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.