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RTA 402 is the lead molecule emerging from Reata’s platform of Antioxidant Inflammation Modulators (AIMs). Like the other AIMs, RTA 402 promotes the resolution of innate and adaptive immune-mediated inflammation by restoring redox homeostasis in inflamed tissues. RTA 402 initiates a pro-resolution program in which the anti-oxidant and anti-inflammatory transcription factor Nrf2 is potently induced and the pro-oxidant and pro-inflammatory transcription factors NF-kB and the STATs are suppressed. This restoration of redox homeostasis causes the cells that host the inflammatory event to revert to a non-inflammatory phenotype, inhibits the production of inflammatory cytokines, and reduces inflammation and cellular damage from pro-oxidant species. Click here for a detailed description of AIM Pharmacology.
| Early clinical data on RTA 402 has demonstrated that the drug is: |
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Well tolerated with an excellent safety profile |
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Modulating target biological pathways (Nrf2, NF-κB , STAT3) |
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Potently inhibiting the production of pro-oxidant mediators (iNOS, COX2, arginase, peroxynitrite, and reactive oxygen and nitrogen species) |
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Regulating levels of important inflammatory cytokines (TNF, VEGF, IL-8, G-CSF) |
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Demonstrating anti-cancer activity, including objective responses when administered as a single agent |
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Combining well with other anti-cancer therapies |
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Suitable for once daily oral dosing |
Based on this emerging clinical profile and extensive preclinical studies, Reata is conducting Phase 2 development programs with RTA 402 in Cancer, Renal/Cardiovascular Disease, and Autoimmune Diseases
The first human studies of RTA 402 have been conducted in cancer patients based on the strong biological rationale supporting the use of AIMs as agents to suppress tumor-supporting inflammation.
| RTA 402 is nearing completion of a Phase 1 study in patients with a variety of advanced solid tumors. This ongoing study has demonstrated the following: |
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A high disease control rate, superior to that of recently approved anti-cancer agents |
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Shrinkage of tumors in multiple patients, including an Objective Response |
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Prolonged stabilization of disease in a high percentage of patients |
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Benign safety profile, significantly better than recently approved targeted therapies |
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No incidence of side effects common to other anti-cancer agents (such as reductions in white or red blood cells or platelets, hair loss, hypertension, cardiac toxicity, or neurotoxicity) |
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Improvements in important markers of renal function |
Because of its pharmacology, RTA 402 is likely to have even greater effects when combined with standard cancer therapies (either chemotherapy or radiation therapy). An initial study combining RTA 402 with standard of care chemotherapy (gemcitabine) is underway in patients with pancreatic cancer. To date, this study has shown that the drugs can be dosed in combination and suggests that the activity of the two drugs may be greater than that of gemcitabine alone.
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Renal dysfunction is an area of significant unmet medical need, affecting up to 9% of the U.S. population and representing over one-quarter of Medicare spending. The few available therapies merely serve to slow down the inevitable progression of the disease, which ultimately leads to dialysis or transplantation.
There is a strong biological rationale for the use of AIM molecules as Disease Modifying Agents in renal and cardiovascular disease. Chronic oxidative stress mediated inflammation is known to play an important role in the degeneration of kidney function. Furthermore, most of the patients that have received RTA 402 in the cancer clinical trials
have experienced improvements in kidney function.
Reata has initiated a Phase 2 development program of RTA 402 in renal and cardiovascular disease. An initial study will establish proof of concept for the use of this drug in patients with diabetes and renal dysfunction. Follow-on studies in both acute and chronic kidney disease are planned for initiation later in 2008.
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Autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and lupus represent significant medical problems caused by dysregulation of the body’s immune system. While protein therapeutics have proven effective against these diseases, many patients do not respond or are unable to take these drugs due to their toxicity. Additionally, their route of administration (intravenous/injection) represents a burden to patients. Thus, there is a significant opportunity for orally available small molecule therapies that are effective against autoimmune diseases. Few such agents are currently in development.
RTA 402 and other AIMs have been shown to affect the biological pathways involved in autoimmune diseases and to be effective in animal models of multiple diseases. Data from the ongoing Phase 1 data indicates that in humans RTA 402 potently modulates important inflammatory signaling molecules (called cytokines) implicated in autoimmune diseases. These include Tumor Necrosis Factor (TNF), which is the target of major biological therapies used to treat these diseases.
Reata is initiating a Phase 2 development program of RTA 402 as a Disease Modifying Agent in rheumatoid arthritis. Proof of concept studies in this indication are expected to begin during the first half of 2008. Additionally, Reata is developing a related AIM, designated RTA 404, for the treatment of another autoimmune disease, multiple sclerosis.
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