To understand is to forgive?
Clearly the clinical development program for Bardoxolone methyl has been a disaster. Did the study published in the NEJM in 2011 by Pablo Pergola et al overestimate a treatment benefit of Bardoxolone?
Recall that Bardoxolone methyl is an oral antioxidant inflammation modulator that entered the limelight as a promising treatment for slowing progression of diabetic nephropathy.
A key finding from the NEJM report:
"The estimated GFR increased within 4 weeks after the initiation of treatment in the three bardoxolone methyl groups. The value peaked at 12 weeks
and remained relatively stable through 52 weeks. At 24 weeks, there was significant improvement in the primary end point (change
from baseline in the estimated GFR) in all bardoxolone methyl groups, as compared with the
placebo group, with mean differences per minute per 1.73 m2 of 8.2±1.5 ml in the 25-mg group,
11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml
in the 150-mg group (P less than 0.001 for all comparisons)."
But, one needs to look to the Supplementary Information section in the NEJM article to understand if an alternative explanation could be invoked to explain this increase in estimated GFR.
The answer?
The patients in the treatment arm had substantial weight loss following treatment with Bardoxolone. Consequently, it is likely that treatment with Bardoxolone resulted in loss of lean body mass. Since only predicted GFR was provided in the paper and not other hard measures of kidney function such as ESRD rates or doubling of creatinine, the progressive loss in body mass might be an explanation for why the estimated GFR increased at 52 weeks (lower levels of creatinine production leads to lower serum creatinine production and excretion).
Another red flag was that albuminuria increased with Bardoxolone treatment. If Bardoxolone was truly slowing the progression of diabetic kidney disease one would have expected a reduction in albuminuria that mirrored the improvement in kidney function.
There were other concerns about the Pergola study - the high rate of hypomagnesemia, the litany of adverse effects - chief among these being nausea, fatigue and muscle spasms.
But, one needs to look to the Supplementary Information section in the NEJM article to understand if an alternative explanation could be invoked to explain this increase in estimated GFR.
The answer?
The patients in the treatment arm had substantial weight loss following treatment with Bardoxolone. Consequently, it is likely that treatment with Bardoxolone resulted in loss of lean body mass. Since only predicted GFR was provided in the paper and not other hard measures of kidney function such as ESRD rates or doubling of creatinine, the progressive loss in body mass might be an explanation for why the estimated GFR increased at 52 weeks (lower levels of creatinine production leads to lower serum creatinine production and excretion).
Another red flag was that albuminuria increased with Bardoxolone treatment. If Bardoxolone was truly slowing the progression of diabetic kidney disease one would have expected a reduction in albuminuria that mirrored the improvement in kidney function.
There were other concerns about the Pergola study - the high rate of hypomagnesemia, the litany of adverse effects - chief among these being nausea, fatigue and muscle spasms.
