The Extinguished BEACON of Bardoxolone: Not a Monday Morning Quarterback Story

Abstract

NIH Public Access Author Manuscript Am J Nephrol. Author manuscript; available in PMC 2014 February 28. NIH-PA Author Manuscript Published in final edited form as: Am J Nephrol. 2013 ; 37(3): 208–211. doi:10.1159/000346950. The Extinguished Beacon of Bardoxolone: Not a Monday Morning Quarterback Story John A. Tayek, MD 1,* and Kamyar Kalantar-Zadeh, MD, MPH, PhD 2,3 1 Division of Endocrinology, Harbor-UCLA Medical Center, Torrance, CA 2 Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology & Hypertension, University of California Irvine Medical Center, Orange, CA 3 Department of Epidemiology, UCLA Fileding School of Public Health, Los Angeles, CA Text of the Editorial NIH-PA Author Manuscript The rise and fall of bardoxolone methyl, an oral antioxidant and anti-inflammatory modulator once hoped to be the ultimate silver bullet against diabetic nephropathy, is not a unique story in medicine. What was distinctive in this story, however, was the dramatically high level of enthusiasm about the miraculous effect of the drug after the publication of its Phase II trial in CKD patients, known as the BEAM Study. 1 In the said double-blind, randomized, placebo-controlled trial, 227 diabetic CKD patients (eGFR 20–45 ml/min/1.73 m 2 ) who had received placebo or bardoxolone at target doses of 25, 75, or 150 mg daily for 24 weeks, showed significant rise in the mean eGFR of +8.2, +11.4, and +10.4 ml/min/1.73 m 2 , respectively, compared to placebo, and the improvements apparently persisted up to 52 weeks. 1 The main mechanism of action of bardoxolone was believed to be the anti- inflammatory feature that was attributed to the activation of Nrf2, a ubiquitous transcription factor involved in the up-regulation of cytoprotective genes, inhibition of NF-κB, and decreased oxidative stress. 2 NIH-PA Author Manuscript The reported kidney function improvement of bardoxolone was remarkable, but so was the adverse event profile of the drug, which included worsening proteinuria, massive weight loss, muscle spasm, hypomagnesemia, liver function disarrays, and gastrointestinal effects, among others 1 (see Table 1). The calculation of eGFR in the BEAM Study was based on the level of serum creatinine, which is influenced by muscle mass and probably dietary meat intake. 3, 4 A dramatic weight loss differential of 10 to 20 lbs. was observed in patients who received bardoxolone vs. placebo; to be exact the bardoxolone weight loss was 7.7 to 10.1 kg, as compared to 2.4 kg in the placebo group. 3, 5 In a study, weight loss in diabetics patients reduced serum creatinine from 2.0 to 1.5 mg/dl (p<0.05), and eGFR increased by 13 ml/min. 6 In another study on obesity, an 8% weight loss increased eGFR by 8.9 ml/min by means of reducing serum creatinine. 7 Similarly fasting for Ramadhan increased eGFR likely due to loss of muscle and/or reduction dietary meat intake. 8 In dialysis patients serum creatinine is a robust correlate of muscle mass. 4 In the BEAM Study the 9% loss of weight, and likely skeletal muscle, probably reduced serum creatinine and increased eGFR by 8 to 11 ml/min. 1 The MDRD equation in this study uses serum creatinine, age, sex and race to estimate GFR. 9 Forty-two to 61% of patients on bardoxolone in the BEAM Study had Correspondence: Kamyar Kalantar-Zadeh, MD, MPH, PhD, Harold Simmons Center for Chronic Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, and 1124 West Carson Street, C1- Annex, Torrance, CA 90502, USA, Phone: 310-222-3891, Fax: 310-782-1837, kamkal@ucla.edu. *JAT is professor-in-residence of medicine at UCLA David Geffen School of Medicine and attending physician at Harbor-UCLA Medical Center,