Kidney Compass: Setanaxib, Alport Syndrome, and RaDaR Updates at Kidney Week 2025

Welcome to Kidney Compass: Navigating Clinical Trials!

In this special edition episode of Kidney Compass: Navigating Clinical Trials, host Brendon Neuen, MBBS, PhD sits down with Daniel Gale, PhD, MB BChir, is the director of the UK-based RaDaR Registry and the St Peter's Chair of Nephrology at University College London, at the American Society of Nephrology (ASN) Kidney Week 2025 to discuss a phase 2 trial of setanaxib in Alport syndrome and the unmet need within the disease.

Interim results from the phase 2a clinical trial suggest setanaxib, a novel enzyme-driven hydrogen peroxide–depleting agent with antifibrotic properties, was safe and associated with trends toward reduced proteinuria in patients with Alport syndrome at risk for disease progression despite optimized background therapy.

Alport syndrome, a rare hereditary kidney disease caused by collagen IV gene abnormalities, leads to interstitial fibrosis and progressive loss of kidney function. Gale explained targeting fibrotic pathways has been proposed as a potential strategy to slow disease progression.

The 24-week, randomized, double-blind, placebo-controlled trial enrolled 20 patients aged 12–40 years with genetically confirmed Alport syndrome (AS), urine protein-to-creatinine ratio (UPCR) ≥0.8 g/g, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m². Participants were randomized 2:1 to receive oral setanaxib (800 mg twice daily for adults 18–40 years; 800 mg + 400 mg daily for adolescents 12–17 years; n = 13) or placebo (n = 7), in addition to stable background therapy, for 24 weeks, followed by a 4-week off-treatment observation period.

Most participants were receiving renin–angiotensin–aldosterone system inhibition and/or SGLT2 inhibitors: 16 were on ACE inhibitors (11 setanaxib, 5 placebo), 11 on SGLT2 inhibitors (7 setanaxib, 4 placebo), and 10 on both (7 setanaxib, 3 placebo).

Primary endpoints of safety and tolerability were met. One patient in the setanaxib group experienced a serious adverse event of acute cholecystitis, deemed unrelated to treatment, and no adverse events of special interest occurred. The overall adverse event rate was similar between groups.

Regarding efficacy, the setanaxib group experienced a 15% mean reduction in UPCR at week 24 versus placebo. Two patients (15.4%) achieved ≥25% reduction in UPCR, and 5 (38.5%) achieved ≥10% reduction compared with 1 (16.7%) in the placebo arm. Of note,, a 27% mean UPCR reduction was observed 4 weeks after treatment discontinuation, suggesting a sustained pharmacodynamic effect.

Shifting to RaDaR registry updates, Gale highlights work evaluating C3 staining on biopsy in more than 500 patients with IgA nephropathy. Independent of proteinuria and eGFR, C3 positivity strongly predicted both eGFR decline and kidney failure, reinforcing the relevance of complement activation. The team also developed a large language model capable of reliably assigning MEST-C scores, performing comparably to expert pathologists. This innovation opens the door to analyzing the >10,000 biopsies across RADAR at scale.

Gale discusses new findings on post-transplant recurrence across glomerular diseases. Patients with recurrent conditions such as nephrotic syndrome, C3 glomerulopathy, and Alport syndrome experience significantly earlier graft loss and higher lifetime transplant needs. Proteinuria ≥0.5 g/day at one year post-transplant was associated with >4-fold higher graft failure risk—underscoring an important, actionable prognostic marker.

Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Gale include Novartis, Alexion, Calliditas, Britannia, Vifor, Judo Bio, Adnovate, Sanofi, Anlylam, Boehringer Ingelheim, and Bayer.

References:

Gale D. Safety and Preliminary Efficacy Findings from a Phase 2A Randomized, Double- Blind, Placebo-Controlled Trial of Setanaxib in Patients with Alport Syndrome. Presented at the American Society of Nephrology (ASN) Kidney Week. Houston, Texas. November 05-09, 2025.

Wong K, Pitcher D, Rogers DJ, Gale D. Urine Albumin-to-Creatinine Ratio and Protein-to-Creatinine to Predict Kidney Failure Rates in Patients with Glomerular and Nonglomerular Diseases in the UK National Registry of Rare Kidney Diseases (RaDaR) Cohort. Presented at the American Society of Nephrology (ASN) Kidney Week. Houston, Texas. November 05-09, 2025.