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• W4294908588 abstract "CKD remains incurable and is a one-way journey leading to kidney failure. Interventions slowing CKD progression are of immense interest. Since the introduction of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers a few decades ago, the emergence of novel mineralocorticoid antagonists and sodium-glucose cotransporter-2 inhibitors revived the enthusiasm for delaying the progression of CKD. Recently, another class of drug that evoked curiosity is bardoxolone, which was termed a “blockbuster drug” foretoken not only to arrest CKD progression but also to improve kidney function. Bardoxolone is a novel drug that is a robust inducer of the Nrf2 pathway, which inhibits NF-κB, leading to antioxidant and anti-inflammatory effects (1). It was initially developed as a therapeutic modulator of inflammation-associated carcinogenesis (2). In a phase 1 first-in-human clinical trial of bardoxolone in cancer patients, an increase in eGFR was accidentally found (3). A pivotal role of inflammation involving the Nrf2 pathway in the pathogenesis and progression of CKD was observed in animal models (4). Next, multiple clinical trials tested the effect of this drug in CKD patients (5,6). The BEAM study (5) showed bardoxolone’s association with improvement in eGFR as early as 24 weeks lasting throughout 52 weeks. This energized nephrologists to execute BEACON study (6), which was terminated prematurely due to an increased risk of heart failure (HF) in the bardoxolone group. Later, a post hoc analysis (7) of the study showed that if patients with B type natriuretic peptide levels >200 pg/ml and a prior history of HF were eliminated, the risk of adverse effects in both the groups was comparably low at 2% (8). As a result, subsequent trials carefully excluded the patients who are at risk for fluid overload. Criticism arose for selecting the surrogate primary end point as eGFR. In response, a prospective phase 2 study—TSUBAKI (9)—used measured GFR with the gold standard inulin clearance method and showed a significant increase in measured GFR and eGFR in the bardoxolone group without any adverse HF events. Reata pharmaceuticals completed the CARDINAL study, where bardoxolone was studied in patients with Alport syndrome (10), and later submitted a New Drug Application to the US Food and Drug Administration (FDA), which was rejected in February 2022. After reviewing the FDA committee meeting report, we found concerns regarding the trial’s design and ability to differentiate bardoxolone’s pharmacodynamic (PD) effect on kidney function from its effect on disease progression. A key issue was to determine if the study’s 4-week washout was long enough for the reversible PD effect on eGFR to be resolved. After sensitivity analyses, the FDA felt that the off-treatment analysis window may have meaningfully been chosen to affect the primary results. The FDA developed a fit-for-purpose pharmacokinetic/PD model, which predicted that the reversible PD effect on eGFR observed with bardoxolone had mostly resolved after 10 weeks. This conclusion is consistent with Reata’s exposure-response model, and thus the FDA did not believe the submitted data demonstrated effectiveness of bardoxolone in slowing the loss of kidney function (11). The important question of whether bardoxolone overworks a failing kidney or safely augments kidney function remains unanswered. There is no evidence for GFR changes on bardoxolone therapy being due to increased intraglomerular pressure because there are no studies of glomerular capillary pressure in animals or humans with CKD on bardoxolone. Although the mechanism(s) of bardoxolone remains to be established, ideally such a therapeutic intervention would have dynamic, structural, and hemodynamics effects. A recent rodent study showed improved GFR with Nrf2 activation without affecting the afferent/efferent arteriole ratio. So, possibly both arterioles expand after Nrf2 activation (12). On the flip side, the persistence of elevated eGFR after 4 weeks of cessation of the drug led to the conclusion that bardoxolone not only has a hemodynamic effect (such as with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) but also plays a key role in decreasing oxidative stress and producing anti-inflammatory molecules via the Nrf2 pathway. Potentially, mechanisms of bardoxolone methyl increasing GFR may include dynamic increases in glomerular filtration surface area by suppressing inflammation and chronic antifibrotic effects (13,14). One could also connect an increase eGFR with creatine metabolism, taking into consideration body weight loss in the treatment groups (8,9). The lack of changes in urinary creatinine clearance and increased inulin clearance with and without corrections for body weight (9) reflect a true increase in GFR. Surprisingly, patients receiving bardoxolone in the BEAM study had a significant increase in albuminuria (5). The mechanism was explained in a study (1) where monkeys on bardoxolone for 1 year showed downregulation of megalin expression in the proximal tubule. Megalin and cubilin in the proximal tubule help in the reabsorption of the albumin that is filtered in the glomerular apparatus. Thus, the increase in albuminuria observed is primarily a reabsorption defect rather than a glomerular filtration defect (15). Decrease in the albuminuria 4 weeks after the discontinuation of bardoxolone indicate the reversibility of the effect. After the conflicting results and years of failed trials for preventing CKD progression, researchers considered bardoxolone for rare causes of kidney disease. The FALCON study for ADPKD patients (16) and the EAGLE study for Alport syndrome patients (17) are currently ongoing (Table 1). Table 1. - Past and ongoing clinical trials of bardoxolone for kidney disease Trial Identifier Study Start Date and Status Trial Population Trial Design Regimen, Number Treated, Duration Primary and Secondary End Points Number of Subjects Outcome and Mean Change in eGFR from Baseline 402-C-0801 Phase 2 April 2008; completed CKD and T2D Open label, randomized, dose ranging Bardoxolone dosage: stratum 1: 25 or 75 or 150 mg/d; stratum 2: 25 mg/d followed by 75 mg/dNumber treated: 170 bardoxolone, 57 placeboDuration: 28 d stratum 1; 28 d followed by 28 d stratum 2 Primary: Effects of three dose strengths on eGFR after 28 d; effect on eGFR 25 mg for 28 d followed by 75 mg for another 28 dSecondary: Safety; effects at three different dosing levels on iohexol serum clearance (one study center only), creatinine clearance, a panel of markers of inflammation, renal injury, oxidative stress, and endothelial cell dysfunctionHbA1c, sCr after 28 and 56 d 80 enrolled No data found 402-C-0804 (BEAM) Phase 2 April 2009; completed CKD and T2D Double blind, randomized, placebo controlled Bardoxolone dosage: 25 or 75 or 150 mg/dNumber treated: 170 bardoxolone, 57 placeboDuration: 52 wk Primary: Change from baseline in eGFR after 24 wk of treatment; safety and tolerability when administered for 12 moSecondary: Effects at two different dosing levels relative to placebo on: HbA1c, sCr, sBUN, urine, PTH, ACR, sPhos, and uric acid after 24 and 52 wk of treatment; change from baseline in eGFR after 52 wk of treatment 227 enrolled ↑ eGFR 8.2±1.5 in 25-mg group, 11.4±1.5 in 75-mg group, 10.4±1.5 in 150- mg group (P<0.001) at wk 24; 5.8±1.8 in 25-mg group, 10.5±1.8 in 75-mg group, 9.3±1.9 in 150-mg group (P<0.001) at wk 52 (8) 402-C-0902 Phase 2 June 2010; completed CKD and T2D Open label, randomized, parallel group, dose ranging Bardoxolone dosage: 5 or 10 or 15 or 30 or 2.5 mg/dNumber treated: 129Duration: 28 d Primary: Trend in mean change from baseline to d 29 in eGFRSecondary: Evaluate safety and tolerability after 28 and 84 d of administration; trend in mean change from baseline to d 85 in eGFR 129 enrolled No data found 402-C-0903 (BEACON) Phase 3 June 2011; terminated for safety concern due to high cardiovascular events CKD and T2D Randomized, double blind, placebo controlled, parallel group Bardoxolone dosage: 20 mg/dNumber treated: 1088 bardoxolone; 1097 placeboDuration: median 7 mo (stopped early due to safety) Primary: Delaying progression to ESKD and cardiovascular deathSecondary: Safety of bardoxolone relative to placebo 2185 enrolled and randomized No reduction in the risk of ESKD or death from cardiovascular causes. Recent post hoc analyses showed that increases in eGFR in bardoxolone group were durable for 1 yr and bardoxolone significantly reduced the risk of reaching a composite renal end point. 402-C-1005 Phase 2 January 2012; terminated CKD and T2D Double blind, randomized, exploratory Bardoxolone dosage: 20 mg/dNumber treated: 18Duration: 24 wk Primary: mGFR assessed by plasma clearance of 99mTc-DTPA at baseline mGFR assessment 1, baseline mGFR assessment 2, and at wk 8, 16, and 20 18 planned and analyzed No data due to termination Secondary: mGFR assessed by γ camera assessment of renal uptake of 99mTc-DTPA at baseline mGFR assessment 1, baseline mGFR assessment 2, and at wk 8, 16, and 20Circulating endothelial cell assessments at baseline mGFR assessment 1 and at wk 8 and 20 402-C-1102 (BEACON) Phase 2 April 2012; terminated CKD and T2D Open label followed by 28-d follow-up Bardoxolone dosage: 20 mg/dNumber treated: 24Duration: 56 d Primary: PharmacokineticsSecondary: Safety 24 planned and analyzed No data due to termination 402–005 (TSUBAKI) Phase 2 December 2014; completed CKD and T2D Randomized, double blind, placebo controlled parallel group with 12-wk follow-up Bardoxolone dosage: 5–15 mg/dNumber treated: 65 bardoxolone; 55 placeboDuration: 16 wk Primary: Safety and change from baseline in GFR measured by inulin clearance at 16 wkSecondary: Change in eGFR after 16 wk; pharmacokinetics 216 enrolled, 124 randomized and analyzed (72 with CKD stage 3 and 36 with CKD stage 4) ↑ mGFR:6.64 intergroup difference after 16 wk (P=0.008)↑ eGFR: 12.08 intergroup difference after 16 wk (P<0.001) 402-C-1603 (CARDINAL) Phase 2 March 2017; completed Alport syndrome Open label, single arm Bardoxolone dosage: 5–20 mg/d or 5–30 mg/dNumber treated: 30Duration: 100 wk Primary: Change from baseline in eGFR after 12 wk of treatment 30 planned, enrolled, and treated 402-C-1603 (CARDINAL) Phase 3 March 2017; completed Alport syndrome Randomized, double blind, placebo controlled, parallel group, with 4-wk treatment washout Bardoxolone dosage: 5–20 mg/d; or 5–30 mg/dNumber treated: 77 bardoxolone; 80 placeboDuration: 100 wk Primary: Change from baseline in eGFR after 48 and 100 wkSecondary: Change from baseline in eGFR at wk 52 and 104 after a 4-wk drug treatment withdrawal period 157 enrolled and treated ↑ eGFR: 9.2 (P<0.001) at wk 48; 7.4 (P<0.001) at wk 100 5.4 (P=<0.001) at wk 52; and 4.4 (P=0.02) at wk 104 402-C-1702 (PHOENIX) Phase 2 December 2017; completed IgA nephropathy CKD with T1D FSGS ADPKD Nonrandomized, open label, parallel, four armed Bardoxolone dosage: 5–20 mg/d or 5–30 mg/dNumber treated: 30Duration: 100 wk Primary: Change from baseline in eGFR at wk 12 103 planned and analyzed (26 IgA, 31 ADPKD, T1D 28, FSGS 18) ↑ eGFR: 9.31 in ADPKD; 8 IgA; 5.46 T1D; 7.83 FSGS (P<0.001) at wk 12 402–006 (AYAME) Phase 3 May 2018; active, not recruiting DKD (CKD and T1D or T2D) Randomized, double blind, placebo controlled Bardoxolone dosage: 5–15 mg/dDuration: approximately 3–4 yr Primary: Time to onset of a ≥30% decrease in eGFR from baseline or ESKD (time frame: through double-blind part completion, approximately 3–4 yr)Secondary: Time to onset of a ≥40% decrease in eGFR or ESKD; ≥53% decrease in eGFR or ESRD; to ESKD onsetChange in eGFR from baseline at each evaluation time point (approximately 3–4 yr) 1323 enrolled No data found; the result was expected in March 2022 402-C-1803 (EAGLE) Phase 3 March 2019; ongoing, recruiting CKD, Alport syndrome, ADPKD Open label, single arm Bardoxolone dosage: 5–30 mg/dDuration: up to 5 yr Primary: Long-term safety: by incidence of adverse events and serious adverse events (time frame: up to 5 yr) 480 planned Intermediate results↑ eGFR after at least 48 wk in EAGLE: 4.2±11.1; n=21 ↑ eGFR after 3 yr (2 yr in CARDINAL and 48 wk in EAGLE) 6.2±11.5; n=29 ↑ eGFR 4.8±15.1; n=16 after 3 yr (2 yr in CARDINAL and 96 wk in EAGLE) 402-C-1808 (FALCON) Phase 3 May 2019; ongoing, recruiting ADPKD Randomized, double blind, placebo controlled Bardoxolone dosage: 5–20 mg/d or 5–30 mg/dDuration: 100 wk Primary: Change from baseline in eGFR at wk 108; count of reported adverse events at wk 112Secondary: Change from baseline in eGFR at wk 100 850 planned 402-C-2002 (MERLIN) Phase 2 February 2021; completed CKD Randomized, double blind, placebo controlled with 5-wk treatment washout Bardoxolone dosage: 5–20 mg/d or 5–30 mg/dDuration: 100 wk Primary: Change from baseline in eGFR at wk 12Secondary: Change from baseline in eGFR by CKD etiology at wk 12 81 enrolled No data found sCr, serum creatinine; PTH, parathyroid hormone; ACR, albumin-creatinine ratio; sPhos, serum phosphorus; mGFR, measured GFR; ADPKD, autosomal dominant polycystic kidney disease; T1D, type 1 diabetes mellitus; T1D, type 2 diabetes mellitus; FSGS, focal segmental glomerulosclerosis; HbA1c, Hemoglobin A1c. Long-term observations are required to establish the true significance of an increase in eGFR. Hopefully, the phase 3 AYAME study (18) with a planned duration up to 4 years will help. In our opinion, to mitigate criticism, studies with isotopic GFR testing and non-creatinine-based GFR markers have to be performed, and morphologic changes in kidneys during the treatment need to be identified. It is much awaited to shed new insights on the safety and efficacy of bardoxolone, which was once considered a “blockbuster drug” in the management of CKD. Disclosures All authors have nothing to disclose. Funding None." @default.
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• W4294908588 date "2022-11-24" @default.
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• W4294908588 title "Bardoxolone for CKD: The Paradox of Confusion and Dogma" @default.
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• W4294908588 doi "https://doi.org/10.34067/kid.0000992022" @default.
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