Bardoxolone Methyl Brings Hope For Prevention Of End Stage Renal Disease In Type 2 Diabetes Patients

By STEPHANIE A. BURTON | Pharm.D. Candidate

The National Institutes of Health (NIH) estimates that 8.3% (25.8 million) of the United States population has diabetes, which is the leading cause of kidney failure.1 The most recent estimation of the annual cost of treatment of end stage renal disease is $42.5 billion.2 Current treatment guidelines recommend controlling blood pressure, glycosylated hemoglobin levels and cholesterol levels, smoking cessation, and  using an angiotensin converting enzyme inhibitor or angiotensin receptor blocker to slow the progression of kidney damage in diabetes patients.3 Given the impact of these disease processes on both quality of life and healthcare costs the development of new agents for use is truly needed.

Bardoxolone methyl is not on pharmacy shelves yet but there are still plenty of reasons to learn about the first agent in a new class of drugs named Antioxidant Inflammation Modulators (AIMs). Developed by Reata Pharmaceuticals, Inc. and now in a phase III trial, bardoxolone methyl could be the next important break in the treatment of chronic kidney disease in type 2 diabetes patients. Beneficial effects of this compound and similar compounds are also being researched for medicinal use in the treatment of several other chronic inflammatory processes, neurological disorders, immunologic disorders, infectious diseases, and cancer.

Development of Bardoxolone Methyl

Born in a laboratory at Dartmouth College in New Hampshire, bardoxolone methyl was the successful result of an attempt to synthesize potent anti-inflammatory agents from the naturally occurring anti-inflammatory, anti-carcinogenic, and anti-microbial compounds oleanolic acid (readily extractable from olive trees) and ursolic acid.4 These compounds are part of a large class of structures called triterpenoids, which are synthesized by many plants and have already been recognized for their beneficial effects. Some common food sources of terpenoids include broccoli, brussel sprouts, and cabbage and terpenoids are also found in common remedies such as menthol and camphor.

Scientists identified the parent molecule of what we now know as bardoxolone methyl by screening derivatives of oleanolic and ursolic acid for their ability to suppress levels of inducible nitric oxide synthase (iNOS). Because iNOS leads to the formation of nitric oxide, which is a signaling molecule in one cascade of biochemical processes that can lead to inflammation,5 researchers sought the most potent inhibitor of this enzyme for further development. The most eligible derivative was from oleanolic acid and, after further modifications, was found to be about 400,000 times more potent than oleanolic acid in the iNOS test4 and 100-500 times more potent than any other known triterpenoid.6 This molecule and similar molecules from oleanolic acid are called synthetic oleanane triterpenoids and bardoxolone methyl is one such molecule.

Mechanism of Action of Bardoxolone Methyl

Although there may be multiple mechanisms through which bardoxolone methyl produces beneficial effects it is known that one mechanism is activation of the nuclear factor erythroid 2-related factor 2 Kelch-like ECH-associating protein 1 (Nrf2-Keap1) pathway. 7 The Nrf2-Keap1 pathway acts as a transcription factor for an antioxidant response element (ARE) that initiates the transcription of genes coding for detoxifying phase II enzymes and proteins that dispose of electrophiles and oxidants.8,9 Increased production of these enzymes and proteins causes increased production of direct antioxidants,10,11 increased production and regeneration of glutathione,12 increased NADPH synthesis,13,14 increased efflux of toxins from cells,14 increased ability of the cell to repair damaged proteins,15 and decreased cytokine-mediated inflammation.16

The potential therapeutic applications for bardoxolone methyl are vast considering many chronic disease processes have been linked to inflammation. Other less defined mechanisms are also being observed specifically in type 2 diabetes. Oleanic acid (the parent molecule of bardoxolone methyl) has been shown to decrease blood glucose, insulin resistance, gluconeogenesis, and weight in animal models with type 2 diabetes.17 Therapeutic application to renal disease is based on research demonstrating that Nrf2-Keap1 pathway activation is decreased in chronic kidney disease as well as the enzymes produced through its activation.18 With beneficial effects for both disease processes, bardoxolone methyl and similar drugs maybe especially useful in type 2 diabetes patients with chronic kidney disease.

Bardoxolone Methyl
in Clinical Research

After recent completion of a Level I trial confirming the positive impact of bardoxolone methyl on kidney function in type 2 diabetes patients with chronic kidney disease it is now in a Phase III trial to evaluate the ability of the drug to delay the onset of end stage renal disease or cardiovascular death.19 In the Phase II BEAM trial the drug improved the estimated glomerular filtration rate (eGFR) by about 10 mL/min/1.73 m2 in just six months with the change sustained at twelve months.20 Although this change is very significant for patients with moderate-to-severe chronic kidney disease the clinical significance of a change in a 10 mL/min/1.73 m2 eGFR is not known. The results of the Phase III study will determine the clinical utility of this drug in improving outcomes of type 2 diabetes patients with chronic kidney disease.

In the BEAM study the main adverse effects of bardoxolone methyl were hypomagnesemia, transient increased alanine aminotransferase levels, and gastrointestinal side effects.20 Interestingly 54% of subjects taking the study drug experienced muscle spasms but this side effect was not associated with increased levels of lactate dehydrogenase (marker of muscle damage) or hypomagnesemia. Investigators believe the muscle spasms are the result of increased glucose uptake in the calf muscle, which has been demonstrated to occur in mice taking bardoxolone methyl and has been previously associated with muscle spasms in humans. Data from the study suggests hypomagnesemia may be dose-dependent and therefore may be less frequent in the Phase III trial in which a smaller dose of bardoxolone methyl is being used.

Conclusion

The development of synthetic triterpenoid compounds may be expanding treatment options for many types of patients while giving others another reason to eat their vegetables. The development of synthetic oleanane triterpenoids has multiple theoretical therapeutic applications with chronic kidney disease in type 2 diabetes patients likely being the first application realized. The delay of end stage renal disease is priceless to patients with chronic kidney disease but would also have a significant impact on healthcare dollars. As bardoxolone methyl continues in Phase III practitioners anticipate the welcomed addition of a new class of agents that may significantly impact the treatment of type 2 diabetes patients with chronic kidney disease.References

1. National Diabetes Statistics, 2011. National Diabetes Information Clearinghouse (NDIC) U.S. Department of Health and Human Services. Available at: http://diabetes.niddk.nih.gov/DM/PUBS/statistics/#Kidney. Accessed: 30 January 2012.

2. 2011 Atlas of CKD & ESRD. United States Renal Data System. Available at: http://www.usrds.org/atlas.aspx. Accessed: 30 January 2012.

3. Handelsman Y, Mechanick JI, Blonde L, et al. AACE Task Force for Developing Diabetes Comprehensive Care Plan. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011 Mar-Apr;17(Suppl 2):1-53.

4. Sporn MB, Liby KT, Yore MM, Fu L, Lopchuk JM, Gribble GW. New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J. Nat. Prod. 2011;74:537-545.

5. Moncada S, Higgs EA. Molecular mechanisms and therapeutic strategies related to nitric oxide. The FASEB Journal. 1995;9:1319-1330.

6. Suh N, Wang Y, Honda T, et al. A novel synthetic oleanane triterpenoid, 1-cyano-2,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antipfroliferative, and anti-inflammatory activity. Cancer Res. 1999;59:336-341.

7. Liby K, Hock T, Yore MM, et al. The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res. 2005;65(11):4789-4798.

8. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 2007;47:89-116.

9. Venugopal R, Jaiswal AK. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene. 1998;17:3145-3156.

10. Prestera T, Talalay P, Alam J, Ahn YI, Lee PJ, Choi AM. Parallel induction of heme oxygenase-1 and chemoprotective phase 2 enzymes by electrophiles and antioxidants: regulation by upstream antioxidant-responsive elements (ARE). Mol. Med. 1995;1:827-837.

11. Primiano T, Kensler TW, Kuppusamy P, Zweier JL, Sutter TR. Induction of hepatic heme oxygenase-1 and ferritin in rats by cancer chemoprotective dithiolethiones. Carcinogenesis. 1996;17:2291-2296.

12. Moinova HR, Mulcahy RT. Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding Nrf-2 to an electrophile responsive element. Biochem. Biophys. Res. Commun. 1999;261:661-668.

13. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S. Identification of Nrf2-regulated genes induced by chemopreventive agent sulforaphane by oligonucleotide microarray. Canc. Res. 2002;62:5196-5203.

14. Hayashi A, Suzuki H, Itoh K, Yamamoto M, Sugiyama Y. Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem. Biophys. Res. Commun. 2003;310:824-829.

15. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol. Cell. Biol. 2003;23:8786-8794.

16. Primiano T, Li Y, Kensler TW, Trush MA, Sutter TR. Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention. Carcinogenesis 1998;19:999-1005.

17. Wang X, Li Y, Wu H, et al. Antidiabetic effect of oleanolic acid: a promising use of a traditional pharmacological agent. Phytother. Res. 2011;25:1031-1040.

18. Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am. J. Physiol. Renal Physiol.2010;298:F662-F671.

19. Bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes (BEACON). Reata Pharmaceuticals, Inc. Available at: http://clinicaltrials.gov/ct2/show/NCT01351675?term=bardoxolone+methyl&rank=5. Accessed 30 January 2012.

20. Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 2011;365(4):327-336.

Comments

  1. Moreover, intake of fibre rich fruits helps in maintaining cholesterol level which often normalizes the
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