Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects

Abstract

Bardoxolone methyl is an antioxidant inflammation modulator acting through induction of Keap1-Nrf2 pathway. Results from a recent phase IIb clinical trial reported that bardoxolone methyl was associated with improvement in the estimated glomerular filtration rate in patients with advanced chronic kidney disease and Type 2 diabetes. However, increases in albuminuria, serum transaminase, and frequency of adverse events were noted. We studied the effect of 3-mo treatment with RTA 405, a synthetic triterpenoid analog of bardoxolone methyl in Zucker diabetic fatty rats with overt Type 2 diabetes. Rats were treated from 3 mo of age with vehicle, RTA 405, ramipril, or RTA 405 plus ramipril. RTA 405 caused severe changes in food intake and diuresis with decline in body weight, worsening of dyslipidemia, and increase in blood pressure. Early elevation in serum transaminase was followed by liver injury. RTA 405 worsened proteinuria, glomerulosclerosis, and tubular damage. Ramipril was renoprotective, but when given with RTA 405 it was not able to limit its worsening effects. These data could be due to degradation products in the drug substance used, as disclosed by the company once the study was concluded. To overcome such a drawback, the company offered to test dh404, a variant of RTA 405, in Zucker diabetic fatty rats. The dh404 did not display beneficial effects on proteinuria, glomerulosclerosis, and interstitial inflammation. Rather, kidneys from three rats receiving dh404 showed the presence of a granulomatous and inflammatory process reminiscent of a pseudotumor. Altogether these data raise serious concerns on the use of bardoxolone analogs in Type 2 diabetic nephropathy.

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…This was associated with attenuation of oxidative stress, inflammation, and glomerular and tubulo-interstitial lesions, and partial improvement of renal function confirming the results of recent studies (30)(31)(32). In contrast, dh404 treatment at 10 mg/kg/day dosage resulted in intensification of proteinuria, deterioration of renal function and histological lesions, and amplification of oxidative stress and inflammation, confirming the effects observed in the Zucker rats with diabetic nephropathy and ApoE deficient mice with streptozoticineinduced diabetes [29,33]. Taken together these findings indicate the dose dependent dimorphic actions of Bardoxolone methyl analogs on CKD progression with favorable effect at a low drug dosage and toxic effects at a high dosage.…”

“…Furthermore due to increased mortality from congestive heart failure the multi-center, randomized, placebo-controlled, Phase 3 clinical trial of a bardoxolone methyl analog in type 2 diabetic patients with stage 4 CKD (BEACON trial) was terminated [28]. Finally in a recent study Zoja et al [29] found substantial weight loss, anorexia, liver injury, exacerbation of proteinuria, dyslipidemia, glomerulosclerosis, and tubular damage with long term administration of the bardoxolone analogues, RTA 405 (50 and 100 mg/kg/day) and dh404 (5 and 25mg/kg/day) in obese Zucker rats with type-2 diabetes and nephropathy. These observations raised doubt about the potential efficacy of the bardoxolone methyl analogs in Type 2 diabetic nephropathy.…”

“…It is of note that, many natural Nrf2 inducing phytochemicals have hormetic properties with beneficial effects at nanomolar concentrations and toxic effects at higher concentrations [34,35]. It is, therefore, conceivable that the divergent response to bardoxolone analogues reported in the experimental animals [29][30][31][32][33] represents a shared hormetic property with their natural counterparts. The present study was undertaken to explore the impact of BARD analogue, dh404, dosage on kidney tissue Nrf2-Keap1, NFkB, fibrotic, and oxidative pathways as well as renal structure and function in rats with CKD induced by 5/6 nephrectomy.…”

Downregulation of Nuclear Factor Erythroid 2–Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension

“…23 On the other hand, in Zucker diabetic fatty rats, a model of type 2 diabetes mellitus with progressive renal disease treatment with RTA 405, a bardoxolone analogue, caused worsening of proteinuria, glomerulosclerosis, and tubular damage. 24,25 Clinical studies have also shown discordant results. In the phase II Trial to Determine the Effects of Bardoxolone Methyl on eGFR in Patients With Type 2 Diabetes and Chronic Kidney Disease (BEAM study), patients with chronic kidney disease treated with bardoxolone had significantly improved renal function.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Recently, triterpenoid analogue, bardoxolone methyl, showed improved renal function in early-stage chronic kidney disease in type 2 diabetes; however, Phase III clinical trial with this compound for very severe-stage patients was halted due to undisclosed safety issues (Reata Phamaceuticals) (Clinical Trials.gov; NCT01351675). Moreover, the recent study by Zoja et al has shown that bardoxolone analogues are ineffective in curing diabetic nephropathy in Zucker diabetic fatty rats but instead, the rats receiving such analogues worsen the outcome of the disease (476). While the CDDO-Im potently activates Nrf2 target genes in multiple tissues, proteomic analysis recently revealed that this CDDO-Im interacts with *600 different proteins, including many different transcription factors (464).…”