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Bardoxolone methyl, previously known as
RTA 402, is the lead molecule emerging from Reata’s platform of
Antioxidant Inflammation Modulators (AIMs).
The AIMs are the most potent known inducers of Nrf2, an important emerging biological target that controls the production of many of the body’s antioxidant and detoxification enzymes. There is a strong biological rationale for the use of agents targeting Nrf2 to treat renal and cardiovascular disease. Chronic oxidative stress-mediated inflammation is known to play an important role in the degeneration of kidney function. Based on data from three clinical studies demonstrating improvements in patients’
markers of kidney function and potential disease-modifying
activity, bardoxolone has been advanced to late-stage
clinical development and is currently undergoing a pivotal Phase
2b trial in chronic
kidney disease patients with type 2 diabetes mellitus.
| Data from three clinical studies of bardoxolone
methyl have demonstrated that the drug is: |
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Producing a significant
increase in estimated glomerular filtration rate (eGFR), which is
consistent in magnitude and in the high degree of patient
response |
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Improving CKD stage from
severe (Stage 4) to moderate (Stage 3) in the majority of
patients |
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Improving multiple
additional measures of renal function, including BUN,
Phosphorus, Uric Acid, and Magnesium, that significantly
correlate with changes in eGFR |
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Improving glycemic control |
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Improving endothelial function |
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Well-tolerated with an excellent safety profile |
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Modulating target biological pathway (Nrf2)
and supporting an anti-inflammatory mechanism |
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Suitable for once-daily oral dosing |
Mechanistic results and data from clinical trials of bardoxolone
methyl have been presented at major scientific meetings. In
2009, there were two oral presentations at the American Diabetes
Association's 69th Annual Meeting in June, two posters at the
National Kidney Foundation's Spring Clinical Meeting in late
March, and four posters at the American Society of Nephrology
Renal Week in late October through early November. Data is
continuing to be presented at key scientific meetings in 2010.
Two Phase 1 clinical studies of bardoxolone
demonstrated that the drug improved markers of renal function in a
high percentage of patients. To confirm these findings, Reata initiated a Phase 2a proof of concept study in patients with moderate to severe chronic kidney disease and type 2 diabetes mellitus. Based on highly promising results in this completed trial, Reata has advanced bardoxolone methyl into a larger
pivotal Phase 2b study
in a similar patient population, and results from the primary,
6-month
endpoint have recently been analyzed. Data from both the
primary endpoint and the secondary, 12-month endpoint for this
Phase 2b trial will be available in the second half of 2010. A second pivotal, Phase 3 trial in
chronic kidney disease patients with type 2 diabetes mellitus is
also scheduled to begin in the second half of 2010. In
addition, pivotal
studies in non-diabetic chronic kidney disease patients are being planned.
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Chronic kidney disease (CKD) is a progressive loss of kidney
function over a period of months or years, which can be caused by a
number of conditions, including diabetes and high blood pressure. As
kidney function declines, wastes can build to high levels in the blood, and patients may develop complications like high blood pressure, anemia (low blood count), weak bones, poor nutritional health and nerve damage. CKD also increases the risk of having heart and blood vessel disease. Early detection and treatment can often keep chronic kidney disease from
worsening. As kidney disease progresses, it may eventually lead to kidney failure, requiring dialysis or a kidney transplant.
Chronic Kidney Disease
Prevalence and Mortality
The prevalence of chronic kidney disease has
increased by 16 percent over the last 10 years as a
result of the increasing incidence of diabetes mellitus,
hypertension, obesity and an aging population. A recent
report by the Centers for Disease Control determined
that more than one in six adults (or 26 million
Americans) have CKD. More than 400,000 patients are
currently on dialysis or have received kidney
transplants. CKD is more prevalent among individuals older than 60 years of age and among Hispanic, African American, Asian or Pacific Islander and Native American populations.
About 67,000 people die each year because of
kidney failure, and the expected remaining lifetimes for the CKD
population on kidney replacement therapy is less than one-fourth of
that of the general US population. The five-year survival rate
for US end-stage renal disease patients is only 38%, a prognosis
that is worse than for many forms of cancer including colon, breast
and prostate.
Risk Factors
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Diabetes - approximately
40 percent of diabetics, or 6 million people, are estimated to
have CKD, classifying them as having diabetic chronic kidney
disease, which results from longstanding diabetes mellitus and
is one of the primary causes of dialysis and kidney
transplantation. The average time from diagnosis of CKD to
end-stage renal disease is 16 years. |
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High blood pressure - independent of diabetic status, hypertension aids in the
progression of CKD and is the second leading cause of
end-stage renal disease. |
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Family history of kidney
failure – individuals who have a blood relative with kidney
failure are at increased risk for CKD. |
Screening Recommendations
The National Kidney Foundation (NKF) recommends that as a measure to control CKD, individuals who are at risk for the disease be tested for undetected kidney disease during routine health care encounters. Three simple, standardized tests are used to detect kidney disease: blood pressure measurement, urine test for protein and blood test for creatinine, which is used to calculate the level of kidney function. NKF recommends that patients with diabetes should be screened annually for CKD, with initial screening beginning five years after the diagnosis of type 1 diabetes and at the diagnosis of type 2 diabetes.
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