Brendon Neuen, MBBS, PhD

Welcome to Kidney Compass: Navigating Clinical Trials!

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 

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—

. 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.

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

Podcasts

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

Kidney Compass: Navigating Clinical Trials

Kidney Compass: CONFIDENCE Trial at ERA 2025, with Rajiv Agarwal, MD, MS

Simultaneous initiation of finerenone (Kerendia) and empagliflozin (Jardiance) in patients with 

 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 

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; 

<.001) and a 32% greater reduction than empagliflozin alone (least squares mean ratio of difference, 0.68; 95% CI, 0.59 to 0.79; 

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 the study results, but also what it means for CKD management landscape in real-world settings.

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

 include Akebia Therapeutics, Alnylam, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Intercept, and Novartis.

Agarwal R, Green JB, Heerspink HJL, et al. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. 

Brendon Neuen, MBBS, PhD, is joined by Rajiv Agarwal, MD, MS to explore the concept of simultaneous initiation of SGLT2i and nsMRA in CKD and T2D. 

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.

Brendon Neuen, MBBS, PhD

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