Sp121a Phase 2/3 Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome

Groß, Oliver; Appel, Gerald R; Block, Geoffrey A.; Chin, Melanie; Goldsberry, Angie; Inker, Lesley A.; Meyer, Colin; Pèrgola, Pablo E.; Simon, James F.; Warady, Bradley A.; Zaoui, P.; Rheault, Michelle N.; Kashtan, Clifford E.

doi:10.1093/ndt/gfy104.sp121

Cited by 5 publications

(3 citation statements)

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“…Several Nrf2 activators were currently being tested in human clinical trials. For instance, bardoxolone methyl is an OA derivative tested in the Phase II/III clinical trials for the treatment of Alport syndrome, a genetic disorder characterized by glomerulonephritis, eye abnormalities, and hearing loss ( Chin et al, 2018 ; Gross et al, 2018 ). Bardoxolone methyl activates Nrf2 by disrupting the Nrf2/Keap1 interaction and inhibits IKKβ kinase activity ( Wang et al, 2014 ).…”

Section: Recent Insights Of the Clinical Investigation Of Nrf2-activamentioning

confidence: 99%

The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches

et al. 2018

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Cardiovascular diseases (CVDs) are closely linked to cellular oxidative stress and inflammation. This may be resulted from the imbalance generation of reactive oxygen species and its role in promoting inflammation, thereby contributing to endothelial dysfunction and cardiovascular complications. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a significant role in regulating expression of antioxidant and cytoprotective enzymes in response to oxidative stress. Natural products have emerged as a potential source of bioactive compounds which have shown to protect against atherogenesis development by activating Nrf2 signaling. This review aims to provide a comprehensive summary of the published data on the function, regulation and activation of Nrf2 as well as the molecular mechanisms of natural products in regulating Nrf2 signaling. The beneficial effects of using natural bioactive compounds as a promising therapeutic approach for the prevention and treatment of CVDs are reviewed.

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Section: Recent Insights Of the Clinical Investigation Of Nrf2-activamentioning

confidence: 99%

The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches

et al. 2018

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“…This includes cerivastatin-a HMG-CoA reductase inhibitor that targets the TGFβ1 pathway, and vasopeptidase inhibitor AVE7688, which had anti-fibrotic and anti-inflammatory effects [315,316], while targeting STAT3 signalling also attenuates disease progression in mice [317]. Finally, phase 3 clinical trials are progressing with bardoxolone (BARD) [318], which has anti-fibrotic and anti-inflammatory effects. BARD does increase glomerular filtration rates in AS patients, which has raised debate as to whether this represents a potential risk [319].…”

Section: Gene Therapy and Therapies Targeting Downstream Mechanismsmentioning

confidence: 99%

Collagen IV-Related Diseases and Therapies

Dean

Agtmael

2021

The Collagen Superfamily and Collagenopathies

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While traditionally the function of the extracellular matrix and the basement membrane was considered to be providing structural support, it is now clear that this only covers one aspect of its multiple functions. This is also illustrated by our growing knowledge of the role of collagen IV, a major component of basement membranes, in development, health and disease. With the extracellular matrix and collagen IV increasingly being recognised as key players in a growing number of diseases from stroke and vascular defects to kidney disease, deafness and eye abnormalities, it is paramount that we increase our fundamental understanding of these complex molecules ranging from their biosynthesis to their role in human disease.Recently, exciting progress has been made in delineating the mechanisms by which mutations in collagen IV cause disease, and these are being exploited to develop mechanism-based treatments. Yet many important questions remain that need addressing to develop treatments for diseases associated which collagen IV.

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“…Interestingly, inhibition of TGF-β signalling using losartan was also effective in RDEB, indicating that convergent downstream pathways represent a potential effective target for different phenotypes. Finally, the compound bardoxolone, which reduces inflammation and fibrosis in chronic kidney disease, is currently in a clinical trial for AS [119]. However as bardoxolone increases glomerular filtration rate, which may elevate the stress on the damaged GBM of Alport patients, this approach remains debated [158].…”

Section: Treatment Interventionmentioning

confidence: 99%

Basement membrane collagens and disease mechanisms

Gatseva

Sin

Brezzo

et al. 2019

Essays in Biochemistry

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Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major BM collagen, collagens VI, VII, XV, XVII and XVIII are also present. Mutations in these collagens cause rare multi-systemic diseases but these collagens have also been associated with major common diseases including stroke. Developing treatments for these conditions will require a collective effort to increase our fundamental understanding of the biology of these collagens and the mechanisms by which mutations therein cause disease. Novel insights into pathomolecular disease mechanisms and cellular responses to these mutations has been exploited to develop proof-of-concept treatment strategies in animal models. Combined, these studies have also highlighted the complexity of the disease mechanisms and the need to obtain a more complete understanding of these mechanisms. The identification of pathomolecular mechanisms of collagen mutations shared between different disorders represent an attractive prospect for treatments that may be effective across phenotypically distinct disorders.

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Sp121a Phase 2/3 Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome

Cited by 5 publications

References 0 publications

The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches

The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches

Collagen IV-Related Diseases and Therapies

Basement membrane collagens and disease mechanisms

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