IRVING, Texas—Today Reata Pharmaceuticals, Inc. announced the digital publication of a research article, “Bardoxolone Methyl Improves Kidney Function in Patients with Chronic Kidney Disease Stage 4 and Type 2 Diabetes – Post-hoc Analyses from BEACON,” in the American Journal of Nephrology. The publication complements previously published safety analyses and reports efficacy analyses that characterize bardoxolone’s longer-term effects on kidney function.
Bardoxolone methyl is an experimental oral, once-daily activator of Nrf2, a transcription factor that induces molecular pathways that promote the resolution of inflammation by restoring mitochondrial function, reducing oxidative stress, and inhibiting pro-inflammatory signaling. The FDA has granted orphan designation to bardoxolone methyl for the treatment of Alport syndrome and pulmonary arterial hypertension.
The study text says, “The BEACON trial was terminated for safety concerns in response to a recommendation from the independent data monitoring committee, which identified a significant increase in the risk of heart failure hospitalizations or death from heart failure with bardoxolone methyl treatment (96 [8.8%] patients randomized to bardoxolone methyl versus 55 [5.0%] patients randomized to placebo). After BEACON was terminated, analyses suggested that the primary reason for the increase in adjudicated heart failure related outcomes in the treatment group was not direct toxicity, but fluid overload, which occurred in the first 4 weeks after randomization.”
Key highlights of the paper demonstrate that for patients treated at least 48 weeks, increases in eGFR (estimated glomerular filtration rate) from baseline and placebo were sustained 4 weeks after cessation of treatment. Early improvements in eGFR with bardoxolone methyl correlate with durable increases through one year of treatment and sustained eGFR increases after cessation of treatment.
Patients randomized to bardoxolone methyl were significantly less likely to experience a newly
validated composite renal endpoint consisting of confirmed ≥30% decline from baseline in
eGFR, confirmed eGFR <15 mL/min/1.73 m2, and end-stage renal disease events, suggesting
that bardoxolone preserves kidney function and may delay the onset of kidney failure in patients
with type 2 diabetes and stage 4 chronic kidney disease.
“The clinical phenotype of fluid overload and heart failure in BEACON was similar to that observed with endothelin receptor antagonists in advanced CKD [chronic kidney disease] patients, and additional post-hoc analyses suggest that through modulation of the endothelin pathway, bardoxolone methyl may pharmacologically promote acute sodium and volume retention and increase blood pressure in patients with more advanced CKD,” the article notes. “Studies are continuing, in patients without identified risk factors for fluid overload, to further evaluate the potential risk-benefit profile for bardoxolone methyl and determine whether the increases in eGFR and with bardoxolone methyl offer the potential to prevent or delay kidney function decline and progression to ESRD [end-stage renal disease].”
“Though BEACON was discontinued early, it was not a failed study, as it yielded critical insights into bardoxolone methyl’s clinical profile,” said Glenn Chertow, M.D., MPH, Professor of Medicine and Chief, Division of Nephrology at Stanford University School of Medicine. “In this post-hoc analysis, we employed an expanded renal composite endpoint and showed that bardoxolone methyl reduced (by half) the likelihood of developing an adverse renal event. If the associated risks of heart failure due to fluid overload can be mitigated, bardoxolone methyl could prove to be an extremely valuable treatment for diabetic kidney disease.”
Bardoxolone methyl is currently being studied in CARDINAL, a Phase 3 study for the treatment of Alport syndrome; PHOENIX, a Phase 2 study for the treatment of autosomal dominant polycystic kidney disease, IgA nephropathy, CKD associated with type 1 diabetes, and focal segmental glomerulosclerosis; and CATALYST, a Phase 3 study for the treatment of connective tissue disease associated pulmonary arterial hypertension. The full text of the BEACON study can be found here.
According to a report from Dr. Dae Gon Ha and Joseph P. Schwartz of Leerink Partners, “These results are encouraging as the 12-week data from the Ph.2 CARDINAL trial reported a mean eGFR improvement of 13.7 ml/ min/BSA over baseline in Alport patients exposed to a maximum daily bardoxolone dose of 20mg or 30mg, which is on par with the reported 12-week mean improvement of 12.6 ml/ min/BSA in BEACON patients on a similar dose.”
“The next milestone for the CARDINAL trial is accelerated approval, whereby [Reata] must demonstrate that bardoxolone therapy significantly increases eGFR at 48 weeks followed by a sustained improvement over baseline 4 weeks after discontinuation of therapy, which we think is likely, given that previous data reported from the BEACON trial demonstrated a statistically significant increase in eGFR in the same time frame,” say Ha and Schwartz.
“We believe the pharmacology of bardoxolone may be broadly relevant to many forms of kidney disease, not just diabetic CKD,” said Colin Meyer, M.D., Chief Medical Officer of Reata. “This publication helps provide additional context and rationale for our expanding kidney clinical programs, including our ongoing Phase 3 trial in Alport syndrome and Phase 2 trials in autosomal dominant polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis, and type 1 diabetic CKD.”