Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON)

Abstract

Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.

Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells both In Vitro and In Vivo

“…Recently, the Nrf2-activating substance bardoxolone methyl, a synthetic triterpenoid, was tested in a phase 3 study due to its potentially nephroprotective effects (10,40). The clinical study had to be stopped due to serious adverse effects (10).…”

“…Recently, the Nrf2-activating substance bardoxolone methyl, a synthetic triterpenoid, was tested in a phase 3 study due to its potentially nephroprotective effects (10,40). The clinical study had to be stopped due to serious adverse effects (10). Additional knowledge on Nrf2 actions in the kidney and on the effects of Nrf2 activators of other substance classes than triterpenoids might give new perspectives for further trials.…”

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

“…On this basis, several natural and synthetic small-molecule Nrf2 activators are currently being evaluated in patients with NASH and CKD ( Table 2). Following early encouraging data, clinical development of bardoxolone methyl, a synthetic Nrf2 activator, was interrupted for safety concerns related to heart failure (77). A reanalysis of the potential risk/benefit ratio of the drug for a Japanese population and the observation that most of the severe adverse effects occurred in the first month of therapy prompted initiation of a dose-escalating RCT in Japan (clinical trial reg.…”

Importance of diabetic nephropathy in childhood. Clinical findings and basic research in the past decades

“…Az elsődleges végpontokat (dialízisigény, cardiovascularis mortalitás) a tanulmány nem értékelte, illetve több mellékhatás (izomgörcsök, vérnyomás-emelkedés) is jelentkezett a betegek egy részében. Új, kettős vak, multicentrikus, placebokontrollált fázis-III tanulmány indul (BEACON), amelyben elsődlegesen a fenti kemény végpontokat vizsgálják, és másodlagos végpont-ként szerepel az eGFR változása [59]. Ezek az eredmé-nyek várhatóan megbízható adatokkal szolgálnak a bardoxolon hatékonyságát és biztonságosságát illetően, és megalapozhatják a szer klinikai bevezetését.…”