes driving immature cancerous cells to differentiate; inhibiting the growth of cancer cells and causing them to undergo programmed cell death (called apoptosis). This activity has been seen in multiple animal models, and has recently been confirmed in a Phase 1 study of RTA 402 in cancer patients being conducted at the M.D. Anderson Cancer Center and the Dana-Farber Cancer Institute.
-- A comparison of the mechanism of the Synthetic Triterpenoids with that of "targeted therapies" currently in vogue in the cancer field. Dr. Sporn argues that the genetic complexity of cancer requires the use of agents with a multi-factorial mode of action, rather than those with high affinity for a single, specific molecular receptor. While multi-factorial mechanisms are often thought to be associated with high drug toxicity, Dr. Sporn notes that these agents are derived from natural products that have been safely used for centuries with no appreciable toxicities. Recent clinical studies have shown that these agents are minimally toxic in humans.
Reata Pharmaceuticals, Inc. is a biopharmaceutical company focused on selecting and discovering promising early drug development opportunities and translating them into successful marketed drugs that target major unmet clinical needs in cancer, inflammation and neurodegenerative disease. The company's two lead programs are entering advanced clinical trials for deadly, late-stage cancers. In parallel with its clinical development, Reata is advancing a breakthrough drug discovery platform using protein misfolding, identified as a key factor in cancer and neurodegenerative disease, to feed its pipeline of small molecule therapeutic candidates. Reata takes a new and different approach to biotechnology, managing its pipeline as a portfolio of opportunities that can be advanced on a single management and physical infrastructure, streamlining the route to human trials and approval. Founded in 2002, Reata is based in the Dallas area. For more information, visit www.reatapharma.com
For Reata Pharmaceuticals, Inc.
Kathryn Morris, 845-635-9828