Safety and preliminary efficacy findings from a phase 2a randomized, double-blind, placebo-controlled trial of setanaxib in patients with Alport syndrome

Abstract

The study (NCT06274489), evaluated setanaxib—a first-in-class NOX1/4 inhibitor—as a treatment to reduce fibrosis and inflammation in Alport syndrome (AS). Key Findings from the Trial 1. Safety (Primary Endpoint) The study met its primary safety objective. Setanaxib was generally well-tolerated over the 24-week period. • Adverse Events (AEs): Occurred at similar frequencies in both the setanaxib and placebo groups. • Serious Adverse Events (SAEs): One SAE (acute cholecystitis) was reported in the setanaxib group, but it was determined to be unrelated to the treatment. • Discontinuations: No patients discontinued the study due to drug-related side effects. 2. Efficacy (Secondary Endpoints) While the study was a small Phase 2a trial (N=20), it showed a positive trend in reducing proteinuria, a key marker of kidney disease progression. • UPCR Reduction: The setanaxib group showed a 15% mean reduction in the Urine Protein-Creatinine Ratio (UPCR) at 24 weeks compared to placebo. • Post-Dosing Effect: Interestingly, the reduction improved to 27% at four weeks after the treatment period ended. • Response Rate: 15.4% of patients on setanaxib achieved a \ge 25\% reduction in UPCR, whereas no patients in the placebo group reached this threshold. 3. Kidney Function (eGFR) • There was a slight mean reduction in eGFR (5% at 24 weeks) in the setanaxib group compared to placebo, which is often observed with therapies that alter glomerular hemodynamics. Study Design Overview • Participants: 20 patients (aged 12–50) with genetically confirmed Alport Syndrome and significant proteinuria (\text{UPCR} \ge 0.8 \text{ g/g}) despite being on standard-of-care ACE inhibitors or ARBs. • Regimen: Randomized 2:1 to receive either setanaxib (1200 mg or 1600 mg daily based on age) or a placebo for 24 weeks. • Mechanism: Setanaxib targets NOX1 and NOX4 enzymes, which produce reactive oxygen species (ROS) that drive the glomerular scarring and podocyte damage characteristic of Alport syndrome. Conclusion The investigators concluded that setanaxib has an acceptable safety profile and shows a clinically meaningful trend toward reducing proteinuria in Alport syndrome patients. These results support further investigation in a larger, Phase 3 clinical trial.