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.
I have a family member who lives in Iran and is very ill. He has found out about this study and has asked me to send him the treatment (bardoxolone 75) and possibly become involved with the third phase of the study as a patient. What is the best way to approach these challenges? Thanks in advance.
hello: I have a family member who lives in Iran and is very ill. He has found out about this study and has asked me to send him the treatment (bardoxolone 75) and possibly become involved with the third phase of the study as a patient. What is the best way to approach these challenges? Thanks in advance.
NEJM publication – now showing *sustained* benefit out to 52 weeks. Also (importantly), benefit seems to persists for at least 4 weeks after the drug is withdrawn, suggesting this is *NOT* merely hyperfiltration effect.
Not sure about the phase III trial. You can always check clinical trials.gov @ http://clinicaltrials.gov/ct2/home I typed in Bardoxolone and didn't see the phase III trial. Its called the BEACON Study and is scheduled to begin enrollment in mid 2011 according to the Reata (drug company that makes the drugs) website.
Has Phasse III started? If so, when did it start?
My wife is in Stage 3 or 4 CKD having first been diagnosed in August of 2010. Can you tell me who to contact about getting into a trial group?
RE: soft endpoints. Strictly speaking, "all cause mortality" has not been convincingly demonstrated for the entire class of statins either, yet surrogate endpoints (i.e., reductions in cholesterol, nonfatal events) are used routinely to judge efficacy.
Similarly, delaying dialysis is a worthwhile goal in its own right for similar quality of life reasons, even if all-cause mortality remains unchanged. If sustainable, improved blood chemistry could produce such delays.
Unless Bardoxolone-induced adverse events over the long haul turn out to be comparable the KNOWN mortality risks of ESRD and dialysis (20%/year)–this still appears to be a significant development.
Reported results seem too dramatic (and too hard to fake) to be just smoke and mirrors aimed at attracting venture capital.
A little optimism!
Thanks for the comments. I changed AIM to Antioxidant Inflammation Modulator. Where did you get the information on the phase 3 study? just curious.
AIM: Antioxidant Inflammation Modulator. Effects on proteinuria were variable. GFR is being measured in a subset of patients in Phase 3 study and there will be hard endpoints.
Gearoid- agree completely… Which is why the word "preliminary" is emphasized. I would be curious to see if weight loss had anything to do with the "increased GFR". The proteinuria and BP effects would be interesting as well. I wonder what the phase III clinical trial will have as end points. My guess it that it will still have "soft" endpoints.
Yet another nephrology study using a surrogate end-point to show effectiveness. Really interesting results but one has to ask how does it increase GFR? Is there a hyperfiltration effect? What is the effect on long-term function? Is there any effect on proteinuria? Patients with diabetes have an increased GFR early in the disease but no-one would suggest that this is good for them. Similarly, as you mentioned, ACEi decrease GFR but improve long-term renal survival.
Wow! Aquarter of pts with more than 50% increase! Too good to be true. I think this would be the first drug that actually 'increases' the gfr