Reata's bardoxolone offers promise in patients with rare kidney disorder
After surprising Wall Street with positive data on its drug, omaveloxolone, in patients suffering from a notoriously hard-to-treat degenerative neuromuscular disorder last month, Reata Pharma on Monday unveiled pivotal results from a trial testing another drug, bardoxolone, in patients with a rare, genetic form of chronic kidney disease for which there exist no approved therapies.
Bardoxolone, like Reata’s other lead drug — omaveloxolone — is a small molecule engineered to bind to a gene called Keap1 to enhance the activity of the protein Nrf2 in order to defuse inflammation.
The Phase III portion of the CARDINAL study enrolled 157 patients with Alport syndrome — which is characterized by progressive loss in the kidney’s capacity to filter blood — were either given bardoxolone or placebo. The main goal of this tranche of the study was a change in eGFR (estimated Glomerular Filtration Rate), a key measure of the kidney’s ability to purify blood, after 48 weeks of treatment. The main secondary endpoint was the change in the retained eGFR after 48 weeks of treatment and four weeks of drug withdrawal.
Data showed patients treated with bardoxolone had a statistically significant improvement compared to placebo in mean eGFR of 9.50 mL/min (p<0.0001) at 48 weeks — (in the bardoxolone arm patients saw an increase of 4.72 mL/min from baseline, while placebo-treated patients saw of decline of -4.78 mL/min).
Meanwhile, at week 52 following a month withdrawal after 48 weeks of treatment — bardoxolone induced a statistically significant placebo-corrected benefit in mean retained eGFR of 5.14 mL/min (p=0.0012). In the bardoxolone arm, patients experienced a mean retained eGFR decline of 0.96 mL/min, while patients treated with placebo saw their rate slump by 6.11 mL/min.
“While the magnitude of retained benefit at 52 weeks in this Phase 3 study may not have been as great as the 8.3mL/min placebo-corrected benefit they had projected, and the active arm saw less of a retained benefit than in previous studies, we still view this result as significant,” Baird’s Brian Skorney wrote in a note, noting that the trouble seems to be if early eGFR improvements match those previously seen on treatment of around 10mL/min, a decline from +10mL/min to +5mL/min could become a concern.
SVB Leerink analyst Joseph Schwartz echoed the same concern. “Upon closer scrutiny, we think bears may interpret the absolute retained benefit data as disappointing (i.e., bardoxolone (Bard) arm falling below baseline) will look for more detailed proteinuria data in order to disprove the potential for hyperfiltration,” he said. Alport syndrome patients typically have elevated protein levels in their urine, or proteinuria.
Shares of the Texas-based drug developer $RETA slipped about 4.4% to $204.25 in Tuesday premarket trading.
But both analysts were largely convinced by the evidence supportive of the drug’s use in this patient population.
“Nevertheless, in light of the high efficacy bar that RETA had set in Ph.3 CARDINAL as well as the high unmet need in a motivated pt. population, we continue to think that bardoxolone offers a valuable therapeutic benefit for pts. in preserving kidney function,” Schwartz said.
Reata, which is testing bardoxolone in a range of rare kidney diseases, should be able to replicate similar results across these indications, Skorney said, bestowing the therapy blockbuster potential.
CARDINAL is a Phase II/III trial — the mid-stage portion of the trial was unveiled last year. On the safety front, Reata said the drug was well tolerated showed a similar safety profile to the Phase II portion of the trial.
“Importantly, treatment emergent SAEs were actually worse for placebo-treated patients. Concerns about fluid overload or MACE seem to be put to bed with this result,” Skorney added.
Bardoxolone engages with the Keap1/Nrf2 pathway, which is pivotal in the resolution of inflammation by stabilizing mitochondrial function, restoring redox balance, and suppressing cytokine production. In October, AbbVie relinquished its license to Reata’s omaveloxolone, bardoxolone and other Nrf2 activators in a $330 million deal.