Bardoxolone: Augmenting the Yin in chronic kidney disease

Abstract

Nrf-2 (NF-E2-related factor 2) is a regulator of anti-oxidant, anti-inflammatory and detoxification pathways. Coordinated augmentation of these key defence pathways via Nrf-2 signalling is being investigated for the treatment of chronic diseases, including diabetes and its complications. The first to reach commercial development is the triterpenoid, bardoxolone methyl. In recent clinical trial, bardoxolone rapidly improved kidney function on average by 5–10 ml/min within 4 weeks of therapy. Importantly, this improvement was sustained during one year of active treatment. This suggests that rather that overworking a failing system, bardoxolone appeared to safely augment renal function, at least to one year. If similar improvements in kidney function can be reproduced in the upcoming BEACON trial, it will represent a major advance on conventional therapy and new way to bring balance to the failing kidney.

In traditional Chinese medicine, health is represented as a balance of Yin and Yang. Yang embodies the lighter, warming forces, while Yin represents darker cooling forces. In this paradigm, the treatment for inflammation is naturally Yin. In the human body, one of the most important Yin forces is the transcription factor Nrf-2 (NF-E2-related factor 2) that with its Yang partner KEAP-1 (Kelch-like ECH-associated protein 1) modulates cytoprotective responses, affecting hundreds of genes involved in antioxidant, anti-inflammatory and detoxification pathways. Augmentation of a coordinated defence via Nrf-2 signalling is currently being investigated for the treatment of a range of chronic diseases, including arthritis, asthma, cancer chemoprevention, cardiovascular disease and neurodegeneration. More recently, the potential utility of Nrf-2 agonists has been explored in diabetes and its complications.

In the diabetic kidney, in particular, inflammation and oxidative stress are key pathogenic factors. At the same time, the expression of Nrf-2 is also modestly increased in the diabetic kidney, ¹ in an attempt to offset or balance these (dark) forces. Although ultimately overwhelmed, the potentially importance of Nrf-2 in forestalling renal damage is illustrated by the effect of diabetes in mice that are deficient in Nrf-2. In this paradigm, renal damage is greatly accelerated following the induction of diabetes, in association with increased oxidative damage.^1,2 Similarly, when fed a high-fat diet, Nrf-2 knockout mice have higher levels of reactive oxygen species (ROS) in the vasculature and more endothelial dysfunction when compared with wild-type mice. ³

A number of structurally different small molecule activators of Nrf-2 have been studied for their potential therapeutic application. Most well known is sulforaphane, a potent activator of Nrf-2 derived from broccoli and other plants of the cabbage family (watercress, Brussels sprouts, cabbage and cauliflower). Diallyl sulfides (from garlic, onion and chives), curcumin (from turmeric), quercetin (from tea, berries, apples and onions), astaxanthine (krill, microalgae), resveratrol (grapes, knotweed) and caffeic acid phenethyl ester (in propolis of bee hives) are also activators of Nrf-2. Interestingly, gold also activates Nrf-2, partly contributing to its anti-inflammatory actions in rheumatic disease. Adding to this collection of strange and wonderful reagents, a number of drug companies are aiming to generate potent, selective activators of Nrf-2. The first to reach full commercial development is the triterpenoid bardoxolone methyl.

Bardoxolone methyl was originally advanced because of its potential anticancer properties. However, in early phase 1 studies in oncology patients improvements in kidney function were also noted. This led directly to a number of short and medium term studies, the largest and longest of which has recently been published in the New England Journal of Medicine. ⁴ In this phase 2 study, 227 adults with diabetes and chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] 20–45 ml/min/1.73 m²) were randomised in a 1:1:1:1 design to receive placebo or bardoxolone methyl at a dose of 25, 75, or 150 mg once daily. Treatment was given in addition to standard therapy that included blockade of the renin–angiotensin system, diuretics and statins in most patients. When compared with placebo, the eGFR increased on average by 5–10 ml/min within 4 weeks in patients receiving bardoxolone methyl. The greatest effects seen in those receiving 75–150 mg, although significant increases were also observed at the lower dose of 25 mg, when compared with placebo. Importantly, this improvement in eGFR was sustained during 1 year of active treatment. This suggests that rather that overworking a failing system, which might be expected to result in its more rapid burnout, bardoxolone appeared to safely augment renal function, at least to 1 year.

The mechanism(s) by which bardoxolone achieves this improvement remains to be established. It is unlikely that there is reversal of structural damage, as advanced glomerulosclerosis, tubular atrophy and nephron dropout are essentially irreversible. However, activation of tubuloglomerular feedback (TGF) may also functionally down-regulate renal function in failing kidneys. It is possible to speculate that bardoxolone increases GFR in patients with CKD by inhibiting TGF, leading to a reduced afferent arteriolar vasoconstriction. Indeed, activation of Nrf-2 in the kidney progressively restores the expression of heme oxygenase and reduces superoxide levels, both of which are known to inhibit TGF. ⁵ Such haemodynamic effects would be consistent with the observation that it took less than 4 weeks to improve renal function and four weeks after stopping bardoxolone renal function had almost returned to baseline levels.

While such data suggest that the actions of bardoxolone on eGFR are most likely haemodynamic, this does not preclude other activities in diabetic kidney disease. Indeed, the antioxidant actions that lead to restoration of heme oxygenase may also affect many other pathways rendered dysfunctional by oxidative stress in diabetes. Clearly, reduced levels of superoxide and other ROS would be expected to be anti-fibrotic. Indeed, experimental studies have suggested that activation of Nrf-2 is also able to inhibit the promoter activity of TGF-β1, ¹ a key growth factor implicated in the development and progression of diabetic nephropathy.

Although the eGFR was improved, bardoxolone is also known to affect muscle functions and muscle spasms are its major side effect. It is possible that bardoxolone may therefore also impact on creatinine metabolism, independent of any renal actions. Against this hypothesis, bardoxolone also reduced serum urea levels and improved 24-hour urinary creatinine clearance. Nonetheless, it is surprising that non-creatinine-based markers of GFR such as cystatin-C or isotopic GFR testing have not been performed to mitigate such criticism.

The management of advanced CKD in patients with diabetes remains difficult, and has few rewards. Although substantial progress has been made towards the understanding the pathogenesis of diabetic kidney disease, at best, conventional therapy achieves only modest slowing in the relentless decline in kidney function and has never come close to the 5–10 ml/min improvement in renal function achieved by bardoxolone. If similar improvements in kidney function can be reproduced in the upcoming BEACON trial, it will represent a major advance on conventional therapy and new way to bring balance to the failing kidney.