Shikha Wadhwani, MD, MS

Welcome to Kidney Compass: Navigating Clinical Trials!

Kidney Compass: Key Updates in IgA Nephropathy at ERA 2025, with Chee Kay Cheung, MBChB, PhD

, 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

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.


 include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Relevant disclosures for 

 include Travere Therapeutics, Alexion, Alpine Immune Sciences, Calliditas Therapeutics, CSL Vifor, Novartis, Otsuka Pharmaceutical, Roche, Vera Therapeutics, and others.

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.

Podcasts

A deep dive into several noteworthy IgAN studies presented during the ERA 2025 Congress. 

Kidney Compass: Sibeprenlimab and the VISIONARY Trial, with Vlado Perkovic, MBBS, PhD, at ERA 2025

, hosts are joined by Vlado Perkovic, MBBS, PhD, dean and scientia professor of Medicine at UNSW Sydney, at the 

. 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—

. 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%; 

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.

 include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for 

 include Boehringer Ingelheim, Calliditas Therapeutics, GSK, Otsuka Pharmaceutical Co., Travere Therapeutics, and others. Relevant disclosures for 

 include Boehringer Ingelheim,AbbVie, Inc., Bristol-Myers Squibb, servier, Astellas Pharma US, Merck, Janssen Pharmaceuticals, GSK, and others.

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

Discover groundbreaking insights on the VISIONARY trial, IgA nephropathy treatment, and the future of kidney care with expert Vlado Perkovic, MBBS, PhD.

Kidney Compass: Applying Hierarchical Composite Endpoints in Kidney Disease Trials

In the final installment of our 4-part episode of 

, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by special guests Dustin Little, MD, and Niels Jongs, PhD, as they discuss the application of hierarchical composite endpoints (HCEs) in specific kidney disease subpopulations and rare disease trials.

Wadhwani highlights the need to tailor HCEs to disease-specific priorities, such as relapse reduction and immunosuppression minimization in lupus nephritis. The discussion then shifts to subgroup analyses in trials using HCEs. While traditional trials are powered for the overall population, subgroup analyses often lack statistical power. Jongs explains that increasing the efficiency of HCE-powered trials may allow for better-powered subgroup analyses, but achieving statistical certainty in smaller populations remains challenging.

The panel explores a real-world example of focal segmental glomerulosclerosis (FSGS) within the DAPA-CKD trial, where traditional analyses showed numerical benefits of dapagliflozin but lacked statistical significance due to wide confidence intervals. Jongs and Little discuss how applying HCEs and win odds in these cases could refine statistical assessments and potentially strengthen findings, offering greater confidence in treatment effects.

The episode concludes with reflections on the future of HCEs in nephrology research, emphasizing their potential to optimize trial efficiency, improve data interpretation, and advance therapies for rare and complex kidney diseases.

For ease of viewing, we've divided this episode into 4 sections and highlighted them below.

Kidney Compass: Hierarchical Composite Endpoints in Nephrology

Part 1: Introductions, HCEs in Nephrology

Part 2: HCEs in Nephrology Clinical Trials

Part 3: Addressing HCE Skepticism, Potential Limitations

Part 4: Applying HCEs in Kidney Disease Trials

 include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for 

 include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas, and Travere Therapeutics. Relevant disclosures for 

In the final segments of this 4-part episode, the discussion focuses on the use of HCEs in different kidney disease trials.

Kidney Compass: Addressing Skepticism Around HCEs in Nephrology

In the third installment of our 4-part episode of 

, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by special guests Dustin Little, MD, and Niels Jongs, PhD, as they discuss the implications of hierarchical composite endpoints (HCEs) for kidney disease trials, regulatory considerations, and patient-centered outcomes.

Wadhwani raises concerns about fixed follow-up requirements in clinical trials, particularly when studies are terminated early due to efficacy, as seen in the FLOW and DAPA-CKD trials. Jongs explains how follow-up variability can be statistically managed by adjusting pairwise comparisons to a minimum follow-up period, ensuring fair assessment across different trial durations. While acknowledging theoretical concerns, he emphasizes that empirical analyses suggest this approach does not significantly alter trial conclusions.

The conversation then shifts to skepticism surrounding HCEs, including how event prioritization is determined and how win odds should be interpreted. Little highlights the flexibility of HCEs, noting that they incorporate only validated clinical and surrogate endpoints, making them suitable for regulatory approval.

A key advantage of HCEs, the panel agrees, is their ability to enhance statistical power, potentially reducing required sample sizes—an especially critical benefit for rare kidney diseases. Wadhwani and Little further explore the potential to integrate patient-reported outcomes, such as symptom burden and quality of life, into HCE frameworks. While acknowledging the complexity of arranging hierarchies that blend clinical and PRO measures, they highlight polycystic kidney disease as a prime example where factors like cyst pain and kidney volume could be incorporated alongside traditional renal endpoints.

The episode concludes with a discussion on future applications of HCEs in nephrology. The panel emphasizes that while methodological refinements are ongoing, HCEs offer a promising strategy to improve trial efficiency, capture a broader range of clinically meaningful outcomes, and ultimately accelerate therapeutic advancements for patients with kidney disease.

In part 3 of 4 from this episode, the discussion focuses on potential limitations to HCEs and addressing skepticism around their use in nephrology.

Shikha Wadhwani, MD, MS

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