Bardoxolone methyl (also known as “RTA 402”, “CDDO-methyl ester”, CDDO-Me, and more formally methyl bardoxolonate) is an experimental and orally-

bioavailable In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

semi-synthetic

triterpenoid Triterpenes are a class of chemical compounds composed of three terpene units with the molecular formula C30H48; they may also be thought of as consisting of six isoprene units. Animals, plants and fungi all produce triterpenes, including squale ...

, based on the scaffold of the natural product

oleanolic acid Oleanolic acid or oleanic acid is a naturally occurring pentacyclic triterpenoid related to betulinic acid. It is widely distributed in food and plants where it exists as a free acid or as an aglycone of triterpenoid saponins. Natural occurre ...

. Pre-clinical studies indicate that the compound acts as an activator of the

Nrf2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regul ...

pathway and an inhibitor of the

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

pathway. A

phase 3 clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

evaluating bardoxolone methyl for the treatment of chro nic kidney disease (CKD) was terminated in October 2012 after patients treated with the drug were found to have experienced a higher rate of heart-related adverse events, including heart failure, hospitalizations, and deaths. An advisory committee meeting of experts voted unanimously that bardoxolone methyl was not effective in slowing the progression of chronic kidney disease in

Alport syndrome Alport syndrome is a genetic disorder affecting around 1 in 5,000-10,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect v ...

and that its benefits did not outweigh its risks. A

Complete Response Letter In United States pharmaceutical regulatory practice, a Complete Response Letter (CRL), or more rarely, a 314.110 letter, is a regulatory action by the Food and Drug Administration in response to a New Drug Application, New Drug Application, Amended ...

from

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

stated a similar opinion.

Clinical development

Investigations of bardoxolone methyl have been conducted by

Reata Pharmaceuticals Reata Pharmaceuticals, Inc. is a pharmaceutical company based in Plano, Texas. Founded in 2002, Reata is primarily focused on investigating experimental oral antioxidative and anti-inflammatory drugs, which dually activate the antioxidative trans ...

in a partnership with

Abbvie AbbVie is an American publicly traded biopharmaceutical company founded in 2013. It originated as a spin-off of Abbott Laboratories. History On October 19, 2011, Abbott Laboratories announced its plan to separate into two publicly traded compan ...

and

Kyowa Hakko Kirin is a Japanese pharmaceutical and biotechnology company under the Kirin Holdings, and is among the 40 largest in the world by revenue. The company is headquartered in Chiyoda-ku, Tokyo and is a member of the Nikkei 225 stock index. History On J ...

. The UK based company e-Therapeutics has announced in late 2020 the possible development of Bardoxolone for anti-viral treatment of COVID 19(Coronavirus), and announced a possible phase 3 program to follow (https://www.etherapeutics.co.uk/wp-content/uploads/2021/02/RNAi-Press-Release.pdf accessed 16 Feb 2021).

Phase 1

Phase 1 clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

, sponsored by Reata, was conducted to determine the safety profile of and appropriate dosing for subsequent phase II studies, as well as to evaluate antitumor activity in patients with advanced solid tumor or lymphoid malignancy. Grade 3 reversible liver transaminase elevations were reported. The maximum tolerated dose was 900 mg/day.

NQO1 NAD(P)H dehydrogenase uinone1 is an enzyme that in humans is encoded by the ''NQO1'' gene. This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a 2-electron reductase (enzyme). This FAD-binding protein ...

mRNA levels, indicative of

pathway activation, were increased in

peripheral blood mononuclear cell A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (neu ...

s (PBMCs), and tumor biopsies showed decreased levels of

and

cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...

. An improvement in estimated

glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood p ...

(eGFR) in patients treated with bardoxolone methyl was noted, and based on this finding it was suggested by the authors that the drug might be beneficial for patients with CKD.

Phase 2

A Reata-funded,

Phase 2 Michael Lawrence Marrow (August 2, 1955 – December 12, 2019), known as PHASE 2 and Lonny Wood, was an American aerosol paint artist based in New York City. Mostly active in the 1970s, Phase 2 is generally credited with originating the "bubble l ...

multi-center RCT (BEAM) in patients with moderate to severe CKD and type 2 diabetes reported that eGFR was increased (> 10 ml/min/1.73 m²) in patients treated with bardoxolone methyl for 24 months. An analysis of secondary endpoints showed that approximately three-quarters of bardoxolone methyl-treated patients experienced at least a 10 percent increase in eGFR, and one-quarter of the patients had an improvement of 50%.

Adverse events An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can ther ...

in bardoxolone methyl-treated patients were generally manageable and mild to moderate in severity, with muscle spasm being reported most frequently. In 2014, Reata announced the initiation of a placebo-controlled, multicenter Phase 2 study (LARIAT), to assess the effects of bardoxolone methyl in pulmonary arterial hypertension.

Phase 3

A Phase 3 multinational RCT (BEACON) designed to test the effect of bardoxolone methyl on progression to

end-stage renal disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...

or cardiovascular death in patients with stage 4 CKD and type 2 diabetes was initiated by Reata in June 2011 and halted in October 2012 after bardoxolone methyl-treated patients were found to have experienced a higher rate of heart-related adverse events, including heart failure, hospitalizations, and deaths. A retrospective

post-hoc analyses In a scientific study, post hoc analysis (from Latin '' post hoc'', "after this") consists of statistical analyses that were specified after the data were seen. They are usually used to uncover specific differences between three or more group mea ...

of the Phase 3 data, conducted by Reata, identified prior hospitalization for

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

and the baseline level of

brain natriuretic peptide Brain natriuretic peptide 32 (BNP), also known as B-type natriuretic peptide, is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume. Along with NT-proBNP, BNP is on ...

, a marker of fluid retention, as predictors of heart failure hospitalizations in the BEACON trial. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl- and placebo-treated patients was similar.

Mechanism of action

Bardoxolone methyl is an activator of the

KEAP1 Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the ''Keap1'' gene. Structure Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 res ...

pathway in mice. Bardoxolone methyl also inhibits the pro-inflammatory transcription factor

in a tissue cultured human cell line.

References

{{DEFAULTSORT:Bardoxolone Methyl Kidney diseases Diabetes Orphan drugs