One of the issues surrounding the study of bardoxolone in animal models was that, because of the way that it is metabolized in rats and mice, it is highly toxic when given for long periods. This specific toxicity is not present in humans. As a result, it was not possible to study the drug directly. An alternative was to study analogues of the drug. A group from Italy have just published the results of a study of an analogue of bardoxolone, RTA 405, in rats with type 2 diabetes. This study was accepted for publication before the termination of the beacon trial but raised some important concerns which are even more salient now.
RTA 405 caused significant weight loss and elevation of transaminases in treated rats. Also, proteinuria increased threefold. When this rat model is treated with ACEi, there is normally a decrease in proteinuria and renal damage. When the rats were treated with RTA 405 and an ACEi simultaneously, there was some reduction in proteinuria but not to baseline. The proteinuria was accompanied by evidence of severe glomerular and tubular damage.
It is possible that these results are due to a metabolite of RTA 405 which may not be present in humans and as a result, the findings are not necessarily generalizable to humans. However, these adverse effects are similar to those initially reported in the NEJM . The mechanism for the increased renal injury is uncertain at this time.