Bardoxolone for CKD: The Paradox of Confusion and Dogma : Kidney360 (2024)

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 pharmaco*kinetic/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).

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.

Acknowledgments

The content of this article reflects the personal experience and views of the authors and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or Kidney360. Responsibility for the information and views expressed herein lies entirely with the authors.

Author Contributions

U.M.R. Avula wrote the original draft of the manuscript; L. Harris prepared the table; U.M.R. Avula and M. Hassanein were responsible for conceptualization; M. Hassanein was responsible for supervision; and all authors reviewed and edited the manuscript.

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