Kidney Compass: Navigating Clinical Trials

Welcome to Kidney Compass: Navigating Clinical Trials! In this special edition episode of Kidney Compass: Navigating Clinical Trials, host Brendon Neuen, MBBS, PhD, is joined by Sophia Zoungas, MBBS, PhD, an endocrinologist and head of the School of Public Health and Preventive Medicine at Monash University, to discuss a post hoc analysis of the phase 3 SURPASS-CVOT trial from American Society of Nephrology (ASN) Kidney Week 2025, which concluded tirzepatide (Mounjaro) significantly slowed kidney function decline and reduced albuminuria progression compared with dulaglutide (Trulicity) in patients with type 2 diabetes, atherosclerotic cardiovascular disease (ASCVD), and very high-risk chronic kidney disease (CKD). The analysis applied the KDIGO 2025 CKD risk classification, defining very high-risk CKD as eGFR <30 mL/min/1.73 m², or eGFR 30 to <45 mL/min/1.73 m² with micro/macroalbuminuria, or eGFR 45 to <60 mL/min/1.73 m² with macroalbuminuria. Among 1241 patients meeting these criteria, the mean age was 68.5 years, mean body mass index (BMI) was 33.0 kg/m², mean HbA1c was 8.5%, and mean diabetes duration was 19.2 years. SGLT2 inhibitor use at baseline was 24.9%. At 36 months, tirzepatide was associated with a significantly smaller decline in eGFR compared to dulaglutide: Change in eGFR: −3.0 (±0.5) mL/min/1.73 m² with tirzepatide vs −7.2 (±0.4) with dulaglutide (between-group difference: +4.1 mL/min/1.73 m²; P <.001). Reductions in urinary albumin-to-creatinine ratio (UACR) also favored tirzepatide: Percent change in UACR: −45.6% with tirzepatide vs −28.0% with dulaglutide (between-group difference: −24.6%; P <.001). The risk of the composite kidney outcome, which was defined as onset of macroalbuminuria, ≥50% eGFR decline, kidney failure, or kidney-related death, was 33% lower with tirzepatide (hazard ratio [HR], 0.67; 95% CI, 0.52 to 0.87; P = .002). Event rates were 16.7% (108/647) with tirzepatide and 23.0% (137/594) with dulaglutide. No new safety concerns were identified, and benefits were consistent regardless of baseline SGLT2 inhibitor use. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Zoungas include AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly Australia, Moderna, MSD Australia, Sanofi and Novo Nordisk. References: Zoungas S, Nicholls S, Miller DL, Nishiyama H, Wiese RJ, D’Alessio DA. Tirzepatide vs. Dulaglutide Is Associated with Reduced Major Kidney Events in Patients with Type 2 Diabetes, CVD, and Very High-Risk Kidney Diseases. Presented at the American Society of Nephrology (ASN) Kidney Week. Houston, Texas. November 05-09, 2025. Eli Lilly and Company. Lilly's Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial, reinforcing its benefit in patients with type 2 diabetes and heart disease. July 31, 2025. Accessed July 31, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-mounjaro-tirzepatide-gipglp-1-dual-agonist-demonstrated

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.

In this special edition episode of Kidney Compass: Navigating Clinical Trials, host Shikha Wadhwani, MD, MS, sits down with Brad Rovin, MD, Lee A. Hebert Distinguished Professor of Nephrology at The Ohio State University Wexner Medical Center, to discuss updates in lupus nephritis at the American Society of Nephrology (ASN) Kidney Week 2025, including a late-breaking analysis of the phase 3 REGENCY trial. Building on the phase 2 NOBILITY signal and addressing lessons from the negative LUNAR rituximab study, where depth of B-cell depletion predicted response, REGENCY is the first successful phase 3 anti-CD20 trial in LN, showing a higher complete renal response (CRR) with obinutuzumab. The phase 3 trial randomized adults with active LN to obinutuzumab (Gazyva) plus standard therapy, which was defined as mycophenolate mofetil (MMF) and glucocorticoids, or placebo plus standard therapy. At week 76, obinutuzumab significantly increased rates of CRR compared with placebo (46.4% vs 33.1%; adjusted difference 13.4%; 95% CI, 2.0–24.8; P = .0232), leading to its FDA approval for lupus nephritis in October 2025. In a prespecified histologic substudy, 64 participants underwent paired baseline and post-week 76 kidney biopsies, and 29 provided additional tissue for B-cell and plasma cell analyses via a novel 5-plex immunofluorescence assay (CD79a, CD19, CD38, CD138, Ki67). Histologic remission (activity index [AI]=0) and near-histologic remission (AI≤1) were achieved in 46.9% and 65.6% of obinutuzumab-treated patients versus 18.8% and 21.9% with placebo (adjusted differences 30.75% and 47.69%; P = .0111 and P = .0002, respectively). The mean reduction in AI was –5.0 (SD 4.7) for obinutuzumab versus –1.8 (SD 4.6) for placebo, while chronicity index changes were minimal in both arms. Notably, more than half of obinutuzumab-treated patients who did not achieve clinical CRR still achieved histologic remission (AI=0), with a rate of 52.6% versus 8.3% among non-responders (adjusted difference 44.9%; P=0.0018), which Rovin suggests is indicative of clinical endpoints underestimating tissue-level improvement. Tissue-level biomarker data confirmed near-complete renal B-cell depletion with obinutuzumab (median change –98.3% from baseline), compared to a +29.8% increase with placebo. Plasma cell counts declined by 57.1% with obinutuzumab versus a +2.7% increase in the placebo arm, confirming deep immunologic inactivation within the kidney. Relevant disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Relevant disclosures for Rovin include Alexion, Artiva, AstraZeneca/MedImmune, Aurinia Pharmaceuticals, Biogen Idec, Bristol Myers Squibb, Calliditas Therapeutics, Genentech/Hoffmann-La Roche, GSK, Omeros, Travere Therapeutics, and others. References: Rovin B. Beyond Clinical Response in the REGENCY Trial: The Impact of Obinutuzumab on Histologic Remission in Patients with Active Lupus Nephritis. Presented at the American Society of Nephrology (ASN) Kidney Week. Houston, Texas. November 05-09, 2025. Genentech. FDA Approves Genentech’s Gazyva for the Treatment of Lupus Nephritis. October 20, 2025. Accessed October 20, 2025. https://www.businesswire.com/news/home/20251019548091/en/FDA-Approves-Genentechs-Gazyva-for-the-Treatment-of-Lupus-Nephritis

In this special edition episode of Kidney Compass: Navigating Clinical Trials, Brendon Neuen, MBBS, PhD, doubles as a host and special guest as he offers host Shikha Wadhwani, MD, MS, a deep dive into the latest data from the the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) at the American Society of Nephrology (ASN) Kidney Week 2025. Published in JAMA, the large-scale meta-analyses provide comprehensive evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently reduce the risk of chronic kidney disease (CKD) progression, kidney failure, and related adverse outcomes across all levels of kidney function and albuminuria, regardless of diabetes status. In the first analysis, the SMART-C team evaluated 70,361 participants from 10 randomized, placebo-controlled trials of SGLT2 inhibitors. Participants had a mean (SD) age of 64.8 (SD, 8.7) years, and 35.0% were female. During a median follow-up of 3 years, 2314 participants (3.3%) experienced CKD progression and 988 (1.4%) reached kidney failure. SGLT2 inhibitors reduced the risk of CKD progression by 38% (25.4 vs 40.3 events per 1000 patient-years; hazard ratio [HR], 0.62 [95% CI, 0.57–0.68]), with consistent efficacy across eGFR categories: ≥60 mL/min/1.73 m²: HR, 0.61 (95% CI, 0.52–0.71) 45 to <60 mL/min/1.73 m²: HR, 0.57 (95% CI, 0.47–0.70) 30 to <45 mL/min/1.73 m²: HR, 0.64 (95% CI, 0.54–0.75) <30 mL/min/1.73 m²: HR, 0.71 (95% CI, 0.60–0.83); P for trend = .16 Similar protection was observed across urinary albumin-to-creatinine ratio (UACR) levels, with HRs of 0.58 (95% CI, 0.44–0.76) for ≤30 mg/g, 0.74 (95% CI, 0.57–0.96) for 30–300 mg/g, and 0.57 (95% CI, 0.52–0.64) for >300 mg/g (P for trend = .49). SGLT2 inhibitors also attenuated annual eGFR decline across all subgroups, including those without diabetes. A complementary meta-analysis of 58,816 participants, including 48,946 with diabetes and 9870 without diabetes, across 8 clinical trials confirmed the broad efficacy and safety of SGLT2 inhibitors. Treatment significantly reduced kidney disease progression (HR, 0.65 [95% CI, 0.60–0.70] in diabetes; HR, 0.74 [95% CI, 0.63–0.85] without diabetes), acute kidney injury (HR, 0.77 [95% CI, 0.69–0.87] and HR, 0.72 [95% CI, 0.56–0.92]), all-cause hospitalization (HR, 0.90 [95% CI, 0.87–0.92] and HR, 0.89 [95% CI, 0.83–0.95]), and all-cause death (HR, 0.86 [95% CI, 0.80–0.91] and HR, 0.91 [95% CI, 0.78–1.05]). Check out this interview with presenting investigator Natalie Staplin, PhD, for more on the 8-trial meta-analysis! The magnitude of benefit was consistent across albuminuria strata (UACR ≥ 200 mg/g vs <200 mg/g), although absolute risk reductions were greater in those with higher baseline albuminuria. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. References: Neuen BL, Fletcher RA, Anker SD, et al. SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis. JAMA. Published online November 07, 2025. doi:10.1001/jama.2025.20834 Staplin N, Roddick AJ, Neuen BL, et al. Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria: A Meta-Analysis. JAMA. Published online November 07, 2025. doi:10.1001/jama.2025.20835

In this special edition episode of Kidney Compass: Navigating Clinical Trials, hosts Brendon Neuen, MBBS, PHD, and Shikha Wadhwani, MD, MS, are joined by Ricahrd Lafayette, MD, from the floor at the American Society of Nephrology (ASN) Kidney Week 2025 to discuss the late-breaking ORIGIN 3 results evaluating atacicept and how it adds to the totality of evidence supporting the use of the dual BAFF/APRIL inhibitor in IgA nephropathy (IgAN).  Lafayette describes the moment as “predictably exciting,” noting that the phase 3 findings strongly mirror the promising signals seen previously in the ORIGIN phase 2 program. The phase 2 trial, which evaluated weekly atacicept dosing, demonstrated a robust biologic impact with approximate reductions of 75% in galactose-deficient IgA1 and 50% in proteinuria at 96 weeks, hematuria resolution in most affected patients, and an annual eGFR decline of only ~0.6 mL/min/1.73 m², which Lafayette noted was far below the expected trajectory in this population. These data guided the design of ORIGIN 3, which enrolled biopsy-proven IgA nephropathy with >1 g/day of proteinuria, eGFR >30 mL/min/1.73 m², and maximally tolerated background therapy. More than half of the participants were also taking an SGLT2 inhibitor.  Lafayette reports the 9-month primary outcome results aligned closely with phase 2. Atacicept achieved >45% reductions in proteinuria, compared with approximately 7% in the placebo group. Gd-IgA1 fell by approximately 75–80%, and hematuria resolved in most atacicept-treated patients with minimal change on placebo. Lafayette highlighted these effects were consistent across prespecified subgroups, including those on SGLT2 inhibitors. Safety findings demonstrated there was no increase in infections or serious adverse events relative to placebo, aside from mild injection-site reactions. Lafayette pointed out, numerically, severe adverse events occurred more often in the placebo arm. While regulatory restrictions prevent release of 9-month eGFR data, Lafayette notes the close resemblance to the phase 2 trajectory supports optimism for the upcoming 2-year readout. However, he emphasizes that atacicept-related biomarker improvements reverse when treatment stops, indicating that ongoing therapy may be necessary for sustained benefit. The discussion concludes by situating atacicept within a rapidly expanding therapeutic landscape, including other B-cell–directed agents targeting APRIL alone. Head-to-head differences remain unknown, but atacicept’s dual BAFF/APRIL inhibition and consistent efficacy across optimized background therapy make it a compelling potential addition. Relevant disclosures for Lafayette include Aurinia, Callidatas, Complexa, Mallinckrodt, Omeros, Pfizer, Vera Therapeutics, and others. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Referneces: Lafayette R, Barbour SJ, Brenner RM, et al. ORIGIN 3: A Phase 3 Trial of Atacicept in IgAN. Presented at the American College of Gastroenterology (ASN) Kidney Week. Houston, Texas. November 05-09, 2025. Vera Therapeutics Announces Atacicept Achieved 46% Proteinuria Reduction in ORIGIN Phase 3 Trial in Adults with IgA Nephropathy. Vera Therapeutics, Inc. June 2, 2025. Accessed June 2, 2025. https://ir.veratx.com/news-releases/news-release-details/vera-therapeutics-announces-atacicept-achieved-46-proteinuria

In this episode of Kidney Compass, host Brendon Neuen, MBBS, PhD, is joined by Tor Biering-Sørensen, MD, MPH, PhD, and Kristoffer Skaarup, MD, to discuss the design, execution, and implications of the NUDGE-CKD trial—a landmark pragmatic study aimed at improving guideline-based care in chronic kidney disease (CKD). NUDGE-CKD tested whether low-cost digital “nudges”—letters sent to patients and their primary care physicians emphasizing evidence-based CKD therapies—could increase use of guideline-directed medical therapies (GDMT) for people with CKD. Using Denmark’s nationwide registries and E-box digital communication system, the team identified > 160,000 individuals with CKD and ultimately randomized nearly 20,000 patients into different trial arms. Key findings showed a modest but meaningful increase in GDMT uptake among patients who received the nudges—particularly when both patients and GPs received communication. While the patient-only letters had little effect, the combined approach led to greater prescribing of key medications and improved risk factor control.

In this special edition of Kidney Compass, Shikha Wadhwani sits down with Chee Kay Cheung, MBChB, PhD, of the University of Leicester, on the floor at the 62nd European Renal Association (ERA 2025) Congress to reflect on how far IgA nephropathy (IgAN) treatment has come—from what used to feel like “tumbleweeds” in nephrology to a pipeline packed with promising therapies. At the top of the conversation: the rise of B-cell modulating therapies targeting APRIL and BAFF. Cheung highlights the interim results from the global phase 3 VISIONARY trial of sibeprenlimab, an APRIL inhibitor that achieved a 51.2% placebo-adjusted reduction in proteinuria at 9 months—the largest seen in any IgAN phase 3 study to date. Safety data were encouraging, with low discontinuation rates and a favorable overall profile. Also on the radar: new long-term data from zigakibart, another anti-APRIL antibody, and promising topline results from atacicept, which targets both APRIL and BAFF. While head-to-head comparisons remain elusive, future eGFR outcomes and biomarker studies may help tailor treatment choices to individual patients. The discussion then shifts to recently approved agents. A post-hoc analysis of the NefIgArd trial found that oral budesonide’s efficacy was consistent across a range of baseline eGFR values. Cheung also spotlights the PROTECT trial’s open-label extension, where patients switching from maximally dosed irbesartan to sparsentan still saw proteinuria reductions of approximately 40%, reinforcing the added value of endothelin receptor antagonism. During the conversation, Cheung also previews upcoming biopsy-based data from the SPARTAN study, which will explore how sparsentan impacts intrarenal inflammation and fibrosis. With innovation accelerating across drug classes, mechanisms, and biomarker strategies, this year’s ERA meeting evidences that nephrology, but more specifically the IgAN treatment landscape, has moved far beyond tumbleweeds—and into a new era of precision and promise. Relevant disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Relevant disclosures for Cheung include Travere Therapeutics, Alexion, Alpine Immune Sciences, Calliditas Therapeutics, CSL Vifor, Novartis, Otsuka Pharmaceutical, Roche, Vera Therapeutics, and others. References: Perkovic V. Sibeprenlimab for Patients With IgA Nephropathy: Results From a Prespecified Interim Analysis of the Phase 3 VISIONARY Study. Presented at: 62nd European Renal Association Congress. June 04 – 07, 2025. Vienna, Austria. Barratt J, Lee E.Y., Kim S.G., et al. Sustained Long-Term Efficacy and Safety of Zigakibart Over 100 Weeks in Patients with IgA Nephropathy. Presented at: 62nd European Renal Association Congress. June 04 – 07, 2025. Vienna, Austria. Vera Therapeutics. Vera Therapeutics Announces Atacicept Achieved 46% Proteinuria Reduction in ORIGIN Phase 3 Trial in Adults with IgA Nephropathy. Vera Therapeutics. Published June 2, 2025. Accessed June 5, 2025. https://ir.veratx.com/news-releases/news-release-details/vera-therapeutics-announces-atacicept-achieved-46-proteinuria Barratt J, Lafayette R, Reich HN, et al. Nefecon provides kidney benefit irrespective of baseline eGFR in patients with IgAN: a subanalysis of the NefIgArd study. Presented at: 62nd European Renal Association Congress. June 04 – 07, 2025. Vienna, Austria. Floege J, Risk DV, Preciado P, et al. Effects of Sparsentan After Maximized Angiotensin Receptor Blocker (ARB) Treatment in Patients With IgA Nephropathy (IgAN) in the PROTECT Trial. Presented at: 62nd European Renal Association Congress. June 04 – 07, 2025. Vienna, Austria.

In this special edition episode of Kidney Compass, hosts are joined by Vlado Perkovic, MBBS, PhD, dean and scientia professor of Medicine at UNSW Sydney, at the 62nd European Renal Association (ERA 2025) Congress. During the episode, Perkovic takes hosts Brendon Neuen, MBBS, PHD, and Shikha Wadhwani, MD, MS, on a deep dive into 1 of the meeting’s most anticipated releases—the VISIONARY trial. Billed as the largest phase 3 trial ever conducted in IgA nephropathy (IgAN), the global study spanned 31 countries and randomized 510 participants in a 1:1 ratio to sibeprenlimab or placebo therapy. Less than 2 weeks prior to the presentation, Otsuka Pharmaceutical Co. announced the US Food and Drug Administration had granted priority review for their BLA and the application has been given a target action date of November 28, 2025. Perkovic, who also serves as a professorial fellow at The George Institute and a staff specialist in Nephrology at the Royal North Shore Hospital in Sydney, shares how sibeprenlimab—a targeted APRIL inhibitor—achieved a significant 50.2% reduction in geometric mean 24-hour urine protein-to-creatinine ratio (uPCR) from baseline after 9 months of treatment while the placebo group saw a slight increase of 2.1%, yielding a between-group difference of 51.2% (96.5% CI, 42.9% to 58.2%; P < 0.0001). According to Perkovic, what makes this data even more compelling is the context: 98% of participants were on renin-angiotensin system inhibitors and 39% were also taking SGLT2 inhibitors at baseline, suggesting that sibeprenlimab delivered a significant additional benefit beyond optimized standard of care. Throughout the conversation, Perkovic offers key insights into the rationale for targeting APRIL in IgAN, the design considerations behind the VISIONARY trial, and what this could mean for the future of therapy. He emphasizes the importance of proteinuria as a prognostic marker and discusses how a reduction of this magnitude could correlate with longer-term eGFR stabilization—data expected in a future analysis. Tune in to hear Perkovic’s expert take on how VISIONARY is not only changing the narrative around IgAN treatment, but also setting a new bar for targeted, precision-driven kidney care. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Relevant disclosures for Perkovic include Boehringer Ingelheim,AbbVie, Inc., Bristol-Myers Squibb, servier, Astellas Pharma US, Merck, Janssen Pharmaceuticals, GSK, and others. References: Perkovic V. Sibeprenlimab for Patients With IgA Nephropathy: Results From a Prespecified Interim Analysis of the Phase 3 VISIONARY Study. Presented at: 62nd European Renal Association Congress. June 04 – 07, 2025. Vienna, Austria. Otsuka Pharmaceutical Co. Otsuka Announces Positive Interim Results from the Phase 3 Trial of Sibeprenlimab for the Treatment of Immunoglobulin A Nephropathy in Adults｜News Releases | Otsuka Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Published October 22, 2024. Accessed June 6, 2025. https://www.otsuka.co.jp/en/company/newsreleases/2024/20241022_1.html

Welcome to Kidney Compass: Navigating Clinical Trials! Simultaneous initiation of finerenone (Kerendia) and empagliflozin (Jardiance) in patients with chronic kidney disease (CKD) and type 2 diabetes was well-tolerated and resulted in significantly greater reductions in urinary albumin-to-creatinine ratio (UACR) than either agent alone, according to results from the CONFIDENCE trial presented at the 62nd European Renal Association (ERA 2025) Congress. Led by Rajiv Agarwal, MD, Professor Emeritus at Indiana University School of Medicine, the phase 2 trial enrolled 800 patients with CKD and type 2 diabetes who were randomized in a 1:1:1 ratio to receive empagliflozin monotherapy, finerenone monotherapy, or combination therapy with simultaneous initiation. Finerenone dosing was stratified by estimated glomerular filtration rate (eGFR): 20 mg daily for eGFR ≥60 mL/min/1.73 m² and 10 mg daily for eGFR <60 mL/min/1.73 m².  The primary endpoint was the relative change in mean UACR from baseline to day 180. Results suggested combination therapy achieved a 52% reduction in UACR from baseline, corresponding to a least-squares mean ratio of 0.48 (95% CI, 0.44 to 0.54). Compared with monotherapy, combination therapy resulted in a 29% greater reduction in UACR than finerenone alone (least squares mean ratio of difference, 0.71; 95% CI, 0.61 to 0.82; P <.001) and a 32% greater reduction than empagliflozin alone (least squares mean ratio of difference, 0.68; 95% CI, 0.59 to 0.79; P <.001). Safety analyses indicated the combination was also well tolerated, with serious adverse events reported in 7.1% of the combination group, 6.1% in the finerenone group, and 6.4% in the empagliflozin group. Hyperkalemia led to treatment discontinuation in 1 patient per group. During the ERA 2025 Congress, Kidney Compass host Brendon Neuen, MBBS, PhD, a senior research fellow with the George Institute for Global Health and the director of the Kidney Trials Unit with Royal North Shore Hospital, holds a discussion with Agarwal about CONFIDENCE results and design, but also what it means for CKD management landscape in real-world settings.  Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Agarwal include Akebia Therapeutics, Alnylam, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Intercept, and Novartis.  References: Agarwal R, Green JB, Heerspink HJL, et al. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. New England Journal of Medicine. Published online June 5, 2025. doi: 10.1056/nejmoa2410659

In this episode of Kidney Compass, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by Dustin Little, MD, and Niels Jongs, PhD, to explore the use of hierarchical composite endpoints (HCEs) in nephrology clinical trials. The discussion highlights the limitations of traditional composite endpoints and the potential advantages of HCEs in improving statistical power, trial efficiency, and the ability to capture meaningful treatment effects. The episode begins with an overview of traditional composite endpoints, which combine multiple clinical outcomes—such as death, dialysis, and significant eGFR decline—but weigh all first events equally, regardless of clinical severity. Little explains how this approach disproportionately relies on rapid disease progressors, leaving much of the trial population underrepresented in efficacy assessments. HCEs address this issue by ranking outcomes hierarchically based on clinical importance, ensuring that all patient data contribute to the analysis. Jongs describes the statistical framework behind HCEs, explaining how win odds—a generalized pairwise comparison method—allows for a more comprehensive evaluation of treatment effects compared to hazard ratios. He emphasizes that win odds maintain strong alignment with hazard ratios while offering enhanced interpretability and increased statistical power. Post hoc analyses of major nephrology trials, including DAPA-CKD, have demonstrated consistency between win odds and traditional hazard ratio-based findings, reinforcing the validity of this approach. The panel explores the practical implications of HCEs, particularly for rare kidney diseases, where large-scale outcomes trials are often unfeasible. By incorporating measures like eGFR slope and expanding the range of contributing patient data, HCEs can reduce required sample sizes and shorten trial durations while maintaining statistical robustness. Wadhwani raises the potential for integrating patient-reported outcomes into HCEs, particularly in diseases like lupus nephritis and polycystic kidney disease, where symptom burden and quality of life are critical considerations. The episode concludes with a discussion on regulatory acceptance, the need for further refinement of HCE methodologies, and the potential of this approach to accelerate therapeutic advancements in nephrology. The panel underscores that while challenges remain, HCEs represent a promising innovation that could reshape kidney disease clinical trial design and improve patient outcomes. Chapters 00:00:00 - Start 00:01:03 - Little & Jongs Introduction 00:02:30 - Traditional Endpoints vs HCEs 00:09:22 - Benefits of HCEs 00:17:58 - Examples of Applying HCEs in Nephrology 00:21:26- Increased Power with HCEs 00:23:59 - Addressing Skepticism, Potential Limitations 00:33:04 - Incorporating PROs in HCEs 00:40:01 - Subgroup Analyses with HCEs 00:48:28 - Conclusions and Outro Check out the video version of the podcast, exclusively on HCPLive: https://www.hcplive.com/view/kidney-compass-hierarchical-composite-endpoints-nephrology-dustin-little-md-niels-jongs-phd

In this episode of Kidney Compass: Navigating Clinical Trials, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, the director of Clinical trials in the Division of Nephrology and the vice chair of Clinical Research in the Department of Medicine at the University of Texas Medical Branch, are joined by Laura Mariani, MD, MS, co-chair of the PARASOL Initiative associate professor in the Division of Nephrology at the University of Michigan, and Daniel Gale, PhD, MB BChir, director of the UK-based RaDaR Registry and the St Peter's Chair of Nephrology at University College London. During the episode, guests take Neuen and Wadhwani on a deep dive into the Proteinuria and GFR as Clinical Trial Endpoints in FSGS (PARASOL) Initiative. An international collaboration launched in 2023, the initiative is aimed at investigating the link between short-term changes in biomarkers, like proteinuria and GFR, and long-term outcomes to support alternative endpoints for drug approval in focal segmental glomerulosclerosis. The video version of this episode is only available on HCPLive.com. Chapters 00:00:00 - Start 00:02:37 - Mariani & Gale Introduction 00:05:03 - Discussing RaDaR Registry Insights 00:09:52 - Challenges and Opportunities in Rare Kidney Disease Research 00:18:44 - PARASOL Initiative Origins 00:25:45- PARASOL Partnership with US FDA  00:35:10 - Key findings from PARASOL 00:46:35 - Proteinuria as a Surrogate Outcome in FSGS 00:53:45 - Applying PARASOL Findings  01:00:30 - Future of PARASOL Initiative Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics. Relevant disclosures for Mariani include Travere Therapeutics, Boehringer Ingelheim, Reliant Glycosciences, Takeda Pharmaceuticals, HI-Bio, and Calliditas Therapeutics. Relevant disclosures for Gale include Novartis, Alexion, Calliditas, Britannia, Vifor, Judo Bio, Adnovate, Sanofi, Anlylam, Boehringer Ingelheim, and Bayer.

In the latest episode of Kidney Compass: Navigating Clinical Trials, Hiddo Heerspink, PhD, PharmD, of the University of Groningen, joins the podcast after he presented the landmark SMART trial, which suggested the benefit of semaglutide (Ozempic/Wegovy) on chronic kidney disease (CKD) extend to patients without diabetes. Video Version During the episode, Heerspink shares the impetus behind the SMART study, explaining how early pandemic lockdowns offered time to explore semaglutide's application for CKD without diabetes. The group delves into the study's design, patient profile, and a 52% reduction in albuminuria observed with semaglutide. They address dose-dependency, how higher doses may amplify albuminuria reduction, and the relationship between creatinine and cystatin C as filtration markers. The conversation shifts to broader implications, including the drug’s anti-inflammatory benefits, its potential for longer-term GFR protection, and specific impacts on blood pressure and BNP levels. As Heerspink elaborates, these results underscore semaglutide’s versatility, suggesting new therapeutic avenues across kidney and cardiovascular care. The episode concludes with a look at future research needs, including additional trials to clarify semaglutide’s role in non-diabetic CKD and broader nephrology applications. Chapters 00:00 - Start 01:45 - SMART Trial Background 04:30 - Study Population Characteristics 06:10 - SMART Trial Results 07:35 - Dose-Dependent Effects of Semaglutide 09:15 - Filtration Markers 14:15 - Hypertension and BNP --- Relevant disclosures for Heerspink include AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Chinook Therapeutics Inc., Gilead Sciences, Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Travere Therapeutics, and others. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.

In the third and final on-site edition of Kidney Compass: Navigating Clinical Trials from the American Society of Nephrology’s Kidney Week 2024, Katherine Tuttle, MD, clinical professor of Medicine at University of Washington Medicine and executive director for Research at Providence Health Care, joins the program for a deep dive into new FLOW trial data at the meeting, the role of semaglutide (Ozempic) and GLP-1 receptor agonists in managing kidney disease, and prescribing responsibilities for new therapies with cardio-kidney-metabolic benefits. To begin the episode, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, ask Tuttle to review findings from the FLOW trial, particularly the effects of semaglutide on kidney and cardiovascular outcomes. Tuttle details the groundbreaking findings, which concluded semaglutide not only lowers the risk of kidney failure and GFR decline in patients with type 2 diabetes but also significantly reduces cardiovascular events and overall mortality. They go on to discuss FLOW’s hierarchy of tested outcomes, confirming its broad efficacy across various levels of kidney function and albuminuria, which they highlight should be a notable reassurance for patients with more advanced CKD stages. Tuttle emphasizes the consistency of benefits regardless of SGLT2 inhibitor usage, pointing to potential additive effects when combining these therapies. The group also addresses semaglutide’s surprising reduction in infection rates, including COVID-19, which may point to its immune-modulating effects. Tuttle encourages nephrologists to take an active role in prescribing GLP-1 receptor agonists to enhance holistic, cross-specialty care for patients with CKD. The episode concludes with a call to action for nephrologists to adopt a comprehensive approach to cardiovascular risk management, integrating these new therapies as a primary tool in improving outcomes for patients with complex, interconnected health needs. ---- Chapters 00:00 - Start 00:50 - FLOW Overview 05:50 - Safety Outcomes 11:30 - Deep Dive into Mortality Data 13:30 - Mechanism Behind Lower Infection Risk 15:30 - Future of Kidney Disease Research 17:30 - Nephrologists Responsibility to Prescribe GLP-1s Relevant disclosures for Tuttle include Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca, Gilead, Goldfinch Bio, Novo Nordisk, Travere Therapeutics, and Bayer. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.

Live from Kidney Week 2024! Hosts Neuen and Wadhwani are joined by Prof. Jonathan Barratt to discuss atacicept's 96-week data from ORIGIN OLE, which he presented as a late-breaker at the meeting. Video Version Here Results of the study indicate atacicept use was associated with sustained reductions across multiple endpoints of interest, including a 66% (SE, 2%) mean reduction in Gd-IgA1 levels, a reduction in percentage of patients with hematuria from baseline (percentage change, 75%; 95% CI, -87% to -59%), and a mean reduction in UPCR of 52% (SE, 5%). The mean eGFR annualized slope was just -0.6 (SE, 0.5) mL/min/1.73m2 per year. As the discussion unfolds, Barratt explains atacicept’s unique approach of targeting disease-causing cytokines and highlights the drug’s practical benefit as a weekly self-administered injection, making it accessible for long-term patient use. The conversation wraps up with insights into the global impact of ongoing phase 3 trials, the sponsor’s commitment to extended access, and how these steps could redefine outcomes for patients with IgA nephropathy. Chapters 00:00 – Start 01:30 – Understanding Atacicept and Its Mechanism 05:00 – Phase 2 Trial Results and Clinical Impact 10:00 – Advantages of At-Home Therapy and Patient Adherence 13:00 – Future of IgA Nephropathy Treatment and Phase 3 Trials Relevant disclosures of interest for Barratt included Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos NV, GSK, Novartis, and Travere Therapeutics. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.

Introducing Kidney Compass: Navigating Clinical Trials, your guide to the latest in clinical trials and relevant updates in the world of nephrology—created by Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS. Hosted on HCPLive, Kidney Compass was created to make the changing landscape of nephrology and clinical trials within the specialty easier to understand and navigate, with insights from Neuen and Wadhwani, but also special guests, including some of the leading trialists in the space. In the inaugural episode of Kidney Compass, the hosts introduce listeners to the podcast’s mission and themselves. After discussing the goals of the podcast, hosts offer the audience insight into their personal journeys in the field, explaining how the need for equitable care and access to innovative therapies for patients with kidney disease has shaped their work. Wadhwani, the director of Clinical trials in the Division of Nephrology and the vice chair of Clinical Research in the Department of Medicine at the University of Texas Medical Branch, provides the audience with insight into her past experiences at Northwestern University, where she launched the institution’s glomerular disease program, but also into what inspired her to pursue a career in nephrology. Later, Neuen, nephrologist and director of the Kidney Trials Unit at Royal North Shore Hospital and senior research fellow at The George Institute for Global Health, describes how his experience in the northern regions of Australia and providing care for Indigenous Australians fueled his desire to pursue an impactful career in public health, with nephrology as his chosen medium to effect this change. Looking ahead, the hosts share their excitement about diving deeper into various aspects of nephrology research in future episodes, including multiple planned episodes at the upcoming American Society of Nephrology’s Kidney Week 2024. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics. Key Timestamps Episode Chapters 00:00 - Start 01:30 - Wadhwani Intro 03:05 - Neuen Intro 05:40 - Wadhwani's Professional Experience 08:05 - Purpose of Kidney Compass