Bardoxolone methyl (other names “RTA 402” and “CDDO-methyl ester”) is a synthetic oleananetriterpenoid that is an orally-available first-in-class antioxidant inflammation modulator (AIM). It is the most potent known inducer of the Keap1-Nrf2pathway to enter clinical development and works to suppress both oxidative stress and inflammation.
Pathogenesis:
Oxidative stress and inflammation are thought to be key drivers of the fibrotic process in CKD inducing structural changes within the glomerulus.
Reactive Oxygen and Nitrogen species (ROS) activate NF-kB, which activates various pro-inflammatory mediators, resulting in oxidative stress.
This then results in chronic inflammation and fibrosis, thus causing chronic kidney diseases.
Scientists at Reata Pharma, explored
this pathway, and developed some compounds, which are potent inducers of the transcription factor Nrf2.
Nuclear factor-erythroid-related factor 2 (Nrf2) plays a critical part in basal activity and coordinated induction of genes encoding numerous antioxidant and phase II detoxifying enzymes (including catalase, superoxide dismutase, glutathionse s-transferase etc.).
Mechanism of Action:
Bardoxolone, their most active compound, acts as an Anti-inflammation Mediators (AIMs) and activates Nrf2, causing causing increased production of over 250 antioxidant enzymes and resulting in the inhibition of pro-inflammatory transcription factors, such as NF-κB and STAT3.
Thus AIMS provide a vital mechanism based relief from oxidative stress and damage to the neprons, thus proving to be a key player in CKD clinical control.
Bardoxolone in Clinical Trials:
Clinical observations in Phase 2 studies with bardoxolone methyl have included the following:
This treatment has the potential to dramatically change the treatment landscape, Current therapies only modestly slow the progression of the disease, while bardoxolone has the potential to markedly improve patient outcomes. It has been proposed to lengthen the lives of patients without the need of undergoing the ardent task of constant dialysis.
With more varied implications of AIMs in many diseases like Parkinson's,alzheimers, Cancer, etc. due to its anti-oxidant and anti-inflammatory action, Bardoxolone sets the right parameters to be a potential Mega Blockbuster in the near future!!
*as per Fierce Pharma report.
Know more about clinical trials of Bardoxolone from: http://www.nejm.org/doi/pdf/10.1056/NEJMc1110239
To know more about Chronic kidney Disease, Click here
The drug: Bardoxolone
The Disease: Chronic Kidney Disease
The Develepors: Reata and Abott Pharma
Peak Projections: Several billion plus*
Bardoxolone methyl is currently being developed in late-stage clinical trials by Reata Pharmaceuticals, Inc. for the treatment of moderate to severe chronic kidney disease (CKD) in type 2 diabetes mellitus patients.
Pathogenesis:
Oxidative stress and inflammation are thought to be key drivers of the fibrotic process in CKD inducing structural changes within the glomerulus.
Reactive Oxygen and Nitrogen species (ROS) activate NF-kB, which activates various pro-inflammatory mediators, resulting in oxidative stress.
This then results in chronic inflammation and fibrosis, thus causing chronic kidney diseases.
In vivo data indicates that the Keap-Nrf2 pathway is suppressed in models of kidney fibrosis whilst there is a simultaneous increase in oxidative stress and inflammation.Thus, activating this pathway, may lead to improved conditions in chronic kidney diseases.
Scientists at Reata Pharma, explored this pathway, and developed some compounds, which are potent inducers of the transcription factor Nrf2.
Nuclear factor-erythroid-related factor 2 (Nrf2) plays a critical part in basal activity and coordinated induction of genes encoding numerous antioxidant and phase II detoxifying enzymes (including catalase, superoxide dismutase, glutathionse s-transferase etc.).
Mechanism of Action:
Bardoxolone, their most active compound, acts as an Anti-inflammation Mediators (AIMs) and activates Nrf2, causing causing increased production of over 250 antioxidant enzymes and resulting in the inhibition of pro-inflammatory transcription factors, such as NF-κB and STAT3.
Thus AIMS provide a vital mechanism based relief from oxidative stress and damage to the neprons, thus proving to be a key player in CKD clinical control.
Bardoxolone in Clinical Trials:
Clinical observations in Phase 2 studies with bardoxolone methyl have included the following:
- Significant and sustained improvements in eGFR.
- Increased creatinine clearance, with no decrease in 24-hour creatinine excretion.
- Parallel improvements in other measures of kidney function, including blood urea nitrogen and uric acid, which correlate with the improvement in eGFR.
- Persisting increase in eGFR from baseline following withdrawal of therapy (when the drug has largely been cleared out of the body).
Reata started enrolling patients for the Phase III on bardoxolone last summer. As per Reata CEO Warren Huff, the process is running ahead of schedule, leaving them on track to wrap in the summer of 2013 with a possible approval in 2014.
A Blockbuster deal:
Recently,Reata Pharmaceuticals snagged a $450 million quick-cash deal with Abbott on the ex-U.S. rights to bardoxolone, which is the focus of a big pivotal study. Now Abbott, is committing itself to a long-term future with Reata in what amounts to an unusually large cash commitment to a preclinical venture.
In the deal, Abbott and Reata have agreed to share the costs and profits on the biotech's antioxidant inflammation modulators(AIM). The two companies also agreed to collaborate on discovery work related to other drugs that can be derived from the AIM program. The first human study of a preclinical drug covered by the partnership is slated to begin in 2012.
This treatment has the potential to dramatically change the treatment landscape, Current therapies only modestly slow the progression of the disease, while bardoxolone has the potential to markedly improve patient outcomes. It has been proposed to lengthen the lives of patients without the need of undergoing the ardent task of constant dialysis.
With more varied implications of AIMs in many diseases like Parkinson's,alzheimers, Cancer, etc. due to its anti-oxidant and anti-inflammatory action, Bardoxolone sets the right parameters to be a potential Mega Blockbuster in the near future!!
*as per Fierce Pharma report.
Know more about clinical trials of Bardoxolone from: http://www.nejm.org/doi/pdf/10.1056/NEJMc1110239
To know more about Chronic kidney Disease, Click here
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