Shikha Wadhwani, MD, MS

Welcome to Kidney Compass: Navigating Clinical Trials!

 Kidney Compass: Future of PARASOL, FSGS Management

03:38 - Proteinuria as a Therapeutic Endpoint

In the fourth and final installment of our episode on the PARASOL Initiative and focal segmental glomerulosclerosis, special guests Laura Mariani, MD, MS, and Daniel Gale, PhD, MB BChir, discuss the next steps for the project and its potential to revolutionize drug development in FSGS. Hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, ask Mariani and Gale to explore how the initiative's findings provide a critical pathway for validating proteinuria as a surrogate endpoint in trials.

Gale underscores the importance of recognizing that proteinuria reduction—even without full remission—can serve as a meaningful measure for drug approval. However, he stresses that the drug's mechanism must directly address the underlying podocyte dysfunction central to FSGS pathology. He notes this flexibility could accelerate therapeutic development across various etiologies of FSGS, including genetic, immunologic, and injury-related forms.

Mariani reflects on the significant unmet need in FSGS, emphasizing that even modest reductions in proteinuria can delay dialysis or kidney transplantation—life-changing outcomes for patients. She calls for trial designs that include specimen banking to advance biomarker discovery and refine surrogate endpoints, further enhancing the precision and feasibility of future studies.

Looking ahead, the PARASOL Initiative will focus on publishing its groundbreaking findings and addressing outstanding questions about trial design. Both guests highlight the collaborative nature of this project as a model for tackling similar challenges in other rare kidney diseases. Dr. Gale notes that the Parasol community is a powerful asset for nephrology, offering infrastructure and partnerships to drive research forward in other conditions with limited treatment options.

PARASOL Findings and Implications for FSGS

 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 Mariani include Travere Therapeutics, Boehringer Ingelheim, Reliant Glycosciences, Takeda Pharmaceuticals, HI-Bio, and Calliditas Therapeutics. Relevant disclosures for 

 include Novartis, Alexion, Calliditas, Britannia, Vifor, Judo Bio, Adnovate, Sanofi, Anlylam, Boehringer Ingelheim, and Bayer.

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The PARASOL Initiative aims to revolutionize drug development for focal segmental glomerulosclerosis (FSGS) by validating proteinuria as a surrogate endpoint in clinical trials. Proteinuria reduction, even without full remission, is highlighted as a meaningful measure for drug approval, provided the drug targets podocyte dysfunction. The initiative emphasizes the need for trial designs that include specimen banking to advance biomarker discovery. The collaborative nature of the project serves as a model for addressing challenges in rare kidney diseases, with plans to publish findings and refine trial designs.

In the final segment of this episode, the discussion focuses on next steps for the PARASOL Initiative and its potential to transform FSGS drug development.

Kidney Compass: Future of PARASOL and FSGS Management

Kidney Compass: PARASOL Findings and Implications for FSGS

13:43 - Challenges in Using GFR as a Surrogate Outcome

17:28 - Exploring Proteinuria as a Surrogate Outcome

In this installment, the third in a 4-part series, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, are joined by Laura Mariani, MD, MS, and Daniel Gale, PhD, MB BChir, to discuss the PARASOL Initiative’s efforts to establish surrogate endpoints for clinical trials in focal segmental glomerulosclerosis (FSGS).

To open the episode, Neuen contextualizes the challenge: FSGS trials require decades of follow-up to measure kidney failure, an endpoint critical to drug approval. Surrogate endpoints like proteinuria reduction offer a feasible alternative, as seen in IgA nephropathy and chronic kidney disease trials, but FSGS presents unique hurdles due to its heterogeneity.

Gale explains the distinction between clinical outcomes (e.g., kidney failure) and surrogate endpoints (e.g., proteinuria reduction or GFR slope). To validate a surrogate, strong evidence must link its reduction to meaningful clinical improvements. Moreover, the treatment effect must convincingly translate into long-term benefits, a high bar for regulatory approval.

Next, Mariani details PARASOL's findings. An analysis of 1600 FSGS patients, results suggested GFR variability was too higreath for practical use in trials. Proteinuria, however, emerged as a robust predictor of kidney failure. According to Mariani, patients achieving proteinuria levels below 0.7 g/g had a dramatically reduced risk of kidney failure (hazard ratio, 0.15), comparable to complete remission. These findings suggest proteinuria could serve as a surrogate endpoint, providing the foundation for smaller, faster trials.

For ease of viewing, we've divided this episode, which contains more than an hour of insights into the PARASOL Initiative and FSGS, into 4 sections and highlighted them below. 

The PARASOL Initiative aims to establish surrogate endpoints for clinical trials in focal segmental glomerulosclerosis (FSGS), addressing the challenge of long follow-up periods required to measure kidney failure. Surrogate endpoints like proteinuria reduction offer a feasible alternative, but FSGS's heterogeneity complicates validation. The initiative's analysis of 1600 FSGS patients found proteinuria to be a strong predictor of kidney failure, suggesting it could serve as a surrogate endpoint. This could enable smaller, faster trials, potentially accelerating drug approval processes for FSGS treatments.

In part 3 of 4 from this episode, the discussion focuses on establishing surrogate endpoints for clinical trials in focal segmental glomerulosclerosis.

Kidney Compass: PARASOL Background and FSGS Landscape

00:00 - Episode Start and RaDaR Background

08:42 - PARASOL Origins, Background Information

In the second installment of our 4-part episode of Kidney Compass, Shikha Wadhwani, MD, MS, and Brendon Neuen, MBBS, PhD, dive into the groundbreaking work of the RADAR Registry and the PARASOL Initiative, with special guests Daniel Gale, PhD, MB BChir, and Laura Mariani, MD, MS. 

RaDaR Registry: A Beacon for Real-World Data

Gale shares insights from the UK-based RaDaR Registry, a vast repository of real-world data from over 35,000 patients with rare kidney diseases. By capturing longitudinal data—spanning decades in some cases—RaDaR has revealed critical patterns in disease progression and the clinical parameters that predict long-term outcomes.

Beyond this, RaDaR has evidenced how partnerships with the UK Kidney Association and numerous investigators can build a community-driven framework for research.

PARASOL Initiative: Tackling FSGS Challenges

Next, Mariani highlights the unique obstacles in studying FSGS, from its biological heterogeneity to the difficulty of designing trials with meaningful endpoints. Unlike diseases like 

, which have benefited from regulatory pathways and increased drug development, FSGS remains a high-hurdle disease.

PARASOL aims to address these challenges b defining robust surrogate endpoints (e.g., proteinuria and GFR slope) to replace long-term kidney failure outcomes in trials and aggregating data from global cohorts, including Cure GN, RADAR, and others, to provide the statistical power necessary for meaningful analyses.

Mariani emphasizes the collaborative spirit behind PARASOL, crediting patient advocacy groups and international nephrologists for their willingness to contribute data and expertise. She notes that the initiative’s success is rooted in a shared mission to create a regulatory pathway for FSGS therapies, enabling innovation and hope for patients.

According to Mariani and Gale, the US FDA’s involvement in PARASOL has been instrumental, guiding data analysis and evidence standards. The duo describe a 2-way learning process:

Nephrologists educate FDA teams on the nuances of rare kidney diseases.

FDA biostatisticians help researchers align their analyses with regulatory expectations, ensuring that findings can support drug approvals.

The second installment of Kidney Compass explores the RADAR Registry and PARASOL Initiative, focusing on rare kidney diseases and FSGS challenges. The RADAR Registry, with data from over 35,000 patients, provides insights into disease progression and outcomes. The PARASOL Initiative addresses FSGS's complexities by defining surrogate endpoints and aggregating global data for robust analyses. Collaboration with patient advocacy groups and nephrologists is crucial, and the FDA's involvement aids in aligning research with regulatory standards. The episode is divided into four parts, covering introductions, background, findings, and future directions.

In part 2 of 4 from this episode, the discussion focuses on the groundbreaking work of the RADAR Registry and the PARASOL Initiative.

Kidney Compass: Introducing the PARASOL Project, with Laura Mariani, MD, MS, and Daniel Gale, PhD, MB BChir

Welcome to the first installment of a 4-part series on 

PARASOL initiative—a global project revolutionizing therapeutic development for rare kidney diseases like FSGS (focal segmental glomerulosclerosis).

In this installment, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, kick off with a deep dive into the backgrounds of their guests PARASOL co-chair Laura Mariani, MD, MS, 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. 

This foundational episode sets the stage for a broader discussion of the methodologies and breakthroughs in kidney disease research.

In the next episode, we’ll delve into the methodological advances and trial designs reshaping the field of nephrology, including the unique challenges of studying rare diseases and emerging therapies like APRIL/BAFF inhibitors for IgA nephropathy and semaglutide for non-diabetic kidney disease.
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The Kidney Compass series introduces the PARASOL initiative, a global project aimed at advancing therapeutic development for rare kidney diseases like FSGS. Hosts Brendon Neuen and Shikha Wadhwani engage with PARASOL co-chair Laura Mariani and Daniel Gale to explore the initiative's background and its impact on kidney disease research. This foundational episode sets the stage for future discussions on methodological advances and trial designs in nephrology, including challenges in studying rare diseases and emerging therapies. The episode is divided into four sections for detailed insights.

In part 1 of 4 from this episode, the discussion focuses on the backgrounds of guests Laura Mariani, MD, MS, and Daniel Gale, PhD, MB BChir.

Shikha Wadhwani, MD, MS

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