Reata Pharmaceuticals has completed patient enrollment for Phase 3 of its CARDINAL study investigating the safety and efficacy of bardoxolone methyl (bardoxolone) for improving kidney function in people with Alport syndrome, the company announced.
The Phase 3 part of the CARDINAL trial (NCT03019185), which has enrolled 157 patients across more than 60 sites worldwide, will randomly select participants for a 48-week treatment with either bardoxolone (up to 30 mg daily) or placebo. This will be followed by a four-week discontinuation, then 48 more weeks of the same treatment, with a final four-week discontinuation.
Researchers will look at changes in eGFR — estimated glomerular filtration rate, which tells how well the kidneys are working — from the study’s start, extending to one and two years post-treatment, and against placebo.
Bardoxolone methyl is a small molecule designed to reduce oxidative stress and inflammation, which may improve kidney function in Alport patients. The therapy binds to a protein called KEAP1, preventing it from degrading the Nrf2 protein, so as to promote the healthy functioning of mitochondria — a cell’s energy source or powerhouse.
The increased activation of Nrf2 stimulates the production of anti-oxidant proteins, reducing the oxidative stress and damage to proteins, and improving mitochondrial energy production.
Results from CARDINAL’s Phase 2 part, announced in July 2018, showed that one year of treatment with bardoxolone has the potential to reverse the damaging effects of Alport, promoting recovery of kidney function. Patients initially were treated with 5 mg of oral bardoxolone once daily, followed by an escalation to 10 mg at week two, and up to 20 mg at week four. Those with urine albumin-to-creatinine ratio levels above 300 mg/g received 30 mg at week six.
The data specifically showed that after completing 48 weeks of treatment, 22 of 25 patients experienced significant improvement in renal function compared with the start of the study, with an improvement of 10.4 mL/min/1.73 m2 in eGFR.
Participants’ kidney function had been declining at an average annual rate of 4.2 mL/min/1.73 m2 at the start of the study. The improvements seen in Phase 2 show bardoxolone led to a recovery of more than two years of average eGFR loss for these patients.
At week 52, after a four-week withdrawal period during which patients did not receive bardoxolone treatment, a positive effect on renal function was noted, with a retained eGFR benefit of about 4.1 mL/min/1.73 m2, compared with the start of the study.
Bardoxolone has been granted orphan drug status from the European Commission and the FDA as a treatment for Alport syndrome. These designations are expected to expedite the therapy’s development, regulatory review, and approval to treat kidney damage due to Alport syndrome.