Kidney Compass: Navigating Clinical Trials

• Key Updates in IgA Nephropathy at ERA 2025, with Chee Kay Cheung, MBChB, PhD

  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.

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• Sibeprenlimab and the VISIONARY Trial, with Vlado Perkovic, MBBS, PhD, at ERA 2025

  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

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  31:47
• CONFIDENCE Trial at ERA 2025, with Rajiv Agarwal, MD, MS

  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

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  21:33
• Kidney Compass: Hierarchical Composite Endpoints in Nephrology, with Dustin Little, MD, and Niels Jongs, PhD

  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

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  49:16
• The PARASOL Initiative and FSGS Management, with Laura Mariani, MD, MS, and Daniel Gale, PhD, MB BChir

  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.

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  1:04:24

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