Preliminary results from a phase IIb clinical trial funded by Reata Pharmaceuticals and Abbott were presented at ASN Renal Week 2010 in Denver, CO last month. This study looked at the novel drug bardoxolone (RTA 420) in diabetic CKD.
Bardoxolone is a first-in-class drug touted as an antioxidant inflammatory modulator (AIM). It is a potent inducer of the Nrf2 pathway. Nuclear factor-erythroid-related factor 2 (Nrf2) plays a critical part in basal activity and coordinated induction of genes encoding numerous antioxidant and phase II detoxifying enzymes (including catalase, superoxide dismutase, glutathionse s-transferase etc.). Nrf2 is ubiquitously expressed, but is dispensable for normal development. Nrf2 KO mice have decreased phase II detoxifying enzymes and endogenous antioxidants. Nrf2 was originally identified for its anti-cancer properties and substantial efforts are underway to develop Nrf2 inducers in a variety of malignancies. Reactive oxygen species generation (oxidative stress) has been linked to the pathogenesis of many human diseases other than cancer. There has been accumulating evidence of a protective role for Nrf2 many diseases such as Alzheimer's, Parkinson's, ischemia, aging, diabetes, cardiovascular disease, autoimmune disease and kidney disease. For a review click here.
This is an ongoing multicenter, randomized, double-blind trial funded by Reata and Abbott. The results are reported at 24 weeks of a planned 52 week study (which the investigators state they will begin to analyze in January 2011). 227 patients with CKD (eGFR 20-45) with type 2 diabetes were randomized to receive once-daily doses of placebo or 25, 75 or 150 mg doses of bardoxolone. Mean age- 67, mean diabetes duration- 18 yrs, average A1c- 7.2, mean BP 130/69, 75% were obese, baseline eGFR average- 32, all were on either ACEi or ARB. The primary endpoint was change in eGFR following 24 weeks of treatment.
At week 24, patients treated with bardoxolone had a mean increase in estimated GFR of over 10, compared with no change in the placebo group. Approximately three-fourths of bardoxolone treated patients experienced an improvement in eGFR of 10% or more, including one-fourth who saw an improvement of 50% or more compared to less than 2% of patients on placebo (P=0.001). Adverse events were higher in the bardoxolone group. The most frequently reported adverse events were muscle spasm (49% vs 12%), nausea (19% vs. 4%, hypomagnesemia (18% vs 4%), decreased appetite (15% vs 2%).
What do we make of these results? First- this is just preliminary results (24 out of 52 weeks) of a phase IIb clinical trial. Results of another phase II clinical trial were presented in 2009 at the American Diabetes Association showed significant reductions in creatinine, BUN, uric acid, A1c and phosphorus in the treatment group. It was refreshing to see several positive studies presented at Renal Week this year. However, we will have to wait for the 52 week results and a larger Phase III clinical trial which is expected to start at the end of this year to make any definitive conclusions. Secondly, the rate of adverse events will need to be addressed as 49% experiencing muscle spasms seems quite high. On a side note- it is well known that ACEi and ARBs cause an initial decrease in eGFR, however in the long term they delay the progression of CKD. So, it will be interesting to see if this increase in eGFR by bardoxolone holds up over time. We will see where this story goes.