Phase 2 Bardoxolone Trial Shows Efficacy for Alport Syndrome- & ADPKD-Caused CKD

Positive data collected from 2 phase 2 trials evaluating bardoxolone methyl in patients with chronic kidney disease (CKD) caused by Alport syndrome and autosomal dominant polycystic kidney disease (ADPKD) have been reported.

Reata Pharmaceuticals has released positive data from 2 phase 2 trials assessing bardoxolone methyl (bardoxolone) in patients with chronic kidney disease (CKD) caused by Alport syndrome and autosomal dominant polycystic kidney disease (ADPKD).

The investigators report a statistically significant improvement in kidney function maintained in patients with Alport Syndrome after 48 weeks of treatment, statistically significant retained benefit of 4.1 mL/min in patients with Alport Syndrome after 48 weeks of treatment and 4 weeks of drug withdrawal, and a statistically significant improvement in kidney function in patients with ADPKD after 12 weeks of treatment.

“The results announced today add to the large body of clinical evidence that bardoxolone treatment has the potential to prevent or delay kidney failure in rare forms of chronic kidney disease” said Reata’s president and chief executive officer, Warren Huff, BBA, JD, in a recent statement. “Importantly, today’s CARDINAL data demonstrate that 1 year of bardoxolone treatment can improve kidney function in Alport syndrome patients that have had progressive loss of kidney function while on standard of care.”

In the phase 2 portion of the CARDINAL trial, investigators assessed bardoxolone in CKD patients caused by Alport syndrome by collecting historical eGFR data for 22 out of the 25 phase 2 study participants. The study’s primary endpoint included an increase in eGFR from baseline as measured in the timeframe of 48 weeks with assessments at week 12 and 48.

Subjects in the experimental study arm were administered oral bardoxolone in titrated doses. Patients with baseline ACR ≤ 300 mg/g were titrated to a maximum dose of 20 mg, and patients with baseline ACR > 300 mg/g were titrated to a maximum dose of 30 mg, according to the clinical trial. Adult patients, years of age or older, receiving bardoxolone began with once-daily dosing at 5 mg and dose-escalated to 10 mg at week 2, to 20 mg at week 4, and then to 30 mg at week 6 (only if baseline ACR >300 mg/g) unless contraindicated clinically and approved by the medical monitor.

Patients under the age of 18 receiving bardoxolone methyl started 5 mg every other day during the first week and began once-daily dosing with 5 mg during the second week of the study. They then continued with once-daily dosing following the same aforementioned dose titration scheme based on baseline ACR at weeks 2, 4, and 6,” according to the clinical trial.

A significant increase in glomerular filtration rate (eGFR) at week 48 from baseline (n=25) of 10.4 mL/min/1.73 m2 (p<0.0001) was also observed. The data indicate that trial participants’ kidney function has been declining at an average annual rate of 4.2 mL/min/1.73 m2 prior to study entry. Afrer 1 year of treatment with bardoxolone; however, an observed 10.4 mL/min/1.73 m2 improvement was noted, signifying a recovery of approximately 2 years of average eGFR loss.

Additionally, a significant increase of eGFR from baseline at week 52 after withdrawal of active drug for 4 weeks (the retained eGFR benefit) by a mean of 4.1 mL/min/1.73 m2 (p<0.05) was also noted in patients who received bardoxolone, suggesting that the drug may delay kidney failure, or prevent it altogether.

No serious adverse events associated with the treatment were reported in the CARDINAL trial; the events that were observed were found to range from mild to moderate in severity.

In the phase 2 PHEONIX trial, investigators evaluated bardoxolone in patients with CKD caused by ADPKD. The investigators collected historical eGFR data for 29 of the 31 phase 2 study participants. The study’s primary endpoint was an increase in eGFR from baseline as measured in the timeframe of 12 weeks. The trial consisted of 2 experimental study arms.

One experimental arm included patients with baseline ACR > 300 mg/g but ≤ 2,500 mg/g. In this cohort, subjects were titrated bardoxolone to a maximum dose of 30 mg, according to the clinical trial. Participants started with once-daily dosing at 5 mg and dose-escalated to 10 mg at week 2, 20 mg at week 4, and then up to 30 mg at week 6.

The other experimental arm of the trial included patients with baseline ACR ≤ 300 mg/g. In this cohort, subjects were titrated bardoxolone to a maximum dose of 20 mg. They started with once-daily dosing at 5 mg and dose-escalated to 10 mg at week 2 and 20 mg at week 4.

A 9.3 mL/min/1.73 m2 (p<0.0001) was observed in patients treated with bardoxolone, reaching the primary endpoint. Investigators noted that the data demonstrated that the phase 2 study participants’ kidney function had been declining at an average annual rate of 4.8 mL/min/1.73 m2 prior to study entry. However, a 9.3 mL/min/1.73 m2 improvement after 12 weeks of treatment with bardoxolone was reported, signifying a recovery of approximately 2 years of average eGFR loss.

Again, no serious adverse events associated with the treatment were reported; the adverse events that were reported ranged from mild to moderate in severity. For the analysis, 28 patients were available, and only 1 patient (3%) discontinued treatment due to a treatment-related adverse event of fatigue.

“The magnitude of the observed retained eGFR benefit after withdrawal of drug versus the historical rate of eGFR loss suggests that the phase 3 portion of CARDINAL is conservatively powered with respect to the key secondary endpoint of retained eGFR benefit,” added Dr Huff. “Additionally, the eGFR increase at week 12 observed in patients with ADPKD suggests that long-term improvements from treatment with bardoxolone in other forms of CKD may translate to patients with ADPKD.”

The US Food and Drug Administration (FDA) has supplied Reata with guidance that a significant improvement in placebo-corrected retained eGFR is noted in patients with Alport syndrome after 1 year of treatment with bardoxolone could support potential accelerated approval of the drug; if observed after 2 years of treatment with bardoxolone, full approval may be supported.